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The dataset generation failed
Error code: DatasetGenerationError
Exception: ArrowInvalid
Message: Failed to parse string: '2010-2011' as a scalar of type int64
Traceback: Traceback (most recent call last):
File "/usr/local/lib/python3.12/site-packages/datasets/builder.py", line 1831, in _prepare_split_single
writer.write_table(table)
File "/usr/local/lib/python3.12/site-packages/datasets/arrow_writer.py", line 714, in write_table
pa_table = table_cast(pa_table, self._schema)
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
File "/usr/local/lib/python3.12/site-packages/datasets/table.py", line 2272, in table_cast
return cast_table_to_schema(table, schema)
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
File "/usr/local/lib/python3.12/site-packages/datasets/table.py", line 2224, in cast_table_to_schema
cast_array_to_feature(
File "/usr/local/lib/python3.12/site-packages/datasets/table.py", line 1795, in wrapper
return pa.chunked_array([func(chunk, *args, **kwargs) for chunk in array.chunks])
^^^^^^^^^^^^^^^^^^^^^^^^^^^^
File "/usr/local/lib/python3.12/site-packages/datasets/table.py", line 2086, in cast_array_to_feature
return array_cast(
^^^^^^^^^^^
File "/usr/local/lib/python3.12/site-packages/datasets/table.py", line 1797, in wrapper
return func(array, *args, **kwargs)
^^^^^^^^^^^^^^^^^^^^^^^^^^^^
File "/usr/local/lib/python3.12/site-packages/datasets/table.py", line 1949, in array_cast
return array.cast(pa_type)
^^^^^^^^^^^^^^^^^^^
File "pyarrow/array.pxi", line 1135, in pyarrow.lib.Array.cast
File "/usr/local/lib/python3.12/site-packages/pyarrow/compute.py", line 412, in cast
return call_function("cast", [arr], options, memory_pool)
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
File "pyarrow/_compute.pyx", line 604, in pyarrow._compute.call_function
File "pyarrow/_compute.pyx", line 399, in pyarrow._compute.Function.call
File "pyarrow/error.pxi", line 155, in pyarrow.lib.pyarrow_internal_check_status
File "pyarrow/error.pxi", line 92, in pyarrow.lib.check_status
pyarrow.lib.ArrowInvalid: Failed to parse string: '2010-2011' as a scalar of type int64
The above exception was the direct cause of the following exception:
Traceback (most recent call last):
File "/src/services/worker/src/worker/job_runners/config/parquet_and_info.py", line 1334, in compute_config_parquet_and_info_response
parquet_operations, partial, estimated_dataset_info = stream_convert_to_parquet(
^^^^^^^^^^^^^^^^^^^^^^^^^^
File "/src/services/worker/src/worker/job_runners/config/parquet_and_info.py", line 911, in stream_convert_to_parquet
builder._prepare_split(
File "/usr/local/lib/python3.12/site-packages/datasets/builder.py", line 1702, in _prepare_split
for job_id, done, content in self._prepare_split_single(
^^^^^^^^^^^^^^^^^^^^^^^^^^^
File "/usr/local/lib/python3.12/site-packages/datasets/builder.py", line 1858, in _prepare_split_single
raise DatasetGenerationError("An error occurred while generating the dataset") from e
datasets.exceptions.DatasetGenerationError: An error occurred while generating the datasetNeed help to make the dataset viewer work? Make sure to review how to configure the dataset viewer, and open a discussion for direct support.
pmid
int64 | title
string | abstract
string | journal
string | year
int64 |
|---|---|---|---|---|
18,784,302
|
Ablation of neurons expressing agouti-related protein activates fos and gliosis in postsynaptic target regions.
|
We have developed a mouse model in which a specific population of inhibitory neurons can be selectively ablated by the action of diphtheria toxin (DT). The model involves targeting the human DT receptor to the agouti-related protein (Agrp) locus so that systemic administration of DT kills all of the AgRP-expressing neurons, resulting in starvation of the mice. Ablation of AgRP neurons results in robust (5- to 10-fold) activation of Fos gene expression in many brain regions that are innervated by AgRP neurons, including the arcuate nucleus (ARC), the paraventricular nucleus, the medial preoptic area, the lateral septum, and nucleus of the solitary tract. As expected, there is robust increase in GFAP staining (astrocytes) as well as IBA1 and CD11b staining (microglia) in the ARC in response to AgRP neuron ablation. There is also a dramatic increase of these markers in most, but not all, postsynaptic targets of AgRP axons. We used a genetic approach to reduce melanocortin signaling, which attenuated Fos activation in some brain regions after ablation of AgRP neurons. We suggest that loss of inhibitory signaling onto target neurons results in unopposed excitation that is responsible for the activation of Fos and that dysregulation of these neuronal circuits is responsible for starvation. Furthermore, glial cell activation in target areas of AgRP neurons appears to be a result of excitotoxicity.
|
The Journal of neuroscience : the official journal of the Society for Neuroscience
| 2,008
|
23,525,087
|
Suppression of inflammation and acute lung injury by Miz1 via repression of C/EBP-δ.
|
Inflammation is essential for host defense but can cause tissue damage and organ failure if unchecked. How the inflammation is resolved remains elusive. Here we report that the transcription factor Miz1 was required for terminating lipopolysaccharide (LPS)-induced inflammation. Genetic disruption of the Miz1 POZ domain, which is essential for the transactivation or repression activity of Miz1, resulted in hyperinflammation, lung injury and greater mortality in LPS-treated mice but a lower bacterial load and mortality in mice with Pseudomonas aeruginosa pneumonia. Loss of the Miz1 POZ domain prolonged the expression of proinflammatory cytokines. After stimulation, Miz1 was phosphorylated at Ser178, which was required for recruitment of the histone deacetylase HDAC1 to repress transcription of the gene encoding C/EBP-δ, an amplifier of inflammation. Our data provide a long-sought mechanism underlying the resolution of LPS-induced inflammation.
|
Nature immunology
| 2,013
|
22,617,116
|
Mathematical model of zinc absorption: effects of dietary calcium, protein and iron on zinc absorption.
|
A previously described mathematical model of Zn absorption as a function of total daily dietary Zn and phytate was fitted to data from studies in which dietary Ca, Fe and protein were also measured. An analysis of regression residuals indicated statistically significant positive relationships between the residuals and Ca, Fe and protein, suggesting that the presence of any of these dietary components enhances Zn absorption. Based on the hypotheses that (1) Ca and Fe both promote Zn absorption by binding with phytate and thereby making it unavailable for binding Zn and (2) protein enhances the availability of Zn for transporter binding, the model was modified to incorporate these effects. The new model of Zn absorption as a function of dietary Zn, phytate, Ca, Fe and protein was then fitted to the data. The proportion of variation in absorbed Zn explained by the new model was 0·88, an increase from 0·82 with the original model. A reduced version of the model without Fe produced an equally good fit to the data and an improved value for the model selection criterion, demonstrating that when dietary Ca and protein are controlled for, there is no evidence that dietary Fe influences Zn absorption. Regression residuals and testing with additional data supported the validity of the new model. It was concluded that dietary Ca and protein modestly enhanced Zn absorption and Fe had no statistically discernable effect. Furthermore, the model provides a meaningful foundation for efforts to model nutrient interactions in mineral absorption.
|
The British journal of nutrition
| 2,013
|
19,588,419
|
Pregabalin for acute and chronic pain in adults.
|
Antiepileptic drugs have been used in pain management since the 1960s. Pregabalin is a recently developed antiepileptic drug also used in management of chronic neuropathic pain conditions. To assess analgesic efficacy and associated adverse events of pregabalin in acute and chronic pain. We searched MEDLINE, EMBASE, and CENTRAL to May 2009 for randomised controlled trials (RCTs). Additional studies were identified from the reference lists of retrieved papers and on-line clinical trial databases. Randomised, double blind trials reporting on the analgesic effect of pregabalin, with subjective pain assessment by the patient as either the primary or a secondary outcome. Two independent review authors extracted data and assessed trial quality. Numbers-needed-to-treat-to-benefit (NNTs) were calculated, where possible, from dichotomous data for effectiveness, adverse events and study withdrawals. There was no clear evidence of beneficial effects of pregabalin in established acute postoperative pain. No studies evaluated pregabalin in chronic nociceptive pain, like arthritis.Pregabalin at doses of 300 mg, 450 mg, and 600 mg daily was effective in patients with postherpetic neuralgia, painful diabetic neuropathy, central neuropathic pain, and fibromyalgia (19 studies, 7003 participants). Pregabalin at 150 mg daily was generally ineffective. Efficacy was demonstrated for dichotomous outcomes equating to moderate or substantial pain relief, alongside lower rates for lack of efficacy discontinuations with increasing dose. The best (lowest) NNT for each condition for at least 50% pain relief over baseline (substantial benefit) for 600 mg pregabalin daily compared with placebo were 3.9 (95% confidence interval 3.1 to 5.1) for postherpetic neuralgia, 5.0 (4.0 to 6.6) for painful diabetic neuropathy, 5.6 (3.5 to 14) for central neuropathic pain, and 11 (7.1 to 21) for fibromyalgia.With 600 mg pregabalin daily somnolence typically occurred in 15% to 25% and dizziness occurred in 27% to 46%. Treatment was discontinued due to adverse events in 18 to 28%. The proportion of participants reporting at least one adverse event was not affected by dose, nor was the number with a serious adverse event, which was not more than with placebo.Higher rates of substantial benefit were found in postherpetic neuralgia and painful diabetic neuropathy than in central neuropathic pain and fibromyalgia. For moderate and substantial benefit on any outcome NNTs for the former were generally six and below for 300 mg and 600 mg daily; for fibromyalgia NNTs were much higher, and generally seven and above. Pregabalin has proven efficacy in neuropathic pain conditions and fibromyalgia. A minority of patients will have substantial benefit with pregabalin, and more will have moderate benefit. Many will have no or trivial benefit, or will discontinue because of adverse events. Individualisation of treatment is needed to maximise pain relief and minimise adverse events. There is no evidence to support the use of pregabalin in acute pain scenarios.
|
The Cochrane database of systematic reviews
| 2,009
|
25,226,218
|
Medication development for agitation and aggression in Alzheimer disease: review and discussion of recent randomized clinical trial design.
|
The management of disruptive neuropsychiatric symptom (NPS) such as agitation and aggression (A/A) is a major priority in caring for people with Alzheimer's disease (AD). Few effective pharmacological or non-pharmacological options are available. Results of randomized clinical trials (RCTs) of drugs for A/A have been disappointing. This may result from the absence of biological efficacy for medications tested in treating A/A. It may also be related to methodological issues such as the choice of outcomes. The aim of this review was to highlight key methodological issues pertaining to RCTs of current and emerging medications for the treatment of A/A in AD. We searched PubMed/Medline, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for RCTs comparing medications with either placebo or other drugs in the treatment of A/A in AD, between January 2008 and December 2013. We identified a total of 18 RCTs; of these, 11 were completed and 7 ongoing. Of the ongoing RCTs, only one is in Phase III. Seven of 10 completed RCTs with reported results did not report greater benefit from drug than placebo. Each of the completed RCTs used a different definition of "clinically significant A/A." There was considerable heterogeneity in study design. The primary endpoints were largely proxy-based but a variety of scales were used. The definition of caregiver and scales used to assess caregiver outcomes were similarly heterogeneous. Placebo response was notable in all trials. This review highlights a great heterogeneity in RCTs design of drugs for A/A in AD and some key methodological issues such as definition of A/A, choice of outcome measures and caregiver participation that could be addressed by an expert consensus to optimize future trials design.
|
International psychogeriatrics
| 2,015
|
25,222,023
|
Neighborhood physical disorder, social cohesion, and insomnia: results from participants over age 50 in the Health and Retirement Study.
|
We determined the association between neighborhood socio-environmental factors and insomnia symptoms in a nationally representative sample of US adults aged >50 years. Data were analyzed from two waves (2006 and 2010) of the Health and Retirement Study using 7,231 community-dwelling participants (3,054 men and 4,177 women) in the United States. Primary predictors were neighborhood physical disorder (e.g. vandalism/graffiti, feeling safe alone after dark, and cleanliness) and social cohesion (e.g. friendliness of people, availability of help when needed, etc.); outcomes were insomnia symptoms (trouble falling asleep, night awakenings, waking too early, and feeling unrested). After adjustment for age, income, race, education, sex, chronic diseases, body mass index, depressive symptoms, smoking, and alcohol consumption, each one-unit increase in neighborhood physical disorder was associated with a greater odds of trouble falling asleep (odds ratio (OR) = 1.09, 95% confidence interval (CI): 1.04-1.14), waking too early (OR = 1.05, 95% CI: 1.00-1.10), and, in adults aged ≥69 years (adjusting for all variables above except age), feeling unrested in the morning (OR = 1.11, 95% CI: 1.02-1.22 in 2006). Each one-unit increase in lower social cohesion was associated with a greater odds of trouble falling asleep (OR = 1.06, 95% CI: 1.01-1.11) and feeling unrested (OR = 1.09, 95% CI: 1.04-1.15). Neighborhood-level factors of physical disorder and social cohesion are associated with insomnia symptoms in middle-aged and older adults. Neighborhood-level factors may affect sleep, and consequently health, in our aging population.
|
International psychogeriatrics
| 2,015
|
26,384,949
|
Psychiatric disorders and adherence to antiretroviral therapy among a population of HIV-infected adults in Nigeria.
|
Psychiatric disorders are common among people living with HIV in Nigeria. Adherence is necessary to optimise the outcome of antiretroviral therapy. In this study, we aimed to identify associations between antiretroviral adherence, measured by one-week and one-month self-reported missed doses, and psychiatric illness in a cohort previously assessed for psychiatric disorders using the Composite International Diagnostic Interview. The study participants comprised 151 adults with major depression, anxiety or suicidal symptoms, and 302 matched-control participants. Two controls were randomly selected for each case within the same gender and education level. We compared participants with psychiatric disorders (WPDs) and no psychiatric disorders (NPDs) on selected demographic and clinical variables, in addition to adherence. Participants with one or more missed doses in the preceding month had twice the odds of having a major depressive episode as those with no missed doses during this period (OR 2.22, 95% CI 1.03, 4.79). This association remained significant after adjusting for selected risk factors. There was no statistically significant difference between WPD and NPD groups on either one-week or one-month adherence, or on age, marital status, occupational class, HIV viral load at enrolment or current CD4 cell count. Among Nigerian adults with HIV, suboptimal antiretroviral adherence is associated with, and could be a sign of, depression. Routine self-report adherence assessments may potentially be utilised in identifying individuals at risk among this population.
|
International journal of STD & AIDS
| 2,016
|
27,055,725
|
Quantum and quasi-classical calculations for the S⁺ + H₂(v,j) → SH⁺(v',j') + H reactive collisions.
|
State-to-state cross-sections for the S(+) + H2(v,j) → SH(+)(v',j') + H endothermic reaction are obtained using quantum wave packet (WP) and quasi-classical (QCT) methods for different initial ro-vibrational H2(v,j) over a wide range of translation energies. The final state distribution as a function of the initial quantum number is obtained and discussed. Additionally, the effect of the internal excitation of H2 on the reactivity is carefully studied. It appears that energy transfer among modes is very inefficient that vibrational energy is the most favorable for the reaction, and rotational excitation significantly enhances the reactivity when vibrational energy is sufficient to reach the product. Special attention is also paid to an unusual discrepancy between classical and quantum dynamics for low rotational levels while agreement improves with rotational excitation of H2. An interesting resonant behaviour found in WP calculations is also discussed and associated with the existence of roaming classical trajectories that enhance the reactivity of the title reaction. Finally, a comparison with the experimental results of Stowe et al. for S(+) + HD and S(+) + D2 reactions exhibits a reasonably good agreement with those results.
