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Hirschsprung disease (HSCR, aganglionic megacolon) is a frequent congenital malformation regarded as a multigenic neurocristopathy. Two susceptibility genes have been recently identified in HSCR, namely the RET proto-oncogene and the endothelin B receptor (EDNRB) gene. Hitherto however, homozygosity for EDNRB mutations accounted for the HSCR-Waardenburg syndrome (WS) association. Here, we report heterozygous EDNRB missense mutations (G57S, R319W and P383L) in isolated HSCR. These data might suggest that EDNRB mutations could be dosage sensitive: heterozygosity would predispose to isolated HSCR with incomplete penetrance, while homozygosity would result in more complex neurocristopathies associating HSCR and WS features. In addition, the present data give further support to the role of the endothelin-signalling pathway in the development of neural crest-derived enteric neurons.	What are the effects of homozygosity of EDNRB mutations in addition to Hirschsprung disease?	Hitherto however, homozygosity for EDNRB mutations accounted for the HSCR-Waardenburg syndrome (WS) association.
Many clinical cases have been reported where epilepsy profoundly influenced the pathophysiological function of the heart; however, the underlying mechanisms were not elucidated. We use the tremor (TRM) rat as an animal model of epilepsy to investigate the potential mechanisms of myocardial injury. Cardiac functions were assessed by arrhythmia score, heart rate, heart:body mass ratio, and hemodynamic parameters including left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), and maximum rate of left ventricular pressure rise and fall (+dp/dtmax and -dp/dtmax). Catecholamine level was detected by HPLC. Apoptotic index was estimated by TUNEL assay. The expressions of Bcl-2, Bax, caspase-3, extracellular signal-regulated protein kinase (ERK), c-Jun NH2-terminal protein kinases (JNK), and p38 were evaluated by Western blot. The results indicated that there existed cardiac dysfunction and cardiomyocyte apoptosis, accompanied by increasing catecholamine levels in TRM rats. Further investigation revealed that apoptosis was mediated by reducing Bcl-2, upregulating Bax, and activating caspase-3. Additional experiments demonstrated that P-ERK1/2 was decreased, whereas P-JNK and P-p38 were up-regulated. Our results suggest that the sympathetic nervous system activation and cardiomyocyte apoptosis are involved in the myocardial injury of TRM rats. The mechanisms of apoptosis might be associated with the activation of the mitochondria-initiated and the mitogen-activated protein kinase pathways.	Which MAP kinase phosphorylates the transcription factor c-jun?	c-Jun NH2-terminal protein kinases (JNK),
Circular DNAs are extra-chromosomal fragments that become circularized by genomic recombination events. We have recently shown that yeast LTR elements generate circular DNAs through recombination events between their flanking long terminal repeats (LTRs). Similarly, circular DNAs can be generated by recombination between LTRs residing at different genomic loci, in which case the circular DNA will contain the intervening sequence. In yeast, this can result in gene copy number variations when circles contain genes and origins of replication. Here, I speculate on the potential and implications of circular DNAs generated through recombination between human transposable elements.	Do yeast LTR give rise to circular DNA?	Similarly, circular DNAs can be generated by recombination between LTRs residing at different genomic loci, in which case the circular DNA will contain the intervening sequence.
Performing AT for patients with ECMO was associated with high failure rate and hemodynamic complications. Our study highlights the variability in practice in regard to the AT and supports the use of ancillary tests to determine BD in patients on ECMO.	What are the main clinical components of the brain death exam?	Our study highlights the variability in practice in regard to the AT and supports the use of ancillary tests to determine BD in patients
Hox genes in vertebrates are clustered, and the organization of the clusters has been highly conserved during evolution. The conservation of Hox clusters has been attributed to enhancers located within and outside the Hox clusters that are essential for the coordinated "temporal" and "spatial" expression patterns of Hox genes in developing embryos. To identify evolutionarily conserved regulatory elements within and outside the Hox clusters, we obtained contiguous sequences for the conserved syntenic blocks from the seven Hox loci in fugu and carried out a systematic search for conserved noncoding sequences (CNS) in the human, mouse, and fugu Hox loci. Our analysis has uncovered unusually large conserved syntenic blocks at the HoxA and HoxD loci. The conserved syntenic blocks at the human and mouse HoxA and HoxD loci span 5.4 Mb and 4 Mb and contain 21 and 19 genes, respectively. The corresponding regions in fugu are 16- and 12-fold smaller. A large number of CNS was identified within the Hox clusters and outside the Hox clusters spread over large regions. The CNS include previously characterized enhancers and overlap with the 5' global control regions of HoxA and HoxD clusters. Most of the CNS are likely to be control regions involved in the regulation of Hox and other genes in these loci. We propose that the regulatory elements spread across large regions on either side of Hox clusters are a major evolutionary constraint that has maintained the exceptionally long syntenic blocks at the HoxA and HoxD loci.	Describe the involvement of conserved noncoding sequences in the regulation of Hox genes.	A large number of CNS was identified within the Hox clusters and outside the Hox clusters spread over large regions. The CNS include previously characterized enhancers and overlap with the 5' global control regions of HoxA and HoxD clusters. Most of the CNS are likely to be control regions involved in the regulation of Hox and other genes in these loci. We propose that the regulatory elements spread across large regions on either side of Hox clusters are a major evolutionary constraint that has maintained the exceptionally long syntenic blocks at the HoxA and HoxD loci
Chronic injury to the liver, such as viral hepatitis, alcoholism, non-alcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH), promotes extracellular matrix deposition and organ scarring, termed hepatic fibrosis. Fibrosis might progress to cirrhosis and predisposes to hepatocellular carcinoma (HCC), but is also associated with extrahepatic morbidity and mortality in NAFLD/NASH. The improved understanding of pathogenic mechanisms underlying chronic inflammation and fibrogenesis in the liver prompted recent advances in antifibrotic therapies. Areas covered: We review recent advances in antifibrotic therapy, of which most are currently tested in clinical trials for NAFLD or NASH. This explains the manifold metabolic pathways as antifibrotic targets, including farnesoid X receptor (FXR) agonism (obeticholic acid, nonsteroidal FXR agonists), acetyl-CoA carboxylase inhibition, peroxisome proliferator-activator receptor agonism (elafibranor, lanifibranor, saroglitazar), and fibroblast growth factor (FGF)-21 or FGF-19 activation. Other antifibrotic drug candidates target cell death or inflammation, such as caspase (emricasan) or ASK1 inhibitors (selonsertib), galectin-3 inhibitors and reducing inflammatory macrophage recruitment by blocking chemokine receptors CCR2/CCR5 (cenicriviroc). Expert commentary: The tremendous advances in translational and clinical research fuels the hope for efficacious antifibrotic therapies within the next 5 years. Very likely, a combination of etiology-specific, metabolic, anti-inflammatory, and direct antifibrotic interventions will be most effective.	What is the mechanism of action of Lanifibranor?	This explains the manifold metabolic pathways as antifibrotic targets, including farnesoid X receptor (FXR) agonism (obeticholic acid, nonsteroidal FXR agonists), acetyl-CoA carboxylase inhibition, peroxisome proliferator-activator receptor agonism (elafibranor, lanifibranor, saroglitazar), and fibroblast growth factor (FGF)-21 or FGF-19 activation.
