Input: Hepatic but not brain iron is rapidly chelated by deferasirox in aceruloplasminemia due to a novel gene mutation . BACKGROUND _ # 38 ; AIMS : Aceruloplasminemia is a rare autosomal recessive neurodegenerative disease associated with brain and liver iron accumulation which typically presents with movement disorders , retinal degeneration , and diabetes mellitus . Ceruloplasmin is a multi - copper ferroxidase that is secreted into plasma and facilitates cellular iron export and iron binding to transferrin . RESULTS : A novel homozygous ceruloplasmin gene mutation , c . 2554 + 1G > T , was identified as the cause of aceruloplasminemia in three affected siblings . Two siblings presented with movement disorders and diabetes . Complementary DNA sequencing showed that this mutation causes skipping of exon 14 and deletion of amino acids 809 - 852 while preserving the open reading frame . Western blotting of liver extracts and sera of affected patients showed retention of the abnormal protein in the liver . Aceruloplasminemia was associated with severe brain and liver iron overload , where hepatic mRNA expression of the iron hormone hepcidin was increased , corresponding to the degree of iron overload . Hepatic iron concentration normalized after 3 and 5months of iron chelation therapy with deferasirox , which was also associated with reduced insulin demands . During short term treatment there was no clinical or imaging evidence for significant effects on brain iron overload . CONCLUSIONS : Aceruloplasminemia can show an incomplete clinical penetrance but is invariably associated with iron accumulation in the liver and in the brain . Iron accumulation in aceruloplasminemia is a result of defective cellular iron export , where hepcidin regulation is appropriate for the degree of iron overload . Iron chelation with deferasirox was effective in mobilizing hepatic iron but has no effect on brain iron .

iron

deferasirox

iron

ferroxidase

iron

iron

iron

iron

iron

deferasirox

iron

Iron

iron

Iron

deferasirox

iron

iron

aceruloplasminemia

Aceruloplasminemia

autosomal recessive neurodegenerative disease

movement disorders

retinal degeneration

diabetes mellitus

aceruloplasminemia

movement disorders

diabetes

Aceruloplasminemia

iron overload

iron overload

iron overload

Aceruloplasminemia

aceruloplasminemia

iron overload

Ceruloplasmin

transferrin

ceruloplasmin

hepcidin

insulin

hepcidin

c . 2554 + 1G > T

deletion of amino acids 809 - 852

patients

hepcidin

iron overload

hepcidin

iron overload

hepcidin

iron overload

hepcidin

iron overload

hepcidin

iron overload

hepcidin

iron overload

hepcidin

iron overload

hepcidin

iron overload

iron overload

deferasirox

iron overload

deferasirox

iron overload

deferasirox

iron overload

deferasirox

iron overload

deferasirox

iron overload

deferasirox

iron overload

deferasirox

iron overload

deferasirox

iron overload

deferasirox

iron overload

deferasirox

iron overload

deferasirox

iron overload

deferasirox

deferasirox

insulin

deferasirox

insulin

deferasirox

insulin

deferasirox

aceruloplasminemia

deferasirox

Aceruloplasminemia

deferasirox

aceruloplasminemia

deferasirox

Aceruloplasminemia

deferasirox

Aceruloplasminemia

deferasirox

aceruloplasminemia

deferasirox

aceruloplasminemia

deferasirox

Aceruloplasminemia

deferasirox

aceruloplasminemia

deferasirox

Aceruloplasminemia

deferasirox

Aceruloplasminemia

deferasirox

aceruloplasminemia

deferasirox

aceruloplasminemia

deferasirox

Aceruloplasminemia

deferasirox

aceruloplasminemia

deferasirox

Aceruloplasminemia

deferasirox

Aceruloplasminemia

deferasirox

aceruloplasminemia

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

Iron

iron overload

iron

iron overload

Iron

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

Iron

iron overload

iron

iron overload

Iron

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

Iron

iron overload

iron

iron overload

Iron

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

iron

iron overload

Iron

iron overload

iron

iron overload

Iron

iron overload

iron

iron overload

iron

c . 2554 + 1G > T

aceruloplasminemia

c . 2554 + 1G > T

Aceruloplasminemia

c . 2554 + 1G > T

aceruloplasminemia

c . 2554 + 1G > T

Aceruloplasminemia

c . 2554 + 1G > T

Aceruloplasminemia

c . 2554 + 1G > T

aceruloplasminemia

aceruloplasminemia

iron

aceruloplasminemia

iron

aceruloplasminemia

iron

aceruloplasminemia

iron

aceruloplasminemia

iron

aceruloplasminemia

iron

aceruloplasminemia

iron

aceruloplasminemia

iron

aceruloplasminemia

Iron

aceruloplasminemia

iron

aceruloplasminemia

Iron

aceruloplasminemia

iron

aceruloplasminemia

iron

Aceruloplasminemia

iron

Aceruloplasminemia

iron

Aceruloplasminemia

iron

Aceruloplasminemia

iron

Aceruloplasminemia

iron

Aceruloplasminemia

iron

Aceruloplasminemia

iron

Aceruloplasminemia

iron

Aceruloplasminemia

Iron

Aceruloplasminemia

iron

Aceruloplasminemia

Iron

Aceruloplasminemia

iron

Aceruloplasminemia

iron

aceruloplasminemia

iron

aceruloplasminemia

iron

aceruloplasminemia

iron

aceruloplasminemia

iron

aceruloplasminemia

iron

aceruloplasminemia

iron

aceruloplasminemia

iron

aceruloplasminemia

iron

aceruloplasminemia

Iron

aceruloplasminemia

iron

aceruloplasminemia

Iron

aceruloplasminemia

iron

aceruloplasminemia

iron

Aceruloplasminemia

iron

Aceruloplasminemia

iron

Aceruloplasminemia

iron

Aceruloplasminemia

iron

Aceruloplasminemia

iron

Aceruloplasminemia

iron

Aceruloplasminemia

iron

Aceruloplasminemia

iron

Aceruloplasminemia

Iron

Aceruloplasminemia

iron

Aceruloplasminemia

Iron

Aceruloplasminemia

iron

Aceruloplasminemia

iron

Aceruloplasminemia

iron

Aceruloplasminemia

iron

Aceruloplasminemia

iron

Aceruloplasminemia

iron

Aceruloplasminemia

iron

Aceruloplasminemia

iron

Aceruloplasminemia

iron

Aceruloplasminemia

iron

Aceruloplasminemia

Iron

Aceruloplasminemia

iron

Aceruloplasminemia

Iron

Aceruloplasminemia

iron

Aceruloplasminemia

iron

aceruloplasminemia

iron

aceruloplasminemia

iron

aceruloplasminemia

iron

aceruloplasminemia

iron

aceruloplasminemia

iron

aceruloplasminemia

iron

aceruloplasminemia

iron

aceruloplasminemia

iron

aceruloplasminemia

Iron

aceruloplasminemia

iron

aceruloplasminemia

Iron

aceruloplasminemia

iron

aceruloplasminemia

iron

iron

retinal degeneration

iron

retinal degeneration

iron

retinal degeneration

iron

retinal degeneration

iron

retinal degeneration

iron

retinal degeneration

iron

retinal degeneration

iron

retinal degeneration

Iron

retinal degeneration

iron

retinal degeneration

Iron

retinal degeneration

iron

retinal degeneration

iron

retinal degeneration

iron

diabetes mellitus

iron

diabetes

iron

diabetes mellitus

iron

diabetes

iron

diabetes mellitus

iron

diabetes

iron

diabetes mellitus

iron

diabetes

iron

diabetes mellitus

iron

diabetes

iron

diabetes mellitus

iron

diabetes

iron

diabetes mellitus

iron

diabetes

iron

diabetes mellitus

iron

diabetes

Iron

diabetes mellitus

Iron

diabetes

iron

diabetes mellitus

iron

diabetes

Iron

diabetes mellitus

Iron

diabetes

iron

diabetes mellitus

iron

diabetes

iron

diabetes mellitus

iron

diabetes

iron

movement disorders

iron

movement disorders

iron

movement disorders

iron

movement disorders

iron

movement disorders

iron

movement disorders

iron

movement disorders

iron

movement disorders

iron

movement disorders

iron

movement disorders

iron

movement disorders

iron

movement disorders

iron

movement disorders

iron

movement disorders

iron

movement disorders

iron

movement disorders

Iron

movement disorders

Iron

movement disorders

iron

movement disorders

iron

movement disorders

Iron

movement disorders

Iron

movement disorders

iron

movement disorders

iron

movement disorders

iron

movement disorders

iron

movement disorders

c . 2554 + 1G > T

diabetes mellitus

c . 2554 + 1G > T

diabetes

c . 2554 + 1G > T

movement disorders

c . 2554 + 1G > T

movement disorders

Ceruloplasmin

diabetes mellitus

Ceruloplasmin

diabetes

ceruloplasmin

diabetes mellitus

ceruloplasmin

diabetes

Ceruloplasmin

movement disorders

Ceruloplasmin

movement disorders

ceruloplasmin

movement disorders

ceruloplasmin

movement disorders

Ceruloplasmin

aceruloplasminemia

Ceruloplasmin

Aceruloplasminemia

Ceruloplasmin

aceruloplasminemia

Ceruloplasmin

Aceruloplasminemia

Ceruloplasmin

Aceruloplasminemia

Ceruloplasmin

aceruloplasminemia

ceruloplasmin

aceruloplasminemia

ceruloplasmin

Aceruloplasminemia

ceruloplasmin

aceruloplasminemia

ceruloplasmin

Aceruloplasminemia

ceruloplasmin

Aceruloplasminemia

ceruloplasmin

aceruloplasminemia

Ceruloplasmin

iron

Ceruloplasmin

iron

Ceruloplasmin

iron

Ceruloplasmin

iron

Ceruloplasmin

iron

Ceruloplasmin

iron

Ceruloplasmin

iron

Ceruloplasmin

iron

Ceruloplasmin

Iron

Ceruloplasmin

iron

Ceruloplasmin

Iron

Ceruloplasmin

iron

Ceruloplasmin

iron

ceruloplasmin

iron

ceruloplasmin

iron

ceruloplasmin

iron

ceruloplasmin

iron

ceruloplasmin

iron

ceruloplasmin

iron

ceruloplasmin

iron

ceruloplasmin

iron

ceruloplasmin

Iron

ceruloplasmin

iron

ceruloplasmin

Iron

ceruloplasmin

iron

ceruloplasmin

iron

aceruloplasminemia

hepcidin

aceruloplasminemia

hepcidin

Aceruloplasminemia

hepcidin

Aceruloplasminemia

hepcidin

aceruloplasminemia

hepcidin

aceruloplasminemia

hepcidin

Aceruloplasminemia

hepcidin

Aceruloplasminemia

hepcidin

Aceruloplasminemia

hepcidin

Aceruloplasminemia

hepcidin

aceruloplasminemia

hepcidin

aceruloplasminemia

hepcidin

iron

transferrin

iron

transferrin

iron

transferrin

iron

transferrin

iron

transferrin

iron

transferrin

iron

transferrin

iron

transferrin

Iron

transferrin

iron

transferrin

Iron

transferrin

iron

transferrin

iron

transferrin

iron

deferasirox

iron

deferasirox

iron

deferasirox

iron

deferasirox

iron

deferasirox

iron

deferasirox

iron

deferasirox

iron

deferasirox

iron

deferasirox

iron

deferasirox

iron

deferasirox

iron

deferasirox

iron

deferasirox

iron

deferasirox

iron

deferasirox

iron

deferasirox

iron

deferasirox

iron

deferasirox

iron

deferasirox

iron

deferasirox

iron

deferasirox

iron

deferasirox

iron

deferasirox

iron

deferasirox

Iron

deferasirox

Iron

deferasirox

Iron

deferasirox

iron

deferasirox

iron

deferasirox

iron

deferasirox

Iron

deferasirox

Iron

deferasirox

Iron

deferasirox

iron

deferasirox

iron

deferasirox

iron

deferasirox

iron

deferasirox

iron

deferasirox

iron

deferasirox


Input: The androgen receptor confers protection against diet - induced atherosclerosis , obesity , and dyslipidemia in female mice . Androgens have important cardiometabolic actions in males , but their metabolic role in females is unclear . To determine the physiologic androgen receptor ( AR ) - dependent actions of androgens on atherogenesis in female mice , we generated female AR - knockout ( ARKO ) mice on an atherosclerosis - prone apolipoprotein E ( apoE ) - deficient background . After 8 weeks on a high - fat diet , but not on a normal chow diet , atherosclerosis in aorta was increased in ARKO females ( + 59 % vs . control apoE - deficient mice with intact AR gene ) . They also displayed increased body weight ( + 18 % ) , body fat percentage ( + 62 % ) , and hepatic triglyceride levels , reduced insulin sensitivity , and a marked atherogenic dyslipidemia ( serum cholesterol , + 52 % ) . Differences in atherosclerosis , body weight , and lipid levels between ARKO and control mice were abolished in mice that were ovariectomized before puberty , consistent with a protective action of ovarian androgens mediated via the AR . Furthermore , the AR agonist dihydrotestosterone reduced atherosclerosis ( - 41 % ; thoracic aorta ) , subcutaneous fat mass ( - 44 % ) , and cholesterol levels ( - 35 % ) in ovariectomized mice , reduced hepatocyte lipid accumulation in hepatoma cells in vitro , and regulated mRNA expression of hepatic genes pivotal for lipid homeostasis . In conclusion , we demonstrate that the AR protects against diet - induced atherosclerosis in female mice and propose that this is mediated by modulation of body composition and lipid metabolism .