|
Physical chemistry chemical physics : PCCP
| 2,016
|
26,686,292
|
Reduced GABA neuron density in auditory cerebral cortex of subjects with major depressive disorder.
|
Although major depressive disorder (MDD) and schizophrenia (SZ) are closely associated with disrupted functions in frontal and limbic areas of cerebral cortex, cellular pathology has also been found in other brain areas, including primary sensory cortex. Auditory cortex is of particular interest, given the prominence of auditory hallucinations in SZ, and sensory deficits in MDD. We used stereological sampling methods in auditory cortex to look for cellular differences between MDD, SZ and non-psychiatric subjects. Additionally, as all of our MDD subjects died of suicide, we evaluated the association of suicide with our measurements by selecting a SZ sample that was divided between suicide and non-suicide subjects. Measurements were done in primary auditory cortex (area A1) and auditory association cortex (area Tpt), two areas with distinct roles in sensory processing and obvious differences in neuron density and size. In MDD, densities of GABAergic interneurons immunolabeled for calretinin (CR) and calbindin (CB) were 23-29% lower than non-psychiatric controls in both areas. Parvalbumin (PV) interneurons (counted only in area Tpt) showed a nominally smaller (16%) reduction that was not statistically significant. Total neuron and glia densities measured in Nissl stained sections did not show corresponding reductions. Analysis of suicide in the SZ sample indicated that reduced CR cell density was associated with suicide, whereas the densities of CB and other cells were not. Our results are consistent with previous studies in MDD that found altered GABA-associated markers throughout the cerebral cortex including primary sensory areas.
|
Journal of chemical neuroanatomy
| 2,016
|
26,796,621
|
Adult oligodendrocyte progenitor cells - Multifaceted regulators of the CNS in health and disease.
|
Oligodendrocyte progenitor cells (OPCs) are the often-overlooked fourth glial cell type in the central nervous system (CNS), comprising about 5% of the CNS. For a long time, our vision of OPC function was limited to the generation of mature oligodendrocytes. However, new studies have highlighted the multifaceted nature of OPCs. During homeostatic and pathological conditions, OPCs are the most proliferative cell type in the CNS, a property not consistent with the need to generate new oligodendrocytes. Indeed, OPCs modulate neuronal activity and OPC depletion in the brain can trigger depressive-like behavior. More importantly, OPCs are actively recruited to injury sites, where they orchestrate glial scar formation and contribute to the immune response. The following is a comprehensive analysis of the literature on OPC function beyond myelination, in the context of the healthy and diseased adult CNS.
|
Brain, behavior, and immunity
| 2,016
|
26,783,026
|
Emotion Socialization in Anxious Youth: Parenting Buffers Emotional Reactivity to Peer Negative Events.
|
Anxious youth exhibit heightened emotional reactivity, particularly to social-evaluative threat, such as peer evaluation and feedback, compared to non-anxious youth. Moreover, normative developmental changes during the transition into adolescence may exacerbate emotional reactivity to peer negative events, particularly for anxious youth. Therefore, it is important to investigate factors that may buffer emotional reactivity within peer contexts among anxious youth. The current study examined the role of parenting behaviors in child emotional reactivity to peer and non-peer negative events among 86 anxious youth in middle childhood to adolescence (Mean age = 11.29, 54 % girls). Parenting behavior and affect was observed during a social-evaluative laboratory speech task for youth, and ecological momentary assessment (EMA) methods were used to examine youth emotional reactivity to typical daily negative events within peer and non-peer contexts. Results showed that parent positive behaviors, and low levels of parent anxious affect, during the stressful laboratory task for youth buffered youth negative emotional reactivity to real-world negative peer events, but not non-peer events. Findings inform our understanding of parenting influences on anxious youth's emotional reactivity to developmentally salient negative events during the transition into adolescence.
|
Journal of abnormal child psychology
| 2,016
|
26,802,985
|
Chronic peripheral inflammation, hippocampal neurogenesis, and behavior.
|
Adult hippocampal neurogenesis is involved in memory and learning, and disrupted neurogenesis is implicated in cognitive impairment and mood disorders, including anxiety and depression. Some long-term peripheral illnesses and metabolic disorders, as well as normal aging, create a state of chronic peripheral inflammation. These conditions are associated with behavioral disturbances linked to disrupted adult hippocampal neurogenesis, such as cognitive impairment, deficits in learning and memory, and depression and anxiety. Pro-inflammatory cytokines released in the periphery are involved in peripheral immune system-to-brain communication by activating resident microglia in the brain. Activated microglia reduce neurogenesis by suppressing neuronal stem cell proliferation, increasing apoptosis of neuronal progenitor cells, and decreasing survival of newly developing neurons and their integration into existing neuronal circuits. In this review, we summarize evolving evidence that the state of chronic peripheral inflammation reduces adult hippocampal neurogenesis, which, in turn, produces the behavioral disturbances observed in chronic inflammatory disorders. As there are no data available on neurogenesis in humans with chronic peripheral inflammatory disease, we focus on animal models and, in parallel, consider the evidence of cognitive disturbance and mood disorders in human patients.
|
Brain, behavior, and immunity
| 2,016
|
26,792,789
|
Heterogeneous mechanics of the mouse pulmonary arterial network.
|
Individualized modeling and simulation of blood flow mechanics find applications in both animal research and patient care. Individual animal or patient models for blood vessel mechanics are based on combining measured vascular geometry with a fluid structure model coupling formulations describing dynamics of the fluid and mechanics of the wall. For example, one-dimensional fluid flow modeling requires a constitutive law relating vessel cross-sectional deformation to pressure in the lumen. To investigate means of identifying appropriate constitutive relationships, an automated segmentation algorithm was applied to micro-computerized tomography images from a mouse lung obtained at four different static pressures to identify the static pressure-radius relationship for four generations of vessels in the pulmonary arterial network. A shape-fitting function was parameterized for each vessel in the network to characterize the nonlinear and heterogeneous nature of vessel distensibility in the pulmonary arteries. These data on morphometric and mechanical properties were used to simulate pressure and flow velocity propagation in the network using one-dimensional representations of fluid and vessel wall mechanics. Moreover, wave intensity analysis was used to study effects of wall mechanics on generation and propagation of pressure wave reflections. Simulations were conducted to investigate the role of linear versus nonlinear formulations of wall elasticity and homogeneous versus heterogeneous treatments of vessel wall properties. Accounting for heterogeneity, by parameterizing the pressure/distention equation of state individually for each vessel segment, was found to have little effect on the predicted pressure profiles and wave propagation compared to a homogeneous parameterization based on average behavior. However, substantially different results were obtained using a linear elastic thin-shell model than were obtained using a nonlinear model that has a more physiologically realistic pressure versus radius relationship.
|
Biomechanics and modeling in mechanobiology
| 2,016
|
26,104,750
|
Derivation of genetic biomarkers for cancer risk stratification in Barrett's oesophagus: a prospective cohort study.
|
The risk of developing adenocarcinoma in non-dysplastic Barrett's oesophagus is low and difficult to predict. Accurate tools for risk stratification are needed to increase the efficiency of surveillance. We aimed to develop a prediction model for progression using clinical variables and genetic markers. In a prospective cohort of patients with non-dysplastic Barrett's oesophagus, we evaluated six molecular markers: p16, p53, Her-2/neu, 20q, MYC and aneusomy by DNA fluorescence in situ hybridisation on brush cytology specimens. Primary study outcomes were the development of high-grade dysplasia or oesophageal adenocarcinoma. The most predictive clinical variables and markers were determined using Cox proportional-hazards models, receiver operating characteristic curves and a leave-one-out analysis. A total of 428 patients participated (345 men; median age 60 years) with a cumulative follow-up of 2019 patient-years (median 45 months per patient). Of these patients, 22 progressed; nine developed high-grade dysplasia and 13 oesophageal adenocarcinoma. The clinical variables, age and circumferential Barrett's length, and the markers, p16 loss, MYC gain and aneusomy, were significantly associated with progression on univariate analysis. We defined an 'Abnormal Marker Count' that counted abnormalities in p16, MYC and aneusomy, which significantly improved risk prediction beyond using just age and Barrett's length. In multivariate analysis, these three factors identified a high-risk group with an 8.7-fold (95% CI 2.6 to 29.8) increased HR when compared with the low-risk group, with an area under the curve of 0.76 (95% CI 0.66 to 0.86). A prediction model based on age, Barrett's length and the markers p16, MYC and aneusomy determines progression risk in non-dysplastic Barrett's oesophagus.
|
Gut
| 2,016
|
26,336,203
|
Medulloblastoma.
|
Medulloblastoma accounts for nearly 10% of all childhood brain tumors. These tumors occur exclusively in the posterior fossa and have the potential for leptomeningeal spread. Treatment includes a combination of surgery, radiation therapy (in patients >3 years old). Patients >3 years old are stratified based on the volume of postoperative residual tumor and the presence or absence of metastases into "standard risk" and "high risk" categories with long-term survival rates of approximately 85% and 70%, respectively. Outcomes are inferior in infants and children younger than 3 years with exception of those patients with the medulloblastoma with extensive nodularity histologic subtype. Treatment for medulloblastoma is associated with significant morbidity, especially in the youngest patients. Recent molecular subclassification of medulloblastoma has potential prognostic and therapeutic implications. Future incorporation of molecular subgroups into treatment protocols will hopefully improve both survival outcomes and posttreatment quality of life.
|
Journal of child neurology
| 2,016
|
27,570,539
|
The impact of weather changes on air quality and health in the United States in 1994-2012.
|
Air quality is heavily influenced by weather conditions. In this study, we assessed the impact of long-term weather changes on air quality and health in the US during 1994-2012. We quantified past weather-related increases, or 'weather penalty', in ozone (O
|
Environmental research letters : ERL [Web site]
| 2,015
|
27,570,834
|
Advancing Cancer Survivorship in a Country with 1.35 Billion People: The China Lymphoma Project.
|
Rates of lymphoma are rising rapidly and lymphoma is now the ninth most common cancer among Chinese males. The China Lymphoma Project was founded to increase awareness of lymphoma in China, including the survivability of the disease and the availability of potentially life-saving treatments, and to provide social support for men, women, and children in China who are living with the disease. The project is working with China government officials, several of the top cancer hospitals in China and the U.S., internationally known oncologists and cancer researchers, pharmaceutical and biotech companies in China and the U.S., healthcare and environmental companies, the Confucius Institute at San Diego State University, and the Asian Heritage Society. Advances in e-Health are being utilized to provide patient education and social support. The project will provide free e-books that profile lymphoma survivors (e.g., Kai-Fu Lee, creator of Google China), new videos, websites, pamphlets, blogs, video logs (vlogs), peer-to-peer counseling and support, and information about the latest treatments and oncology clinical trials.
|
Journal of environment and health sciences
| 2,016
|
27,553,415
|
Sputum is a surrogate for bronchoalveolar lavage for monitoring Mycobacterium tuberculosis transcriptional profiles in TB patients.
|
Pathogen-targeted transcriptional profiling in human sputum may elucidate the physiologic state of Mycobacterium tuberculosis (M. tuberculosis) during infection and treatment. However, whether M. tuberculosis transcription in sputum recapitulates transcription in the lung is uncertain. We therefore compared M. tuberculosis transcription in human sputum and bronchoalveolar lavage (BAL) samples from 11 HIV-negative South African patients with pulmonary tuberculosis. We additionally compared these clinical samples with in vitro log phase aerobic growth and hypoxic non-replicating persistence (NRP-2). Of 2179 M. tuberculosis transcripts assayed in sputum and BAL via multiplex RT-PCR, 194 (8.9%) had a p-value <0.05, but none were significant after correction for multiple testing. Categorical enrichment analysis indicated that expression of the hypoxia-responsive DosR regulon was higher in BAL than in sputum. M. tuberculosis transcription in BAL and sputum was distinct from both aerobic growth and NRP-2, with a range of 396-1020 transcripts significantly differentially expressed after multiple testing correction. Collectively, our results indicate that M. tuberculosis transcription in sputum approximates M. tuberculosis transcription in the lung. Minor differences between M. tuberculosis transcription in BAL and sputum suggested lower oxygen concentrations or higher nitric oxide concentrations in BAL. M. tuberculosis-targeted transcriptional profiling of sputa may be a powerful tool for understanding M. tuberculosis pathogenesis and monitoring treatment responses in vivo.
|
Tuberculosis (Edinburgh, Scotland)
| 2,016
|
26,991,777
|
Limitations, depressive symptoms, and quality of life among a population-based sample of young adults with congenital heart defects.
|
Little population-based data exist on limitations and health-related quality of life (HRQoL) in adults with congenital heart defects (CHD). We used 2004 to 2012 Medical Expenditure Panel Survey data to identify a population-based sample of young adults ages 18 to 40 years reporting health symptoms or healthcare encounters in the previous year. Comparing adults reporting CHD to others, we examined the prevalence of cognitive, physical, and activity limitations, depressive symptoms, and physical and mental HRQoL. We used chi square tests to examine differences in demographic characteristics, logistic regression to generate adjusted prevalence ratios (aPR), and linear regression to examine HRQoL. Multivariable associations were adjusted for sex, age, race/ethnicity, and smoking status. All analyses were conducted in SUDAAN using weights to account for clustering within sampling units and nonresponse. Fifty-nine adults reported CHD (weighted prevalence = 0.1%; representing 700,000 U.S. adults from 2004 to 2012 or, on average, 80,000 per year) and 54,011 did not. No demographic characteristics differed significantly by CHD status except health insurance; 31.5% of adults with CHD, compared with 11.0% without, reported public insurance (p = 0.01). Compared with their counterparts, adults reporting CHD had a higher prevalence of cognitive (aPR = 2.7, 95% confidence interval (CI): 1.0, 7.2), physical (aPR = 4.0, 95% CI: 1.9, 8.2), and activity limitations (aPR = 4.8, 95% CI: 2.6, 9.1), and poorer physical HRQoL (p = 0.004). No differences were observed in depressive symptoms and mental HRQoL by CHD status. Physical health and cognitive abilities of adults with CHD were compromised compared with adults without CHD. Birth Defects Research (Part A) 106:580-586, 2016. © 2016 Wiley Periodicals, Inc.
|
Birth defects research. Part A, Clinical and molecular teratology
| 2,016
|
27,318,148
|
ETS-Transcription Factor ETV1 Regulates Stromal Expansion and Metastasis in Pancreatic Cancer.
|
The ETS-transcription factor ETV1 is involved in epithelial-mesenchymal transition during pancreatic development and is induced in mouse pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC). We investigated the function of ETV1 in stromal expansion of PDAC and metastasis, as well as its effects on a novel downstream target Sparc, which encodes a matricellular protein found in PDAC stroma that has been associated with invasiveness, metastasis and poor patient outcomes. Pancreatic ductal cells were isolated from Pdx1Cre;Kras(G12D/+) mice (PanIN), Pdx1Cre;Kras(G12D/+);p53(fl/+) and Pdx1Cre;Kras(G12D/+);p53(fl/+);Rosa26(YFP) mice (PDAC), and Pdx1Cre;Kras(G12D/+);p53(fl/+);Sparc(-/-) mice. Cells were grown in 3-dimensional organoid culture to analyze morphology, proliferation, and invasion. Human PanIN and PDAC tissues were evaluated for ETV1 expression. Orthotopic pancreatic transplants of ETV1-overexpressing PDAC and respective control cells were performed. ETV1 expression was significantly increased in human PanINs and, even more so, in primary and metastatic PDAC. Analyses of mouse orthotopic xenografts revealed that ETV1 induced significantly larger primary tumors than controls, with significantly increased stromal expansion, ascites and metastases. In 3-dimensional organoids, ETV1 disrupted cyst architecture, induced EMT, and increased invasive capacity. Furthermore, we identified Sparc as a novel functional gene target of Etv1 by luciferase assays, and SPARC and ETV1 proteins co-localized in vivo. Disruption of Sparc abrogates the phenotype of stromal expansion and metastasis found with ETV1 overexpression in vivo. We identified hyaluronan synthase 2 (Has2) as another novel downstream factor of Etv1; that may mediate ETV1's significant expansion of hyaluronic acid in PDAC stroma. Conversely, disruption of Etv1 in PDAC mice (Pdx1Cre;Kras(G12D/+);p53(fl/+);Rosa26(YFP);Cre;Etv1(fl/fl)) reduced levels of SPARC and hyaluronic acid in the stroma. ETV1 is critical in the desmoplastic stromal expansion and metastatic progression of pancreatic cancer in mice, mediated functionally in part through Sparc and Has2.