Inherited mutations in the gene coding for the intermediate filament protein desmin have been demonstrated to cause severe skeletal and cardiac myopathies. Unexpectedly, some of the mutated desmins, in particular those carrying single amino acid alterations in the non-alpha-helical carboxy-terminal domain ("tail"), have been demonstrated to form apparently normal filaments both in vitro and in transfected cells. Thus, it is not clear if filament properties are affected by these mutations at all. For this reason, we performed oscillatory shear experiments with six different desmin "tail" mutants in order to characterize the mesh size of filament networks and their strain stiffening properties. Moreover, we have carried out high-frequency oscillatory squeeze flow measurements to determine the bending stiffness of the respective filaments, characterized by the persistence length l(p). Interestingly, mesh size was not altered for the mutant filament networks, except for the mutant DesR454W, which apparently did not form proper filament networks. Also, the values for bending stiffness were in the same range for both the "tail" mutants (l(p)=1.0-2.0 microm) and the wild-type desmin (l(p)=1.1+/-0.5 microm). However, most investigated desmin mutants exhibited a distinct reduction in strain stiffening compared to wild-type desmin and promoted nonaffine network deformation. Therefore, we conclude that the mutated amino acids affect intrafilamentous architecture and colloidal interactions along the filament in such a way that the response to applied strain is significantly altered. In order to explore the importance of the "tail" domain as such for filament network properties, we employed a "tail"-truncated desmin. Under standard conditions, it formed extended regular filaments, but failed to generate strain stiffening. Hence, these data strongly indicate that the "tail" domain is responsible for attractive filament-filament interactions. Moreover, these types of interactions may also be relevant to the network properties of the desmin cytoskeleton in patient muscle.	Are there any desmins present in plants?	Inherited mutations in the gene coding for the intermediate filament protein desmin have been demonstrated to cause severe skeletal and cardiac myopathies.
RNA transcripts are subjected to post-transcriptional gene regulation by interacting with hundreds of RNA-binding proteins (RBPs) and microRNA-containing ribonucleoprotein complexes (miRNPs) that are often expressed in a cell-type dependently. To understand how the interplay of these RNA-binding factors affects the regulation of individual transcripts, high resolution maps of in vivo protein-RNA interactions are necessary. A combination of genetic, biochemical and computational approaches are typically applied to identify RNA-RBP or RNA-RNP interactions. Microarray profiling of RNAs associated with immunopurified RBPs (RIP-Chip) defines targets at a transcriptome level, but its application is limited to the characterization of kinetically stable interactions and only in rare cases allows to identify the RBP recognition element (RRE) within the long target RNA. More direct RBP target site information is obtained by combining in vivo UV crosslinking with immunoprecipitation followed by the isolation of crosslinked RNA segments and cDNA sequencing (CLIP). CLIP was used to identify targets of a number of RBPs. However, CLIP is limited by the low efficiency of UV 254 nm RNA-protein crosslinking, and the location of the crosslink is not readily identifiable within the sequenced crosslinked fragments, making it difficult to separate UV-crosslinked target RNA segments from background non-crosslinked RNA fragments also present in the sample. We developed a powerful cell-based crosslinking approach to determine at high resolution and transcriptome-wide the binding sites of cellular RBPs and miRNPs that we term PAR-CliP (Photoactivatable-Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation) (see Fig. 1A for an outline of the method). The method relies on the incorporation of photoreactive ribonucleoside analogs, such as 4-thiouridine (4-SU) and 6-thioguanosine (6-SG) into nascent RNA transcripts by living cells. Irradiation of the cells by UV light of 365 nm induces efficient crosslinking of photoreactive nucleoside-labeled cellular RNAs to interacting RBPs. Immunoprecipitation of the RBP of interest is followed by isolation of the crosslinked and coimmunoprecipitated RNA. The isolated RNA is converted into a cDNA library and deep sequenced using Solexa technology. One characteristic feature of cDNA libraries prepared by PAR-CliP is that the precise position of crosslinking can be identified by mutations residing in the sequenced cDNA. When using 4-SU, crosslinked sequences thymidine to cytidine transition, whereas using 6-SG results in guanosine to adenosine mutations. The presence of the mutations in crosslinked sequences makes it possible to separate them from the background of sequences derived from abundant cellular RNAs. Application of the method to a number of diverse RNA binding proteins was reported in Hafner et al.	What is the principle of the PAR-CLIP methodology?	The method relies on the incorporation of photoreactive ribonucleoside analogs, such as 4-thiouridine (4-SU) and 6-thioguanosine (6-SG) into nascent RNA transcripts by living cells.
PUVA-bath therapy has proven to avoid many side effects associated with oral 8-methoxypsoralen (8-MOP) treatment. In order to investigate the effectiveness of topical PUVA-bath therapy (PUVA-soak therapy) on chronic palmoplantar dermatoses, 30 patients with plaque-type psoriasis, pustular psoriasis, endogenous eczema, dyshidrotic eczema and hyperkeratotic dermatitis of the palms and soles were treated over 8 weeks with PUVA-soak using 8-MOP. No additional treatment except skin moisturising cream such as unguentum emulsificans aquosum was used during the study period. The single UVA-doses applied ranged from 0.3 to 3.0 J/cm2 (mean single dose of 1.8 J/cm2), with a mean cumulative dose of 48.6 J/cm2 per patient. Altogether 26 of 30 patients responded well within 8 weeks of treatment with 63% of all patients showing a complete remission and 23% showing considerable improvement, as shown by flattening of plaques, decreased scaling and erythema, as well as decreased vesicle and pustule formation. The condition responding best to our therapy was palmoplantar psoriasis followed by atopic eczema. Hyperkeratotic dermatitis displayed the poorest responding rates in this study. Unwanted side effects such as erythema, pain, blistering or patchy hyperpigmentation were not observed in any of the patients. We conclude that PUVA-soak therapy can be highly efficient in the treatment of palmoplantar dermatoses, especially in the management of palmoplantar psoriasis.	Is PUVA therapy indicated for eczema treatment?	In order to investigate the effectiveness of topical PUVA-bath therapy (PUVA-soak therapy) on chronic palmoplantar dermatoses, 30 patients with plaque-type psoriasis, pustular psoriasis, endogenous eczema, dyshidrotic eczema and hyperkeratotic dermatitis of the palms and soles were treated over 8 weeks with PUVA-soak using 8-MOP.