androgen receptor

androgen receptor

AR

AR

ARKO

apolipoprotein E

apoE

ARKO

apoE

AR

triglyceride

insulin

ARKO

AR

AR

AR

atherosclerosis

obesity

dyslipidemia

atherogenesis

atherosclerosis

atherosclerosis

atherogenic

dyslipidemia

atherosclerosis

atherosclerosis

hepatoma

atherosclerosis

mice

mice

mice

mice

mice

mice

mice

mice

Androgens

androgens

cholesterol

lipid

androgens

dihydrotestosterone

cholesterol

lipid

lipid

lipid

dihydrotestosterone

lipid

dihydrotestosterone

lipid

dihydrotestosterone

lipid

dihydrotestosterone

lipid

dihydrotestosterone

cholesterol

dihydrotestosterone

cholesterol

dihydrotestosterone

atherosclerosis

dihydrotestosterone

atherogenesis

dihydrotestosterone

atherosclerosis

dihydrotestosterone

atherosclerosis

dihydrotestosterone

atherogenic

dihydrotestosterone

atherosclerosis

dihydrotestosterone

atherosclerosis

dihydrotestosterone

atherosclerosis

dyslipidemia

androgen receptor

dyslipidemia

androgen receptor

dyslipidemia

AR

dyslipidemia

AR

dyslipidemia

ARKO

dyslipidemia

ARKO

dyslipidemia

AR

dyslipidemia

ARKO

dyslipidemia

AR

dyslipidemia

AR

dyslipidemia

AR

dyslipidemia

androgen receptor

dyslipidemia

androgen receptor

dyslipidemia

AR

dyslipidemia

AR

dyslipidemia

ARKO

dyslipidemia

ARKO

dyslipidemia

AR

dyslipidemia

ARKO

dyslipidemia

AR

dyslipidemia

AR

dyslipidemia

AR

triglyceride

androgen receptor

triglyceride

androgen receptor

triglyceride

AR

triglyceride

AR

triglyceride

ARKO

triglyceride

ARKO

triglyceride

AR

triglyceride

ARKO

triglyceride

AR

triglyceride

AR

triglyceride

AR

androgen receptor

atherosclerosis

androgen receptor

atherogenesis

androgen receptor

atherosclerosis

androgen receptor

atherosclerosis

androgen receptor

atherogenic

androgen receptor

atherosclerosis

androgen receptor

atherosclerosis

androgen receptor

atherosclerosis

androgen receptor

atherosclerosis

androgen receptor

atherogenesis

androgen receptor

atherosclerosis

androgen receptor

atherosclerosis

androgen receptor

atherogenic

androgen receptor

atherosclerosis

androgen receptor

atherosclerosis

androgen receptor

atherosclerosis

AR

atherosclerosis

AR

atherogenesis

AR

atherosclerosis

AR

atherosclerosis

AR

atherogenic

AR

atherosclerosis

AR

atherosclerosis

AR

atherosclerosis

AR

atherosclerosis

AR

atherogenesis

AR

atherosclerosis

AR

atherosclerosis

AR

atherogenic

AR

atherosclerosis

AR

atherosclerosis

AR

atherosclerosis

ARKO

atherosclerosis

ARKO

atherogenesis

ARKO

atherosclerosis

ARKO

atherosclerosis

ARKO

atherogenic

ARKO

atherosclerosis

ARKO

atherosclerosis

ARKO

atherosclerosis

ARKO

atherosclerosis

ARKO

atherogenesis

ARKO

atherosclerosis

ARKO

atherosclerosis

ARKO

atherogenic

ARKO

atherosclerosis

ARKO

atherosclerosis

ARKO

atherosclerosis

AR

atherosclerosis

AR

atherogenesis

AR

atherosclerosis

AR

atherosclerosis

AR

atherogenic

AR

atherosclerosis

AR

atherosclerosis

AR

atherosclerosis

ARKO

atherosclerosis

ARKO

atherogenesis

ARKO

atherosclerosis

ARKO

atherosclerosis

ARKO

atherogenic

ARKO

atherosclerosis

ARKO

atherosclerosis

ARKO

atherosclerosis

AR

atherosclerosis

AR

atherogenesis

AR

atherosclerosis

AR

atherosclerosis

AR

atherogenic

AR

atherosclerosis

AR

atherosclerosis

AR

atherosclerosis

AR

atherosclerosis

AR

atherogenesis

AR

atherosclerosis

AR

atherosclerosis

AR

atherogenic

AR

atherosclerosis

AR

atherosclerosis

AR

atherosclerosis

AR

atherosclerosis

AR

atherogenesis

AR

atherosclerosis

AR

atherosclerosis

AR

atherogenic

AR

atherosclerosis

AR

atherosclerosis

AR

atherosclerosis

androgen receptor

obesity

androgen receptor

obesity

AR

obesity

AR

obesity

ARKO

obesity

ARKO

obesity

AR

obesity

ARKO

obesity

AR

obesity

AR

obesity

AR

obesity

atherosclerosis

lipid

atherosclerosis

lipid

atherosclerosis

lipid

atherosclerosis

lipid

atherogenesis

lipid

atherogenesis

lipid

atherogenesis

lipid

atherogenesis

lipid

atherosclerosis

lipid

atherosclerosis

lipid

atherosclerosis

lipid

atherosclerosis

lipid

atherosclerosis

lipid

atherosclerosis

lipid

atherosclerosis

lipid

atherosclerosis

lipid

atherogenic

lipid

atherogenic

lipid

atherogenic

lipid

atherogenic

lipid

atherosclerosis

lipid

atherosclerosis

lipid

atherosclerosis

lipid

atherosclerosis

lipid

atherosclerosis

lipid

atherosclerosis

lipid

atherosclerosis

lipid

atherosclerosis

lipid

atherosclerosis

lipid

atherosclerosis

lipid

atherosclerosis

lipid

atherosclerosis

lipid

atherosclerosis

cholesterol

atherosclerosis

cholesterol

atherogenesis

cholesterol

atherogenesis

cholesterol

atherosclerosis

cholesterol

atherosclerosis

cholesterol

atherosclerosis

cholesterol

atherosclerosis

cholesterol

atherogenic

cholesterol

atherogenic

cholesterol

atherosclerosis

cholesterol

atherosclerosis

cholesterol

atherosclerosis

cholesterol

atherosclerosis

cholesterol

atherosclerosis

cholesterol

atherosclerosis

cholesterol

dyslipidemia

cholesterol

dyslipidemia

cholesterol

dyslipidemia

cholesterol

dyslipidemia

cholesterol

androgen receptor

dihydrotestosterone

androgen receptor

dihydrotestosterone

AR

dihydrotestosterone

AR

dihydrotestosterone

ARKO

dihydrotestosterone

ARKO

dihydrotestosterone

AR

dihydrotestosterone

ARKO

dihydrotestosterone

AR

dihydrotestosterone

AR

dihydrotestosterone

AR

dihydrotestosterone

androgen receptor

insulin

androgen receptor

insulin

AR

insulin

AR

insulin

ARKO

insulin

ARKO

insulin

AR

insulin

ARKO

insulin

AR

insulin

AR

insulin

AR

insulin

androgen receptor

Androgens

androgen receptor

androgens

androgen receptor

androgens

androgen receptor

Androgens

androgen receptor

androgens

androgen receptor

androgens

AR

Androgens

AR

androgens

AR

androgens

AR

Androgens

AR

androgens

AR

androgens

ARKO

Androgens

ARKO

androgens

ARKO

androgens

ARKO

Androgens

ARKO

androgens

ARKO

androgens

AR

Androgens

AR

androgens

AR

androgens

ARKO

Androgens

ARKO

androgens

ARKO

androgens

AR

Androgens

AR

androgens

AR

androgens

AR

Androgens

AR

androgens

AR

androgens

AR

Androgens

AR

androgens

AR

androgens


Input: Circulating Fatty Acid Synthase in pregnant women : Relationship to blood pressure , maternal metabolism and newborn parameters . The enzyme FASN ( fatty acid synthase ) is potentially related with hypertension and metabolic dysfunction . FASN is highly expressed in the human placenta . We aimed to investigate the relationship circulating FASN has with blood pressure , maternal metabolism and newborn parameters in healthy pregnant women . Circulating FASN was assessed in 115 asymptomatic pregnant women in the second trimester of gestation along with C - peptide , fasting glucose and insulin , post - load glucose lipids , HMW - adiponectin and blood pressure ( the latter was assessed in each trimester of gestation ) . At birth , newborns and placentas were weighed . FASN expression was also able to be assessed in 80 placentas . Higher circulating FASN was associated with lower systolic blood pressure ( SBP ) , with a more favourable metabolic phenotype ( lower fasting glucose and insulin , post load glucose , HbAc1 , HOMA - IR and C - peptide ) , and with lower placental and birth weight ( all p < 0 . 05 to p < 0 . 001 ) . Placental FASN expression related positively to circulating FASN ( p < 0 . 005 ) and negatively to placental weight ( p < 0 . 05 ) . Our observations suggest a physiological role of placental FASN in human pregnancy . Future studies will clarify whether circulating FASN of placental origin does actually regulate placental and fetal growth , and ( thereby ) has a favourable influence on the pregnant mother ' s insulin sensitivity and blood pressure .