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Gastroenterology
| 2,016
|
27,583,259
|
Glomerular Filtration Barrier Assembly: An insight.
|
A glomerulus is the network of capillaries that resides in the Bowman's capsule that functions as a filtration unit of kidney. The glomerular function ensures that essential plasma proteins are retained in blood and the filtrate is passed on as urine. The glomerular filtration assembly is composed of three main cellular barriers that are critical for the ultrafiltration process, the fenestrated endothelium, glomerular basement membrane and highly specialized podocytes. The podocytes along with their specialized junctions "slit diaphragm" form the basic backbone of this filtration assembly. The presence of high amounts of protein in urine a condition commonly referred as proteinuria indicates a defective glomerular filtration barrier. Various glomerular disorders including Nephrotic syndrome are characterized by significant alteration in the structure of podocytes that is associated with prolonged increase in the glomerular permeability leading to heavy proteinuria. Recent identification of proteins that are specifically localized at the slit diaphragm whose mutations and knockouts are known to result in loss of renal function has significantly advanced our understanding of the molecular makeup of this filtration assembly. The present review is an effort to summarize the recent developments in this field and highlight our understanding of the glomerular filtration barrier assembly.
|
Postdoc journal : a journal of postdoctoral research and postdoctoral affairs
| 2,013
|
27,479,328
|
A far-red fluorescent protein evolved from a cyanobacterial phycobiliprotein.
|
Far-red fluorescent proteins (FPs) are desirable for in vivo imaging because with these molecules less light is scattered, absorbed, or re-emitted by endogenous biomolecules compared with cyan, green, yellow, and orange FPs. We developed a new class of FP from an allophycocyanin α-subunit (APCα). Native APC requires a lyase to incorporate phycocyanobilin. The evolved FP, which we named small ultra-red FP (smURFP), covalently attaches a biliverdin (BV) chromophore without a lyase, and has 642/670-nm excitation-emission peaks, a large extinction coefficient (180,000 M(-1)cm(-1)) and quantum yield (18%), and photostability comparable to that of eGFP. smURFP has significantly greater BV incorporation rate and protein stability than the bacteriophytochrome (BPH) FPs. Moreover, BV supply is limited by membrane permeability, and smURFPs (but not BPH FPs) can incorporate a more membrane-permeant BV analog, making smURFP fluorescence comparable to that of FPs from jellyfish or coral. A far-red and near-infrared fluorescent cell cycle indicator was created with smURFP and a BPH FP.
|
Nature methods
| 2,016
|
27,070,266
|
Germline Stem Cell Competition, Mutation Hot Spots, Genetic Disorders, and Older Fathers.
|
Some de novo human mutations arise at frequencies far exceeding the genome average mutation rate. Examples include the common mutations at one or a few sites in the genes that cause achondroplasia, Apert syndrome, multiple endocrine neoplasia type 2B, and Noonan syndrome. These mutations are recurrent, provide a gain of function, are paternally derived, and are more likely to be transmitted as the father ages. Recent experiments have tested whether the high mutation frequencies are due to an elevated mutation rate per cell division, as expected, or to an advantage of the mutant spermatogonial stem cells over wild-type stem cells. The evidence, which includes the surprising discovery of testis mutation clusters, rules out the former model but not the latter. We propose how the mutations might alter spermatogonial stem cell function and discuss how germline selection contributes to the paternal age effect, the human mutational load, and adaptive evolution.
|
Annual review of genomics and human genetics
| 2,016
|
27,148,848
|
The Valjean effect: Visceral states and cheating.
|
Visceral states like thirst, hunger, and fatigue can alter motivations, predictions, and even memory. Across 3 studies, we demonstrate that such "hot" states can also shift moral standards and increase dishonest behavior. Compared to participants who had just eaten or who had not yet exercised, hungry and thirsty participants were more likely to behave dishonestly to win a prize. Consistent with the specificity of motivation that is characteristic of visceral states, participants were only more likely to cheat for a prize that could alleviate their current deprived state (such as a bottle of water). Interestingly, this increase in dishonest behavior did not seem to be driven by an increase in the perceived monetary value of the prize. (PsycINFO Database Record
|
Emotion (Washington, D.C.)
| 2,016
|
27,579,810
|
Real-time assessment of alcohol drinking and drug use in opioid-dependent polydrug users.
|
We investigated relationships between drinking, other drug use, and drug craving, using ecological momentary assessment (EMA), in a sample of polydrug users who were not heavy drinkers. In a prospective longitudinal cohort study, 114 heroin and cocaine users on methadone-maintenance treatment carried handheld electronic diaries during waking hours and were screened for drug and alcohol use for up to 25 weeks. Individuals who fulfilled the Diagnostic and Statistical Manual of Mental Disorders criteria for alcohol abuse or dependence were excluded. Participants responded to 2-5 random prompts per day to report on their moods, cravings, and activities and initiated entries when they used or acutely craved heroin or cocaine. Drinking alcohol was assessed in both types of entries. Breath alcohol was measured three times weekly. Participants reported drinking alcohol in 1.6% of random-prompt entries, 3.7% of event-contingent entries when craving cocaine and/or heroin, and 11.6% of event-contingent entries when using cocaine and/or heroin. Alcohol drinking was also associated with higher craving ratings and prestudy alcohol use. More drinking was detected by ambulatory self-report than by in-clinic breath testing. Even though we had screened out heavy drinkers from our sample of polydrug users, drinking was associated with heroin and cocaine craving and actual use.
|
Behavioural pharmacology
| 2,016
|
27,462,993
|
Water-Soluble Molecularly Imprinted Nanoparticle Receptors with Hydrogen-Bond-Assisted Hydrophobic Binding.
|
Molecularly imprinted nanoparticles (MINPs) were prepared when surfactants with a tripropargylammonium headgroup and a methacrylate-functionalized hydrophobic tail were cross-linked in the micelle form on the surface and in the core in the presence of hydrophobic template molecules. With the surfactants containing an amide bond near the headgroup, the MINPs had a layer of hydrogen-bonding groups in the interior that strongly influenced their molecular recognition. Templates/guests with strong hydrogen-bonding groups in the midsection of the molecule benefited most, especially if the hydrophobe of the template could penetrate the amide layer to reach the hydrophobic core of the cross-linked micelles. The location and the orientation of the hydrophilic groups were also important, as they determined how the template interacted with the surfactant micelles and, ultimately, with the MINP receptors.
|
The Journal of organic chemistry
| 2,016
|
27,130,711
|
Hypereosinophilia in Children and Adults: A Retrospective Comparison.
|
The differential diagnosis of hypereosinophilia is broad and includes asthma, atopic disease, drug hypersensitivity, parasitic infection, connective tissue disorders, malignancy, and rare hypereosinophilic disorders. Hypereosinophilia in children has not been well characterized to date. The objective of this study was to identify the common causes of marked eosinophilia in children and to characterize and compare the clinical symptoms at presentation, laboratory findings, final diagnosis, and therapeutic responses between children and adults with hypereosinophilic syndromes. A retrospective analysis of consecutive subjects evaluated for unexplained eosinophilia ≥ 1.5 × 10(9)/L was conducted. All subjects underwent standardized clinical and laboratory evaluations with yearly follow-up. Clinical and laboratory parameters, final diagnoses, treatment responses, and outcomes were assessed. Medians and proportions were compared using Mann-Whitney U and Fisher Exact tests, respectively. Of the 291 subjects evaluated, 37 (13%) were children and 254 were adults (87%). Whereas the frequencies of clinical hypereosinophilic syndrome (HES) variants were similar between children and adults, primary immunodeficiency was a more common secondary cause of HES in children (5% vs 0.4% in adults). Excluding subjects with treatable secondary causes, the median peak absolute eosinophil count was increased in pediatric subjects (9376 vs 5543/μL; P = .002), and children had more gastrointestinal complaints (62% vs 34%; P = .003) and less pulmonary involvement (34% vs 59%; P = .01) than adults. Despite these differences, corticosteroid responsiveness and overall prognosis were similar between the 2 groups. Although children with HES often present with higher peak eosinophil counts than adults, the differential diagnosis, clinical characteristics, and prognosis of HES are similar in the 2 groups.
|
The journal of allergy and clinical immunology. In practice
| 2,016
|
27,340,104
|
Effect of leaf digestion and artemisinin solubility for use in oral consumption of dried Artemisia annua leaves to treat malaria.
|
Artemisia annua L. produces the antimalarial sesquiterpene lactone, artemisinin (AN), and was traditionally used by the Chinese to treat fever, which was often caused by malaria. To measure effects of plant-based and dietary components on release of artemisinin and flavonoids from A. annua dried leaves (DLA) after simulated digestion. Simulated digestion was performed on DLA in four types of capsules, or in conjunction with protein, and protein-based foods: dry milk, casein, bovine serum albumin, peanuts, peanut butter, Plumpy'nut(®), and A. annua essential oils. Artemisinin and total flavonoids were measured in the liquid phase of the intestinal stage of digestion. After simulated digestion, peanuts and Plumpy'nut(®) lowered AN and flavonoids, respectively, recovered from the liquid digestate fraction. None of the compositions of the tested capsules altered AN or flavonoid release. Surprisingly, bovine serum albumin (BSA) increased both AN and flavonoids recovered from liquid simulated digestate fractions while casein had no effect. AN delivered as DLA was about 4 times more soluble in digestates than AN delivered as pure drug. Addition of a volume of essential oil equivalent to that found in a high essential oil producing A. annua cultivar also significantly increased AN solubility in simulated digestates. These results indicate encapsulating DLA may provide a way to mask the taste of A. annua without altering bioavailability. Similarly, many peanut-based products can be used to mask the flavor with appropriate dosing. Finally, the essential oil fraction of A. annua contributes to the increased AN solubility in DLA after simulated digestion. Our results suggest that use of DLA in the treatment of malaria and other artemisinin-susceptible diseases should be further tested in animals and humans.
|
Journal of ethnopharmacology
| 2,016
|
27,189,922
|
Rodent-Adapted Filoviruses and the Molecular Basis of Pathogenesis.
|
Ebola, Marburg, and Ravn viruses, all filoviruses, are the causative agents of severe hemorrhagic fever. Much of what we understand about the pathogenesis of filovirus disease is derived from work with animal models, including nonhuman primates, which are considered the "gold standard" filovirus model since they faithfully recapitulate the clinical hallmarks of filovirus disease. However, rodent models, including the mouse, guinea pig, and hamster, also exist for Ebola, Marburg, and Ravn viruses, and although they may not reproduce all the clinical signs of filovirus disease, thanks to their relative ease of use and low cost, they are often the first choice for initial descriptions of virus pathogenesis and evaluation of antiviral prophylactics and therapeutics. Since filoviruses do not cause significant disease in adult, immunocompetent rodents, these models rely on "rodent-adapted" viruses that have been passaged several times through their host until virulence and lethality are achieved. In the process of adaptation, the viruses acquire numerous nucleotide/amino acid mutations that contribute to virulence in their rodent host. Interestingly, virus protein 24 (VP24) and nucleoprotein (NP) appear to be major virulence factors for ebolaviruses in rodents, whereas VP40 appears to be the major virulence factor for marburgviruses. By characterizing these mutations and understanding the molecular mechanisms that lead to the acquisition of virulence, we can gain better insight into the pathogenic processes that underlie filovirus disease in humans. These processes, and the viral and/or cellular proteins that contribute to them, will make attractive targets for the development of novel therapeutics and counter-measures.
|
Journal of molecular biology
| 2,016
|
27,586,827
|
Assessment of Chronic Pain: Domains, Methods, and Mechanisms.
|
Accurate classification of chronic pain conditions requires reliable and valid pain assessment. Moreover, pain assessment serves several additional functions, including documenting the severity of the pain condition, tracking the longitudinal course of pain, and providing mechanistic information. Thorough pain assessment must address multiple domains of pain, including the sensory and affective qualities of pain, temporal dimensions of pain, and the location and bodily distribution of pain. Where possible, pain assessment should also incorporate methods to identify pathophysiological mechanisms underlying the pain. This article discusses assessment of chronic pain, including approaches available for assessing multiple pain domains and for addressing pathophysiological mechanisms. We conclude with recommendations for optimal pain assessment. Pain assessment is a critical prerequisite for accurate pain classification. This article describes important features of pain that should be assessed, and discusses methods that can be used to assess the features and identify pathophysiological mechanisms contributing to pain.
|
The journal of pain
| 2,016
|
27,404,940
|
In vivo imaging reveals impaired connectivity across cortical and subcortical networks in a mouse model of DYT1 dystonia.
|
Developing in vivo functional and structural neuroimaging assays in Dyt1 ΔGAG heterozygous knock-in (Dyt1 KI) mice provide insight into the pathophysiology underlying DYT1 dystonia. In the current study, we examined in vivo functional connectivity of large-scale cortical and subcortical networks in Dyt1 KI mice and wild-type (WT) controls using resting-state functional magnetic resonance imaging (MRI) and an independent component analysis. In addition, using diffusion MRI we examined how structural integrity across the basal ganglia and cerebellum directly relates to impairments in functional connectivity. Compared to WT mice, Dyt1 KI mice revealed increased functional connectivity across the striatum, thalamus, and somatosensory cortex; and reduced functional connectivity in the motor and cerebellar cortices. Further, Dyt1 KI mice demonstrated elevated free-water (FW) in the striatum and cerebellum compared to WT mice, and increased FW was correlated with impairments in functional connectivity across basal ganglia, cerebellum, and sensorimotor cortex. The current study provides the first in vivo MRI-based evidence in support of the hypothesis that the deletion of a 3-base pair (ΔGAG) sequence in the Dyt1 gene encoding torsinA has network level effects on in vivo functional connectivity and microstructural integrity across the sensorimotor cortex, basal ganglia, and cerebellum.
|
Neurobiology of disease
| 2,016
|
27,292,318
|
CYP2U1 mutations in two Iranian patients with activity induced dystonia, motor regression and spastic paraplegia.
|
Hereditary spastic paraplegia (HSP) is a heterogeneous condition characterized by progressive spasticity and weakness in the lower limbs. It is divided into two major groups, complicated and uncomplicated, based on the presence of additional features such as intellectual disability, ataxia, seizures, peripheral neuropathy and visual problems. SPG56 is an autosomal recessive form of HSP with complicated and uncomplicated manifestations, complicated being more common. CYP2U1 gene mutations have been identified as responsible for SPG56. Intellectual disability, dystonia, subclinical sensory motor neuropathy, pigmentary degenerative maculopathy, thin corpus callosum and periventricular white-matter hyperintensities were additional features noted in previous cases of SPG56. Here we identified two novel mutations in CYP2U1 in two unrelated patients by whole exome sequencing. Both patients had complicated HSP with activity-induced dystonia, suggesting dystonia as an additional finding in SPG56. Two out of 14 previously reported patients had dystonia, and the addition of our patients suggests dystonia in a quarter of SPG56 patients. Developmental regression has not been reported in SPG56 patients so far but both of our patients developed motor regression in infancy.
|
European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society
| 2,016
|
27,586,832
|
The Role of Psychosocial Processes in the Development and Maintenance of Chronic Pain.
