Distinct mechanisms of FAK mechanoactivation by different extracellular matrix proteins

Introduction Cells can sense and respond to the mechanical microenvironment by converting forces into biochemical signals inside the cells,i.e.mechanotransduction[1-3].Focal adhesions are the major sites of interaction between a cell and its extracellular matrix（ECM）microenvironment,thus outside mechanical signals can be sensed at focal adhesions through transmembrane receptor integrins.In particular,it has been shown that matrix elasticity can control the cell fate[4]by modulating the interactions between ECM proteins and their receptor integrins[5,6].For example,different rigidity of polyacrylamide（PA）gels can lead to different density of ECM ancho-

Loss of Hox5 function results in myofibroblast mislocalization and distal lung matrix defects during postnatal development

Alveologenesis is the final stage of lung development and is responsible for the formation of the principle gas exchange units called alveoli. The lung mesenchyme, in particular the alveolar myofibroblasts, are drivers of alveolar development, however,few key regulators that govern the proper distribution and behavior of these cells in the distal lung during alveologenesis have been identified. While Hox5 triple mutants(Hox5 aabbcc) exhibit neonatal lethality, four-allele, compound mutant mice(Hox5 AabbCc) are born in Mendelian ratios and are phenotypically normal at birth. However, they exhibit defects in alveologenesis characterized by a BPD-like phenotype by early postnatal stages that becomes more pronounced at adult stages. Invasive pulmonary functional analyses demonstrate significant increases in total lung volume and compliance and a decrease in elastance in Hox5 compound mutants. SMA+ myofibroblasts in the distal lung are distributed abnormally during peak stages of alveologenesis and aggregate, resulting in the formation of a disrupted elastin network. Examination of other key components of the distal lung ECM, as well as other epithelial cells and lipofibroblasts reveal no differences in distribution. Collectively, these data indicate that Hox5 genes play a critical role in alveolar development by governing the proper cellular behavior of myofibroblasts during alveologenesis.

他汀类药物与结肠直肠癌风险

Statins are inhibitors of 3- hydroxy-3-methylglutaryl coenzyme A reductase and effective lipid-lowering agents. Statins inhibit the growth of coloncancer cell lines, and secondary analyses of some, but not all, clinical trials suggest that they reduce the risk of colorectal cancer. METHODS: The Molecular Epidemiology of Colorectal Cancer study is a population-based case-control study of patients who received a diagnosis of colorectal cancer in northern Israel between 1998 and 2004 and controls matched according to age, sex, clinic, and ethnic group. We used a structured interview to determine the use of statins in the two groups and verified self-reported statin use by examining prescription records in a subgroup of patients for whom prescription records were available. RESULTS: In analyses including 1953 patients with colorectal cancer and 2015 controls, the use of statins for at least five years(vs. the nonuse of statins) was associated with a significantly reduced relative risk of colorectal cancer(odds ratio, 0.50; 95 percent confidence interval, 0.40 to 0.63). This association remained significant after adjustment for the use or nonuse of aspirin or other nonsteroidal antiinflammatory drugs; the presence or absence of physical activity, hypercholesterolemia, and a family history of colorectal cancer; ethnic group; and level of vegetable consumption(odds ratio, 0.53; 95 percent confidence interval, 0.38 to 0.74). The use of fibric-acid derivatives was not associated with a significantly reduced risk of colorectal cancer(odds ratio, 1.08; 95 percent confidence interval, 0.59 to 2.01). Self-reported statin use was confirmed for 276 of the 286 participants(96.5 percent) who reported using statins and whose records were available. CONCLUSIONS: The use of statins was associated with a 47 percent relative reduction in the risk of colorectal cancer after adjustment for other known risk factors. Because the absolute risk reduction is likely low, further investigation of the overall benefits of statins in preventing colorectal cancer is warranted.

The role of BRCA1 in DNA damage response

BRCA1 is a well-established tumor suppressor gene,which is frequently mutated in familial breast and ovarian cancers.The gene product of BRCA1 functions in a number of cellular pathways that maintain genomic stability,including DNA damage-induced cell cycle checkpoint activation,DNA damage repair,protein ubiquitination,chromatin remodeling,as well as transcriptional regulation and apoptosis.In this review,we discuss recent advances regarding our understanding of the role of BRCA1 in tumor suppression and DNA damage response,including DNA damage-induced cell cycle checkpoint activation and DNA damage repair.