Oncogene addiction in non-small cell lung cancer: focus on ROS1 inhibition

Publication date: Available online 12 March 2017
Source:Cancer Treatment Reviews
Author(s): Francesco Facchinetti, Giulio Rossi, Emilio Bria, Jean-Charles Soria, Benjamin Besse, Roberta Minari, Luc Friboulet, Marcello Tiseo
Detection of molecular aberrations driving the biology and the clinical behavior of advanced non-small cell lung cancer (NSCLC) allows the adoption of specific therapeutic strategies dramatically impacting disease courses. Among these, ROS1 rearrangements are present in1-2% of lung adenocarcinomas. Thanks to similarities between ALK and ROS1 oncogenes, lessons inferred from ALK can be applied to ROS1-positive NSCLC; nevertheless, disparities exist between diseases mastered by these two fusion genes. In the absence of more common genetic alterations detected in NSCLC (e. g. EGFR and KRAS mutations, ALK gene fusions), seeking for ROS1 rearrangements is crucial. Dedicated molecular diagnostics should be standardized, hopefully relying upon practical and efficient algorithms, comprehending immunohistochemistry and fluorescence in situ hybridisation. The major clinical impact exerted by crizotinib represents the main reason for which not even a sole ROS1-positive tumor should be undetected. The recent approval of the inhibitor by both American and European health agencies would hopefully boost the widespread testing for ROS1, eventually increasing the absolute number of positive cases, potential further source of information regarding molecular and clinical resistance. In vitro and clinical evidence have already been generated concerning crizotinib resistance and strategies to maintain patients under specific driver-inhibition are being successfully developed. Gathering data concerning diagnostics, preclinical evidence, clinical practice and ongoing studies, the present review depicts the current scenario of ROS1 inhibition in NSCLC.



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Astaxanthin attenuated pressure overload-induced cardiac dysfunction and myocardial fibrosis: Partially by activating SIRT1

Publication date: Available online 12 March 2017
Source:Biochimica et Biophysica Acta (BBA) - General Subjects
Author(s): Jun Zhang, Quan-zhen Wang, Shao-hua Zhao, Xiang Ji, Jie Qiu, Jian Wang, Yi Zhou, Qian Cai, Jie Zhang, Hai-qing Gao
BackgroundMyocardial fibrosis contributes to cardiac dysfunction. Astaxanthin (AST), a member of the carotenoid family, is a well-known antioxidant, but its effect on and underlying mechanisms in myocardial fibrosis are poorly understood.MethodsIn vivo, myocardial fibrosis and cardiac dysfunction were induced using transverse aortic constriction (TAC). AST was administered to mice for 12 weeks post-surgery. In vitro, transforming growth factor β1 (TGF-β1) was used to stimulate human cardiac fibroblasts (HCFs). EX-527 (6-chloro-2, 3, 4, 9-tetrahydro-1H-carbazole-1-carboxamide) and SIRT1 siRNA were used to inhibit SIRT1 in vivo and in vitro, respectively. The effects of AST on cardiac function and fibrosis were determined. SIRT1 expression and activity were measured to explore the mechanisms underlying its effects.ResultsAST improved cardiac function and attenuated fibrosis. Receptor activated-SMADs (R-SMADs), including SMAD2 and SMAD3, played important roles in these processes. The TAC surgery-induced increases in the expression of phosphorylated and acetylated R-SMADs were attenuated by treatment with AST, the translocation and transcriptional activity of R-SMADs were also restrained. These effects were accompanied by an increase in the expression and activity of SIRT1. Inhibiting SIRT1 attenuated the acetylation and transcriptional activity of R-SMADs, but not their phosphorylation and translocation.ConclusionsOur data demonstrate that AST improves cardiac function and attenuates fibrosis by decreasing phosphorylation and deacetylation of R-SMADs. SIRT1 contributes to AST’s protective function by reducing acetylation of R-SMADs.General SignificanceThese data suggest that AST may be useful as a preventive/therapeutic agent for cardiac dysfunction and myocardial fibrosis.



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Clinical Thyroidology for the Public – Highlighted Article

From Clinical Thyroidology for the Public: There are clear effects of thyroid hormone on the heart. Some clinical studies have shown an increased risk of heart disease and death in patients with hypothyroidism, both mild and overt. Read More….