|
The recently proposed Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION)-American Pain Society (APS) Pain Taxonomy (AAPT) provides an evidence-based, multidimensional, chronic pain classification system. Psychosocial factors play a crucial role within several dimensions of the taxonomy. In this article, we discuss the evaluation of psychosocial factors that influence the diagnosis and trajectory of chronic pain disorders. We review studies in individuals with a variety of persistent pain conditions, and describe evidence that psychosocial variables play key roles in conferring risk for the development of pain, in shaping long-term pain-related adjustment, and in modulating pain treatment outcomes. We consider "general" psychosocial variables such as negative affect, childhood trauma, and social support, as well as "pain-specific" psychosocial variables that include pain-related catastrophizing, self-efficacy for managing pain, and pain-related coping. Collectively, the complexity and profound variability in chronic pain highlights the need to better understand the multidimensional array of interacting forces that determine the trajectory of chronic pain conditions. The AAPT is an evidence-based chronic pain classification system in which psychosocial concepts and processes are essential in understanding the development of chronic pain and its effects. In this article we review psychosocial processes that influence the onset, exacerbation, and maintenance of chronic pain disorders.
|
The journal of pain
| 2,016
|
27,586,831
|
Toward a Mechanism-Based Approach to Pain Diagnosis.
|
The past few decades have witnessed a huge leap forward in our understanding of the mechanistic underpinnings of pain, in normal states where it helps protect from injury, and also in pathological states where pain evolves from a symptom reflecting tissue injury to become the disease itself. However, despite these scientific advances, chronic pain remains extremely challenging to manage clinically. Although the number of potential treatment targets has grown substantially and a strong case has been made for a mechanism-based and individualized approach to pain therapy, arguably clinicians are not much more advanced now than 20 years ago, in their capacity to either diagnose or effectively treat their patients. The gulf between pain research and pain management is as wide as ever. We are still currently unable to apply an evidence-based approach to chronic pain management that reflects mechanistic understanding, and instead, clinical practice remains an empirical and often unsatisfactory journey for patients, whose individual response to treatment cannot be predicted. In this article we take a common and difficult to treat pain condition, chronic low back pain, and use its presentation in clinical practice as a framework to highlight what is known about pathophysiological pain mechanisms and how we could potentially detect these to drive rational treatment choice. We discuss how present methods of assessment and management still fall well short, however, of any mechanism-based or precision medicine approach. Nevertheless, substantial improvements in chronic pain management could be possible if a more strategic and coordinated approach were to evolve, one designed to identify the specific mechanisms driving the presenting pain phenotype. We present an analysis of such an approach, highlighting the major problems in identifying mechanisms in patients, and develop a framework for a pain diagnostic ladder that may prove useful in the future, consisting of successive identification of 3 steps: pain state, pain mechanism, and molecular target. Such an approach could serve as the foundation for a new era of individualized/precision pain medicine. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION)-American Pain Society (APS) Pain Taxonomy (AAPT) includes pain mechanisms as 1 of the 5 dimensions that need to be considered when making a diagnostic classification. The diagnostic ladder proposed in this article is consistent with and an extension of the AAPT. We discuss how identifying the specific mechanisms that operate in the nervous system to produce chronic pain in individual patients could provide the basis for a targeted and rational precision medicine approach to controlling pain, using chronic low back pain as our example.
|
The journal of pain
| 2,016
|
27,588,601
|
Do DNA Double-Strand Breaks Drive Aging?
|
DNA double-strand breaks (DSBs) are rare, but highly toxic, lesions requiring orchestrated and conserved machinery to prevent adverse consequences, such as cell death and cancer-causing genome structural mutations. DSBs trigger the DNA damage response (DDR) that directs a cell to repair the break, undergo apoptosis, or become senescent. There is increasing evidence that the various endpoints of DSB processing by different cells and tissues are part of the aging phenotype, with each stage of the DDR associated with specific aging pathologies. In this Perspective, we discuss the possibility that DSBs are major drivers of intrinsic aging, highlighting the dynamics of spontaneous DSBs in relation to aging, the distinct age-related pathologies induced by DSBs, and the segmental progeroid phenotypes in humans and mice with genetic defects in DSB repair. A model is presented as to how DSBs could drive some of the basic mechanisms underlying age-related functional decline and death.
|
Molecular cell
| 2,016
|
25,416,442
|
Epigenetic regulation of human hedgehog interacting protein in glioma cell lines and primary tumor samples.
|
Glioma constitutes one of the most common groups of brain tumors, and its prognosis is influenced by different genetic and epigenetic modulations. In this study, we demonstrated low or no expression of hedgehog interacting protein (HHIP) in most of the cell lines and primary glioma tumor samples. We further proceeded to promoter methylation study of this gene in the same cell lines and primary tumor samples and found 87 % (7/8) HHIP methylation in glioblastoma cell lines and 75 % (33/44) in primary tumor samples. These methylation pattern correlates with low or unexpressed HHIP in both cell lines and primary tumor samples. Our results suggest the possibility of epigenetic regulation of this gene in glioma, similarly to medulloblastoma, gastric, hepatic, and pancreatic cancers. Also, HHIP might be a diagnostic or prognostic marker in glioma and help to the detection of these tumors in early stages of disease.
|
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine
| 2,015
|
27,103,607
|
Is there a future for biologics in the management of chronic rhinosinusitis?
|
Chronic rhinosinusitis (CRS) is a heterogeneous inflammatory condition of the sinonasal mucosa consisting of poorly defined subtypes and characterized by variable clinical manifestations, responses to therapy, and underlying pathophysiologies. In the related disorder of asthma, progress has been made in defining disease subtypes on both clinical and pathophysiologic levels, facilitating the development of targeted biologic pharmacotherapy. The potential role of these drugs for the management of CRS will be reviewed. The objective of this work is to highlight the emerging therapeutic targets in CRS in light of evolving treatment options for asthma and enhanced understandings of the clinical manifestations and pathophysiology of CRS. This article is a review of recent studies regarding current and future advances in biomarker-directed therapies in the medical treatment of CRS. Various biologic therapies used in the management of asthma have demonstrated clinical promise for CRS, particularly within the CRS with nasal polyposis (CRSwNP) phenotype. Several randomized, double-blind, placebo-controlled studies increasingly support the targeting of immunoglobulin E (IgE) and interleukin (IL)-5 pathways to improve outcome measures in CRSwNP patients. The IL-4/IL-13 pathway and other type 2 inflammatory pathways have also shown potential as targets for CRSwNP, but all pathways require further investigation. Recalcitrant CRS in the United States and Europe is most commonly associated with nasal polyposis and a type 2 cytokine skewing in the tissue, resulting in tissue infiltration of eosinophils, mast cells, and basophils. Targeting biomarkers of the associated type 2 pathways may be a practical treatment option for recalcitrant CRSwNP in the future.
|
International forum of allergy & rhinology
| 2,016
|
28,131,617
|
BetaB2-crystallin mutations associated with cataract and glaucoma leads to mitochondrial alterations in lens epithelial cells and retinal neurons.
|
Crystallin proteins are the most prominent protein of the lens and have been increasingly shown to play critical roles in other tissues, especially the retina. Members of all 3 sub-families of crystallins, alpha-, beta- and gamma-crystallins have been reported in the retina during diabetes, traumatic injury and other retinal diseases. While their specific role in the retina is still unclear and may vary, beta-crystallin proteins have been shown to play a critical role in ganglion cell survival following trauma. We recently reported the correlation between a gene conversion in the betaB2-crystallin gene and a phenotype of familial congenital cataract. Interestingly, in half of the patients, this phenotype was associated with glaucoma. Taken together, these data suggested that the mutations we recently reported could have an impact on the role of betaB2-crystallin in both lens epithelial cells and retinal neurons. Consistent with this hypothesis, we show in the current study that the gene conversion leading to an amino acid conversion lead to a loss of solubility and a change of subcellular localization of betaB2-crystallin in both cell types. While the overall observations were similar in both cell types, there were some important nuances between them, suggesting different roles and regulation of betaB2-crystallin in lens cells versus retinal neurons. The data reported in this study strongly support a significant role of betaB2-crystallin in both lenticular and retinal ocular tissues and warrant further analysis of its regulation and its impact not only in cataract formation but also in retinal neurodegenerative diseases.
|
Experimental eye research
| 2,017
|
28,396,501
|
Mechanism of Progressive Heart Failure and Significance of Pulmonary Hypertension in Obstructive Hypertrophic Cardiomyopathy.
|
There are limited data on the prevalence, pathophysiology, and management implications of pulmonary hypertension in patients with obstructive hypertrophic cardiomyopathy and advanced heart failure. To assess the clinical significance of measured cardiopulmonary hemodynamics in hypertrophic cardiomyopathy patients with heart failure, we retrospectively assessed right heart catheterization data in 162 consecutive patients with outflow tract gradients (median [interquartile range], 90 mm Hg [70-110 mm Hg]), 59±11 years old, and 49% men, predominately New York Heart Association class III/IV status. Pulmonary hypertension (mean pulmonary artery pressure, ≥25 mm Hg) was present in 82 patients (51%), including 29 (18%) regarded as moderate-severe (mean pulmonary artery pressure, ≥35 mm Hg) and 28 (34%) also had increased pulmonary vascular resistance >3.0 WU. The pulmonary artery wedge pressure was ≤15 mm Hg in 54%, indicating that left atrial hypertension was absent in a majority of patients. Notably, 9 patients (11%) met hemodynamic criteria for precapillary pulmonary hypertension (mean pulmonary artery pressure, ≥25 mm Hg; pulmonary vascular resistance, >3.0 WU; pulmonary artery wedge pressure, ≤15 mm Hg). Over a median follow-up of 327 days (90-743 days) after surgical myectomy (or alcohol septal ablation), 92% and 95% of patients with or without preoperative pulmonary hypertension, respectively, were asymptomatic or mildly symptomatic. One postoperative death occurred in a 59-year-old woman with acute respiratory failure and mean pulmonary artery pressure of 65 mm Hg. Pulmonary hypertension was common in obstructive hypertrophic cardiomyopathy patients with advanced heart failure. Although possibly a contributor to preoperative heart failure, pulmonary hypertension did not significantly influence clinical and surgical outcome. Notably, a novel patient subgroup was identified with resting invasive hemodynamics consistent with pulmonary vascular disease.
|
Circulation. Heart failure
| 2,017
|
28,054,444
|
Heterozygous Pathogenic Variant in DACT1 Causes an Autosomal-Dominant Syndrome with Features Overlapping Townes-Brocks Syndrome.
|
A heterozygous nonsense variant was identified in dapper, antagonist of beta-catenin, 1 (DACT1) via whole-exome sequencing in family members with imperforate anus, structural renal abnormalities, genitourinary anomalies, and/or ear anomalies. The DACT1 c.1256G>A;p.Trp419
|
Human mutation
| 2,017
|
28,232,190
|
Amyloid and tau PET demonstrate region-specific associations in normal older people.
|
β-amyloid (Aβ) and tau pathology become increasingly prevalent with age, however, the spatial relationship between the two pathologies remains unknown. We examined local (same region) and non-local (different region) associations between these 2 aggregated proteins in 46 normal older adults using [
|
NeuroImage
| 2,017
|
27,735,922
|
Improving biobank consent comprehension: a national randomized survey to assess the effect of a simplified form and review/retest intervention.
|
To determine the individual and combined effects of a simplified form and a review/retest intervention on biobanking consent comprehension. We conducted a national online survey in which participants were randomized within four educational strata to review a simplified or traditional consent form. Participants then completed a comprehension quiz; for each item answered incorrectly, they reviewed the corresponding consent form section and answered another quiz item on that topic. Consistent with our first hypothesis, comprehension among those who received the simplified form was not inferior to that among those who received the traditional form. Contrary to expectations, receipt of the simplified form did not result in significantly better comprehension compared with the traditional form among those in the lowest educational group. The review/retest procedure significantly improved quiz scores in every combination of consent form and education level. Although improved, comprehension remained a challenge in the lowest-education group. Higher quiz scores were significantly associated with willingness to participate. Ensuring consent comprehension remains a challenge, but simplified forms have virtues independent of their impact on understanding. A review/retest intervention may have a significant effect, but assessing comprehension raises complex questions about setting thresholds for understanding and consequences of not meeting them.Genet Med advance online publication 13 October 2016.
|
Genetics in medicine : official journal of the American College of Medical Genetics
| 2,017
|
27,890,240
|
Melanocytic Nevi and the Genetic and Epigenetic Control of Oncogene-Induced Senescence.
|
Melanocytic nevi represent benign clonal proliferations of the melanocytes in the skin that usually remain stable in size and behavior or disappear during life. Infrequently, melanocytic nevi undergo malignant transformation to melanoma. Understanding molecular and cellular mechanisms underlying oncogene-induced senescence should help identify pathways underlying melanoma development, leading to the development of new strategies for melanoma prevention and early detection.
|
Dermatologic clinics
| 2,017
|
25,987,503
|
Biology and pathobiology of lipid droplets and their potential role in the protection of the organ of Corti.
|
The current review article seeks to extend our understanding on the role of lipid droplets within the organ of Corti. In addition to presenting an overview of the current information about the origin, structure and function of lipid droplets we draw inferences from the collective body of knowledge about this cellular organelle to build a conceptual framework to better understanding their role in auditory function. This conceptual model considers that lipid droplets play a significant role in the synthesis, storage, and release of lipids and proteins for energetic use and/or modulating cell signaling pathways. We describe the role and mechanism by which LD play a role in human diseases, and we also review emerging data from our laboratory revealing the potential role of lipid droplets from Hensen cells in the auditory organ. We suggest that lipid droplets might help to develop rapidly and efficiently the resolution phase of inflammatory responses in the mammalian cochlea, preventing inflammatory damage of the delicate inner ear structures and, consequently, sensorineural hearing loss.
|
Hearing research
| 2,015
|
27,923,814
|
miR-483 Targeting of CTGF Suppresses Endothelial-to-Mesenchymal Transition: Therapeutic Implications in Kawasaki Disease.
|
Endothelial-mesenchymal transition (EndoMT) is implicated in myofibroblast-like cell-mediated damage to the coronary arterial wall in acute Kawasaki disease (KD) patients, as evidenced by positive staining for connective tissue growth factor (CTGF) and EndoMT markers in KD autopsy tissues. However, little is known about the molecular basis of EndoMT involved in KD. We investigated the microRNA (miRNA) regulation of CTGF and the consequent EndoMT in KD pathogenesis. As well, the modulation of this process by statin therapy was studied. Sera from healthy children and KD subjects were incubated with human umbilical vein endothelial cells. Cardiovascular disease-related miRNAs, CTGF, and EndoMT markers were quantified using reverse transcriptase quantitative polymerase chain reaction, ELISA, and Western blotting. Compared with healthy controls, human umbilical vein endothelial cell incubated with sera from acute KD patients had decreased miR-483, increased CTGF, and increased EndoMT markers. Bioinformatics analysis followed by functional validation demonstrated that Krüppel-like factor 4 (KLF4) transactivates miR-483, which in turn targets the 3' untranslated region of CTGF mRNA. Overexpression of KLF4 or pre-miR-483 suppressed, whereas knockdown of KLF4 or anti-miR-483 enhanced, CTGF expression in endothelial cells in vitro and in vivo. Furthermore, atorvastatin, currently being tested in a phase I/IIa clinical trial in KD children, induced KLF4-miR-483, which suppressed CTGF and EndoMT in endothelial cells. KD sera suppress the KLF4-miR-483 axis in endothelial cells, leading to increased expression of CTGF and induction of EndoMT. This detrimental process in the endothelium may contribute to coronary artery abnormalities in KD patients. Statin therapy may benefit acute KD patients, in part, through the restoration of KLF4-miR-483 expression. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01431105.