Results in 136 hyperprolactinaemic women who presented with infertility, amenorrhoea, menstrual irregularities and/or galactorrhoea are reported. There was radiographic evidence of pituitary microadenoma in 21 (15.4%) patients and 5 (3.7%) had macroadenoma. Four patients were taking antidepressants, 2 antihypertensive drugs and 7 had taken oral contraceptives for a period of 6 months to 5 years. The remaining patients had no obvious cause for elevated prolactin levels. Patients with pituitary adenoma had a significantly higher (p less than 0.001) baseline serum prolactin level (182 +/- 4.6 ng/ml) than those with no adenoma (59.2 +/- 4.2 ng/ml). All patients in the study were treated with bromocriptine (2.5-10 mg) to normalize serum prolactin or to achieve a pregnancy. The patients without an adenoma required a significantly smaller dose of bromocriptine (2.5-5.0 mg) (p less than 0.005) than those with an adenoma. Galactorrhoea disappeared in all 64 patients within 2-4 months of treatment, sixty-six (71%) of the 93 patients who desired pregnancy achieved it within 3 to 8 months of bromocriptine therapy; 32 of these patients received additional treatment with clomiphene and human chorionic gonadotrophins for induction of ovulation. In the remaining 70 patients menstruation became regular and ovulation was evident in 40% of them. There was no significant difference in the pregnancy rate between the patients with or without pituitary adenoma. Similarly, presence of galactorrhoea or a high level of prolactin did not influence the pregnancy rate. No complications were observed during pregnancy related to pituitary adenomas; 8 (12%) pregnancies ended in first trimester abortion. No lethal congenital fetal abnormalities were observed in the patients treated with bromocriptine.(ABSTRACT TRUNCATED AT 250 WORDS)	Which pituitary adenoma is common cause of infertility is women?	Patients with pituitary adenoma had a significantly higher (p less than 0.001) baseline serum prolactin level (182 +/- 4.6 ng/ml) than those with no adenoma (59.2 +/- 4.2 ng/ml). All patients in the study were treated with bromocriptine (2.5-10 mg) to normalize serum prolactin or to achieve a pregnancy.
The present study was designed to explore the role of IQ motif-containing GTPase activating protein 1 (IQGAP1) in the cell proliferation of multiple myeloma (MM) via the MAP kinase (ERK) pathway. Reverse transcription‑polymerase chain reaction (RT-PCR) and western blot analysis were carried out to evaluate the expression of IQGAP1 in RPMI8226, U266 and KM3 cell lines and in primary MM cells from 4 MM patients. shRNA-expressing plasmids were used in RPMI8226 cells to knock down IQGAP1 and an MTT assay was used to examine the proliferative activity of the RPMI8226-shIQGAP1 (clone 1), RPMI8226-shRNA negative and untransfected RPMI8226 cells in subgroups stimulated with VEGF/IL-6 or without. Western blot analyses were then performed to examine the protein levels of p-ERK1/2, ERK1/2, AKT, p-AKT, STAT3, p-STAT3 in the RPMI8226-shIQGAP1 (clone 1), RPMI8226-shRNA negative and untransfected RPMI8226 cells. Co-immunoprecipitation was used to verify the interaction between the IQGAP1 scaffold and the MAP ERK kinase. We found that IQGAP1 was overexpressed in the human myeloma cell lines and in the patient MM cells. The proliferation rate in the RPMI8226 cells was decreased when IQGAP1 was knocked down with shRNA. IQGAP1 was found to affect RPMI8226 cell proliferation by regulation of the MAP kinase (ERK1/2) pathway; IQGAP1 scaffold-MAP kinase (ERK) interaction was noted in the human myeloma RPMI8226 cell lines. In conclusion, IQGAP1 plays an important role in the cell proliferation of MM via the MAP kinase (ERK) pathway.	List scaffold proteins of the ERK signaling pathway.	IQGAP1 scaffold-MAP kinase (ERK) interaction was noted in the human myeloma RPMI8226 cell lines. In conclusion, IQGAP1 plays an important role in the cell proliferation of MM via the MAP kinase (ERK) pathway.
A promoter is a region in the DNA sequence that defines where the transcription of a gene by RNA polymerase initiates, which is typically located proximal to the transcription start site (TSS). How to correctly identify the gene TSS and the core promoter is essential for our understanding of the transcriptional regulation of genes. As a complement to conventional experimental methods, computational techniques with easy-to-use platforms as essential bioinformatics tools can be effectively applied to annotate the functions and physiological roles of promoters. In this work, we propose a deep learning-based method termed Depicter (Deep learning for predicting promoter), for identifying three specific types of promoters, i.e. promoter sequences with the TATA-box (TATA model), promoter sequences without the TATA-box (non-TATA model), and indistinguishable promoters (TATA and non-TATA model). Depicter is developed based on an up-to-date, species-specific dataset which includes Homo sapiens, Mus musculus, Drosophila melanogaster and Arabidopsis thaliana promoters. A convolutional neural network coupled with capsule layers is proposed to train and optimize the prediction model of Depicter. Extensive benchmarking and independent tests demonstrate that Depicter achieves an improved predictive performance compared with several state-of-the-art methods. The webserver of Depicter is implemented and freely accessible at https://depicter.erc.monash.edu/.	What are promoters?	A promoter is a region in the DNA sequence that defines where the transcription of a gene by RNA polymerase initiates, which is typically located proximal to the transcription start site (TSS).
Much research has gone into developing medications that can be used to alleviate endometriosis-associated symptoms. In addition to already established medications, a new GnRH antagonist, elagolix, is in development. The novelty of this drug compared to other GnRH antagonists, is its nonpeptide structure, allowing it to be administered orally. Areas covered: We analyzed several Phase I, II and III clinical trials that have evaluated the safety and efficacy of this new medication. Expert opinion: Since many medications have been put on the market and have gained popularity for the treatment of endometriosis-associated symptoms, the demonstration of equality or superiority of effect, tolerability, as well as patient compliance should be assessed when introducing a new drug. While elagolix may have an advantage over established GnRH agonists, in that it does not lead to a 'flare-up' effect, it too, takes a toll on bone mineral density. Nevertheless, studies have shown that this new oral GnRH antagonist is well tolerated, and the side effects have been described as 'mild or moderate'. However, in order to examine whether elagolix can compete with or even surpass established gold-standard medical treatments in this field, further studies that directly compare elagolix to said treatments, might be necessary.	Describe the mechanism of action of a drug Elagolix.	In addition to already established medications, a new GnRH antagonist, elagolix, is in development.