The post Clinical Thyroidology for the Public – Highlighted Article appeared first on American Thyroid Association.

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Structural, rheological and nutraceutical potential of β-glucan from barley and oat

Publication date: Available online 12 March 2017
Source:Bioactive Carbohydrates and Dietary Fibre
Author(s): Asima Shah, Adil Gani, F.A. Masoodi, Shoib M. Wani, Bilal Ahmad Ashwar
β-glucan in oat and barley were characterized by FT-IR spectroscopy, size-exclusion chromatography and purity estimation by Megazyme β-glucan assay kit. Oat and barley β-glucan had average molecular weights of 2.0×103kDa and 1.79 ×10³kDa, respectively. Rheological analysis suggested that β-glucan consisted of interchain aggregations and showed shear thinning behavior as revealed from Herschel-Bulkely model and frequency sweep. Antioxidant activity was evaluated by three complementary assays. Oat β- glucan showed increased DPPH scavenging activity, reducing power, and protection against DNA damage than barley β-glucan. Further, the antiproliferative potential of β-glucan was tested against three human cancer cell lines using MTT assay (3- (4,5-dimethylthiazol-2-yl)−2,5-diphenyltetrazolium bromide). β-glucan exhibited dose dependent cancer cell growth inhibition with oat β-glucan being more potent than barley β-glucan. This study demonstrates that barley and oat beta glucans hold nutraceutical potential of importance for functional food development and human health in general.

Graphical abstract

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Anticoagulant

Anticoagulant: An agent that is used to prevent the formation of blood clots. Anticoagulants have various uses. Some are used for the prevention or treatment of disorders characterized by abnormal blood clots and emboli. Examples of diseases and conditions that require anticoagulant treatment to reduce the risk of blood clots include heart attack, stroke, deep venous thrombosis, pulmonary embolism, and atrial fibrillation. There are different classes of anticoagulant drugs:

• Vitamin K antagonists
• Low molecular weight heparins
• Direct thrombin inhibitors
• Factor Xa inhibitors

MedTerms (TM) is the Medical Dictionary of MedicineNet.com.
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Biophysical basis of cadherin mediated cell-cell adhesion

Publication date: Available online 12 March 2017
Source:Experimental Cell Research
Author(s): Andrew Vae Priest, Omer Shafraz, Sanjeevi Sivasankar
Classical cadherin transmembrane cell-cell adhesion proteins play essential roles in tissue morphogenesis and in mediating tissue integrity. Cadherin ectodomains from opposing cells interact to form load-bearing trans dimers that mechanically couple cells. Cell-cell adhesion is believed to be strengthened by cis clustering of cadherins on the same cell surface. This review summarizes biophysical studies of the structure, interaction kinetics and biomechanics of classical cadherin ectodomains. We first discuss the structure and equilibrium binding kinetics of classical cadherin trans and cis dimers. We then discuss how mechanical stimuli alters the kinetics of cadherin interaction and tunes adhesion. Finally, we highlight open questions on the role of mechanical forces in influencing cadherin structure, function and organization on the cell surface.



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Hypoxia and B cells

Publication date: Available online 12 March 2017
Source:Experimental Cell Research
Author(s): Natalie Burrows, Patrick Henry Maxwell
The ability of cells to sense and adapt to changes in oxygen is mediated by hypoxia-inducible factor (HIF). Immune cells function in physiologically complex and varying environments whereby oxygen, pH, nutrients, metabolites and cytokines are continuously fluctuating. HIF is well known to play an important role in coordinating the adaptation and function of both innate immune cells and T cells in these complex environments. This review summarises recent discoveries concerning how hypoxia and HIF control B cell behaviour, and regulate antibody quality and decisions concerning tolerance. Hypoxia and HIF activation may provide an important context; coordinating metabolism with variable demands for quiescence, rapid proliferation, and differentiation. Understanding when and how HIF is activated during B cell development and response is important as drugs targeting HIF could influence antibody responses, providing novel therapeutic opportunities for vaccine adjuvants and in treating autoimmunity.



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