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Circulation research
| 2,017
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28,404,607
|
Interpreting Incidentally Identified Variants in Genes Associated With Catecholaminergic Polymorphic Ventricular Tachycardia in a Large Cohort of Clinical Whole-Exome Genetic Test Referrals.
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The rapid expansion of genetic testing has led to increased utilization of clinical whole-exome sequencing (WES). Clinicians and genetic researchers are being faced with assessing risk of disease vulnerability from incidentally identified genetic variants which is typified by variants found in genes associated with sudden death-predisposing catecholaminergic polymorphic ventricular tachycardia (CPVT). We sought to determine whether incidentally identified variants in genes associated with CPVT from WES clinical testing represent disease-associated biomarkers. CPVT-associated genes The prevalence of incidentally identified CPVT-associated variants is ≈9% among WES tests. Variants of undetermined significances in CPVT-associated genes in WES genetic testing, in the absence of clinical suspicion for CPVT, are unlikely to represent markers of CPVT pathogenicity.
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Circulation. Arrhythmia and electrophysiology
| 2,017
|
28,330,898
|
Antigen-Presenting Human γδ T Cells Promote Intestinal CD4
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The cytokine IL-22 plays a critical role in mucosal barrier defense, but the mechanisms that promote IL-22 expression in the human intestine remain poorly understood. As human microbe-responsive Vγ9/Vδ2 T cells are abundant in the gut and recognize microbiota-associated metabolites, we assessed their potential to induce IL-22 expression by intestinal CD4
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Journal of immunology (Baltimore, Md. : 1950)
| 2,017
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26,341,457
|
Impact of late fluid balance on clinical outcomes in the critically ill surgical and trauma population.
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Management of fluid status in critically ill patients poses a significant challenge due to limited literature. This study aimed to determine the impact of late fluid balance management after initial adequate fluid resuscitation on in-hospital mortality for critically ill surgical and trauma patients. This single-center retrospective cohort study included 197 patients who underwent surgical procedure within 24 hours of surgical intensive care unit admission. Patients with high fluid balance on postoperative day 7 (>5 L) were compared with those with a low fluid balance (≤5 L) with a primary end point of in-hospital mortality. Subgroup analyses were performed based on diuretic administration, diuretic response, and type of surgery. High fluid balance was associated with significantly higher in-hospital mortality (30.2 vs 3%, P<.001) compared with low fluid balance; this relationship remained after multivariable regression analysis. High fluid balance was associated with increased mortality, independent of diuretic administration, diuretic response, and type of surgery. Consistent with previous literature, high fluid balance on postoperative day 7 was associated with increased in-hospital mortality. Patients who received and responded to diuretic therapy did not demonstrate improved clinical outcomes, which questions their use in the postoperative period.
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Journal of critical care
| 2,015
|
27,497,945
|
Mitochondrial Ca
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The mitochondrial permeability transition pore was originally described in the 1970's as a Ca
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Journal of bioenergetics and biomembranes
| 2,017
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28,115,200
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Androgen receptor expression in mantle cell lymphoma: Potential novel therapeutic implications.
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Mantle cell lymphoma (MCL) affects approximately 4500 patients/year in the US and demonstrates a male to female ratio of approximately 4:1. While the pathobiology underlying this ratio is unknown, the hematopoietic system is characterized by sex-related differences in androgen receptor (AR) expression, leading us to hypothesize that the male-biased incidence of MCL may reflect sex-related differences in AR signaling during MCL lymphomagenesis. To explore the AR axis in MCL, we evaluated AR expression in MCL cell lines and human tumors, and tested the impact of androgen pathway inhibition on MCL proliferation. AR transcript levels ranged up to ~2
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Experimental hematology
| 2,017
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28,034,760
|
Insulin resistance in Alzheimer's disease.
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The links between systemic insulin resistance (IR), brain-specific IR, and Alzheimer's disease (AD) have been an extremely productive area of current research. This review will cover the fundamentals and pathways leading to IR, its connection to AD via cellular mechanisms, the most prominent methods and models used to examine it, an introduction to the role of extracellular vesicles (EVs) as a source of biomarkers for IR and AD, and an overview of modern clinical studies on the subject. To provide additional context, we also present a novel analysis of the spatial correlation of gene expression in the brain with the aid of Allen Human Brain Atlas data. Ultimately, examining the relation between IR and AD can be seen as a means of advancing the understanding of both disease states, with IR being a promising target for therapeutic strategies in AD treatment. In conclusion, we highlight the therapeutic potential of targeting brain IR in AD and the main strategies to pursue this goal.
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Translational research : the journal of laboratory and clinical medicine
| 2,017
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27,326,668
|
Maternal inflammation leads to impaired glutamate homeostasis and up-regulation of glutamate carboxypeptidase II in activated microglia in the fetal/newborn rabbit brain.
|
Astrocyte dysfunction and excessive activation of glutamatergic systems have been implicated in a number of neurologic disorders, including periventricular leukomalacia (PVL) and cerebral palsy (CP). However, the role of chorioamnionitis on glutamate homeostasis in the fetal and neonatal brains is not clearly understood. We have previously shown that intrauterine endotoxin administration results in intense microglial 'activation' and increased pro-inflammatory cytokines in the periventricular region (PVR) of the neonatal rabbit brain. In this study, we assessed the effect of maternal inflammation on key components of the glutamate pathway and its relationship to astrocyte and microglial activation in the fetal and neonatal New Zealand white rabbit brain. We found that intrauterine endotoxin exposure at gestational day 28 (G28) induced acute and prolonged glutamate elevation in the PVR of fetal (G29, 1day post-injury) and postnatal day 1 (PND1, 3days post-injury) brains along with prominent morphological changes in the astrocytes (soma hypertrophy and retracted processes) in the white matter tracts. There was a significant increase in glutaminase and N-Methyl-d-Aspartate receptor (NMDAR) NR2 subunit expression along with decreased glial L-glutamate transporter 1 (GLT-1) in the PVR at G29, that would promote acute dysregulation of glutamate homeostasis. This was accompanied with significantly decreased TGF-β1 at PND1 in CP kits indicating ongoing neuroinflammation. We also show for the first time that glutamate carboxypeptidase II (GCPII) was significantly increased in the activated microglia at the periventricular white matter area in both G29 and PND1 CP kits. This was confirmed by in vitro studies demonstrating that LPS activated primary microglia markedly upregulate GCPII enzymatic activity. These results suggest that maternal intrauterine endotoxin exposure results in early onset and long-lasting dysregulation of glutamate homeostasis, which may be mediated by impaired astrocyte function and GCPII upregulation in activated microglia.
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Neurobiology of disease
| 2,016
|
28,153,763
|
Multiply repeatable and adjustable on-demand phototriggered local anesthesia.
|
A phototriggerable system whereby patients could repeatedly and non-invasively control the timing and dosage of local anesthesia according to their needs would be beneficial for perioperative pain and perhaps obviate the need for oral narcotics. However, clinical application of phototriggerable systems have been limited by concerns over phototoxicity of lasers and limited tissue penetration of light. To address these limitations, we increased the devices' effective sensitivity to light by co-delivering a second compound, dexmedetomidine, that potentiates the effect of delivered local anesthetics. The concurrent release of dexmedetomidine enhanced the efficacy of released local anesthetics, greatly increasing the number of triggerable nerve blocks (up to nine triggerable events upon a single injection) and reducing the irradiance needed to induce nerve block by 94%. The intensity and duration of on-demand analgesia could be adjusted by varying the intensity and duration of irradiance, which could not only be delivered by lasers, but also by light-emitting diodes, which are less expensive, safer, and more portable.
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Journal of controlled release : official journal of the Controlled Release Society
| 2,017
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28,220,259
|
Mutations in KIAA0753 cause Joubert syndrome associated with growth hormone deficiency.
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Joubert syndrome and related disorders (JSRD) are a heterogeneous group of ciliopathies defined based on the mid-hindbrain abnormalities that result in the characteristic "molar tooth sign" on brain imaging. The core clinical findings of JSRD are hypotonia, developmental delay, abnormal eye movements and breathing abnormalities. To date, more than 30 JSRD genes that encode proteins important for structure and/or function of cilia have been identified. Here, we present 2 siblings with Joubert syndrome associated with growth hormone deficiency. Whole exome sequencing of the family identified compound heterozygous mutations in KIAA0753, i.e., a missense mutation (p.Arg257Gly) and an intronic mutation (c.2359-1G>C). The intronic mutation alters normal splicing by activating a cryptic acceptor splice site in exon 16. The novel acceptor site skips nine nucleotides, deleting three amino acids from the protein coding frame. KIAA0753 (OFIP) is a centrosome and pericentriolar satellite protein, previously not known to cause Joubert syndrome. We present comprehensive clinical descriptions of the Joubert syndrome patients as well as the cellular phenotype of defective ciliogenesis in the patients' fibroblasts.
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Human genetics
| 2,017
|
27,753,106
|
Dopaminergic activity and altered reward modulation in anorexia nervosa-insight from multimodal imaging.
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Individuals with anorexia nervosa (AN) have anxious and inhibited temperaments with high concern for consequences. Studies using either positron emission tomography (PET) or functional magnetic resonance imaging (fMRI) suggest involvement of the middle and dorsal caudate (DC) in individuals recovered (REC) from AN. For example, dopamine (DA) D2/D3 receptor binding in the middle caudate and DC was associated with anxiety and harm avoidance, and blood-oxygen-level-dependent (BOLD) response in the DC was positively related to trait anxiety. It has not been shown yet whether BOLD response in individuals REC from AN was related to DA function. Post-hoc correlation analyses between the PET and fMRI studies by correlating D2/D3 binding in striatal regions and BOLD signal in the anteroventral striatum (AVS) and DC for wins and losses respectively in 12 individuals REC from AN. Individuals REC from AN with the greatest BOLD response in the DC in a monetary choice task had higher middle caudate D2/D3 binding, and greater anxiety and/or harm avoidance. Though preliminary, these findings suggest that increased dorsal striatal D2/D3 binding is associated with enhanced cognitive response to feedback, potentially related to anxious anticipation of consequences. © 2016 Wiley Periodicals, Inc.(Int J Eat Disord 2017; 50:593-596).
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The International journal of eating disorders
| 2,017
|
28,025,748
|
Patient-derived xenograft (PDX) models in basic and translational breast cancer research.
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Patient-derived xenograft (PDX) models of a growing spectrum of cancers are rapidly supplanting long-established traditional cell lines as preferred models for conducting basic and translational preclinical research. In breast cancer, to complement the now curated collection of approximately 45 long-established human breast cancer cell lines, a newly formed consortium of academic laboratories, currently from Europe, Australia, and North America, herein summarizes data on over 500 stably transplantable PDX models representing all three clinical subtypes of breast cancer (ER+, HER2+, and "Triple-negative" (TNBC)). Many of these models are well-characterized with respect to genomic, transcriptomic, and proteomic features, metastatic behavior, and treatment response to a variety of standard-of-care and experimental therapeutics. These stably transplantable PDX lines are generally available for dissemination to laboratories conducting translational research, and contact information for each collection is provided. This review summarizes current experiences related to PDX generation across participating groups, efforts to develop data standards for annotation and dissemination of patient clinical information that does not compromise patient privacy, efforts to develop complementary data standards for annotation of PDX characteristics and biology, and progress toward "credentialing" of PDX models as surrogates to represent individual patients for use in preclinical and co-clinical translational research. In addition, this review highlights important unresolved questions, as well as current limitations, that have hampered more efficient generation of PDX lines and more rapid adoption of PDX use in translational breast cancer research.
|
Cancer metastasis reviews
| 2,016
|
28,074,478
|
Ultrastructural analysis of parvalbumin synapses in human dorsolateral prefrontal cortex.
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Coordinated activity of neural circuitry in the primate dorsolateral prefrontal cortex (DLPFC) supports a range of cognitive functions. Altered DLPFC activation is implicated in a number of human psychiatric and neurological illnesses. Proper DLPFC activity is, in part, maintained by two populations of neurons containing the calcium-binding protein parvalbumin (PV): local inhibitory interneurons that form Type II synapses, and long-range glutamatergic inputs from the thalamus that form Type I synapses. Understanding the contributions of each PV neuronal population to human DLPFC function requires a detailed examination of their anatomical properties. Consequently, we performed an electron microscopic analysis of (1) the distribution of PV immunoreactivity within the neuropil, (2) the properties of dendritic shafts of PV-IR interneurons, (3) Type II PV-IR synapses from PV interneurons, and (4) Type I PV-IR synapses from long-range projections, within the superficial and middle laminar zones of the human DLPFC. In both laminar zones, Type II PV-IR synapses from interneurons comprised ∼60% of all PV-IR synapses, and Type I PV-IR synapses from putative thalamocortical terminals comprised the remaining ∼40% of PV-IR synapses. Thus, the present study suggests that innervation from PV-containing thalamic nuclei extends across superficial and middle layers of the human DLPFC. These findings contrast with previous ultrastructural studies in monkey DLPFC where Type I PV-IR synapses were not identified in the superficial laminar zone. The presumptive added modulation of DLPFC circuitry by the thalamus in human may contribute to species-specific, higher-order functions.
|
The Journal of comparative neurology
| 2,017
|
28,097,645
|
Bacterial subversion of cAMP signalling inhibits cathelicidin expression, which is required for innate resistance to Mycobacterium tuberculosis.
|
Antimicrobial peptides such as cathelicidins are important components of innate immune defence against inhaled microorganisms, and have shown antimicrobial activity against Mycobacterium tuberculosis in in vitro models. Despite this, little is known about the regulation and expression of cathelicidin during tuberculosis in vivo. We sought to determine whether the cathelicidin-related antimicrobial peptide gene (Cramp), the murine functional homologue of the human cathelicidin gene (CAMP or LL-37), is required for regulation of protective immunity during M. tuberculosis infection in vivo. We used Cramp
|
The Journal of pathology
| 2,017
|
28,152,160
|
New or Worsening Symptoms and Signs in Community-Dwelling Persons with Dementia: Incidence and Relation to Use of Acute Medical Services.
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To understand the range of symptoms that present to family caregivers of community-dwelling persons with Alzheimer's disease and related dementias (ADRD). Six-month longitudinal prospective study to identify the incidence of new or worsening symptoms and their association with acute care medical service use. Community-based sample of volunteers from multiple states. A total of 136 patient-caregiver dyads with a range of dementia severity. Forty four symptoms and signs common in older persons and/or persons with dementia; frequency of emergency department visits, hospitalizations, and death; and associations between reported symptoms and acute medical care. During a mean of 5.7 months' follow-up, new or worsening organ-specific (90% of participants), nonspecific (89%), and behavioral (88%) symptoms were common, with the average caregiver reporting seven new or worsening symptoms. Most common were worsening confusion (74%), decreased activity (64%), agitation (57%), hallucinations/delusions (45%), voice and speaking problems (45%), not eating or drinking (44%), and stress/anxiety (41%). Hospitalization and emergency department use occurred respectively in 19% and 20% of participants, and were associated with organ-specific symptoms (OR 3.15, P = .02), less so with nonspecific symptoms (OR 2.27, P = .07), and very little with behavioral symptoms (OR 1.44, P = .38). Within each symptom category, certain symptoms were significantly associated with acute medical service use. Family caregivers of persons with ADRD must respond to a variety of medical, nonspecific, and behavioral symptoms. The high incidence of new or worsening symptoms and of acute medical care use suggests a need to better target symptom evaluation and management in caregiver education.
|
Journal of the American Geriatrics Society
| 2,017
|
27,869,163
|
Wwox-Brca1 interaction: role in DNA repair pathway choice.
|
In this study, loss of expression of the fragile site-encoded Wwox protein was found to contribute to radiation and cisplatin resistance of cells, responses that could be associated with cancer recurrence and poor outcome. WWOX gene deletions occur in a variety of human cancer types, and reduced Wwox protein expression can be detected early during cancer development. We found that Wwox loss is followed by mild chromosome instability in genomes of mouse embryo fibroblast cells from Wwox-knockout mice. Human and mouse cells deficient for Wwox also exhibit significantly enhanced survival of ionizing radiation and bleomycin treatment, agents that induce double-strand breaks (DSBs). Cancer cells that survive radiation recur more rapidly in a xenograft model of irradiated breast cancer cells; Wwox-deficient cells exhibited significantly shorter tumor latencies vs Wwox-expressing cells. This Wwox effect has important consequences in human disease: in a cohort of cancer patients treated with radiation, Wwox deficiency significantly correlated with shorter overall survival times. In examining mechanisms underlying Wwox-dependent survival differences, we found that Wwox-deficient cells exhibit enhanced homology directed repair (HDR) and decreased non-homologous end-joining (NHEJ) repair, suggesting that Wwox contributes to DNA DSB repair pathway choice. Upon silencing of Rad51, a protein critical for HDR, Wwox-deficient cells were resensitized to radiation. We also demonstrated interaction of Wwox with Brca1, a driver of HDR, and show via immunofluorescent detection of repair proteins at ionizing radiation-induced DNA damage foci that Wwox expression suppresses DSB repair at the end-resection step of HDR. We propose a genome caretaker function for WWOX, in which Brca1-Wwox interaction supports NHEJ as the dominant DSB repair pathway in Wwox-sufficient cells. Taken together, the experimental results suggest that reduced Wwox expression, a common occurrence in cancers, dysregulates DSB repair, enhancing efficiency of likely mutagenic repair, and enabling radiation and cisplatin treatment resistance.
|
Oncogene
| 2,017
|
27,773,791
|
Mir363-3p improves ischemic stroke outcomes in female but not male rats.