Huntington's disease (HD) is a neurodegenerative disease characterized by progressive motor, cognitive and psychiatric deficits, associated with predominant loss of striatal neurons and caused by a polyglutamine expansion in the huntingtin protein. There is so far neither cure nor approved disease-slowing therapy for HD, though recent clinical studies have shown a beneficial long-term effect of pridopidine in patients with HD. The nature of this effect, purely symptomatic or, in addition, neuroprotective, is difficult to elucidate in clinical trials. Pridopidine and (-)-OSU6162 are members of a new family of compounds referred to as dopaminergic stabilizers, which normalize abnormal dopamine neurotransmission. We investigated the effects of (-)-OSU6162 on huntingtin knocked-in striatal neurons in culture. Control neurons had normal full-length huntingtin with 7 glutamines while "mutant" neurons had large expansions (Q=111). We studied the dose-effect curves of (-)-OSU6162 on mitochondrial activity, LDH levels, necrosis and apoptosis in untreated Q7 and Q111 cells. In addition, we investigated the effects of (-)-OSU6162 on Q7 and Q111 neurons challenged with different neurotoxins such as sodium glutamate, H(2)O(2), rotenone and 3-nitropropionic acid (3NP). As we found prevention of toxicity of some of these neurotoxins, we investigated the putative neuroprotective mechanisms of action of (-)-OSU6162 measuring the effects of this dopaminergic stabilizer on expression and release of BDNF, the ratios of Bcl2/Bax proteins and of p-ERK/ERK, the levels of chaperones and GSH, and the effects of (-)-OSU6162 on dopamine uptake and release. We found that (-)-OSU6162, 3-150 μM, produces a dose dependent increase of mitochondrial activity and a reduction of cell death. (-)-OSU6162 does not change glutamate toxicity, but it partially prevents that of H(2)O(2), rotenone and 3-nitropropionic acid. (-)-OSU6162 increases the intracellular levels of BDNF and Bcl2/Bax and decreases those of p-ERK/ERK and CHIP in Q111 cells. (-)-OSU6162 increased (3)H-dopamine uptake and amphetamine-induced (3)H-dopamine release in E13 mouse mid brain neurons. Our studies demonstrate that (-)-OSU6162 improves survival and mitochondrial function in striatal Q111 neurons and the resistance of these cells to several striatal neurotoxins, suggesting that (-)-OSU6162 and related compounds should be tested for neuroprotection in animal models and, eventually, in patients with HD.	Pridopidine has been tested for treatment of which disorder?	There is so far neither cure nor approved disease-slowing therapy for HD, though recent clinical studies have shown a beneficial long-term effect of pridopidine in patients with HD.
The Radiation Therapy Oncology Group (RTOG) initiated the single-arm, phase II study 9806 to determine the safety and efficacy of daily thalidomide with radiation therapy in patients with newly diagnosed glioblastoma. Patients were treated with thalidomide (200 mg daily) from day one of radiation therapy, increasing by 100-200 to 1,200 mg every 1-2 weeks until tumor progression or unacceptable toxicity. The median survival time (MST) of all 89 evaluable patients was 10 months. When compared with the historical database stratified by recursive partitioning analysis (RPA) class, this end point was not different [hazard ratio (HR) = 1.18; 95 % CI: 0.95-1.46; P = 0.93]. The MST of RPA class III and IV patients was 13.9 versus 12.5 months in controls (HR = 0.99; 95 % CI: 0.73-1.36; P = 0.48), and 4.3 versus 8.6 months in RPA class V controls (HR = 1.63, 95 % CI: 1.17-2.27; P = 0.99). In all, 34 % of patients discontinued thalidomide because of adverse events or refusal. The most common grade 3-4 toxicities were venous thrombosis, fatigue, skin reactions, encephalopathy, and neuropathy. In conclusion, thalidomide given simultaneously with radiation therapy was safe, but did not improve survival in patients with newly diagnosed glioblastoma.	What is known about thalidomide therapy and survival of glioblastoma patients?	In conclusion, thalidomide given simultaneously with radiation therapy was safe, but did not improve survival in patients with newly diagnosed glioblastoma.
We describe the effects of iopanoic acid on daily levels of free triiodothyronine (FT(3)) and free thyroxine (FT(4)) in a patient with progressive type II amiodarone-induced thyrotoxicosis (AIT) who was undergoing thyroidectomy. The patient was a 59-year-old man who was undergoing amiodarone therapy while awaiting cardiac transplantation; the use of beta blockers and corticosteroids to control the AIT was contraindicated in this patient. Prior to thyroidectomy, the patient was started on iopanoic acid at 1.0 g twice a day; in response to gastrointestinal side effects, the dosage was subsequently reduced to 0.5 g twice a day. The patient responded to iopanoic acid with a rapid decrease in his FT(3) level and slight increase in his FT(4) level. This control of thyrotoxicosis allowed for an uneventful thyroidectomy, which was later followed by successful cardiac transplantation. Based on our findings in this single case, we believe that iopanoic can be used to rapidly lower FT(3) levels and to treat symptoms of thyrotoxicosis in a preoperative setting. We also discuss the different pharmacodynamic effects that iopanoic acid has on FT(3) and FT(4) levels.	What is the treatment of amiodarone-induced thyrotoxicosis?	The patient responded to iopanoic acid with a rapid decrease in his FT(3) level and slight increase in his FT(4) level.
Ameloblastoma is an odontogenic tumor, usually benign, which rarely metastasizes to distant organs. The case of a 27-year-old white woman is described, who presented a metastatic pulmonary ameloblastoma 7 years after the removal of a mandibular ameloblastoma. She presented no pulmonary symptoms, but a lung nodule was found in a chest x-ray during a routine check-up for job admission. Computed tomography (CT) revealed a 2-cm well-defined solitary round nodule without calcifications, leading to the hypothesis of a metastatic tumor. Clinical and CT investigation confirmed no ameloblastoma recurrence in the jaw and no other primary tumor. The diagnosis of metastatic ameloblastoma was confirmed by microscopic evaluation of the pulmonary nodule.	Is Ameloblastoma (AB) a benign tumor that never metastasizes?	Ameloblastoma is an odontogenic tumor, usually benign, which rarely metastasizes to distant organs.