Fatty Acid Synthase

FASN

fatty acid synthase

FASN

FASN

FASN

insulin

HMW

adiponectin

FASN

FASN

insulin

FASN

FASN

FASN

FASN

insulin

women

human

women

women

human

hypertension

metabolic dysfunction

C - peptide

glucose

glucose

lipids

glucose

glucose

C - peptide

Fatty Acid Synthase

metabolic dysfunction

FASN

metabolic dysfunction

fatty acid synthase

metabolic dysfunction

FASN

metabolic dysfunction

FASN

metabolic dysfunction

FASN

metabolic dysfunction

FASN

metabolic dysfunction

FASN

metabolic dysfunction

FASN

metabolic dysfunction

FASN

metabolic dysfunction

FASN

metabolic dysfunction

FASN

metabolic dysfunction

Fatty Acid Synthase

hypertension

FASN

hypertension

fatty acid synthase

hypertension

FASN

hypertension

FASN

hypertension

FASN

hypertension

FASN

hypertension

FASN

hypertension

FASN

hypertension

FASN

hypertension

FASN

hypertension

FASN

hypertension

HMW

adiponectin

Fatty Acid Synthase

C - peptide

Fatty Acid Synthase

C - peptide

FASN

C - peptide

FASN

C - peptide

fatty acid synthase

C - peptide

fatty acid synthase

C - peptide

FASN

C - peptide

FASN

C - peptide

FASN

C - peptide

FASN

C - peptide

FASN

C - peptide

FASN

C - peptide

FASN

C - peptide

FASN

C - peptide

FASN

C - peptide

FASN

C - peptide

FASN

C - peptide

FASN

C - peptide

FASN

C - peptide

FASN

C - peptide

FASN

C - peptide

FASN

C - peptide

FASN

C - peptide

FASN

C - peptide

Fatty Acid Synthase

FASN

fatty acid synthase

FASN

FASN

FASN

FASN

FASN

FASN

FASN

FASN

FASN

Fatty Acid Synthase

insulin

Fatty Acid Synthase

insulin

Fatty Acid Synthase

insulin

FASN

insulin

FASN

insulin

FASN

insulin

fatty acid synthase

insulin

fatty acid synthase

insulin

fatty acid synthase

insulin

FASN

insulin

FASN

insulin

FASN

insulin

FASN

insulin

FASN

insulin

FASN

insulin

FASN

insulin

FASN

insulin

FASN

insulin

FASN

insulin

FASN

insulin

FASN

insulin

FASN

insulin

FASN

insulin

FASN

insulin

FASN

insulin

FASN

insulin

FASN

insulin

FASN

insulin

FASN

insulin

FASN

insulin

FASN

insulin

FASN

insulin

FASN

insulin

FASN

insulin

FASN

insulin

FASN

insulin

Fatty Acid Synthase

glucose

Fatty Acid Synthase

glucose

Fatty Acid Synthase

glucose

Fatty Acid Synthase

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

fatty acid synthase

glucose

fatty acid synthase

glucose

fatty acid synthase

glucose

fatty acid synthase

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose

FASN

glucose


Input: Sildenafil attenuates hypoxic pulmonary remodelling by inhibiting bone marrow progenitor cells . The recruitment of bone marrow ( BM ) - derived progenitor cells to the lung is related to pulmonary remodelling and the pathogenesis of pulmonary hypertension ( PH ) . Although sildenafil is a known target in PH treatment , the underlying molecular mechanism is still elusive . To test the hypothesis that the therapeutic effect of sildenafil is linked to the reduced recruitment of BM - derived progenitor cells , we induced pulmonary remodelling in rats by two - week exposure to chronic hypoxia ( CH , 10 % oxygen ) , a trigger of BM - derived progenitor cells . Rats were treated with either placebo ( saline ) or sildenafil ( 1 . 4 mg / kg / day ip ) during CH . Control rats were kept in room air ( 21 % oxygen ) with no treatment . As expected , sildenafil attenuated the CH - induced increase in right ventricular systolic pressure and right ventricular hypertrophy . However , sildenafil suppressed the CH - induced increase in c - kit ( + ) cells in the adventitia of pulmonary arteries . Moreover , sildenafil reduced the number of c - kit ( + ) cells that colocalize with tyrosine kinase receptor 2 ( VEGF - R2 ) and CD68 ( a marker for macrophages ) , indicating a positive effect on moderating hypoxia - induced smooth muscle cell proliferation and inflammation without affecting the pulmonary levels of hypoxia - inducible factor ( HIF ) - 1a . Furthermore , sildenafil depressed the number of CXCR4 ( + ) cells . Collectively , these findings indicate that the improvement in pulmonary haemodynamic by sildenafil is linked to decreased recruitment of BM - derived c - kit ( + ) cells in the pulmonary tissue . The attenuation of the recruitment of BM - derived c - kit ( + ) cells by sildenafil may provide novel therapeutic insights into the control of pulmonary remodelling .

Sildenafil

sildenafil

sildenafil

oxygen

sildenafil

oxygen

sildenafil

sildenafil

sildenafil

sildenafil

sildenafil

sildenafil

hypoxic pulmonary remodelling

pulmonary remodelling

pulmonary hypertension

PH

PH

pulmonary remodelling

hypoxia

CH

CH

CH

right ventricular hypertrophy

CH

hypoxia

inflammation

pulmonary remodelling

rats

Rats

rats

c - kit

c - kit

tyrosine kinase receptor 2

VEGF - R2

hypoxia - inducible factor ( HIF ) - 1a

c - kit

c - kit

Sildenafil

pulmonary hypertension

Sildenafil

PH

Sildenafil

PH

sildenafil

pulmonary hypertension

sildenafil

PH

sildenafil

PH

sildenafil

pulmonary hypertension

sildenafil

PH

sildenafil

PH

sildenafil

pulmonary hypertension

sildenafil

PH

sildenafil

PH

sildenafil

pulmonary hypertension

sildenafil

PH

sildenafil

PH

sildenafil

pulmonary hypertension

sildenafil

PH

sildenafil

PH

sildenafil

pulmonary hypertension

sildenafil

PH

sildenafil

PH

sildenafil

pulmonary hypertension

sildenafil

PH

sildenafil

PH

sildenafil

pulmonary hypertension

sildenafil

PH

sildenafil

PH

sildenafil

pulmonary hypertension

sildenafil

PH

sildenafil

PH

Sildenafil

hypoxic pulmonary remodelling

Sildenafil

pulmonary remodelling

Sildenafil

pulmonary remodelling

Sildenafil

pulmonary remodelling

sildenafil

hypoxic pulmonary remodelling

sildenafil

pulmonary remodelling

sildenafil

pulmonary remodelling

sildenafil

pulmonary remodelling

sildenafil

hypoxic pulmonary remodelling

sildenafil

pulmonary remodelling

sildenafil

pulmonary remodelling

sildenafil

pulmonary remodelling

sildenafil

hypoxic pulmonary remodelling

sildenafil

pulmonary remodelling

sildenafil

pulmonary remodelling

sildenafil

pulmonary remodelling

sildenafil

hypoxic pulmonary remodelling

sildenafil

pulmonary remodelling

sildenafil

pulmonary remodelling

sildenafil

pulmonary remodelling

sildenafil

hypoxic pulmonary remodelling

sildenafil

pulmonary remodelling

sildenafil

pulmonary remodelling

sildenafil

pulmonary remodelling

sildenafil

hypoxic pulmonary remodelling

sildenafil

pulmonary remodelling

sildenafil

pulmonary remodelling

sildenafil

pulmonary remodelling

sildenafil

hypoxic pulmonary remodelling

sildenafil

pulmonary remodelling

sildenafil

pulmonary remodelling

sildenafil

pulmonary remodelling

sildenafil

hypoxic pulmonary remodelling

sildenafil

pulmonary remodelling

sildenafil

pulmonary remodelling

sildenafil

pulmonary remodelling

sildenafil

hypoxic pulmonary remodelling

sildenafil

pulmonary remodelling

sildenafil

pulmonary remodelling

sildenafil

pulmonary remodelling

Sildenafil

sildenafil

sildenafil

sildenafil

sildenafil

sildenafil

sildenafil

sildenafil

sildenafil

sildenafil

Sildenafil

inflammation

sildenafil

inflammation

sildenafil

inflammation

sildenafil

inflammation

sildenafil

inflammation

sildenafil

inflammation

sildenafil

inflammation

sildenafil

inflammation

sildenafil

inflammation

sildenafil

inflammation

Sildenafil

right ventricular hypertrophy

sildenafil

right ventricular hypertrophy

sildenafil

right ventricular hypertrophy

sildenafil

right ventricular hypertrophy

sildenafil

right ventricular hypertrophy

sildenafil

right ventricular hypertrophy

sildenafil

right ventricular hypertrophy

sildenafil

right ventricular hypertrophy

sildenafil

right ventricular hypertrophy

sildenafil

right ventricular hypertrophy

Sildenafil

hypoxia

Sildenafil

CH

Sildenafil

CH

Sildenafil

CH

Sildenafil

CH

Sildenafil

hypoxia

sildenafil

hypoxia

sildenafil

CH

sildenafil

CH

sildenafil

CH

sildenafil

CH

sildenafil

hypoxia

sildenafil

hypoxia

sildenafil

CH

sildenafil

CH

sildenafil

CH

sildenafil

CH

sildenafil

hypoxia

sildenafil

hypoxia

sildenafil

CH

sildenafil

CH

sildenafil

CH

sildenafil

CH

sildenafil

hypoxia

sildenafil

hypoxia

sildenafil

CH

sildenafil

CH

sildenafil

CH

sildenafil

CH

sildenafil

hypoxia

sildenafil

hypoxia

sildenafil

CH

sildenafil

CH

sildenafil

CH

sildenafil

CH

sildenafil

hypoxia

sildenafil

hypoxia

sildenafil

CH

sildenafil

CH

sildenafil

CH

sildenafil

CH

sildenafil

hypoxia

sildenafil

hypoxia

sildenafil

CH

sildenafil

CH

sildenafil

CH

sildenafil

CH

sildenafil

hypoxia

sildenafil

hypoxia

sildenafil

CH

sildenafil

CH

sildenafil

CH

sildenafil

CH

sildenafil

hypoxia

sildenafil

hypoxia

sildenafil

CH

sildenafil

CH

sildenafil

CH

sildenafil

CH

sildenafil

hypoxia

Sildenafil

sildenafil

sildenafil

sildenafil

sildenafil

sildenafil

sildenafil

sildenafil

sildenafil

sildenafil

Sildenafil

tyrosine kinase receptor 2

Sildenafil

VEGF - R2

sildenafil

tyrosine kinase receptor 2

sildenafil

VEGF - R2

sildenafil

tyrosine kinase receptor 2

sildenafil

VEGF - R2

sildenafil

tyrosine kinase receptor 2

sildenafil

VEGF - R2

sildenafil

tyrosine kinase receptor 2

sildenafil

VEGF - R2

sildenafil

tyrosine kinase receptor 2

sildenafil

VEGF - R2

sildenafil

tyrosine kinase receptor 2

sildenafil

VEGF - R2

sildenafil

tyrosine kinase receptor 2

sildenafil

VEGF - R2

sildenafil

tyrosine kinase receptor 2

sildenafil

VEGF - R2

sildenafil

tyrosine kinase receptor 2

sildenafil

VEGF - R2


Input: Genetic variants of the T - cell immunoglobulin mucin 1 but not the T - cell immunoglobulin mucin 3 gene are associated with asthma in an African American population . BACKGROUND : The T - cell immunoglobulin mucin ( TIM ) proteins and their genetic variants have been suggested to play a role in regulating allergic diseases . OBJECTIVE : Genetic association of the sequence variants for TIM - 1 and TIM - 3 genes with asthma in an African American population was investigated . METHODS : Both case - control and family - based association analyses were performed for a total of 7 polymorphisms , including 3 single nucleotide polymorphism ( SNPs ) and 1 insertion / deletion polymorphism in the TIM - 1 and 3 SNPs in the TIM - 3 genes . The exposure to hepatitis A virus as judged by seropositivity was also examined . RESULTS : In the case - control design , the frequencies of the TT genotype for SNP rs2277025 and the homozygous deletion variant ( 157delMTTTVP ) in the fourth exon of the TIM - 1 gene were higher among patients with patients with asthma compared with the controls ( odds ratio [ OR ] , 2 . 779 , P = . 016 ; and OR , 3 . 09 , P = . 022 , respectively ) . This association was substantiated by haplotype analysis of these and 2 additional SNPs ( OR , 2 . 48 ; P = . 004 ) , and also by family - based tests for the allele and haplotype carrying 157delMTTTVP ( P = . 009 and P = . 048 , respectively ) . Furthermore , this association seems to exist even in the hepatitis A virus - seronegative subjects in our data . None of the 3 variants in TIM - 3 genes yielded significant association with either asthma or asthma - related phenotypes . CONCLUSION : Our findings suggest that the genetic variants of the TIM - 1 but not the TIM - 3 gene contribute to asthma susceptibility in this African - American population .