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With age, stroke prevalence is higher, and stroke outcome, worse, in women. Thus there is an urgent need to identify stroke neuroprotectants for this population. Using a preclinical stroke model, our studies focused on microRNAs (miRNAs), a class of translational repressors, as neuroprotectants. Analysis of circulating miRNA in the acute phase of stroke indicated potential neuroprotective capacity for miR363. Specifically, mir363 is elevated in serum of adult female rats that typically have small infarct volumes, but is deficient in age-matched males or middle-aged males and females, groups that have greater stroke-associated impairment. To directly test the effect of mir363 on stroke outcomes, first, adult females were treated with antagomirs to mir363 post stroke and next, middle-aged females were treated with mimic to mir363-3p post stroke. Antagomir treatment to adult females significantly increased infarct volume and impaired sensory motor performance. Reciprocally, mir363 mimic to middle-aged females reduced infarct volume, preserved forebrain microvessels and improved sensory motor performance. In the early acute stroke phase, mir363-3p mimic reduced the expression and functional activity of caspase-3, a critical component of the apoptotic cell cascade. In contrast, mir363-3p mimic treatment had no effect on stroke outcomes or caspase regulation in young males. Collectively, these studies show that mir363 is neuroprotective for stroke in females and implicates caspase-3 as a sex-specific miRNA-sensitive node for recovery from ischemic stroke.
|
Neurochemistry international
| 2,017
|
28,045,213
|
Longitudinal diffusion changes in prodromal and early HD: Evidence of white-matter tract deterioration.
|
Huntington's disease (HD) is a genetic neurodegenerative disorder that primarily affects striatal neurons. Striatal volume loss is present years before clinical diagnosis; however, white matter degradation may also occur prior to diagnosis. Diffusion-weighted imaging (DWI) can measure microstructural changes associated with degeneration that precede macrostructural changes. DWI derived measures enhance understanding of degeneration in prodromal HD (pre-HD). As part of the PREDICT-HD study, N = 191 pre-HD individuals and 70 healthy controls underwent two or more (baseline and 1-5 year follow-up) DWI, with n = 649 total sessions. Images were processed using cutting-edge DWI analysis methods for large multicenter studies. Diffusion tensor imaging (DTI) metrics were computed in selected tracts connecting the primary motor, primary somato-sensory, and premotor areas of the cortex with the subcortical caudate and putamen. Pre-HD participants were divided into three CAG-Age Product (CAP) score groups reflecting clinical diagnosis probability (low, medium, or high probabilities). Baseline and longitudinal group differences were examined using linear mixed models. Cross-sectional and longitudinal differences in DTI measures were present in all three CAP groups compared with controls. The high CAP group was most affected. This is the largest longitudinal DWI study of pre-HD to date. Findings showed DTI differences, consistent with white matter degeneration, were present up to a decade before predicted HD diagnosis. Our findings indicate a unique role for disrupted connectivity between the premotor area and the putamen, which may be closely tied to the onset of motor symptoms in HD. Hum Brain Mapp 38:1460-1477, 2017. © 2017 Wiley Periodicals, Inc.
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Human brain mapping
| 2,017
|
27,942,837
|
Refining prognosis in patients with hepatocellular carcinoma through incorporation of metabolic imaging biomarkers.
|
We retrospectively analyzed the records of patients with HCC who underwent FDG PET/CT before initial treatment from May 2013 through May 2014. Four PET/CT parameters were measured: maximum standardized uptake value (SUV The analysis included 56 patients. Univariate analysis of the association between OS and continuous variables, including the PET/CT parameters SUV Pretreatment FDG PET/CT in patients with HCC can add to the prognostic value of standard clinical measures. Incorporation of imaging biomarkers derived from FDG PET/CT into HCC staging systems should be considered.
|
European journal of nuclear medicine and molecular imaging
| 2,017
|
27,264,171
|
Type I Interferon Induction by Neisseria gonorrhoeae: Dual Requirement of Cyclic GMP-AMP Synthase and Toll-like Receptor 4.
|
The innate immune system is the first line of defense against Neisseria gonorrhoeae (GC). Exposure of cells to GC lipooligosaccharides induces a strong immune response, leading to type I interferon (IFN) production via TLR4/MD-2. In addition to living freely in the extracellular space, GC can invade the cytoplasm to evade detection and elimination. Double-stranded DNA introduced into the cytosol binds and activates the enzyme cyclic-GMP-AMP synthase (cGAS), which produces 2'3'-cGAMP and triggers STING/TBK-1/IRF3 activation, resulting in type I IFN expression. Here, we reveal a cytosolic response to GC DNA that also contributes to type I IFN induction. We demonstrate that complete IFN-β induction by live GC depends on both cGAS and TLR4. Type I IFN is detrimental to the host, and dysregulation of iron homeostasis genes may explain lower bacteria survival in cGAS(-/-) and TLR4(-/-) cells. Collectively, these observations reveal cooperation between TLRs and cGAS in immunity to GC infection.
|
Cell reports
| 2,016
|
28,223,054
|
Epicardial Adipose Tissue Removal Potentiates Outward Remodeling and Arrests Coronary Atherogenesis.
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Pericoronary epicardial adipose tissue (cEAT) serves as a metabolic and paracrine organ that contributes to inflammation and is associated with macrovascular coronary artery disease (CAD) development. Although there is a strong correlation in humans between cEAT volume and CAD severity, there remains a paucity of experimental data demonstrating a causal link of cEAT to CAD. The current study tested the hypothesis that surgical resection of cEAT attenuates inflammation and CAD progression. Female Ossabaw miniature swine (n = 12) were fed an atherogenic diet for 8 months and randomly allocated into sham (n = 5) or adipectomy (n = 7) groups. Both groups underwent a thoracotomy, opening of the pericardial sac, and placement of radioopaque clips to mark the proximal left anterior descending artery. Adipectomy swine underwent removal of 1 to 1.5 cm Severity of CAD as assessed by percent stenosis was reduced in the adipectomy cohort compared with shams; however, plaque size remained unaltered, whereas larger plaque sizes developed in sham-operated swine. Adipectomy resulted in an expanded arterial diameter, similar to the Glagov phenomenon of positive outward remodeling. No differences in inflammatory marker expression were observed. These data indicate that cEAT resection did not alter inflammatory marker expression, but arrested CAD progression through increased positive outward remodeling and arrest of atherogenesis.
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The Annals of thoracic surgery
| 2,017
|
27,989,792
|
Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health.
|
Recent insights into the bioactivation and signaling actions of inorganic, dietary nitrate and nitrite now suggest a critical role for the microbiome in the development of cardiac and pulmonary vascular diseases. Once thought to be the inert, end-products of endothelial-derived nitric oxide (NO) heme-oxidation, nitrate and nitrite are now considered major sources of exogenous NO that exhibit enhanced vasoactive signaling activity under conditions of hypoxia and stress. The bioavailability of nitrate and nitrite depend on the enzymatic reduction of nitrate to nitrite by a unique set of bacterial nitrate reductase enzymes possessed by specific bacterial populations in the mammalian mouth and gut. The pathogenesis of pulmonary hypertension (PH), obesity, hypertension and CVD are linked to defects in NO signaling, suggesting a role for commensal oral bacteria to shape the development of PH through the formation of nitrite, NO and other bioactive nitrogen oxides. Oral supplementation with inorganic nitrate or nitrate-containing foods exert pleiotropic, beneficial vascular effects in the setting of inflammation, endothelial dysfunction, ischemia-reperfusion injury and in pre-clinical models of PH, while traditional high-nitrate dietary patterns are associated with beneficial outcomes in hypertension, obesity and CVD. These observations highlight the potential of the microbiome in the development of novel nitrate- and nitrite-based therapeutics for PH, CVD and their risk factors.
|
Free radical biology & medicine
| 2,017
|
26,510,751
|
Circulating levels of plasminogen and oxidized phospholipids bound to plasminogen distinguish between atherothrombotic and non-atherothrombotic myocardial infarction.
|
Oxidized phospholipids (OxPL) are abundant in atherosclerotic plaques. They are also bound to circulating plasminogen after myocardial infarction (MI), and their binding to plasminogen may accentuate fibrinolysis. We sought to assess whether circulating levels of plasminogen and OxPL bound to plasminogen (OxPL-PLG) increase following acute MI and whether this increase differs between atherothrombotic (Type 1) and non-atherothrombotic (Type 2) MI. We measured circulating levels of plasminogen and OxPL-PLG at 0, 6, 24, 48 h, and >3 months (stable state) following acute MI and following an angiogram for stable coronary artery disease (CAD). Forty-nine subjects met the criteria for acute MI, of whom 34 had clearly defined atherothrombotic (n = 22) or non-atherothrombotic (n = 12) MI; 15 patients met the criteria for stable CAD. Mean baseline levels of plasminogen and OxPL-PLG were lower in the acute MI group than in the stable CAD group (9.75 vs 20.2, p < 0.0001 for plasminogen and 165.5 vs 275.1, p = 0.0002 for OxPL-PLG) and did not change over time or between time points, including the 3-month follow-up. Mean baseline levels of plasminogen and OxPL-PLG were also lower in atherothrombotic (Type 1) than in non-atherothrombotic (Type 2) MI subjects (8.65 vs 12.1, p < 0.03 for plasminogen and 164.5 vs 245.7, p = 0.02 for OxPL-PLG), and this relationship did not change over time or between time points. Plasminogen and OxPL-PLG were lower in patients presenting with an acute MI than in those with stable CAD and also in those with atherothrombotic MI (Type 1) vs. those with non-atherothrombotic MI (Type 2). These findings persisted at a median follow-up of 3 months post-MI. The association of plasminogen and OxPL-PLG with acute MI, particularly atherothrombotic MI (Type 1), could reflect a reduced fibrinolytic capacity, associated with an increased risk of atherothrombotic events differentiating stable CAD from unstable CAD and atherothrombotic MI (Type 1) from non-atherothrombotic MI (Type 2). Additional study with a larger sample size is warranted.
|
Journal of thrombosis and thrombolysis
| 2,016
|
28,451,465
|
Intimate Partner Violence Victimization in LGBT Young Adults: Demographic Differences and Associations with Health Behaviors.
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Intimate partner violence (IPV) is an important public health problem with high prevalence and serious costs. Although literature has largely focused on IPV among heterosexuals, studies have recently begun examining IPV in LGBT samples, with mounting evidence suggesting IPV may be more common among LGBT individuals than heterosexuals. Less research has examined the specific health consequences of IPV in this population, particularly across time and among young people, and it remains unclear whether experiences of IPV differ between subgroups within the LGBT population (e.g. race, gender identity, and sexual orientation). An ethnically diverse sample of 172 LGBT young adults completed self-report measures of IPV, sexual behavior, mental health, and substance abuse at two time points (4- and 5-year follow-up) of an ongoing longitudinal study of LGBT youth. IPV was experienced non-uniformly across demographic groups. Specifically, female, male-to-female transgender, and Black/African-American young adults were at higher risk compared to those who identified as male, female-to-male transgender, and other races. Being a victim of IPV was associated with concurrent sexual risk taking and prospective mental health outcomes but was not associated with substance abuse. Demographic differences in IPV found in heterosexuals were replicated in this LGBT sample, though additional research is needed to clarify why traditional risk factors found in heterosexual young people may not translate to LGBT individuals. Studies examining the impact of IPV on negative outcomes and revictimization over time may guide our understanding of the immediate and delayed consequences of IPV for LGBT young people.
|
Psychology of violence
| 2,017
|
26,493,732
|
Prefrontal Cortex Activation While Walking Under Dual-Task Conditions in Stroke: A Multimodal Imaging Study.
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Background Walking while performing another task (eg, talking) is challenging for many stroke survivors, yet its neural basis are not fully understood. Objective To investigate prefrontal cortex activation and its relationship to gait measures while walking under single-task (ST) and dual-task (DT) conditions (ie, walking while simultaneously performing a cognitive task) in stroke survivors. Methods We acquired near-infrared spectroscopy (NIRS) data from the prefrontal cortex during treadmill walking in ST and DT conditions in chronic stroke survivors and healthy controls. We also acquired functional magnetic resonance imaging (fMRI) and NIRS during simulated walking under these conditions. Results NIRS revealed increased oxygenated hemoglobin concentration in DT-walking compared with ST-walking for both groups. For simulated walking, NIRS showed a significant effect of group and group × task, being greater on both occasions, in stroke survivors. A greater increase in brain activation observed from ST to DT walking/ simulated walking was related to a greater change in motor performance in stroke survivors. fMRI revealed increased activity during DT relative to ST conditions in stroke patients in areas including the inferior temporal gyri, superior frontal gyri and cingulate gyri bilaterally, and the right precentral gyrus. The DT-related increase in fMRI activity correlated with DT-related change in behavior in stroke participants in the bilateral inferior temporal gyrus, left cingulate gyrus, and left frontal pole. Conclusion Our results provide novel evidence that enhanced brain activity changes relate to dual task motor decrements.
