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About 313,698 results

FXR is a molecular target for the effects of vertical sleeve gastrectomy.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4016120
Nature Ryan KK, Tremaroli V et. al.

Mar 28th, 2014 - Bariatric surgical procedures, such as vertical sleeve gastrectomy (VSG), are at present the most effective therapy for the treatment of obesity, and are associated with considerable improvements in co-morbidities, including type-2 diabetes mellitus. The underlying molecular mechanisms contributing to these benefits remain largely undetermined, despite offering the potential to reveal new targe...

Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4191900
The New England Journal of Medicine; Roberts KG, Li Y et. al.

Sep 10th, 2014 - Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCR-ABL1-positive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and ad...

Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity.
https://doi.org/10.1038/nature14404
Nature Spranger S, Bao R et. al.

May 14th, 2015 - Melanoma treatment is being revolutionized by the development of effective immunotherapeutic approaches. These strategies include blockade of immune-inhibitory receptors on activated T cells; for example, using monoclonal antibodies against CTLA-4, PD-1, and PD-L1 (refs 3-5). However, only a subset of patients responds to these treatments, and data suggest that therapeutic benefit is preferenti...

Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Ind...
https://doi.org/10.1053/j.gastro.2016.01.038
Gastroenterology Ratziu V, Harrison SA et. al.

Feb 13th, 2016 - Elafibranor is an agonist of the peroxisome proliferator-activated receptor-α and peroxisome proliferator-activated receptor-δ. Elafibranor improves insulin sensitivity, glucose homeostasis, and lipid metabolism and reduces inflammation. We assessed the safety and efficacy of elafibranor in an international, randomized, double-blind placebo-controlled trial of patients with nonalcoholic steatoh...

The sonic hedgehog factor GLI1 imparts drug resistance through inducible glucuronidation.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4138053
Nature Zahreddine HA, Culjkovic-Kraljacic B et. al.

May 29th, 2014 - Drug resistance is a major hurdle in oncology. Responses of acute myeloid leukaemia (AML) patients to cytarabine (Ara-C)-based therapies are often short lived with a median overall survival of months. Therapies are under development to improve outcomes and include targeting the eukaryotic translation initiation factor (eIF4E) with its inhibitor ribavirin. In a Phase II clinical trial in poor pr...

eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies.
https://doi.org/10.1038/nature13572
Nature Boussemart L, Malka-Mahieu H et. al.

Jul 31st, 2014 - In BRAF(V600)-mutant tumours, most mechanisms of resistance to drugs that target the BRAF and/or MEK kinases rely on reactivation of the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signal transduction pathway, on activation of the alternative, PI(3)K-AKT-mTOR, pathway (which is ERK independent) or on modulation of the caspase-dependent apoptotic cascade. All three pathways converge ...

Notch1 Overexpression Correlates to Improved Survival in Cancer of the Oropharynx.
https://doi.org/10.1177/0194599816688178
Otolaryngology--head and Neck Surgery : Official Journal ... Kaka AS, Nowacki NB et. al.

Feb 14th, 2017 - Objectives The Notch1 signaling pathway has recently been shown to be highly dysregulated in head and neck squamous cell carcinoma, but the value of Notch1 as a predictive biomarker is yet to be elucidated in oropharyngeal squamous cell carcinoma (OPSCC). The objective of this study is to evaluate Notch1 expression in surgical OPSCC specimens and determine clinicopathologic correlates. Study De...

NOTCH1 mutations occur early during cutaneous squamous cell carcinogenesis.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753672
The Journal of Investigative Dermatology; South AP, Purdie KJ et. al.

Mar 25th, 2014 - Cutaneous SCC (cSCC) is the most frequently occuring skin cancer with metastatic potential and can manifest rapidly as a common side effect in patients receiving systemic kinase inhibitors. Here, we use massively parallel exome and targeted level sequencing of 132 sporadic cSCCs and of 39 squamoproliferative lesions and cSCCs arising in patients receiving the BRAF inhibitor vemurafenib, as well...

β-catenin mediates stress resilience through Dicer1/microRNA regulation.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4257892
Nature Dias C, Feng J et. al.

Nov 10th, 2014 - β-catenin is a multi-functional protein that has an important role in the mature central nervous system; its dysfunction has been implicated in several neuropsychiatric disorders, including depression. Here we show that in mice β-catenin mediates pro-resilient and anxiolytic effects in the nucleus accumbens, a key brain reward region, an effect mediated by D2-type medium spiny neurons. Using ge...

Leptin receptor deficiency confers resistance to behavioral effects of fluoxetine and d...
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270309
Translational Psychiatry; Guo M, Lu XY

Dec 2nd, 2014 - Depression is a complex, heterogeneous mental disorder. Currently available antidepressants are only effective in about one-third to one-half of all patients. The mechanisms underlying antidepressant response and treatment resistance are poorly understood. Recent clinical evidence implicates the involvement of leptin in treatment response to antidepressants. In this study, we determined the fun...

Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart dise...
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376609
Nature Lee DI, Zhu G et. al.

Mar 24th, 2015 - Cyclic guanosine monophosphate (cGMP) is a second messenger molecule that transduces nitric-oxide- and natriuretic-peptide-coupled signalling, stimulating phosphorylation changes by protein kinase G. Enhancing cGMP synthesis or blocking its degradation by phosphodiesterase type 5A (PDE5A) protects against cardiovascular disease. However, cGMP stimulation alone is limited by counter-adaptions in...

LPA signaling initiates schizophrenia-like brain and behavioral changes in a mouse mode...
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462599
Translational Psychiatry; Mirendil H, Thomas EA et. al.

Apr 7th, 2015 - Genetic, environmental and neurodevelopmental factors are thought to underlie the onset of neuropsychiatric disorders such as schizophrenia. How these risk factors collectively contribute to pathology is unclear. Here, we present a mouse model of prenatal intracerebral hemorrhage--an identified risk factor for schizophrenia--using a serum-exposure paradigm. This model exhibits behavioral, neuro...

Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5769922
Nature Cell Biology; Costa-Silva B, Aiello NM et. al.

May 19th, 2015 - Pancreatic ductal adenocarcinomas (PDACs) are highly metastatic with poor prognosis, mainly due to delayed detection. We hypothesized that intercellular communication is critical for metastatic progression. Here, we show that PDAC-derived exosomes induce liver pre-metastatic niche formation in naive mice and consequently increase liver metastatic burden. Uptake of PDAC-derived exosomes by Kupff...

Ligand-independent EPHA2 signaling drives the adoption of a targeted therapy-mediated m...
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4355213
Cancer Discovery; Paraiso KH, Das Thakur M et. al.

Dec 29th, 2014 - Many patients with BRAF inhibitor resistance can develop disease at new sites, suggesting that drug-induced selection pressure drives metastasis. Here, we used mass spectrometry-based phosphoproteomic screening to uncover ligand-independent EPHA2 signaling as an adaptation to BRAF inhibitor therapy that led to the adoption of a metastatic phenotype. The EPHA2-mediated invasion was AKT-dependent...

Smoothened variants explain the majority of drug resistance in basal cell carcinoma.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357167
Cancer Cell; Atwood SX, Sarin KY et. al.

Mar 11th, 2015 - Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here we identify SMO mutations in 50% (22 of 44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants...

Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877694/
International Journal of Molecular Sciences;

Mar 12th, 2018 - The biological effects of cannabinoids, the major constituents of the ancient medicinal plant Cannabis sativa (marijuana) are mediated by two members of the G-protein coupled receptor family, cannabinoid receptors 1 (CB1R) and 2. The CB1R is the prominent subtype in the central nervous system (CNS) and has drawn great attention as a potential therapeutic avenue in several pathological condition...

Epicardial FSTL1 reconstitution regenerates the adult mammalian heart.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4762253
Nature Wei K, Serpooshan V et. al.

Sep 16th, 2015 - The elucidation of factors that activate the regeneration of the adult mammalian heart is of major scientific and therapeutic importance. Here we found that epicardial cells contain a potent cardiogenic activity identified as follistatin-like 1 (Fstl1). Epicardial Fstl1 declines following myocardial infarction and is replaced by myocardial expression. Myocardial Fstl1 does not promote regenerat...

Molecular Alterations and Everolimus Efficacy in Human Epidermal Growth Factor Receptor...
https://doi.org/10.1200/JCO.2015.63.9161
Journal of Clinical Oncology : Official Journal of the Am... André F, Hurvitz S et. al.

Apr 19th, 2016 - Two recent phase III trials, BOLERO-1 and BOLERO-3 (Breast Cancer Trials of Oral Everolimus), evaluated the addition of everolimus to trastuzumab and chemotherapy in human epidermal growth factor receptor 2-overexpressing advanced breast cancer. The current analysis aimed to identify biomarkers to predict the clinical efficacy of everolimus treatment. Archival tumor samples from patients in BOL...

Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on...
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5159705
Blood Kavanagh D, McGlasson S et. al.

Sep 24th, 2016 - Many drugs have been reported to cause thrombotic microangiopathy (TMA), yet evidence supporting a direct association is often weak. In particular, TMA has been reported in association with recombinant type I interferon (IFN) therapies, with recent concern regarding the use of IFN in multiple sclerosis patients. However, a causal association has yet to be demonstrated. Here, we adopt a combined...

TMC1 Forms the Pore of Mechanosensory Transduction Channels in Vertebrate Inner Ear Hai...
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360533
Neuron Pan B, Akyuz N et. al.

Aug 23rd, 2018 - The proteins that form the permeation pathway of mechanosensory transduction channels in inner-ear hair cells have not been definitively identified. Genetic, anatomical, and physiological evidence support a role for transmembrane channel-like protein (TMC) 1 in hair cell sensory transduction, yet the molecular function of TMC proteins remains unclear. Here, we provide biochemical evidence sugge...