T - cell immunoglobulin mucin 1

T - cell immunoglobulin mucin 3

T - cell immunoglobulin mucin

TIM

TIM - 1

TIM - 3

TIM - 1 and 3

TIM - 3

TIM - 1

TIM - 3

TIM - 1

TIM - 3

asthma

allergic diseases

asthma

asthma

asthma

asthma

asthma

hepatitis A virus

patients

patients

hepatitis A virus

T - cell immunoglobulin mucin 3

allergic diseases

T - cell immunoglobulin mucin

allergic diseases

TIM

allergic diseases

TIM - 3

allergic diseases

TIM - 1 and 3

allergic diseases

TIM - 3

allergic diseases

TIM - 3

allergic diseases

TIM - 3

allergic diseases

T - cell immunoglobulin mucin 1

allergic diseases

TIM - 1

allergic diseases

TIM - 1

allergic diseases

TIM - 1

allergic diseases

T - cell immunoglobulin mucin 1

asthma

T - cell immunoglobulin mucin 1

asthma

T - cell immunoglobulin mucin 1

asthma

T - cell immunoglobulin mucin 1

asthma

T - cell immunoglobulin mucin 1

asthma

T - cell immunoglobulin mucin 1

asthma

T - cell immunoglobulin mucin

asthma

T - cell immunoglobulin mucin

asthma

T - cell immunoglobulin mucin

asthma

T - cell immunoglobulin mucin

asthma

T - cell immunoglobulin mucin

asthma

T - cell immunoglobulin mucin

asthma

TIM

asthma

TIM

asthma

TIM

asthma

TIM

asthma

TIM

asthma

TIM

asthma

TIM - 1

asthma

TIM - 1

asthma

TIM - 1

asthma

TIM - 1

asthma

TIM - 1

asthma

TIM - 1

asthma

TIM - 1 and 3

asthma

TIM - 1 and 3

asthma

TIM - 1 and 3

asthma

TIM - 1 and 3

asthma

TIM - 1 and 3

asthma

TIM - 1 and 3

asthma

TIM - 1

asthma

TIM - 1

asthma

TIM - 1

asthma

TIM - 1

asthma

TIM - 1

asthma

TIM - 1

asthma

TIM - 1

asthma

TIM - 1

asthma

TIM - 1

asthma

TIM - 1

asthma

TIM - 1

asthma

TIM - 1

asthma

asthma

asthma

asthma

asthma

asthma

asthma

asthma

asthma

asthma

asthma

asthma

asthma

asthma

asthma

asthma

asthma

asthma

asthma


Input: Identification of the BRAF V600E mutation in gastroenteropancreatic neuroendocrine tumors . Genomic profiles of gastroenteropancreatic neuroendocrine tumors ( GEP - NETs ) are still insufficiently understood , and the genetic alterations associated with drug responses have not been studied . Here , we performed whole exome sequencing of 12 GEP - NETs from patients enrolled in a nonrandomized , open - labeled , single - center phase II study for pazopanib , and integrated our results with previously published results on pancreas ( n = 12 ) and small intestine NETs ( n = 50 ) . The mean numbers of somatic mutations in each case varied widely from 20 to 4682 . Among 12 GEP - NETs , eight showed mutations of more than one cancer - related gene , including TP53 , CNBD1 , RB1 , APC , BCOR , BRAF , CTNNB1 , EGFR , EP300 , ERBB3 , KDM6A , KRAS , MGA , MLL3 , PTEN , RASA1 , SMARCB1 , SPEN , TBC1D12 , and VHL . TP53 was recurrently mutated in three cases , whereas CNBD1 and RB1 mutations were identified in two cases . Three GEP - NET patients with TP53 mutations demonstrated a durable response and one small intestinal grade ( G ) 1 NET patient with BRAF V600E mutation showed progression after pazopanib treatment . We found BRAF V600E ( G1 NET from rectum and two G3 NETs from colon ) and BRAF G593S ( G2 NET from pancreas ) missense mutations ( 9 . 1 % ) in an independent cohort of 44 GEP - NETs from the rectum ( n = 26 ) , colon ( n = 7 ) , pancreas ( n = 4 ) , small intestine ( n = 3 ) , stomach ( n = 3 ) and appendix ( n = 1 ) by Sanger sequencing . All tumor specimens were obtained before chemotherapy . In conclusion , BRAF V600E mutation is likely to result in resistance to pazopanib but may be a potentianally actionable mutation in metastatic GEP - NETs patients .