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Neurorehabilitation and neural repair
| 2,016
|
28,163,084
|
Research Needs for Effective Transition in Lifelong Care of Congenital Genitourinary Conditions: A Workshop Sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases.
|
Over the last 5 decades, health-care advances have yielded quantum improvements in the life expectancy of individuals with congenital genitourinary conditions (CGCs), leading to a crisis of care. Many individuals with CGC enter adulthood unprepared to manage their condition. Pediatric CGC specialists lack training to manage adulthood-related health-care issues, whereas adult genitourinary specialists lack training within the context of CGCs. To address these challenges, the National Institutes of Diabetes and Digestive and Kidney Diseases convened individuals with CGCs and experts from a variety of fields to identify research needs to improve transitional urology care. This paper outlines identified research needs.
|
Urology
| 2,017
|
28,181,347
|
Biomechanical Forces Promote Immune Regulatory Function of Bone Marrow Mesenchymal Stromal Cells.
|
Mesenchymal stromal cells (MSCs) are believed to mobilize from the bone marrow in response to inflammation and injury, yet the effects of egress into the vasculature on MSC function are largely unknown. Here we show that wall shear stress (WSS) typical of fluid frictional forces present on the vascular lumen stimulates antioxidant and anti-inflammatory mediators, as well as chemokines capable of immune cell recruitment. WSS specifically promotes signaling through NFκB-COX2-prostaglandin E
|
Stem cells (Dayton, Ohio)
| 2,017
|
28,152,381
|
Binding of the chemokine CXCL12α to its natural extracellular matrix ligand heparan sulfate enables myoblast adhesion and facilitates cell motility.
|
The chemokine CXCL12α is a potent chemoattractant that guides the migration of muscle precursor cells (myoblasts) during myogenesis and muscle regeneration. To study how the molecular presentation of chemokines influences myoblast adhesion and motility, we designed multifunctional biomimetic surfaces as a tuneable signalling platform that enabled the response of myoblasts to selected extracellular cues to be studied in a well-defined environment. Using this platform, we demonstrate that CXCL12α, when presented by its natural extracellular matrix ligand heparan sulfate (HS), enables the adhesion and spreading of myoblasts and facilitates their active migration. In contrast, myoblasts also adhered and spread on CXCL12α that was quasi-irreversibly surface-bound in the absence of HS, but were essentially immotile. Moreover, co-presentation of the cyclic RGD peptide as integrin ligand along with HS-bound CXCL12α led to enhanced spreading and motility, in a way that indicates cooperation between CXCR4 (the CXCL12α receptor) and integrins (the RGD receptors). Our findings reveal the critical role of HS in CXCL12α induced myoblast adhesion and migration. The biomimetic surfaces developed here hold promise for mechanistic studies of cellular responses to different presentations of biomolecules. They may be broadly applicable for dissecting the signalling pathways underlying receptor cross-talks, and thus may guide the development of novel biomaterials that promote highly specific cellular responses.
|
Biomaterials
| 2,017
|
23,744,146
|
Glucagon's yin and yang effects on hepatic glucose production.
|
New insights into the actions of the hormone glucagon are provided by a recent study in rodents, which shows that glucagon can suppress hepatic glucose production by acting through the mediobasal hypothalamic region of the brain. This central regulatory mechanism is impaired in rats fed a high-fat diet, suggesting that hypothalamic glucagon resistance may be relevant to the hyperglycemia observed in obesity, diabetes or both (pages 766–772).
|
Nature medicine
| 2,013
|
28,458,405
|
Improving Community Readiness for Change through Coalition Capacity Building: Evidence from a Multi-Site Intervention.
|
Often, community coalitions are facilitators of community-level changes when addressing underage drinking. Although studies have shown that enhancing coalition capacity is related to improved internal functioning, the relationship between enhanced capacity and community readiness for change is not well established. The present study used a pretest-posttest design to examine whether enhancing coalition capacity through training and technical assistance was associated with improved community readiness and coalition-facilitated community-level changes. Seven Kansas communities engaged in an intensive capacity building intervention through implementation of the Strategic Prevention Framework. The results indicated strong correlations between increased coalition capacity, changes in community readiness stages, and the number of community changes facilitated. The results suggest that strengthening coalition capacity through training and technical assistance may improve community readiness for change and enable the implementation of community-wide program and environmental changes.
|
Journal of community psychology
| 2,017
|
28,398,664
|
Rare copy number variants in patients with congenital conotruncal heart defects.
|
Previous studies using different cardiac phenotypes, technologies and designs suggest a burden of large, rare or de novo copy number variants (CNVs) in subjects with congenital heart defects. We sought to identify disease-related CNVs, candidate genes, and functional pathways in a large number of cases with conotruncal and related defects that carried no known genetic syndrome. Cases and control samples were divided into two cohorts and genotyped to assess each subject's CNV content. Analyses were performed to ascertain differences in overall CNV prevalence and to identify enrichment of specific genes and functional pathways in conotruncal cases relative to healthy controls. Only findings present in both cohorts are presented. From 973 total conotruncal cases, a burden of rare CNVs was detected in both cohorts. Candidate genes from rare CNVs found in both cohorts were identified based on their association with cardiac development or disease, and/or their reported disruption in published studies. Functional and pathway analyses revealed significant enrichment of terms involved in either heart or early embryonic development. Our study tested one of the largest cohorts specifically with cardiac conotruncal and related defects. These results confirm and extend previous findings that CNVs contribute to disease risk for congenital heart defects in general and conotruncal defects in particular. As disease heterogeneity renders identification of single recurrent genes or loci difficult, functional pathway and gene regulation network analyses appear to be more informative. Birth Defects Research 109:271-295, 2017. © 2017 Wiley Periodicals, Inc.
|
Birth defects research
| 2,017
|
28,065,669
|
The Role of Chromatin Structure in Gene Regulation of the Human Malaria Parasite.
|
The human malaria parasite, Plasmodium falciparum, depends on a coordinated regulation of gene expression for development and propagation within the human host. Recent developments suggest that gene regulation in the parasite is largely controlled by epigenetic mechanisms. Here, we discuss recent advancements contributing to our understanding of the mechanisms controlling gene regulation in the parasite, including nucleosome landscape, histone modifications, and nuclear architecture. In addition, various processes involved in regulation of parasite-specific genes and gene families are examined. Finally, we address the use of epigenetic processes as targets for novel antimalarial therapies. Collectively, these topics highlight the unique biology of P. falciparum, and contribute to our understanding of mechanisms regulating gene expression in this deadly parasite.
|
Trends in parasitology
| 2,017
|
27,956,239
|
RNAcompete methodology and application to determine sequence preferences of unconventional RNA-binding proteins.
|
RNA-binding proteins (RBPs) participate in diverse cellular processes and have important roles in human development and disease. The human genome, and that of many other eukaryotes, encodes hundreds of RBPs that contain canonical sequence-specific RNA-binding domains (RBDs) as well as numerous other unconventional RNA binding proteins (ucRBPs). ucRBPs physically associate with RNA but lack common RBDs. The degree to which these proteins bind RNA, in a sequence specific manner, is unknown. Here, we provide a detailed description of both the laboratory and data processing methods for RNAcompete, a method we have previously used to analyze the RNA binding preferences of hundreds of RBD-containing RBPs, from diverse eukaryotes. We also determine the RNA-binding preferences for two human ucRBPs, NUDT21 and CNBP, and use this analysis to exemplify the RNAcompete pipeline. The results of our RNAcompete experiments are consistent with independent RNA-binding data for these proteins and demonstrate the utility of RNAcompete for analyzing the growing repertoire of ucRBPs.
|
Methods (San Diego, Calif.)
| 2,017
|
23,872,591
|
MRI-measured regression of carotid atherosclerosis induced by statins with and without niacin in a randomised controlled trial: the NIA plaque study.
|
To evaluate the benefit of niacin in addition to statin therapy on plaque regression among older individuals with established atherosclerosis. Randomised, controlled, double-blind clinical trial. University outpatient center. 145 patients older than 65 years, half of them older than 75 years of age, with established atherosclerosis were enrolled. Participants received either extended release niacin (1500 mg daily) or placebo in addition to statin therapy to reach their National Cholesterol Education Program-defined low density lipoprotein (LDL) cholesterol target. The primary endpoint was reduction in the wall volume of the internal carotid artery (ICA) measured by MRI. After 18 months, high density lipoprotein cholesterol was higher with statins plus niacin compared with statins alone (1.6 ± 0.4 vs 1.4 ± 0.4 mmol/L p<0.001). Both groups had significant decreases in the main outcome measure of ICA wall volume, which regressed at 0.5%/month (SEM 0.2, p=0.004) in the statins plus placebo group and at 0.7%/month in the statins plus niacin group (SEM 0.2, p<0.001). There was no difference in the rate of regression between groups (p=0.49). Treatment with statin therapy to presently recommended LDL levels, with or without niacin, resulted in significant atherosclerosis reduction.
|
Heart (British Cardiac Society)
| 2,013
|
28,322,922
|
Antiviral lectins: Selective inhibitors of viral entry.
|
Many natural lectins have been reported to have antiviral activity. As some of these have been put forward as potential development candidates for preventing or treating viral infections, we have set out in this review to survey the literature on antiviral lectins. The review groups lectins by structural class and class of source organism we also detail their carbohydrate specificity and their reported antiviral activities. The review concludes with a brief discussion of several of the pertinent hurdles that heterologous proteins must clear to be useful clinical candidates and cites examples where such studies have been reported for antiviral lectins. Though the clearest path currently being followed is the use of antiviral lectins as anti-HIV microbicides via topical mucosal administration, some investigators have also found systemic efficacy against acute infections following subcutaneous administration.
|
Antiviral research
| 2,017
|
28,994,423
|
Cholangiocarcinoma - evolving concepts and therapeutic strategies.
|
Cholangiocarcinoma is a disease entity comprising diverse epithelial tumours with features of cholangiocyte differentiation: cholangiocarcinomas are categorized according to anatomical location as intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA). Each subtype has a distinct epidemiology, biology, prognosis, and strategy for clinical management. The incidence of cholangiocarcinoma, particularly iCCA, has increased globally over the past few decades. Surgical resection remains the mainstay of potentially curative treatment for all three disease subtypes, whereas liver transplantation after neoadjuvant chemoradiation is restricted to a subset of patients with early stage pCCA. For patients with advanced-stage or unresectable disease, locoregional and systemic chemotherapeutics are the primary treatment options. Improvements in external-beam radiation therapy have facilitated the treatment of cholangiocarcinoma. Moreover, advances in comprehensive whole-exome and transcriptome sequencing have defined the genetic landscape of each cholangiocarcinoma subtype. Accordingly, promising molecular targets for precision medicine have been identified, and are being evaluated in clinical trials, including those exploring immunotherapy. Biomarker-driven trials, in which patients are stratified according to anatomical cholangiocarcinoma subtype and genetic aberrations, will be essential in the development of targeted therapies. Targeting the rich tumour stroma of cholangiocarcinoma in conjunction with targeted therapies might also be useful. Herein, we review the evolving developments in the epidemiology, pathogenesis, and management of cholangiocarcinoma.
|
Nature reviews. Clinical oncology
| 2,018
|
29,509,826
|
Enriched Chicken Bone Broth as a Dietary Supplement Reduces Nociception and Sensitization Associated with Prolonged Jaw Opening.
|
To test a commercially available enriched chicken bone broth (ECBB) product for its potential anti-inflammatory properties and to evaluate its ability to reduce nociception and expression of protein kinase A (PKA) in a clinically relevant model of temporomandibular disorder (TMD) caused by prolonged jaw opening in rats. The potential of the ECBB and of a homemade broth was investigated using the Folin-Ciocalteu reagent and percent inhibition of cyclooxygenase-2 (COX-2) activity, which was determined using a commercially available kit. Additionally, the effect of ECBB and homemade broth on nocifensive head withdrawal responses to mechanical stimulation in male Sprague-Dawley rats subjected to prolonged jaw opening was evaluated. Differences were considered significant at P < .025. Changes in PKA expression in the medullary dorsal horn region of the spinal trigeminal nucleus associated with prolonged jaw opening were assessed using immunofluorescence, and these changes were considered significant at P < .05. Behavioral data were analyzed by using multiple nonparametric tests, and immunohistochemistry data were analyzed by using one-way analysis of variance with Games-Howell post hoc tests in SPSS software. ECBB exhibited greater reducing potential and inhibition of COX-2 activity compared to homemade broth. Near maximal jaw opening was sufficient to induce sustained nocifensive responses to mechanical stimuli for 7 days. This increased sensitivity was correlated with elevated levels of the active form of PKA. Importantly, dietary inclusion of ECBB, but not of homemade broth, for 2 weeks prior to jaw opening was sufficient to reduce nocifensive behaviors and PKA expression. Findings from this study provide evidence that ECBB attenuates nociception and expression of the pro-inflammatory protein PKA and thus may be beneficial as a nutraceutical supplement to manage inflammatory pain associated with TMD.
|
Journal of oral & facial pain and headache
| 2,018
|
38,799,703
|
Fossil marine vertebrates (Chondrichthyes, Actinopterygii, Reptilia) from the Upper Cretaceous of Akkermanovka (Orenburg Oblast, Southern Urals, Russia).
|
Upper Cretaceous coastal marine deposits are widespread in the Southern Urals with a number of marine vertebrates previously reported from this region. However, previous studies on the vertebrate faunas in this region often lack detailed taxonomic descriptions and illustrations, rendering comparisons to other faunal assemblages difficult. A new diverse vertebrate assemblage comprising cartilaginous and bony fishes, as well as marine reptiles, is described here from the Orenburg region near Akkermanovka (Southern Urals, Russia). Thirty five taxa are identified, including three holocephalans (
|
Cretaceous research
| 2,024
|
36,325,647
|
Sulfation of Heparan and Chondroitin Sulfate Ligands Enables Cell-Specific Homing of Nanoprobes.
|
Demystifying the sulfation code of glycosaminoglycans (GAGs) to induce precise homing of nanoparticles in tumor cells or neurons influences the development of a potential drug- or gene-delivery system. However, GAGs, particularly heparan sulfate (HS) and chondroitin sulfate (CS), are structurally highly heterogeneous, and synthesizing well-defined HS/CS composed nanoparticles is challenging. Here, we decipher how specific sulfation patterns on HS and CS regulate receptor-mediated homing of nanoprobes in primary and secondary cells. We discovered that aggressive cancer cells such as MDA-MB-231 displayed a strong uptake of GAG-nanoprobes compared to mild or moderately aggressive cancer cells. However, there was no selectivity towards the GAG sequences, thus indicating the presence of more than one form of receptor-mediated uptake. However, U87 cells, olfactory bulb, and hippocampal primary neurons showed selective or preferential uptake of CS-E-coated nanoprobes compared to other GAG-nanoprobes. Furthermore, mechanistic studies revealed that the 4,6-O-disulfated-CS nanoprobe used the CD44 and caveolin-dependent endocytosis pathway for uptake. These results could lead to new opportunities to use GAG nanoprobes in nanomedicine.
|
Chemistry (Weinheim an der Bergstrasse, Germany)
| 2,023
|
39,027,420
|
Odor cues rather than personality affect tadpole deposition in a neotropical poison frog.
|
Animals constantly need to evaluate available external and internal information to make appropriate decisions. Identifying, assessing, and acting on relevant cues in contexts such as mate choice, intra-sexual competition, and parental care is particularly important for optimizing individual reproductive success. Several factors can influence decision-making, such as external environmental cues and the animal's own internal state, yet, we have limited knowledge on how animals integrate available information. Here, we used an entire island population (57 males, 53 females, and 1,109 tadpoles) of the neotropical brilliant-thighed poison frog
|
Current zoology
| 2,024
|
39,321,790
|
Offline hippocampal reactivation during dentate spikes supports flexible memory.
|
Stabilizing new memories requires coordinated neuronal spiking activity during sleep. Hippocampal sharp-wave ripples (SWRs) in the cornu ammonis (CA) region and dentate spikes (DSs) in the dentate gyrus (DG) are prime candidate network events for supporting this offline process. SWRs have been studied extensively, but the contribution of DSs remains unclear. By combining triple-ensemble (DG-CA3-CA1) recordings and closed-loop optogenetics in mice, we show that, like SWRs, DSs synchronize spiking across DG and CA principal cells to reactivate population-level patterns of neuronal coactivity expressed during prior waking experience. Notably, the population coactivity structure in DSs is more diverse and higher dimensional than that seen during SWRs. Importantly, suppressing DG granule cell spiking selectively during DSs impairs subsequent flexible memory performance during multi-object recognition tasks and associated hippocampal patterns of neuronal coactivity. We conclude that DSs constitute a second offline network event central to hippocampal population dynamics serving memory-guided behavior.
|
Neuron
| 2,024
|
39,476,057
|
H4K20me3-Mediated Repression of Inflammatory Genes Is a Characteristic and Targetable Vulnerability of Persister Cancer Cells.