Arimoclomol is an investigational drug for amyotrophic lateral sclerosis (ALS) that amplifies heat shock protein gene expression during cell stress. The objectives of the present study were to assess the safety, tolerability, and pharmacokinetics of arimoclomol in ALS. Eighty-four participants with ALS received arimoclomol at one of three oral doses (25, 50, or 100 mg three times daily) or placebo. The primary outcome measure was safety and tolerability. A subset of 44 participants provided serum and cerebrospinal fluid (CSF) samples for pharmacokinetic analysis. Participants who completed 12 weeks of treatment could enroll in a 6-month open-label study. Arimoclomol at doses up to 300 mg/day was well tolerated and safe. Arimoclomol resulted in dose-linear pharmacologic exposures and the half-life did not change with continued treatment. Arimoclomol CSF levels increased with dose. Arimoclomol was shown to be safe, and it crosses the blood-brain barrier. Serum pharmacokinetic profiles support dosing of three times per day. An efficacy study in ALS is planned.	Is arimoclomol a co-inducer of the heat shock response?	Arimoclomol is an investigational drug for amyotrophic lateral sclerosis (ALS) that amplifies heat shock protein gene expression during cell stress.
Lung cancer (LC) represents the most common solid tumor in survivors of Hodgkin's disease (HD), and the assessment of the mutational status of oncogenic driver mutations in LC is now standard. We compiled clinical and mutation data (EGFR, KRAS, and ALK) from the medical records of patients with LC and a remote history of HD. 13 cases of LC following HD were seen, including seven with mutational data. Two had EGFR mutations, none had KRAS mutations or ALK translocations. Our conclusions are limited by the small sample size, however this report reinforces the need to identify driver mutations in lung cancers.	Does radiotherapy for Hodgkin disease increases risk for lung cancer?	Lung cancer (LC) represents the most common solid tumor in survivors of Hodgkin's disease (HD), and the assessment of the mutational status of oncogenic driver mutations in LC is now standard.
Cytosolic proteins can be selectively delivered to lysosomes for degradation through a type of autophagy known as chaperone-mediated autophagy (CMA). CMA contributes to intracellular quality control and to the cellular response to stress. Compromised CMA has been described in aging and in different age-related disorders. CMA substrates cross the lysosomal membrane through a translocation complex; consequently, changes in the properties of the lysosomal membrane should have a marked impact on CMA activity. In this work, we have analyzed the impact that dietary intake of lipids has on CMA activity. We have found that chronic exposure to a high-fat diet or acute exposure to a cholesterol-enriched diet both have an inhibitory effect on CMA. Lysosomes from livers of lipid-challenged mice had a marked decrease in the levels of the CMA receptor, the lysosome-associated membrane protein type 2A, because of loss of its stability at the lysosomal membrane. This accelerated degradation of lysosome-associated membrane protein type 2A, also described as the mechanism that determines the decline in CMA activity with age, results from its increased mobilization to specific lipid regions at the lysosomal membrane. Comparative lipidomic analyses revealed qualitative and quantitative changes in the lipid composition of the lysosomal membrane of the lipid-challenged animals that resemble those observed with age. Our findings identify a previously unknown negative impact of high dietary lipid intake on CMA and underscore the importance of diet composition on CMA malfunction in aging.	Which is the receptor for substrates of Chaperone Mediated Autophagy?	Lysosomes from livers of lipid-challenged mice had a marked decrease in the levels of the CMA receptor, the lysosome-associated membrane protein type 2A,
Stem cell-like cells have recently been identified in melanoma cell lines, but their relevance for melanoma pathogenesis is controversial. To characterize the stem cell signature of melanoma, expression of stem cell markers BMI-1 and nestin was studied in 64 cutaneous melanomas, 165 melanoma metastases as well as 53 melanoma cell lines. Stem cell renewal factor BMI-1 is a transcriptional repressor of the Ink4a/Arf locus encoding p16(ink4a) and p14(Arf). Increased nuclear BMI-1 expression was detectable in 41 of 64 (64%) primary melanomas, 117 of 165 melanoma metastases (71%) and 15 of 53 (28%) melanoma cell lines. High nestin expression was observed in 14 of 56 primary melanomas (25%), 84 of 165 melanoma metastases (50%) and 21 of 53 melanoma cell lines (40%). There was a significant correlation between BMI-1 and nestin expression in cell lines (p = 0.001) and metastases (p = 0.02). These data indicate that cells in primary melanomas and their metastases may have stem cell properties. Cell lines obtained from melanoma metastases showed a significant higher BMI-1 expression compared to cell lines from primary melanoma (p = 0.001). Further, primary melanoma lacking lymphatic metastases at presentation (pN0, n = 40) was less frequently BMI-1 positive than melanomas presenting with lymphatic metastases (pN1; n = 24; 52% versus 83%; p = 0.01). Therefore, BMI-1 expression appears to induce a metastatic tendency. Because BMI-1 functions as a transcriptional repressor of the Ink4a/Arf locus, p16(ink4a) and p14(Arf) expression was also analyzed. A high BMI-1/low p16(ink4a) expression pattern was a significant predictor of metastasis by means of logistic regression analysis (p = 0.005). This suggests that BMI-1 mediated repression of p16(ink4a) may contribute to an increased aggressive behavior of stem cell-like melanoma cells.	Which cyclin- dependent kinase inhibitor is regulated by Bmi-1?	BMI-1 is a transcriptional repressor of the Ink4a/Arf locus encoding p16(ink4a)
The cellular cytoskeleton is composed of three fibrillar systems, namely actin microfilaments, microtubules and intermediate filaments (IFs). It not only is a structural system, which mediates functional compartmentalization, but also contributes to many cellular processes such as transport, mitosis, secretion, formation of cell extensions, intercellular communication and apoptosis. In this study, we have examined the distribution of four groups of IFs [cytokeratins (CKs), vimentin, desmin and lamins] in the somatic and germinal cells of the bovine ovary using RT-PCR and immunohistochemical techniques. Using RT-PCR, specific transcripts for all intermediate proteins studied (CK8, CK18, desmin, vimentin, lamin A/C and lamin B1) were detected. A characteristic immunohistochemical staining pattern was observed for the different IFs within the ovary. In this study, we used antibodies against type I CK (acidic CKs: CK14, CK18 and CK19) and type II CK (basic CKs: CK5 and CK8). Among these, only antibodies against CK18 gave a characteristic pattern of immunostaining in the ovary, which included the surface epithelium, the follicle cells, the endothelium of blood vessels and rete ovarii. Antibodies against all other CKs resulted in a weak staining of a limited number of cellular structures (CK5 and CK19) or were completely negative (CK8 and CK14, apart from the surface epithelium). Vimentin antibodies resulted occasionally in a weak staining of the granulosa cells of primary and secondary follicles. In late secondary follicles, the basal and the most apical follicle cells contacting the zona pellucida usually showed a marked immunostaining for vimentin. In antral follicles, three different immunostaining patterns for vimentin were observed. Desmin immunostaining was confined to the smooth muscle cells of blood vessels. Although mRNA for lamin A/C and lamin B1 could be demonstrated using RT-PCR, no immunostaining was found for lamins, neither in the follicle cells nor in the oocytes.	What are the structures formed when keratin molecules come together?	In this study, we have examined the distribution of four groups of IFs [cytokeratins (CKs), vimentin, desmin and lamins]