BRAF

APC

BCOR

BRAF

EGFR

KRAS

MGA

PTEN

SPEN

VHL

BRAF

BRAF

BRAF

BRAF

gastroenteropancreatic neuroendocrine tumors

gastroenteropancreatic neuroendocrine tumors

GEP - NETs

GEP - NETs

intestine NETs

GEP - NETs

cancer

GEP - NET

intestinal grade ( G ) 1 NET

NET

NETs

NET

GEP - NETs

tumor

GEP - NETs

patients

patients

patient

patients

pazopanib

pazopanib

pazopanib

NET

NETs

NET

intestine NETs

intestine NETs

intestine NETs

intestine NETs

intestinal grade ( G ) 1 NET

intestinal grade ( G ) 1 NET

intestinal grade ( G ) 1 NET

intestinal grade ( G ) 1 NET

intestine NETs

BRAF

intestine NETs

BRAF

intestine NETs

BRAF

intestine NETs

BRAF

intestine NETs

BRAF

intestine NETs

BRAF

intestinal grade ( G ) 1 NET

BRAF

intestinal grade ( G ) 1 NET

BRAF

intestinal grade ( G ) 1 NET

BRAF

intestinal grade ( G ) 1 NET

BRAF

intestinal grade ( G ) 1 NET

BRAF

intestinal grade ( G ) 1 NET

BRAF

VHL

cancer

VHL

tumor

cancer

tumor

SPEN

cancer

SPEN

tumor

cancer

tumor

cancer

tumor

PTEN

cancer

PTEN

tumor

cancer

tumor

MGA

cancer

MGA

tumor

KRAS

cancer

KRAS

tumor

cancer

tumor

cancer

tumor

EGFR

cancer

EGFR

tumor

cancer

tumor

BCOR

cancer

BCOR

tumor

APC

cancer

APC

tumor

cancer

tumor

cancer

tumor

cancer

tumor

cancer

tumor

cancer

tumor

cancer

tumor

cancer

tumor

cancer

tumor

NET

NETs

NET

NET

NETs

NET

NET

NETs

NET

NET

NETs

NET

gastroenteropancreatic neuroendocrine tumors

gastroenteropancreatic neuroendocrine tumors

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NET

GEP - NETs

GEP - NETs

gastroenteropancreatic neuroendocrine tumors

gastroenteropancreatic neuroendocrine tumors

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NET

GEP - NETs

GEP - NETs

gastroenteropancreatic neuroendocrine tumors

gastroenteropancreatic neuroendocrine tumors

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NET

GEP - NETs

GEP - NETs

gastroenteropancreatic neuroendocrine tumors

gastroenteropancreatic neuroendocrine tumors

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NET

GEP - NETs

GEP - NETs

gastroenteropancreatic neuroendocrine tumors

gastroenteropancreatic neuroendocrine tumors

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NET

GEP - NETs

GEP - NETs

gastroenteropancreatic neuroendocrine tumors

VHL

gastroenteropancreatic neuroendocrine tumors

VHL

GEP - NETs

VHL

GEP - NETs

VHL

GEP - NETs

VHL

GEP - NET

VHL

GEP - NETs

VHL

GEP - NETs

VHL

gastroenteropancreatic neuroendocrine tumors

gastroenteropancreatic neuroendocrine tumors

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NET

GEP - NETs

GEP - NETs

gastroenteropancreatic neuroendocrine tumors

SPEN

gastroenteropancreatic neuroendocrine tumors

SPEN

GEP - NETs

SPEN

GEP - NETs

SPEN

GEP - NETs

SPEN

GEP - NET

SPEN

GEP - NETs

SPEN

GEP - NETs

SPEN

gastroenteropancreatic neuroendocrine tumors

gastroenteropancreatic neuroendocrine tumors

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NET

GEP - NETs

GEP - NETs

gastroenteropancreatic neuroendocrine tumors

gastroenteropancreatic neuroendocrine tumors

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NET

GEP - NETs

GEP - NETs

gastroenteropancreatic neuroendocrine tumors

PTEN

gastroenteropancreatic neuroendocrine tumors

PTEN

GEP - NETs

PTEN

GEP - NETs

PTEN

GEP - NETs

PTEN

GEP - NET

PTEN

GEP - NETs

PTEN

GEP - NETs

PTEN

gastroenteropancreatic neuroendocrine tumors

gastroenteropancreatic neuroendocrine tumors

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NET

GEP - NETs

GEP - NETs

gastroenteropancreatic neuroendocrine tumors

MGA

gastroenteropancreatic neuroendocrine tumors

MGA

GEP - NETs

MGA

GEP - NETs

MGA

GEP - NETs

MGA

GEP - NET

MGA

GEP - NETs

MGA

GEP - NETs

MGA

gastroenteropancreatic neuroendocrine tumors

KRAS

gastroenteropancreatic neuroendocrine tumors

KRAS

GEP - NETs

KRAS

GEP - NETs

KRAS

GEP - NETs

KRAS

GEP - NET

KRAS

GEP - NETs

KRAS

GEP - NETs

KRAS

gastroenteropancreatic neuroendocrine tumors

gastroenteropancreatic neuroendocrine tumors

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NET

GEP - NETs

GEP - NETs

gastroenteropancreatic neuroendocrine tumors

gastroenteropancreatic neuroendocrine tumors

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NET

GEP - NETs

GEP - NETs

gastroenteropancreatic neuroendocrine tumors

gastroenteropancreatic neuroendocrine tumors

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NET

GEP - NETs

GEP - NETs

gastroenteropancreatic neuroendocrine tumors

EGFR

gastroenteropancreatic neuroendocrine tumors

EGFR

GEP - NETs

EGFR

GEP - NETs

EGFR

GEP - NETs

EGFR

GEP - NET

EGFR

GEP - NETs

EGFR

GEP - NETs

EGFR

gastroenteropancreatic neuroendocrine tumors

gastroenteropancreatic neuroendocrine tumors

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NET

GEP - NETs

GEP - NETs

gastroenteropancreatic neuroendocrine tumors

BCOR

gastroenteropancreatic neuroendocrine tumors

BCOR

GEP - NETs

BCOR

GEP - NETs

BCOR

GEP - NETs

BCOR

GEP - NET

BCOR

GEP - NETs

BCOR

GEP - NETs

BCOR

gastroenteropancreatic neuroendocrine tumors

APC

gastroenteropancreatic neuroendocrine tumors

APC

GEP - NETs

APC

GEP - NETs

APC

GEP - NETs

APC

GEP - NET

APC

GEP - NETs

APC

GEP - NETs

APC

gastroenteropancreatic neuroendocrine tumors

gastroenteropancreatic neuroendocrine tumors

gastroenteropancreatic neuroendocrine tumors

gastroenteropancreatic neuroendocrine tumors

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NET

GEP - NET

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NETs

gastroenteropancreatic neuroendocrine tumors

gastroenteropancreatic neuroendocrine tumors

gastroenteropancreatic neuroendocrine tumors

gastroenteropancreatic neuroendocrine tumors

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NET

GEP - NET

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NETs

gastroenteropancreatic neuroendocrine tumors

gastroenteropancreatic neuroendocrine tumors

gastroenteropancreatic neuroendocrine tumors

gastroenteropancreatic neuroendocrine tumors

gastroenteropancreatic neuroendocrine tumors

gastroenteropancreatic neuroendocrine tumors

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NET

GEP - NET

GEP - NET

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NETs

GEP - NETs

BRAF

NET

BRAF

NETs

BRAF

NET

BRAF

NET

BRAF

NETs

BRAF

NET

BRAF

NET

BRAF

NETs

BRAF

NET

BRAF

NET

BRAF

NETs

BRAF

NET

BRAF

NET

BRAF

NETs

BRAF

NET

BRAF

NET

BRAF

NETs

BRAF

NET

BRAF

cancer

BRAF

tumor

BRAF

cancer

BRAF

tumor

BRAF

cancer

BRAF

tumor

BRAF

cancer

BRAF

tumor

BRAF

cancer

BRAF

tumor

BRAF

cancer

BRAF

tumor

BRAF

gastroenteropancreatic neuroendocrine tumors

BRAF

gastroenteropancreatic neuroendocrine tumors

BRAF

GEP - NETs

BRAF

GEP - NETs

BRAF

GEP - NETs

BRAF

GEP - NET

BRAF

GEP - NETs

BRAF

GEP - NETs

BRAF

gastroenteropancreatic neuroendocrine tumors

BRAF

gastroenteropancreatic neuroendocrine tumors

BRAF

GEP - NETs

BRAF

GEP - NETs

BRAF

GEP - NETs

BRAF

GEP - NET

BRAF

GEP - NETs

BRAF

GEP - NETs

BRAF

gastroenteropancreatic neuroendocrine tumors

BRAF

gastroenteropancreatic neuroendocrine tumors

BRAF

GEP - NETs

BRAF

GEP - NETs

BRAF

GEP - NETs

BRAF

GEP - NET

BRAF

GEP - NETs

BRAF

GEP - NETs

BRAF

gastroenteropancreatic neuroendocrine tumors

BRAF

gastroenteropancreatic neuroendocrine tumors

BRAF

GEP - NETs

BRAF

GEP - NETs

BRAF

GEP - NETs

BRAF

GEP - NET

BRAF

GEP - NETs

BRAF

GEP - NETs

BRAF

gastroenteropancreatic neuroendocrine tumors

BRAF

gastroenteropancreatic neuroendocrine tumors

BRAF

GEP - NETs

BRAF

GEP - NETs

BRAF

GEP - NETs

BRAF

GEP - NET

BRAF

GEP - NETs

BRAF

GEP - NETs

BRAF

gastroenteropancreatic neuroendocrine tumors

BRAF

gastroenteropancreatic neuroendocrine tumors

BRAF

GEP - NETs

BRAF

GEP - NETs

BRAF

GEP - NETs

BRAF

GEP - NET

BRAF

GEP - NETs

BRAF

GEP - NETs

intestine NETs

pazopanib

intestine NETs

pazopanib

intestine NETs

pazopanib

intestinal grade ( G ) 1 NET

pazopanib

intestinal grade ( G ) 1 NET

pazopanib

intestinal grade ( G ) 1 NET

pazopanib

pazopanib

pazopanib

pazopanib

pazopanib

pazopanib

pazopanib

pazopanib

pazopanib

pazopanib

pazopanib

pazopanib

pazopanib

gastroenteropancreatic neuroendocrine tumors

pazopanib

gastroenteropancreatic neuroendocrine tumors

pazopanib

gastroenteropancreatic neuroendocrine tumors

pazopanib

gastroenteropancreatic neuroendocrine tumors

pazopanib

gastroenteropancreatic neuroendocrine tumors

pazopanib

gastroenteropancreatic neuroendocrine tumors

pazopanib

GEP - NETs

pazopanib

GEP - NETs

pazopanib

GEP - NETs

pazopanib

GEP - NETs

pazopanib

GEP - NETs

pazopanib

GEP - NETs

pazopanib

GEP - NETs

pazopanib

GEP - NETs

pazopanib

GEP - NETs

pazopanib

GEP - NET

pazopanib

GEP - NET

pazopanib

GEP - NET

pazopanib

GEP - NETs

pazopanib

GEP - NETs

pazopanib

GEP - NETs

pazopanib

GEP - NETs

pazopanib

GEP - NETs

pazopanib

GEP - NETs

pazopanib

BRAF

pazopanib

BRAF

pazopanib

BRAF

pazopanib

BRAF

pazopanib

BRAF

pazopanib

BRAF

pazopanib

BRAF

pazopanib

BRAF

pazopanib

BRAF

pazopanib

BRAF

pazopanib

BRAF

pazopanib

BRAF

pazopanib

BRAF

pazopanib

BRAF

pazopanib

BRAF

pazopanib

BRAF

pazopanib

BRAF

pazopanib

BRAF

pazopanib


Input: MicroRNA deep sequencing in two adult stem cell populations identifies miR - 501 as a novel regulator of myosin heavy chain during muscle regeneration . MicroRNAs ( miRNAs ) are important regulators of skeletal muscle regeneration , but the underlying mechanisms are still incompletely understood . Here , comparative miRNA sequencing analysis of myogenic progenitor cells ( MPs ) and non - myogenic fibroblast - adipocyte progenitors ( FAPs ) during cardiotoxin ( CTX ) - induced muscle injury uncovered miR - 501 as a novel muscle - specific miRNA . miR - 501 is an intronic miRNA and its expression levels in MPs correlated with its host gene , chloride channel , voltage - sensitive 5 ( Clcn5 ) . Pharmacological inhibition of miR - 501 dramatically blunted the induction of embryonic myosin heavy chain ( MYH3 ) and , to a lesser extent , adult myosin isoforms during muscle regeneration , and promoted small - diameter neofibers . An unbiased target identification approach in primary myoblasts validated gigaxonin as a target of miR - 501 that mimicked the effect of miR - 501 inhibition on MYH3 expression . In the mdx mouse model , which models a pathological disease state , not only was miR - 501 induced in regenerating skeletal muscle , but also its serum levels were increased , which correlated with the disease state of the animals . Our results suggest that miR - 501 plays a key role in adult muscle regeneration and might serve as a novel serum biomarker for the activation of adult muscle stem cells .

miR - 501

myosin heavy chain

miR - 501

miR - 501

chloride channel , voltage - sensitive 5

miR - 501

myosin heavy chain

adult myosin isoforms

gigaxonin

miR - 501

miR - 501

miR - 501

miR - 501

cardiotoxin

CTX

muscle injury

mouse

cardiotoxin

muscle injury

CTX

muscle injury

miR - 501

chloride channel , voltage - sensitive 5

miR - 501

miR - 501

chloride channel , voltage - sensitive 5

miR - 501

miR - 501

chloride channel , voltage - sensitive 5

miR - 501

miR - 501

chloride channel , voltage - sensitive 5

miR - 501

miR - 501

chloride channel , voltage - sensitive 5

miR - 501

miR - 501

chloride channel , voltage - sensitive 5

miR - 501

miR - 501

chloride channel , voltage - sensitive 5

miR - 501

miR - 501

chloride channel , voltage - sensitive 5

miR - 501

miR - 501

muscle injury

miR - 501

muscle injury

miR - 501

muscle injury

miR - 501

muscle injury

miR - 501

muscle injury

miR - 501

muscle injury

miR - 501

muscle injury

miR - 501

muscle injury

miR - 501

myosin heavy chain

miR - 501

myosin heavy chain

miR - 501

miR - 501

miR - 501

myosin heavy chain

miR - 501

myosin heavy chain

miR - 501

miR - 501

miR - 501

myosin heavy chain

miR - 501

myosin heavy chain

miR - 501

miR - 501

miR - 501

myosin heavy chain

miR - 501

myosin heavy chain

miR - 501

miR - 501

miR - 501

myosin heavy chain

miR - 501

myosin heavy chain

miR - 501

miR - 501

miR - 501

myosin heavy chain

miR - 501

myosin heavy chain

miR - 501

miR - 501

miR - 501

myosin heavy chain

miR - 501

myosin heavy chain

miR - 501

miR - 501

miR - 501

myosin heavy chain

miR - 501

myosin heavy chain

miR - 501

miR - 501

gigaxonin

miR - 501

gigaxonin

miR - 501

gigaxonin

miR - 501

gigaxonin

miR - 501

gigaxonin

miR - 501

gigaxonin

miR - 501

gigaxonin

miR - 501

gigaxonin

miR - 501


Input: Strong association of 677 C > T substitution in the MTHFR gene with male infertility - - a study on an indian population and a meta - analysis . BACKGROUND : Methylenetetrahydrofolate reductase ( MTHFR ) is an important enzyme of folate and methionine metabolism , making it crucial for DNA synthesis and methylation . The objective of this study was to analyze MTHFR gene 677C > T polymorphism in infertile male individuals from North India , followed by a meta - analysis on our data and published studies . METHODOLOGY / PRINCIPAL FINDINGS : We undertook genotyping on a total of 837 individuals including well characterized infertile ( N = 522 ) and confirmed fertile ( N = 315 ) individuals . The SNP was typed by direct DNA sequencing . Chi square test was done for statistical analysis . Published studies were searched using appropriate keywords . Source of data collection for meta - analysis included ' Pubmed ' , ' Ovid ' and ' Google Scholar ' . Those studies analyzing 677C > T polymorphism in male infertility and presenting all relevant data were included in meta - analysis . The genotype data for infertile subjects and fertile controls was extracted from each study . Chi square test was done to obtain odds ratio ( OR ) and p - value . Meta - analysis was performed using Comprehensive Meta - analysis software ( Version 2 ) . The frequency of mutant ( T ) allele ( p = 0 . 0025 ) and genotypes ( CT + TT ) ( p = 0 . 0187 ) was significantly higher in infertile individuals in comparison to fertile controls in our case - control study . The overall summary estimate ( OR ) for allele and genotype meta - analysis were 1 . 304 ( p = 0 . 000 ) , 1 . 310 ( p = 0 . 000 ) , respectively , establishing significant association of 677C > T polymorphism with male infertility . CONCLUSIONS / SIGNIFICANCE : 677C > T substitution associated strongly with male infertility in Indian population . Allele and genotype meta - analysis also supported its strong correlation with male infertility , thus establishing it as a risk factor .

677 C > T

677C > T

677C > T

677C > T

677C > T

MTHFR

Methylenetetrahydrofolate reductase

MTHFR

MTHFR

male infertility

male infertility

male infertility

male infertility

male infertility

folate

methionine

677 C > T

male infertility

677 C > T

male infertility

677 C > T

male infertility

677 C > T

male infertility

677 C > T

male infertility

677C > T

male infertility

677C > T

male infertility

677C > T

male infertility

677C > T

male infertility

677C > T

male infertility

677C > T

male infertility

677C > T

male infertility

677C > T

male infertility

677C > T

male infertility

677C > T

male infertility

677C > T

male infertility

677C > T

male infertility

677C > T

male infertility

677C > T

male infertility

677C > T

male infertility

677C > T

male infertility

677C > T

male infertility

677C > T

male infertility

677C > T

male infertility

677C > T

male infertility

MTHFR

methionine

Methylenetetrahydrofolate reductase

methionine

MTHFR

methionine

MTHFR

methionine

MTHFR

folate

Methylenetetrahydrofolate reductase

folate

MTHFR

folate

MTHFR

folate

MTHFR

male infertility

MTHFR

male infertility

MTHFR

male infertility

MTHFR

male infertility

MTHFR

male infertility

Methylenetetrahydrofolate reductase

male infertility

Methylenetetrahydrofolate reductase

male infertility

Methylenetetrahydrofolate reductase

male infertility

Methylenetetrahydrofolate reductase

male infertility

Methylenetetrahydrofolate reductase

male infertility

MTHFR

male infertility

MTHFR

male infertility

MTHFR

male infertility

MTHFR

male infertility

MTHFR

male infertility

MTHFR

male infertility

MTHFR

male infertility

MTHFR

male infertility

MTHFR

male infertility

MTHFR

male infertility


Input: Screening for exonic copy number mutations at MSH2 and MLH1 by MAPH . BACKGROUND : Exonic deletions in MSH2 and MLH1 are significant contributors to the mutation spectrum in HNPCC , and heterozygous changes in exon copy number are not detected by conventional mutation screening methods . AIMS : We aimed to develop methods for screening copy number changes in all the exons of the MLH1 and MSH2 genes using a single multiplex amplifiable probe hybridisation ( MAPH ) assay . METHODS : We developed a probe set consisting of probes from the 19 exons of MLH1 and 16 exons of MSH2 , and 3 control probes , and applied it to screening for deletions and duplications using fluorescent detection of amplified fragments . RESULTS : We tested 73 DNA samples from controls and 50 from HNPCC patients in whom no point mutations had been found , and detected 10 copy number changes among the patient samples . A deletion of about 1 . 4 kb including exon 3 of MSH2 was confirmed by amplification of a junction fragment , and was shown to be the result of an unequal recombination between intronic Alu elements . CONCLUSIONS : MAPH can detect exonic copy number changes in MLH1 and MSH2 in DNA from HNPCC patients . Since finding an exonic deletion or duplication makes full sequence analysis unnecessary , it may be most cost - effective to pre - screen samples by MAPH or MLPA before screening for point mutations .