|
Anticancer therapies can induce cellular senescence or drug-tolerant persistence, two types of proliferative arrest that differ in their stability. While senescence is highly stable, persister cells efficiently resume proliferation upon therapy termination, resulting in tumor relapse. Here, we used an ATP-competitive mTOR inhibitor to induce and characterize persistence in human cancer cells of various origins. Using this model and previously described models of senescence, we compared the same cancer cell lines under the two types of proliferative arrest. Persister and senescent cancer cells shared an expanded lysosomal compartment and hypersensitivity to BCL-XL inhibition. However, persister cells lacked other features of senescence, such as loss of lamin B1, senescence-associated β-galactosidase activity, upregulation of MHC-I, and an inflammatory and secretory phenotype (senescence-associated secretory phenotype or SASP). A genome-wide CRISPR/Cas9 screening for genes required for the survival of persister cells revealed that they are hypersensitive to the inhibition of one-carbon (1C) metabolism, which was validated by the pharmacologic inhibition of serine hydroxymethyltransferase, a key enzyme that feeds methyl groups from serine into 1C metabolism. Investigation into the relationship between 1C metabolism and the epigenetic regulation of transcription uncovered the presence of the repressive heterochromatic mark H4K20me3 at the promoters of SASP and IFN response genes in persister cells, whereas it was absent in senescent cells. Moreover, persister cells overexpressed the H4K20 methyltransferases KMT5B/C, and their downregulation unleashed inflammatory programs and compromised the survival of persister cells. In summary, this study identifies distinctive features and actionable vulnerabilities of persister cancer cells and provides mechanistic insight into their low inflammatory activity. Significance: Cell persistence and senescence are distinct states of proliferative arrest induced by cancer therapy, with persister cells being characterized by the silencing of inflammatory genes through the heterochromatic mark H4K20me3. See related commentary by Schmitt, p. 7.
|
Cancer research
| 2,025
|
39,776,490
|
Contribution of Ryugu-like material to Earth's volatile inventory by Cu and Zn isotopic analysis.
|
Initial analyses showed that asteroid Ryugu's composition is close to CI (Ivuna-like) carbonaceous chondrites -the chemically most primitive meteorites, characterized by near-solar abundances for most elements. However, some isotopic signatures (e.g., Ti, Cr) overlap with other carbonaceous chondrite (CC) groups, so the details of the link between Ryugu and the CI chondrites are not fully clear yet. Here we show that Ryugu and CI chondrites have the same zinc and copper isotopic composition. As the various chondrite groups have very distinct Zn and Cu isotopic signatures, our results point at a common genetic heritage between Ryugu and CI chondrites, ruling out any affinity with other CC groups. Since Ryugu's pristine samples match the solar elemental composition for many elements, their Zn and Cu isotopic compositions likely represent the best estimates of the solar composition. Earth's mass-independent Zn isotopic composition is intermediate between Ryugu/CC and non-carbonaceous chondrites, suggesting a contribution of Ryugu-like material to Earth's budgets of Zn and other moderately volatile elements.
|
Nature astronomy
| 2,022
|
39,666,794
|
Diverse phage communities are maintained stably on a clonal bacterial host.
|
Bacteriophages are the most abundant and phylogenetically diverse biological entities on Earth, yet the ecological mechanisms that sustain this extraordinary diversity remain unclear. In this study, we discovered that phage diversity consistently outstripped the diversity of their bacterial hosts under simple experimental conditions. We assembled and passaged dozens of diverse phage communities on a single, nonevolving strain of
|
Science (New York, N.Y.)
| 2,024
|
38,623,934
|
In vivo T2 measurements of the fetal brain using single-shot fast spin echo sequences.
|
We propose a quantitative framework for motion-corrected T2 fetal brain measurements in vivo and validate the single-shot fast spin echo (SS-FSE) sequence to perform these measurements. Stacks of two-dimensional SS-FSE slices are acquired with different echo times (TE) and motion-corrected with slice-to-volume reconstruction (SVR). The quantitative T2 maps are obtained by a fit to a dictionary of simulated signals. The sequence is selected using simulated experiments on a numerical phantom and validated on a physical phantom scanned on a 1.5T system. In vivo quantitative T2 maps are obtained for five fetuses with gestational ages (GA) 21-35 weeks on the same 1.5T system. The simulated experiments suggested that a TE of 400 ms combined with the clinically utilized TEs of 80 and 180 ms were most suitable for T2 measurements in the fetal brain. The validation on the physical phantom confirmed that the SS-FSE T2 measurements match the gold standard multi-echo spin echo measurements. We measured average T2s of around 200 and 280 ms in the fetal brain grey and white matter, respectively. This was slightly higher than fetal T2* and the neonatal T2 obtained from previous studies. The motion-corrected SS-FSE acquisitions with varying TEs offer a promising practical framework for quantitative T2 measurements of the moving fetus.
|
Magnetic resonance in medicine
| 2,024
|
39,723,542
|
Genetic Variants Associated With Preeclampsia and Maternal Serum sFLT1 Levels.
|
Elevated maternal serum sFLT1 (soluble fms-like tyrosine kinase 1) has a key role in the pathophysiology of preeclampsia. We sought to determine the relationship between the maternal and fetal genome and maternal levels of sFLT1 at 12, 20, 28, and 36 weeks of gestational age (wkGA). We studied a prospective cohort of nulliparous women (3968 mother-child pairs). We related maternal and fetal genotype to the adjusted sFLT1 Four variants from the fetal preeclampsia genome-wide association study were positively associated with sFLT1 and sFLT1:PlGF The current data are consistent with a causal association between sFLT1 released by the placenta in late pregnancy and the pathophysiology of preeclampsia. The data are also consistent with maternal components to the protective effect of high sFLT1 in the first trimester and the rise in third-trimester sFLT1 levels and preeclampsia.
|
Hypertension (Dallas, Tex. : 1979)
| 2,025
|
39,665,294
|
Development of a Synthetic Platform for Ent-Pimaranes Reveals their Potential as Novel Non-Redox Active Ferroptosis Inhibitors.
|
We present a comprehensive account on the evolution of a synthetic platform for a subfamily of ent-pimaranes. For the most complex member, norflickinflimiod C, five distinct strategies relying on either cationic or radical polyene cyclizations to construct the requisite tricyclic carbon scaffold were explored. Insights from early and late stage oxidative and reductive dearomatization studies ultimately led to a mild, rhodium-catalyzed arene hydrogenation for the final synthetic route. A Sharpless asymmetric dihydroxylation was found to be suitable to render the platform enantioselective and diversification of a late-stage key intermediate culminated in the total synthesis of eight ent-pimaranes in 11-16 steps. These compounds were found to inhibit the formation of pro-inflammatory leukotrienes and other 5-lipoxygenase products. Notably, three ent-pimaranes exhibited low micromolar, non-redox active ferroptosis inhibition with remarkable structural specificity.
|
Chemistry (Weinheim an der Bergstrasse, Germany)
| 2,025
|
36,794,486
|
Efficacy of propofol-supplemented cardioplegia on biomarkers of organ injury in patients having cardiac surgery using cardiopulmonary bypass: A protocol for a randomised controlled study (ProMPT2).
|
Cardiac surgery with cardiopulmonary bypass and cardioplegic arrest is known to be responsible for ischaemia and reperfusion organ injury. In a previous study, ProMPT, in patients undergoing coronary artery bypass or aortic valve surgery we demonstrated improved cardiac protection when supplementing the cardioplegia solution with propofol (6 mcg/ml). The aim of the ProMPT2 study is to determine whether higher levels of propofol added to the cardioplegia could result in increased cardiac protection. The ProMPT2 study is a multi-centre, parallel, three-group, randomised controlled trial in adults undergoing non-emergency isolated coronary artery bypass graft surgery with cardiopulmonary bypass. A total of 240 patients will be randomised in a 1:1:1 ratio to receive either cardioplegia supplementation with high dose of propofol (12 mcg/ml), low dose of propofol (6 mcg/ml) or placebo (saline). The primary outcome is myocardial injury, assessed by serial measurements of myocardial troponin T up to 48 hours after surgery. Secondary outcomes include biomarkers of renal function (creatinine) and metabolism (lactate). The trial received research ethics approval from South Central - Berkshire B Research Ethics Committee and Medicines and Healthcare products Regulatory Agency in September 2018. Any findings will be shared though peer-reviewed publications and presented at international and national meetings. Participants will be informed of results through patient organisations and newsletters. ISRCTN15255199. Registered in March 2019.
|
Perfusion
| 2,024
|
39,781,101
|
Dehydrogenase
|
Redox enzymes, mostly equipped with metal or organic cofactors, can vary their reactivity with oxygen by orders of magnitudes. Understanding how oxygen reactivity is controlled by the protein milieu remains an open issue with broad implications for mechanistic enzymology and enzyme design. Here, we address this problem by focusing on a widespread group of flavoenzymes that oxidize phenolic compounds derived from microbial lignin degradation, using either oxygen or a cytochrome c as electron acceptors. A comprehensive phylogenetic analysis revealed conserved amino acid motifs in their flavin-binding site. Using a combination of kinetics, mutagenesis, structural, and computational methods, we examined the role of these residues. Our results demonstrate that subtle and localized changes in the flavin environment can drastically impact on oxygen reactivity. These effects are afforded through the creation or blockade of pathways for oxygen diffusion. Substrate binding plays a crucial role by potentially obstructing oxygen access to the flavin, thus influencing the enzyme's reactivity. The switch between oxidase and dehydrogenase functionalities is thereby achieved through targeted, site-specific amino acid replacements that finely tune the microenvironment around the flavin. Our findings explain how very similar enzymes can exhibit distinct functional properties, operating as oxidases or dehydrogenases. They further provide valuable insights for the rational design and engineering of enzymes with tailored functions.
|
ACS catalysis
| 2,025
|
39,701,465
|
Machine learning models for diagnosis and risk prediction in eating disorders, depression, and alcohol use disorder.
|
Early diagnosis and treatment of mental illnesses is hampered by the lack of reliable markers. This study used machine learning models to uncover diagnostic and risk prediction markers for eating disorders (EDs), major depressive disorder (MDD), and alcohol use disorder (AUD). Case-control samples (aged 18-25 years), including participants with Anorexia Nervosa (AN), Bulimia Nervosa (BN), MDD, AUD, and matched controls, were used for diagnostic classification. For risk prediction, we used a longitudinal population-based sample (IMAGEN study), assessing adolescents at ages 14, 16 and 19. Regularized logistic regression models incorporated broad data domains spanning psychopathology, personality, cognition, substance use, and environment. The classification of EDs was highly accurate, even when excluding body mass index from the analysis. The area under the receiver operating characteristic curves (AUC-ROC [95 % CI]) reached 0.92 [0.86-0.97] for AN and 0.91 [0.85-0.96] for BN. The classification accuracies for MDD (0.91 [0.88-0.94]) and AUD (0.80 [0.74-0.85]) were also high. The models demonstrated high transdiagnostic potential, as those trained for EDs were also accurate in classifying AUD and MDD from healthy controls, and vice versa (AUC-ROCs, 0.75-0.93). Shared predictors, such as neuroticism, hopelessness, and symptoms of attention-deficit/hyperactivity disorder, were identified as reliable classifiers. In the longitudinal population sample, the models exhibited moderate performance in predicting the development of future ED symptoms (0.71 [0.67-0.75]), depressive symptoms (0.64 [0.60-0.68]), and harmful drinking (0.67 [0.64-0.70]). Our findings demonstrate the potential of combining multi-domain data for precise diagnostic and risk prediction applications in psychiatry.
|
Journal of affective disorders
| 2,025
|
39,291,806
|
Demonstrating the data integrity of routinely collected healthcare systems data for clinical trials (DEDICaTe): A proof-of-concept study.
| null |
Health informatics journal
| 2,024
|
39,217,077
|
Randomised Trial of No, Short-term, or Long-term Androgen Deprivation Therapy with Postoperative Radiotherapy After Radical Prostatectomy: Results from the Three-way Comparison of RADICALS-HD (NCT00541047).
|
The use and duration of androgen deprivation therapy (ADT) with postoperative radiotherapy (RT) have been uncertain. RADICALS-HD compared adding no ("None"), 6-months ("Short"), or 24-mo ("Long") ADT to study efficacy in the long term. Participants with prostate cancer were indicated for postoperative RT and agreed randomisation between all durations. ADT was allocated for 0, 6, or 24 mo. The primary outcome measure (OM) was metastasis-free survival (MFS). The secondary OMs included freedom from distant metastasis, overall survival, and initiation of nonprotocol ADT. Sample size was determined by two-way comparisons. Analyses followed standard time-to-event approaches and intention-to-treat principles. Between 2007 and 2015, 492 participants were randomised one of three groups: 166 None, 164 Short, and 162 Long. The median age at randomisation was 66 yr; Gleason scores at surgery were as follows: <7 = 64 (13%), 3+4 = 229 (47%), 4+3 = 127 (26%), and 8+ = 72 (15%); T3b was 112 (23%); and T4 was 5 (1%). The median follow-up was 9.0 yr and, with MFS events reported for 89 participants (32 None, 31 Short, and 26 Long), there was no evidence of difference in MFS overall (logrank p = 0.98), and, for Long versus None, hazard ratio = 0.948 (95% confidence interval 0.54-1.68). After 10 yr, 80% None, 77% Short, and 81% Long patients were alive without metastatic disease. The three-way randomisation was not powered to conventional levels for assessment, yet provides a fair comparison. Long-term outcomes after radical prostatectomy are usually favourable. In those indicated for postoperative RT and considered suitable for no, short-term, or long-term ADT, there was no evidence of improvement with addition of ADT. Future research should focus on patients at a higher risk of metastases in whom improvements are required more urgently.
|
European urology
| 2,024
|
33,112,430
|
Cardiolipin deficiency in Barth syndrome is not associated with increased superoxide/H
|
Barth syndrome (BTHS) is a rare X-linked genetic disorder caused by mutations in the gene encoding the transacylase tafazzin and characterized by loss of cardiolipin and severe cardiomyopathy. Mitochondrial oxidants have been implicated in the cardiomyopathy in BTHS. Eleven mitochondrial sites produce superoxide/hydrogen peroxide (H
|
FEBS letters
| 2,021
|
34,368,204
|
Climate Trends and Consumption of Foods and Beverages by Processing Level in Mexican Cities.
| null |
Frontiers in nutrition
| 2,021
|
33,833,410
|
Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain.
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We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA). Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.
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Genetics in medicine : official journal of the American College of Medical Genetics
| 2,021
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36,649,146
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Incorporating Alternative Polygenic Risk Scores into the BOADICEA Breast Cancer Risk Prediction Model.
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The multifactorial risk prediction model BOADICEA enables identification of women at higher or lower risk of developing breast cancer. BOADICEA models genetic susceptibility in terms of the effects of rare variants in breast cancer susceptibility genes and a polygenic component, decomposed into an unmeasured and a measured component - the polygenic risk score (PRS). The current version was developed using a 313 SNP PRS. Here, we evaluated approaches to incorporating this PRS and alternative PRS in BOADICEA. The mean, SD, and proportion of the overall polygenic component explained by the PRS (α2) need to be estimated. $\alpha $ was estimated using logistic regression, where the age-specific log-OR is constrained to be a function of the age-dependent polygenic relative risk in BOADICEA; and using a retrospective likelihood (RL) approach that models, in addition, the unmeasured polygenic component. Parameters were computed for 11 PRS, including 6 variations of the 313 SNP PRS used in clinical trials and implementation studies. The logistic regression approach underestimates $\alpha $, as compared with the RL estimates. The RL $\alpha $ estimates were very close to those obtained by assuming proportionality to the OR per 1 SD, with the constant of proportionality estimated using the 313 SNP PRS. Small variations in the SNPs included in the PRS can lead to large differences in the mean. BOADICEA can be readily adapted to different PRS in a manner that maintains consistency of the model. : The methods described facilitate comprehensive breast cancer risk assessment.
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Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
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