We conclude that marked variations exist in the efficacy and safety of medications between severe and non-severe patients with COVID-19. It seems that monoclonal antibodies (e.g., low dosage bamlanivimab, baricitinib, imatinib, and sotrovimab) are a better choice for treating severe or non-severe COVID-19 patients. Clinical decisions to use preferentially medications should carefully consider the risk-benefit profile based on efficacy and safety of all active interventions in patients with COVID-19 at different levels of infection.	Is Sotrovimab effective for COVID-19?	ms that monoclonal antibodies (e.g., low dosage bamlanivimab, baricitinib, imatinib, and sotrovimab) are a better choice for treating severe or non-severe COVID-19 patients. Clini
Telomerase is highly expressed in essentially all cancer forms, while the expression in normal tissues is restricted. Moreover, telomerase activity is considered indispensable for tumor immortalization and growth. Human telomerase reverse transcriptase (hTERT), the rate-limiting subunit of the telomerase complex, is therefore an attractive target for cancer vaccination. The present review provides an update on the development of GV1001, a peptide vaccine representing a 16-aa hTERT sequence. GV1001 binds multiple HLA class II molecules and harbors putative HLA class I epitopes. The peptide may therefore elicit combined CD4/CD8 T-cell responses, considered important to initiate tumor eradication and long-term memory. Phase I/II trials in advanced pancreatic and pulmonary cancer patients have demonstrated GV1001-specific T-cell responses in > 50% of subjects, without clinically important toxicity. The results indicate a correlation between development of GV1001-specific responses and prolonged survival. However, as in most cancer vaccine trials, a large proportion of immune responders experience no clinical benefit. Long-term survivors harbor durable GV1001-specific T-cell responses with high IFN-gamma/IL-10 ratios and polyfunctional cytokine patterns. Interestingly, the cytokine profiles do not follow a T(H)1/T(H)2 delineation. Here, the author discusses how immunomonitoring may be improved to discriminate between efficient and pointless immune responses, and which questions to address in the further development of GV1001.	GV1001 vaccine targets which enzyme?	Human telomerase reverse transcriptase (hTERT), the rate-limiting subunit of the telomerase complex, is therefore an attractive target for cancer vaccination. The present review provides an update on the development of GV1001, a peptide vaccine representing a 16-aa hTERT sequence.
Polyadenylation [poly(A)] is an essential process during the maturation of most mRNAs in eukaryotes. Alternative polyadenylation (APA) as an important layer of gene expression regulation has been increasingly recognized in various species. Here, a web platform for visualization and analysis of alternative polyadenylation (VAAPA) was developed. This platform can visualize the distribution of poly(A) sites and poly(A) clusters of a gene or a section of a chromosome. It can also highlight genes with switched APA sites among different conditions. VAAPA is an easy-to-use web-based tool that provides functions of poly(A) site query, data uploading, downloading, and APA sites visualization. It was designed in a multi-tier architecture and developed based on Smart GWT (Google Web Toolkit) using Java as the development language. VAAPA will be a valuable addition to the community for the comprehensive study of APA, not only by making the high quality poly(A) site data more accessible, but also by providing users with numerous valuable functions for poly(A) site analysis and visualization.	Mention computational tools that have been developed for alternative polyadenylation (APA) sites analysis	Here, a web platform for visualization and analysis of alternative polyadenylation (VAAPA) was developed.
We demonstrated that comparative glycomic profiling of esophageal adenocarcinoma reveals a subset of glycans that can be selected as candidate biomarkers. These markers can differentiate normal from high-grade dysplasia, normal from esophageal adenocarcinoma, and high-grade dysplasia from esophageal adenocarcinoma. Further validation will be necessary to determine the clinical utility of these glycan biomarkers.	Is esophageal adenocarcinoma associated with aberrant glycosylation?	comparative glycomic profiling of esophageal adenocarcinoma reveals a subset of glycans that can be selected as candidate biomarkers
Changes in DNA methylation patterns are an important characteristic of human cancer. Tumors have reduced levels of genomic DNA methylation and contain hypermethylated CpG islands, but the full extent and sequence context of DNA hypomethylation and hypermethylation is unknown. Here, we used methylated CpG island recovery assay-assisted high-resolution genomic tiling and CpG island arrays to analyze methylation patterns in lung squamous cell carcinomas and matched normal lung tissue. Normal tissues from different individuals showed overall very similar DNA methylation patterns. Each tumor contained several hundred hypermethylated CpG islands. We identified and confirmed 11 CpG islands that were methylated in 80-100% of the SCC tumors, and many hold promise as effective biomarkers for early detection of lung cancer. In addition, we find that extensive DNA hypomethylation in tumors occurs specifically at repetitive sequences, including short and long interspersed nuclear elements and LTR elements, segmental duplications, and subtelomeric regions, but single-copy sequences rarely become demethylated. The results are consistent with a specific defect in methylation of repetitive DNA sequences in human cancer.	Is cancer related to global DNA hypo or hypermethylation?	The results are consistent with a specific defect in methylation of repetitive DNA sequences in human cancer.
Women during perimenopausal period experience a range of symptoms, which interfere with physical, sexual, and social life. About 65-75% of symptoms connected with postmenopausal period are vasomotor symptoms (VMS), such as hot flushes and night sweats. Hot flushes are subjective sensation of heat associated with cutaneous vasodilatation and drop in core temperature. It is suspected that VMS are strongly correlated with pulsatile oversecretion of gonadotropin-releasing hormone (GnRH) and subsequently luteinizing hormone (LH). Evidence has accumulated in parallel showing that lack of negative feedback of steroid hormones synthesized in ovary causes overactivation of hypertrophied kisspeptin/neurokinin B/dynorphin (KNDy) neurons, located in infundibular nucleus. Oversecretion of both kisspeptin (KISS1) and neurokinin B (NKB), as well as downregulation of dynorphin, plays dominant role in creation of GnRH pulses. This in turn causes VMS. Administration of senktide, highly potent and selective NK3R agonist, resulted in increase of serum LH concentration, induction of VMS, increase in heart rate, and skin temperature in postmenopausal women. These finding suggest that modulation of KNDy neurons may become new therapeutic approach in the treatment of VMS.	Name a selective NK3R agonist.	Administration of senktide, highly potent and selective NK3R agonist, resulted in increase of serum LH concentration, induction of VMS, increase in heart rate, and skin temperature in postmenopausal women.