HNPCC

HNPCC

HNPCC

patients

patient

patients

HNPCC

HNPCC

HNPCC

HNPCC

HNPCC

HNPCC

HNPCC

HNPCC

HNPCC

HNPCC

HNPCC

HNPCC

HNPCC

HNPCC

HNPCC

HNPCC

HNPCC

HNPCC

HNPCC

HNPCC

HNPCC

HNPCC

HNPCC

HNPCC

HNPCC

HNPCC

HNPCC

HNPCC

HNPCC

HNPCC

HNPCC

HNPCC

HNPCC


Input: Analysis of - 1082 IL - 10 gene polymorphism in Iranian patients with generalized aggressive periodontitis . BACKGROUND : Periodontitis is a multifactorial disease and its severe forms , such as aggressive periodontitis , are suggested to have a genetic basis . Among the genetic factors , polymorphisms in cytokine genes have recently been described in susceptibility to periodontitis . IL - 10 is a multi - functional cytokine thought to play a role in the pathogenesis of periodontitis . A substitution G / A polymorphism in the promoter region of the IL - 10 gene at position - 1082 has been associated with different amounts of IL - 10 production . The aim of the present study was to investigate the possible links between - 1082 ( G / A ) polymorphism of the IL - 10 gene and the generalized form of aggressive periodontitis . MATERIAL / METHODS : This study included 52 Iranian Khorasanian ( north - east province of Iran ) subjects suffering from generalized aggressive periodontitis referred to the Periodontology Department of Mashhad Dental School . They were compared to 61 age and sex - matched healthy controls of the same race . DNA was isolated from peripheral blood cells and genotyping was performed by means of the amplification refractory mutation system polymerase chain reaction ( ARMS - PCR ) method . Data were analyzed using the chi - squared test . RESULTS : There was no marked difference in genotype frequencies between the controls and generalized aggressive periodontitis patients ( p = 0 . 585 ) . Moreover , no association between patients and normal subjects was found in their allele frequency ( p = 0 . 329 ) . CONCLUSIONS : We conclude that the polymorphic nucleotide A at position - 1082 of the IL - 10 gene is not associated with generalized aggressive periodontitis in the Iranian population .

IL - 10

IL - 10

IL - 10

IL - 10

IL - 10

IL - 10

patients

patients

patients

aggressive periodontitis

Periodontitis

aggressive periodontitis

periodontitis

periodontitis

aggressive periodontitis

aggressive periodontitis

aggressive periodontitis

aggressive periodontitis

G / A

- 1082 ( G / A )

A at position - 1082

IL - 10

Periodontitis

IL - 10

periodontitis

IL - 10

periodontitis

IL - 10

Periodontitis

IL - 10

periodontitis

IL - 10

periodontitis

IL - 10

Periodontitis

IL - 10

periodontitis

IL - 10

periodontitis

IL - 10

Periodontitis

IL - 10

periodontitis

IL - 10

periodontitis

IL - 10

Periodontitis

IL - 10

periodontitis

IL - 10

periodontitis

IL - 10

Periodontitis

IL - 10

periodontitis

IL - 10

periodontitis


Input: U87MG decoded : the genomic sequence of a cytogenetically aberrant human cancer cell line . U87MG is a commonly studied grade IV glioma cell line that has been analyzed in at least 1 , 700 publications over four decades . In order to comprehensively characterize the genome of this cell line and to serve as a model of broad cancer genome sequencing , we have generated greater than 30x genomic sequence coverage using a novel 50 - base mate paired strategy with a 1 . 4kb mean insert library . A total of 1 , 014 , 984 , 286 mate - end and 120 , 691 , 623 single - end two - base encoded reads were generated from five slides . All data were aligned using a custom designed tool called BFAST , allowing optimal color space read alignment and accurate identification of DNA variants . The aligned sequence reads and mate - pair information identified 35 interchromosomal translocation events , 1 , 315 structural variations ( > 100 bp ) , 191 , 743 small ( < 21 bp ) insertions and deletions ( indels ) , and 2 , 384 , 470 single nucleotide variations ( SNVs ) . Among these observations , the known homozygous mutation in PTEN was robustly identified , and genes involved in cell adhesion were overrepresented in the mutated gene list . Data were compared to 219 , 187 heterozygous single nucleotide polymorphisms assayed by Illumina 1M Duo genotyping array to assess accuracy : 93 . 83 % of all SNPs were reliably detected at filtering thresholds that yield greater than 99 . 99 % sequence accuracy . Protein coding sequences were disrupted predominantly in this cancer cell line due to small indels , large deletions , and translocations . In total , 512 genes were homozygously mutated , including 154 by SNVs , 178 by small indels , 145 by large microdeletions , and 35 by interchromosomal translocations to reveal a highly mutated cell line genome . Of the small homozygously mutated variants , 8 SNVs and 99 indels were novel events not present in dbSNP . These data demonstrate that routine generation of broad cancer genome sequence is possible outside of genome centers . The sequence analysis of U87MG provides an unparalleled level of mutational resolution compared to any cell line to date .

human

cancer

grade IV glioma

cancer

cancer

cancer

PTEN

PTEN

cancer

PTEN

cancer

PTEN

cancer

PTEN

cancer


Input: Repeated otilonium bromide administration prevents neurotransmitter changes in colon of rats underwent to wrap restraint stress . Otilonium bromide ( OB ) is a spasmolytic drug successfully used for the treatment of irritable bowel syndrome ( IBS ) . Its efficacy has been attributed to the block of L - and T - type Ca ( 2 + ) channels and muscarinic and tachykinin receptors in the smooth muscle . Furthermore , in healthy rats , repeated OB administration modified neurotransmitter expression and function suggesting other mechanisms of action . On this basis , we investigated whether repeated OB treatment prevented the functional and neurochemical changes observed in the colon of rats underwent to wrap restrain stress ( WRS ) a psychosocial stressor considered suitable to reproduce the main IBS signs and symptoms . In control , WRS and OB / WRS rats functional parameters were measured in vivo and morphological investigations were done ex vivo in the colon . The results showed that OB counteracts most of the neurotransmitters changes caused by WRS . In particular , the drug prevents the decrease in SP - , NK1r - , nNOS - , VIP - , and S100b - immunoreactivity ( IR ) and the increase in CGRP - , and CRF1r - IR . On the contrary , OB does not affect the increase in CRF2r - IR neurons observed in WRS rats and does not interfere with the mild mucosal inflammation due to WRS . Finally , OB per se increases the Mr2 expression in the muscle wall and decreases the number of the myenteric ChAT - IR neurons . Functional findings show a significantly reduction in the number of spontaneous abdominal contraction in OB treated rats . The ability of OB to block L - type Ca ( 2 + ) channels , also expressed by enteric neurons , might represent a possible mechanism through which OB exerts its actions .