The spread of carbapenemase-producing gram-negative bacteria is one of the major challenges of the present. Since 2009, the National Reference Laboratory for gram-negative nosocomial pathogens has observed the molecular epidemiology of carbapenemases in Germany. In 2011, 1,454 referred bacterial isolates were tested for the presence of carbapenemases. Carbapenemase was found in 34.4% of Enterobacteriaceae isolates, in 19.9% of Pseudomonas aeruginosa isolates and in 96.3% of Acinetobacter baumannii isolates. The most frequent carbapenemases in Enterobacteriaceae were OXA-48, KPC and VIM-1; in P. aeruginosa it was VIM-2 and in A. baumannii OXA-23.	Carbapenemase-producing gram-negative bacteria is a major health concern because their resistance to antibiotics.	null
CREB is an ubiquitous transcription factor regulating diverse cellular responses. Its phosphorylation at S133 is an essential event for its activation in both nervous and visual systems. The activated CREB is implicated in the regulation of development, protection, learning, memory and plasticity in the nerve system. Moreover, sumoylation, an important post-translational modification of protein, plays a key role in sustaining CREB activation in the rat hippocampus in order to enhance the long-term memory and other aspects. In the visual system, although the CREB activation by phosphorylation at S133 is similar to that as observed in the nervous system, the role of CREB sumoylation remains to be explored. This review will discuss the aspects of CREB functions and their regulation by phosphorylation and sumoylation in both systems.	Is CREB a key memory protein?	The activated CREB is implicated in the regulation of development, protection, learning, memory and plasticity in the nerve system.
The purpose of this study is to review the development of BRAF inhibitors, with emphasis on the trials conducted with dabrafenib (GSK2118436) and the evolving role of dabrafenib in treatment for melanoma patients. Fifty percent of cutaneous melanomas have mutations in BRAF, resulting in elevated activity of the mitogen-activated protein kinase signaling pathway. Dabrafenib inhibits the mutant BRAF (BRAF(mut)) protein in melanomas with BRAF(V600E) and BRAF(V600K) genotypes. BRAF(V600E) metastatic melanoma patients who receive dabrafenib treatment exhibit high clinical response rates and compared with dacarbazine chemotherapy, progression-free survival. Efficacy has also been demonstrated in BRAF(V600K) patients and in those with brain metastases. Dabrafenib has a generally mild and manageable toxicity profile. Cutaneous squamous cell carcinomas and pyrexia are the most significant adverse effects. Dabrafenib appears similar to vemurafenib with regard to efficacy but it is associated with less toxicity. It is expected that new combinations of targeted drugs, such as the combination of dabrafenib and trametinib (GSK1120212, a MEK inhibitor), will provide higher response rates and more durable clinical benefit than dabrafenib monotherapy.	List BRAF inhibitors that have been tested in clinical trials for treatment of melanoma patients	Dabrafenib inhibits the mutant BRAF (BRAF(mut)) protein in melanomas with BRAF(V600E) and BRAF(V600K) genotypes.
The study of rare genetic diseases usually inspires the research of cancer biology. Fanconi anemia (FA), is a rare cancer susceptibility syndrome with an incidence of only 1 per 350,000 births. FA is an autosomal recessive disease with three main features: chromosome instability, hypersensitivity to DNA cross-linking agents such as mitomycin C (MMC), cisplatin and so on, and susceptible to a number of cancer types, mainly leukemia and squamous cell carcinomas of the head and neck or gynecologic system. DNA crosslinking agents may led to DNA cross-linking lesion, and Fanconi anemia pathway plays a key role in repairing its cross-linking. However, FA pathway is closely linked with carcinogenesis and tumor drug resistance. This paper mainly focuses on the FA pathway and its progress in cancer research.	Is hypersensitivity to DNA crosslinking agents a hallmark of Fanconi anemia?	DNA crosslinking agents may led to DNA cross-linking lesion, and Fanconi anemia pathway plays a key role in repairing its cross-linking.
Botulinum neurotoxins (BoNTs), which are highly toxic proteins responsible for botulism, are produced by different strains of Clostridium botulinum. These various strains of bacteria produce seven distinct serotypes, labeled A-G. Once inside cells, the zinc-dependent proteolytic light chain (LC) degrades specific proteins involved in acetylcholine release at neuromuscular junctions causing flaccid paralysis, specifically synaptosomal-associated protein 25 (SNAP-25) for botulinum neurotoxin type A (BoNT/A). BoNT endopeptidase assays using short substrate homologues have been widely used and developed because of their ease of synthesis, detection limits, and cost. SNAPtide, a 13-amino acid fluorescence resonance energy transfer (FRET) peptide, was used in this study as a SNAP-25 homologue for the endopeptidase kinetics study of BoNT/A LC. SNAPtide uses a fluorescein isothiocyanate/4-((4-(dimethylamino)phenyl)azo) benzoic acid (FITC/DABCYL) FRET pair to produce a signal upon substrate cleavage. Signal quenching can become an issue after cleavage since quencher molecules can quench cleaved fluorophore molecules in close proximity, reducing the apparent signal. This reduction in apparent signal provides an inherent error as SNAPtide concentrations are increased. In this study, fluorescence internal quenching (FIQ) correction factors were derived using an unquenched SNAPtide peptide to quantify the signal quenching over a range of SNAPtide concentrations and temperatures. The BoNT/A LC endopeptidase kinetics at the optimally active temperature (37 °C) using SNAPtide were studied and used to demonstrate the FIQ correction factors in this study. The FIQ correction factors developed provide a convenient method to allow for improved accuracy in determining and comparing BoNT/A LC activity and kinetics using SNAPtide over a broad range of concentrations and temperatures.	How is active neurotoxin of Clostridium botulinum detected?	BoNT endopeptidase assays
Arachidonic acid metabolites contribute to the regulation of vascular tone and therefore tissue blood flow. The vascular endothelium metabolizes arachidonic acid by cytochrome P450 epoxygenases to epoxyeicosatrienoic acids or EETs. The placement of the epoxide group can occur on any of the double bonds of arachidonic acid resulting in four EET regioisomers; 5,6-, 8,9-, 11,12- and 14,15-EET. In the vasculature, EETs are key components of cellular signaling cascades that culminate in the activation of smooth muscle potassium channels to induce membrane hyperpolarization and vascular relaxation. In some vasculatures such as bovine coronary arteries, EET regioisomers are equipotent in inducing relaxations, while in other arteries, a specific EET regioisomer induces relaxation while others do not. Therefore, the position of the double bonds and/or the epoxide group may alter vascular agonist activity. This observation suggests that small alterations in the chemical structure of EETs can significantly impact vascular activity. To explore this hypothesis, we synthesized a series of EET analogs and characterized their vasodilator agonist and antagonist activity in bovine coronary arteries. In this chapter, we first review the mechanisms of EET-dependent relaxations in bovine coronary arteries to familiarize the reader with the role of EETs in these arteries. The second component is a synopsis of the functional characterization of the 14,15-EET analogs and the resulting description of structural components required for vascular dilator activity. Lastly, we discussed the characterization of three 14,15-EET analogs with specific EET-antagonist activity and compared this to the activity of similar 11,12-EET analogs. These studies have revealed that specific structural components of the 14,15-EET molecule are critical for dilator activity and that alteration of these components influences agonist activity and may confer antagonist properties.	Are Epoxyeicosatrienoic acids (EETs) synthesized by cytochrome P450 epoxygenases from arachidonic acid?	he vascular endothelium metabolizes arachidonic acid by cytochrome P450 epoxygenases to epoxyeicosatrienoic acids or EETs.