otilonium bromide

neurotransmitter

Otilonium bromide

OB

OB

neurotransmitter

OB

OB

OB

neurotransmitters

OB

OB

OB

OB

OB

rats

rats

rats

rats

rats

rats

irritable bowel syndrome

IBS

IBS

mucosal inflammation

L - and T - type Ca ( 2 + ) channels

muscarinic and tachykinin receptors

SP

nNOS

VIP

CGRP

ChAT

L - type Ca ( 2 + ) channels

L - and T - type Ca ( 2 + ) channels

irritable bowel syndrome

L - and T - type Ca ( 2 + ) channels

IBS

L - and T - type Ca ( 2 + ) channels

IBS

L - type Ca ( 2 + ) channels

irritable bowel syndrome

L - type Ca ( 2 + ) channels

IBS

L - type Ca ( 2 + ) channels

IBS

muscarinic and tachykinin receptors

irritable bowel syndrome

muscarinic and tachykinin receptors

IBS

muscarinic and tachykinin receptors

IBS

otilonium bromide

neurotransmitter

otilonium bromide

neurotransmitter

otilonium bromide

neurotransmitters

Otilonium bromide

neurotransmitter

Otilonium bromide

neurotransmitter

Otilonium bromide

neurotransmitters

OB

neurotransmitter

OB

neurotransmitter

OB

neurotransmitters

OB

neurotransmitter

OB

neurotransmitter

OB

neurotransmitters

OB

neurotransmitter

OB

neurotransmitter

OB

neurotransmitters

OB

neurotransmitter

OB

neurotransmitter

OB

neurotransmitters

OB

neurotransmitter

OB

neurotransmitter

OB

neurotransmitters

OB

neurotransmitter

OB

neurotransmitter

OB

neurotransmitters

OB

neurotransmitter

OB

neurotransmitter

OB

neurotransmitters

OB

neurotransmitter

OB

neurotransmitter

OB

neurotransmitters

OB

neurotransmitter

OB

neurotransmitter

OB

neurotransmitters

OB

neurotransmitter

OB

neurotransmitter

OB

neurotransmitters

L - and T - type Ca ( 2 + ) channels

otilonium bromide

L - and T - type Ca ( 2 + ) channels

Otilonium bromide

L - and T - type Ca ( 2 + ) channels

OB

L - and T - type Ca ( 2 + ) channels

OB

L - and T - type Ca ( 2 + ) channels

OB

L - and T - type Ca ( 2 + ) channels

OB

L - and T - type Ca ( 2 + ) channels

OB

L - and T - type Ca ( 2 + ) channels

OB

L - and T - type Ca ( 2 + ) channels

OB

L - and T - type Ca ( 2 + ) channels

OB

L - and T - type Ca ( 2 + ) channels

OB

L - and T - type Ca ( 2 + ) channels

OB

L - type Ca ( 2 + ) channels

otilonium bromide

L - type Ca ( 2 + ) channels

Otilonium bromide

L - type Ca ( 2 + ) channels

OB

L - type Ca ( 2 + ) channels

OB

L - type Ca ( 2 + ) channels

OB

L - type Ca ( 2 + ) channels

OB

L - type Ca ( 2 + ) channels

OB

L - type Ca ( 2 + ) channels

OB

L - type Ca ( 2 + ) channels

OB

L - type Ca ( 2 + ) channels

OB

L - type Ca ( 2 + ) channels

OB

L - type Ca ( 2 + ) channels

OB

muscarinic and tachykinin receptors

otilonium bromide

muscarinic and tachykinin receptors

Otilonium bromide

muscarinic and tachykinin receptors

OB

muscarinic and tachykinin receptors

OB

muscarinic and tachykinin receptors

OB

muscarinic and tachykinin receptors

OB

muscarinic and tachykinin receptors

OB

muscarinic and tachykinin receptors

OB

muscarinic and tachykinin receptors

OB

muscarinic and tachykinin receptors

OB

muscarinic and tachykinin receptors

OB

muscarinic and tachykinin receptors

OB

otilonium bromide

Otilonium bromide

OB

OB

OB

OB

OB

OB

OB

OB

OB

OB

CGRP

otilonium bromide

CGRP

Otilonium bromide

CGRP

OB

CGRP

OB

CGRP

OB

CGRP

OB

CGRP

OB

CGRP

OB

CGRP

OB

CGRP

OB

CGRP

OB

CGRP

OB

otilonium bromide

irritable bowel syndrome

otilonium bromide

IBS

otilonium bromide

IBS

Otilonium bromide

irritable bowel syndrome

Otilonium bromide

IBS

Otilonium bromide

IBS

OB

irritable bowel syndrome

OB

IBS

OB

IBS

OB

irritable bowel syndrome

OB

IBS

OB

IBS

OB

irritable bowel syndrome

OB

IBS

OB

IBS

OB

irritable bowel syndrome

OB

IBS

OB

IBS

OB

irritable bowel syndrome

OB

IBS

OB

IBS

OB

irritable bowel syndrome

OB

IBS

OB

IBS

OB

irritable bowel syndrome

OB

IBS

OB

IBS

OB

irritable bowel syndrome

OB

IBS

OB

IBS

OB

irritable bowel syndrome

OB

IBS

OB

IBS

OB

irritable bowel syndrome

OB

IBS

OB

IBS

otilonium bromide

ChAT

Otilonium bromide

ChAT

OB

ChAT

OB

ChAT

OB

ChAT

OB

ChAT

OB

ChAT

OB

ChAT

OB

ChAT

OB

ChAT

OB

ChAT

OB

ChAT

otilonium bromide

Otilonium bromide

OB

OB

OB

OB

OB

OB

OB

OB

OB

OB

VIP

otilonium bromide

VIP

Otilonium bromide

VIP

OB

VIP

OB

VIP

OB

VIP

OB

VIP

OB

VIP

OB

VIP

OB

VIP

OB

VIP

OB

VIP

OB

nNOS

otilonium bromide

nNOS

Otilonium bromide

nNOS

OB

nNOS

OB

nNOS

OB

nNOS

OB

nNOS

OB

nNOS

OB

nNOS

OB

nNOS

OB

nNOS

OB

nNOS

OB

otilonium bromide

Otilonium bromide

OB

OB

OB

OB

OB

OB

OB

OB

OB

OB

otilonium bromide

Otilonium bromide

OB

OB

OB

OB

OB

OB

OB

OB

OB

OB

SP

otilonium bromide

SP

Otilonium bromide

SP

OB

SP

OB

SP

OB

SP

OB

SP

OB

SP

OB

SP

OB

SP

OB

SP

OB

SP

OB


Input: Clusters of multidrug - resistant Mycobacterium tuberculosis cases , Europe . Molecular surveillance of multidrug - resistant tuberculosis ( MDR TB ) was implemented in Europe as case reporting in 2005 . For all new MDR TB cases detected from January 2003 through June 2007 , countries reported case - based epidemiologic data and DNA fingerprint patterns of MDR TB strains when available . International clusters were detected and analyzed . From 2003 through mid - 2007 in Europe , 2 , 494 cases of MDR TB were reported from 24 European countries . Epidemiologic and molecular data were linked for 593 ( 39 % ) cases , and 672 insertion sequence 6110 DNA fingerprint patterns were reported from 19 countries . Of these patterns , 288 ( 43 % ) belonged to 18 European clusters ; 7 clusters ( 242 / 288 cases , 84 % ) were characterized by strains of the Beijing genotype family , including the largest cluster ( 175 / 288 cases , 61 % ) . Both clustering and the Beijing genotype were associated with strains originating in eastern European countries . Molecular cluster detection contributes to identification of transmission profile , risk factors , and control measures .

Mycobacterium tuberculosis

multidrug - resistant tuberculosis

MDR TB

MDR TB

MDR TB

MDR TB


Input: An inducible mouse model of podocin - mutation - related nephrotic syndrome . Mutations in the NPHS2 gene , encoding podocin , cause hereditary nephrotic syndrome . The most common podocin mutation , R138Q , is associated with early disease onset and rapid progression to end - stage renal disease . Knock - in mice carrying a R140Q mutation , the mouse analogue of human R138Q , show developmental arrest of podocytes and lethal renal failure at neonatal age . Here we created a conditional podocin knock - in model named NPHS2 R140Q / - , using a tamoxifen - inducible Cre recombinase , which permits to study the effects of the mutation in postnatal life . Within the first week of R140Q hemizygosity induction the animals developed proteinuria , which peaked after 4 - 5 weeks . Subsequently the animals developed progressive renal failure , with a median survival time of 12 ( 95 % CI : 11 - 13 ) weeks . Foot process fusion was observed within one week , progressing to severe and global effacement in the course of the disease . The number of podocytes per glomerulus gradually diminished to 18 % compared to healthy controls 12 - 16 weeks after induction . The fraction of segmentally sclerosed glomeruli was 25 % , 85 % and 97 % at 2 , 4 and 8 weeks , respectively . Severe tubulointerstitial fibrosis was present at later disease stage and was correlated quantitatively with the level of proteinuria at early disease stages . While R140Q podocin mRNA expression was elevated , protein abundance was reduced by more than 50 % within one week following induction . Whereas miRNA21 expression persistently increased during the first 4 weeks , miRNA - 193a expression peaked 2 weeks after induction . In conclusion , the inducible R140Q - podocin mouse model is an auspicious model of the most common genetic cause of human nephrotic syndrome , with a spontaneous disease course strongly reminiscent of the human disorder . This model constitutes a valuable tool to test the efficacy of novel pharmacological interventions aimed to improve podocyte function and viability and attenuate proteinuria , glomerulosclerosis and progressive renal failure .

mouse

mice

mouse

human

mouse

human

human

podocin

podocin

podocin

podocin

podocin

miRNA - 193a

podocin

nephrotic syndrome

nephrotic syndrome

renal disease

renal failure

proteinuria

renal failure

tubulointerstitial fibrosis

proteinuria

nephrotic syndrome

proteinuria

glomerulosclerosis

renal failure

tamoxifen

renal disease

tubulointerstitial fibrosis

podocin

renal disease

podocin

tubulointerstitial fibrosis

podocin

renal disease

podocin

tubulointerstitial fibrosis

nephrotic syndrome

nephrotic syndrome

nephrotic syndrome

podocin

nephrotic syndrome

podocin

nephrotic syndrome

podocin

nephrotic syndrome

podocin

nephrotic syndrome

podocin

nephrotic syndrome

podocin

nephrotic syndrome

proteinuria

proteinuria

proteinuria

podocin

proteinuria

podocin

proteinuria

podocin

proteinuria

podocin

proteinuria

podocin

proteinuria

podocin

proteinuria

renal failure

renal failure

renal failure

podocin

renal failure

podocin

renal failure

podocin

renal failure

podocin

renal failure

podocin

renal failure

podocin

renal failure

podocin

nephrotic syndrome

podocin

nephrotic syndrome

podocin

nephrotic syndrome

podocin

nephrotic syndrome

podocin

nephrotic syndrome

podocin

nephrotic syndrome

nephrotic syndrome

nephrotic syndrome

nephrotic syndrome

podocin

nephrotic syndrome

podocin

nephrotic syndrome

podocin

nephrotic syndrome

podocin

nephrotic syndrome

podocin

nephrotic syndrome

podocin

nephrotic syndrome

podocin

proteinuria

podocin

proteinuria

podocin

proteinuria

podocin

proteinuria

podocin

proteinuria

podocin

proteinuria

proteinuria

proteinuria

proteinuria

podocin

proteinuria

podocin

proteinuria

podocin

proteinuria

podocin

proteinuria

podocin

proteinuria

podocin

proteinuria

podocin

renal failure

podocin

renal failure

podocin

renal failure

podocin

renal failure

podocin

renal failure

podocin

renal failure

renal failure

renal failure

renal failure

podocin

renal failure

podocin

renal failure

podocin

renal failure

podocin

renal failure

podocin

renal failure

podocin

renal failure

renal disease

tubulointerstitial fibrosis

renal disease

tubulointerstitial fibrosis

renal failure

renal failure

renal failure

renal failure

renal failure

renal failure

nephrotic syndrome

nephrotic syndrome

nephrotic syndrome

nephrotic syndrome

nephrotic syndrome

nephrotic syndrome

nephrotic syndrome

nephrotic syndrome

nephrotic syndrome

nephrotic syndrome

nephrotic syndrome

nephrotic syndrome

nephrotic syndrome

nephrotic syndrome

nephrotic syndrome

proteinuria

proteinuria

proteinuria

proteinuria

proteinuria

proteinuria

proteinuria

proteinuria

proteinuria

proteinuria

proteinuria

proteinuria

proteinuria

proteinuria

proteinuria

renal failure

renal failure

renal failure

renal failure

renal failure

renal failure

renal failure

renal failure

renal failure

renal failure

renal failure

renal failure

renal failure

renal failure

renal failure


Input: Over - expression of BMP4 and BMP5 in a child with axial skeletal malformations and heterotopic ossification : a new syndrome . Bone morphogenetic proteins ( BMPs ) are a highly conserved class of signaling molecules that induce ectopic cartilage and bone formation in vivo . Dysregulated expression of bone morphogenetic protein 4 ( BMP4 ) is found in the cells of patients who have fibrodysplasia ossificans progressiva ( FOP ) , a genetic disorder of axial and appendicular skeletal malformation and progressive heterotopic ossification . Loss of function mutations in the bone morphogenetic protein 5 ( bmp5 ) gene leading to under - expression of BMP5 cause the murine short ear syndrome , characterized by small malformed ears and a broad range of axial skeletal malformations . We found features reminiscent of both the short ear mouse and FOP in a child with malformed external ears , multiple malformations of the axial skeleton , and progressive heterotopic ossification in the neck and back . We examined BMP mRNA expression in transformed lymphocytes by semi - quantitative RT - PCR and protein expression by ELISA assays and immunohistochemistry . Elevated levels of BMP4 and BMP5 mRNA and protein were detected in the patient ' s cells while levels of BMP2 mRNA were unchanged . Our data suggest that dysregulated expression of BMP4 and BMP5 genes is associated with an array of human axial skeletal abnormalities similar to the short ear mouse and FOP .

Bone morphogenetic proteins

BMPs

bone morphogenetic protein 4

bone morphogenetic protein 5

BMP

axial skeletal malformations

heterotopic ossification

ectopic cartilage and bone formation

fibrodysplasia ossificans progressiva

FOP

axial and appendicular skeletal malformation

heterotopic ossification

short ear syndrome

axial skeletal malformations

FOP

malformed external ears

multiple malformations of the axial skeleton

heterotopic ossification

axial skeletal abnormalities

FOP

patients

murine

mouse

patient

human

mouse

ectopic cartilage and bone formation

Bone morphogenetic proteins

ectopic cartilage and bone formation

BMPs

ectopic cartilage and bone formation

BMP

ectopic cartilage and bone formation

ectopic cartilage and bone formation

ectopic cartilage and bone formation

bone morphogenetic protein 5

ectopic cartilage and bone formation

ectopic cartilage and bone formation

ectopic cartilage and bone formation

ectopic cartilage and bone formation

ectopic cartilage and bone formation

ectopic cartilage and bone formation

bone morphogenetic protein 4

ectopic cartilage and bone formation

ectopic cartilage and bone formation

ectopic cartilage and bone formation

fibrodysplasia ossificans progressiva

FOP

FOP

FOP

Bone morphogenetic proteins

fibrodysplasia ossificans progressiva

Bone morphogenetic proteins

FOP

Bone morphogenetic proteins

FOP

Bone morphogenetic proteins

FOP

BMPs

fibrodysplasia ossificans progressiva

BMPs

FOP

BMPs

FOP

BMPs

FOP

bone morphogenetic protein 5

fibrodysplasia ossificans progressiva

bone morphogenetic protein 5

FOP

bone morphogenetic protein 5

FOP

bone morphogenetic protein 5

FOP

fibrodysplasia ossificans progressiva

FOP

FOP

FOP

fibrodysplasia ossificans progressiva

FOP

FOP

FOP

BMP

fibrodysplasia ossificans progressiva

BMP

FOP

BMP

FOP

BMP

FOP

fibrodysplasia ossificans progressiva

FOP

FOP

FOP

fibrodysplasia ossificans progressiva

FOP

FOP

FOP

short ear syndrome

Bone morphogenetic proteins

short ear syndrome

BMPs

short ear syndrome

bone morphogenetic protein 5

short ear syndrome

short ear syndrome

short ear syndrome

BMP

short ear syndrome

short ear syndrome

short ear syndrome

heterotopic ossification

heterotopic ossification

Bone morphogenetic proteins

heterotopic ossification

BMPs

heterotopic ossification

bone morphogenetic protein 5

heterotopic ossification

heterotopic ossification

heterotopic ossification

BMP

heterotopic ossification

heterotopic ossification

heterotopic ossification

heterotopic ossification

Bone morphogenetic proteins

heterotopic ossification

BMPs

heterotopic ossification

bone morphogenetic protein 5

heterotopic ossification

heterotopic ossification

heterotopic ossification

BMP

heterotopic ossification

heterotopic ossification

heterotopic ossification

heterotopic ossification

Bone morphogenetic proteins

heterotopic ossification

BMPs

heterotopic ossification

bone morphogenetic protein 5

heterotopic ossification

heterotopic ossification

heterotopic ossification

BMP

heterotopic ossification

heterotopic ossification

heterotopic ossification

heterotopic ossification

bone morphogenetic protein 4

heterotopic ossification

heterotopic ossification

heterotopic ossification

heterotopic ossification

heterotopic ossification

bone morphogenetic protein 4

heterotopic ossification

heterotopic ossification

heterotopic ossification

heterotopic ossification

heterotopic ossification

bone morphogenetic protein 4

heterotopic ossification

heterotopic ossification

heterotopic ossification

fibrodysplasia ossificans progressiva

FOP

FOP

FOP

bone morphogenetic protein 4

fibrodysplasia ossificans progressiva

bone morphogenetic protein 4

FOP

bone morphogenetic protein 4

FOP

bone morphogenetic protein 4

FOP

fibrodysplasia ossificans progressiva

FOP

FOP

FOP

fibrodysplasia ossificans progressiva

FOP

FOP

FOP

fibrodysplasia ossificans progressiva

FOP

FOP

FOP

short ear syndrome

bone morphogenetic protein 4

short ear syndrome

short ear syndrome

short ear syndrome

short ear syndrome

axial skeletal malformations

axial skeletal malformations

Bone morphogenetic proteins

axial skeletal malformations

BMPs

axial skeletal malformations

bone morphogenetic protein 5

axial skeletal malformations

axial skeletal malformations

axial skeletal malformations

BMP

axial skeletal malformations

axial skeletal malformations

axial and appendicular skeletal malformation

axial and appendicular skeletal malformation

Bone morphogenetic proteins

axial and appendicular skeletal malformation

BMPs

axial and appendicular skeletal malformation

bone morphogenetic protein 5

axial and appendicular skeletal malformation

axial and appendicular skeletal malformation

axial and appendicular skeletal malformation

BMP

axial and appendicular skeletal malformation

axial and appendicular skeletal malformation

axial skeletal malformations

axial skeletal malformations

Bone morphogenetic proteins

axial skeletal malformations

BMPs

axial skeletal malformations

bone morphogenetic protein 5

axial skeletal malformations

axial skeletal malformations

axial skeletal malformations

BMP

axial skeletal malformations

axial skeletal malformations

multiple malformations of the axial skeleton

multiple malformations of the axial skeleton

Bone morphogenetic proteins

multiple malformations of the axial skeleton

BMPs

multiple malformations of the axial skeleton

bone morphogenetic protein 5

multiple malformations of the axial skeleton

multiple malformations of the axial skeleton

multiple malformations of the axial skeleton

BMP

multiple malformations of the axial skeleton

multiple malformations of the axial skeleton

axial skeletal abnormalities

axial skeletal abnormalities

Bone morphogenetic proteins

axial skeletal abnormalities

BMPs

axial skeletal abnormalities

bone morphogenetic protein 5

axial skeletal abnormalities

axial skeletal abnormalities

axial skeletal abnormalities

BMP

axial skeletal abnormalities

axial skeletal abnormalities

axial skeletal malformations

axial skeletal malformations

bone morphogenetic protein 4

axial skeletal malformations

axial skeletal malformations

axial skeletal malformations

axial and appendicular skeletal malformation

axial and appendicular skeletal malformation

bone morphogenetic protein 4

axial and appendicular skeletal malformation

axial and appendicular skeletal malformation

axial and appendicular skeletal malformation

axial skeletal malformations

axial skeletal malformations

bone morphogenetic protein 4

axial skeletal malformations

axial skeletal malformations

axial skeletal malformations

multiple malformations of the axial skeleton

multiple malformations of the axial skeleton

bone morphogenetic protein 4

multiple malformations of the axial skeleton

multiple malformations of the axial skeleton

multiple malformations of the axial skeleton

axial skeletal abnormalities

axial skeletal abnormalities

bone morphogenetic protein 4

axial skeletal abnormalities

axial skeletal abnormalities

axial skeletal abnormalities


Input: Sex - differential genetic effect of phosphodiesterase 4D ( PDE4D ) on carotid atherosclerosis . BACKGROUND : The phosphodiesterase 4D ( PDE4D ) gene was reported as a susceptibility gene to stroke . The genetic effect might be attributed to its role in modulating the atherogenic process in the carotid arteries . Using carotid intima - media thickness ( IMT ) and plaque index as phenotypes , the present study sought to determine the influence of this gene on subclinical atherosclerosis . METHODS : Carotid ultrasonography was performed on 1013 stroke - free subjects who participated in the health screening programs ( age 52 . 6 + / - 12 . 2 ; 47 . 6 % men ) . Genotype distribution was compared among the high - risk ( plaque index > or = 4 ) , low - risk ( index = 1 - 3 ) , and reference ( index = 0 ) groups . We analyzed continuous IMT data and further dichotomized IMT data using mean plus one standard deviation as the cutoff level . Because the plaque prevalence and IMT values displayed a notable difference between men and women , we carried out sex - specific analyses in addition to analyzing the overall data . Rs702553 at the PDE4D gene was selected because it conferred a risk for young stroke in our previous report . Previous young stroke data ( 190 cases and 211 controls ) with an additional 532 control subjects without ultrasonic data were shown as a cross - validation for the genetic effect . RESULTS : In the overall analyses , the rare homozygote of rs702553 led to an OR of 3 . 1 ( p = 0 . 034 ) for a plaque index > or = 4 . When subjects were stratified by sex , the genetic effect was only evident in men but not in women . Comparing male subjects with plaque index > or = 4 and those with plaque index = 0 , the TT genotype was over - represented ( 27 . 6 % vs . 13 . 4 % , p = 0 . 008 ) . For dichotomized IMT data in men , the TT genotype had an OR of 2 . 1 ( p = 0 . 032 ) for a thicker IMT at the common carotid artery compared with the ( AA + AT ) genotypes . In women , neither IMT nor plaque index was associated with rs702553 . Similarly , SNP rs702553 was only significant in young stroke men ( OR = 1 . 8 , p = 0 . 025 ) but not in women ( p = 0 . 27 ) . CONCLUSIONS : The present study demonstrates a sex - differential effect of PDE4D on IMT , plaque index and stroke , which highlights its influence on various aspects of atherogenesis .

phosphodiesterase 4D

phosphodiesterase 4D

carotid atherosclerosis

stroke

atherogenic

atherosclerosis

stroke

stroke

stroke

stroke

stroke

atherogenesis

men

men

women

men

women

men

women

men

women

atherogenic

atherogenic

atherogenic

atherogenic

atherosclerosis

atherosclerosis

atherosclerosis

atherosclerosis

atherogenesis

atherogenesis

atherogenesis

atherogenesis

phosphodiesterase 4D

atherogenic

phosphodiesterase 4D

atherosclerosis

phosphodiesterase 4D

atherogenesis

atherogenic

atherosclerosis

atherogenesis

phosphodiesterase 4D

atherogenic

phosphodiesterase 4D

atherosclerosis

phosphodiesterase 4D

atherogenesis

atherogenic

atherosclerosis

atherogenesis

atherogenic

atherosclerosis

atherogenesis

atherogenic

atherosclerosis

atherogenesis

phosphodiesterase 4D

stroke

phosphodiesterase 4D

stroke

phosphodiesterase 4D

stroke

phosphodiesterase 4D

stroke

phosphodiesterase 4D

stroke

phosphodiesterase 4D

stroke

stroke

stroke

stroke

stroke

stroke

stroke

phosphodiesterase 4D

stroke

phosphodiesterase 4D

stroke

phosphodiesterase 4D

stroke

phosphodiesterase 4D

stroke

phosphodiesterase 4D

stroke

phosphodiesterase 4D

stroke

stroke

stroke

stroke

stroke

stroke

stroke

stroke

stroke

stroke

stroke

stroke

stroke

stroke

stroke

stroke

stroke

stroke

stroke

phosphodiesterase 4D

carotid atherosclerosis

carotid atherosclerosis

phosphodiesterase 4D

carotid atherosclerosis

carotid atherosclerosis

carotid atherosclerosis

carotid atherosclerosis

stroke

stroke

stroke

stroke

stroke

stroke

stroke

stroke

stroke

stroke

stroke

stroke

stroke

stroke

stroke

stroke

stroke

stroke

stroke

stroke

stroke

stroke

stroke

stroke


Input: Detection of EGFR mutations in plasma DNA from lung cancer patients by mass spectrometry genotyping is predictive of tumor EGFR status and response to EGFR inhibitors . AIMS : EGFR mutations now guide the clinical use of EGFR - targeted therapy in lung cancer . However , standard EGFR mutation analysis requires a minimum amount of tumor tissue , which may not be available in certain situations . In this study , we combined a mass spectrometry genotyping assay ( Sequenom ) with a mutant - enriched PCR ( ME - PCR ) to detect EGFR mutations in free plasma DNA from patients with lung cancer . METHOD : DNAs were extracted from 31 plasma samples from 31 patients and analyzed by both methods for EGFR Exon 19 deletion and EGFR L858R mutation . Results in plasma DNA samples were compared with EGFR mutation status obtained in tumor DNA ( 18 / 31 EGFR mutant ) . The relationship of EGFR mutation status in tumor and / or plasma samples to overall survival was assessed . RESULTS : The EGFR mutation status in plasma DNA was identical to the primary tumor in 61 % of patients ( 19 / 31 ) . By mass spectrometry genotyping , the plasma samples contained mutant DNA corresponding to 5 / 14 EGFR Exon 19 deletions and 3 / 4 EGFR L858R mutations previously diagnosed in the matched tumors . Two samples were positive in plasma DNA but negative in primary tumor tissue . Results were similar for samples studied by ME - PCR . For patients treated with erlotinib , overall survival was correlated with the presence of EGFR mutation in plasma and / or tumor tissue ( p = 0 . 002 ) , with the two patients positive only in plasma DNA showing responses and favorable outcomes . CONCLUSION : The detection of EGFR mutations in plasma DNA samples by mass spectrometry genotyping and ME - PCR is feasible . A positive EGFR result in plasma DNA has a high predictive value for tumor EGFR status and for favorable clinical course on EGFR - targeted therapy and could therefore be useful in guiding clinical decisions in patients with insufficient or unavailable tumor specimens .

EGFR

EGFR

EGFR

EGFR

EGFR

EGFR

EGFR

EGFR

EGFR

EGFR

EGFR

EGFR

EGFR

EGFR

EGFR

EGFR

EGFR

EGFR

EGFR

EGFR

lung cancer

tumor

lung cancer

tumor

lung cancer

tumor

tumor

tumor

tumors

tumor

tumor

tumor

tumor

patients

patients

patients

patients

patients

patients

patients

erlotinib

tumor

tumor

tumor

tumor

tumor

tumors

tumor

tumor

tumor

tumor

tumor

tumor

tumor

tumor

tumor

tumors

tumor

tumor

tumor

tumor

erlotinib

erlotinib

erlotinib

EGFR

erlotinib

EGFR

erlotinib

EGFR

erlotinib

EGFR

erlotinib

EGFR

erlotinib

EGFR

erlotinib

EGFR

erlotinib

EGFR

erlotinib

EGFR

erlotinib

EGFR

erlotinib

EGFR

erlotinib

EGFR

erlotinib

EGFR

erlotinib

EGFR

erlotinib

EGFR

erlotinib

EGFR

erlotinib

EGFR

erlotinib

EGFR

erlotinib

EGFR

erlotinib

EGFR

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

lung cancer

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumors

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumors

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumors

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumors

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumors

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumors

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumors

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumors

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumors

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumors

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumors

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumors

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumors

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumors

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumors

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumors

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumors

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumors

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumors

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumors

EGFR

tumor

EGFR

tumor

EGFR

tumor

EGFR

tumor

erlotinib

tumor

erlotinib

tumor

erlotinib

tumor

erlotinib

tumor

erlotinib

tumor

erlotinib

tumors

erlotinib

tumor

erlotinib

tumor

erlotinib

tumor

erlotinib

tumor