Tuberous sclerosis is a rare genetic disease with autosomal dominant inheritance, associated with multiple hamartomas in several organs, such as the brain, skin, lung, kidney, heart and eyes. The authors of this study report a case of a 30 years old female patient with tuberous sclerosis, presenting multiple angiofibromas on face treated with high frequency equipment (radiofrequency), and discuss the therapeutic options for treatment of individuals with extensive cutaneous involvement in tuberous sclerosis.	Is Tuberous Sclerosis a genetic disease?	Tuberous sclerosis is a rare genetic disease
DOOR syndrome (deafness, onychodystrophy, osteodystrophy, and mental retardation) is a rarely described disorder with less than 35 reports in the literature. The hallmarks of the syndrome, represented in the DOOR acronym, include sensorineural hearing loss, hypoplastic or absent nails on the hands and feet, small or absent distal phalanges of the hands and feet, and mental retardation. The purpose of our communication is to report on an additional patient with DOOR syndrome, delineate common as well as less frequent manifestations of DOOR syndrome, bring attention to the under appreciated facial features in DOOR syndrome, document the natural history of this disorder, and propose a suggested workup of those suspected of DOOR syndrome. DOOR syndrome is associated with characteristic, coarse facial features with large nose with wide nasal bridge, bulbous tip and anteverted nares, a long prominent philtrum and downturned corners of the mouth. The natural history is one of a deteriorative course, with progressive neurological manifestations including sensorineural deafness, seizures from infancy, optic atrophy, and a peripheral polyneuropathy. The majority of patients with DOOR syndrome have elevated levels of 2-oxoglutarate in the urine and plasma. In this report, we present a newborn with manifestations consistent with DOOR syndrome and a progressive clinical course. A comprehensive literature review reveals 32 patients with DOOR syndrome. In conclusion, DOOR syndrome is a neurometabolic disorder with recognizable facial features and a progressive natural history.	List features of the DOOR syndrome.	DOOR syndrome (deafness, onychodystrophy, osteodystrophy, and mental retardation) is a rarely described disorder with less than 35 reports in the literature.
Over 190 independent insertions into target plasmids of the retrovirus-like element Ty3 were recovered and mapped. Ty3 was shown to insert upstream of tRNA, 5S, and U6 genes, all of which are transcribed by RNA polymerase III. Integration sites were within 1-4 nucleotides of the position of transcription initiation, even for one mutant gene where the polymerase III initiation site was shifted to a completely new context. Mutagenesis of a SUP2 tRNA gene target showed that integration required functional promoter elements but that it did not correlate in a simple way with target transcription. This is the first report directly linking a discrete genomic function with preferential insertion of a retrotransposon.	Where is the yeast transpozable element Ty3 preferentially inserted?	Ty3 was shown to insert upstream of tRNA, 5S, and U6 genes, all of which are transcribed by RNA polymerase III
Five per cent of patients with primary Sjogren's syndrome (pSS) develop malignant non-Hodgkin's lymphoma (NHL), usually of the mucosa-associated lymphoid tissue (MALT) and most frequently located in the major salivary glands. Rituximab (RTX), a chimeric monoclonal antibody against the CD20 molecule expressed on the surface of mature B cells that has been approved for the treatment of NHL, has been used to treat pSS-associated lymphoma. We have described two cases: one with MALT lymphoma in the parotid glands and the other with a rare thymus lymphoma accompanied by the rare complication of a bullous pneumopathy. Both were treated with RTX at haematological doses, which was unsuccessful in the patient with a salivary lymphoma; in the case of the patient with a thymus lymphoma, the mediastinum mass disappeared and did not relapse. Both patients experienced an improvement in the subjective symptoms of dryness, and their Schirmer's test and scialoscintigraphy results stabilised. The pulmonary bullae remained unchanged.	Are patients with Sjogren syndrome at increased risk for lymphoma?	Five per cent of patients with primary Sjogren's syndrome (pSS) develop malignant non-Hodgkin's lymphoma (NHL), usually of the mucosa-associated lymphoid tissue (MALT) and most frequently located in the major salivary glands.
CD44v5 expression is independently positively correlated with the aggressiveness of thymic epithelial tumors. The expression of CD44v5 may be a potential trigger of tumor invasion in thymomas.	Are CD44 variants (CD44v) associated with poor prognosis of metastasis?	CD44v5 expression is independently positively correlated with the aggressiveness of thymic epithelial tumors. The expression of CD44v5 may be a potential trigger of tumor invasion in thymomas
Candida albicans and Candida glabrata are predominant fungi associated with oral candidiasis. Histatin 5 (Hst 5) is a small cationic human salivary peptide with high fungicidal activity against C. albicans, however many strains of C. glabrata are resistant. Since Hst 5 requires fungal binding to cell wall components prior to intracellular translocation, reduced Hst 5 binding to C. glabrata may be the reason for its insensitivity. C. glabrata has higher surface levels of β-1,3-glucans as compared with C. albicans; however these differences did not account for reduced Hst 5 uptake and killing in C. glabrata. Similarly, the biofilm matrix of C. glabrata contained significantly higher levels of β-1,3-glucans compared with C. albicans, but it did not reduce the percentage of Hst 5 positive fungal cells in the biofilm. Hst 5 enters C. albicans cell through polyamine transporters Dur3p and Dur31p that are uncharacterized in C. glabrata. C. glabrata strains expressing CaDur3 and CaDur31 had two-fold higher killing and uptake of Hst 5. Thus, neither C. glabrata cell surface or biofilm matrix β-1,3-glucan levels affected Hst 5 toxicity; rather the crucial rate limiting step is reduced uptake that can be overcome by expression of C. albicans Dur proteins in C. glabrata.	How does Hst5 (histatin 5) affect infections by Candida glabrata?	the crucial rate limiting step is reduced uptake that can be overcome by expression of C. albicans Dur proteins in C. glabrata.