Somatic mutations in the chromatin remodeling gene ARID1A occur in several tumor types

Mutations in the chromatin remodeling gene ARID1A have recently been identified in the majority of ovarian clear cell carcinomas (OCCCs). To determine the prevalence of mutations in other tumor types, we evaluated 759 malignant neoplasms including those of the pancreas, breast, colon, stomach, lung, prostate, brain, and blood (leukemias). We identified truncating mutations in 6% of the neoplasms studied; nontruncating somatic mutations were identified in an additional 0.4% of neoplasms. Mutations were most commonly found in gastrointestinal samples with 12 of 119 (10%) colorectal and 10 of 100 (10%) gastric neoplasms, respectively, harboring changes. More than half of the mutated colorectal and gastric cancers displayed microsatellite instability (MSI) and the mutations in these tumors were out-of-frame insertions or deletions at mononucleotide repeats. Mutations were also identified in 2-8% of tumors of the pancreas, breast, brain (medulloblastomas), prostate, and lung, and none of these tumors displayed MSI. These findings suggest that the aberrant chromatin remodeling consequent to ARID1A inactivation contributes to a variety of different types of neoplasms.     

Comparative analysis of two types of methanol dehydrogenase from Methylophaga aminisulfidivorans MPT grown on methanol

Two types of methanol dehydrogenase (MDH) were obtained from a novel marine methylotrophic bacterium, Methylophaga aminisulfidivorans MP(T), grown on methanol. Type I MDH consisted of two identical dimers of α (65.98 kDa) and β (7.58 kDa) subunits organized to form the α(2)β(2) tetramer. Type II MDH contained an additional MxaJ protein (27.86 kDa) and had more specific activity than type I MDH. The K(m) values of type I and II MDH for methanol under cytochrome c(L) reduction assay system were estimated to be 50.3 and 13.0 μM, respectively, and the isoelectric points of type I and II MDH were determined to be 5.4 and 5.8, respectively. The average molar ratios of α:β, α:MxaJ, and β:MxaJ in type II MDH were approximately 1:0.99, 1:0.41 and 1:0.42, respectively. Based on these results, the original conformation of the MDH of M. aminisulfidivorans MP(T) is most likely the α(2)β(2)-MxaJ complex. During purification, the lysozyme and freeze-thawing cell disruption method significantly increased the amount of type II MDH in the soluble fraction compared with strong physical disruption methods such as sonication and French Press.     

The role of BCL11B in regulating the proliferation of human naive T cells

The effect of the B-cell chronic lymphocytic leukemia/lymphoma 11B gene (BCL11B) on human T-cell regulation remains unclear. To characterize the functions of BCL11B, recombinant BCL11B and BCL11B siRNA were transfected into human naive T cells to overexpress or knock down BCL11B expression, respectively. After BCL11B overexpression, the proliferation ability and the T-helper (Th) subset were increased, whereas no significant alteration in the expression pattern and clonality of the T-cell receptor Vβ subfamilies was observed. After BCL11B knockdown, a similar distribution of Vβ subfamilies was detected in the naive T cells; however, the proliferation capacity substantially decreased. Global gene expression profiling revealed that the dysregulated genes were mainly involved in T-cell activation and proliferation. BCL11B could selectively promote Th-cell differentiation because of increased CXCL10 and CXCL11 expression. BCL11B suppression may inhibit proliferation and induce apoptosis, which may relate to changes in the expression of CFLAR-CASP8-CASP10 in the mitochondrial pathways. In conclusion, BCL11B is required for T-cell survival; its overexpression could effectively increase the T-cell activation and proliferation abilities and Th-cell differentiation as well.     

JAK-STAT pathway modulates the roles of iNOS and COX-2 in the cytoprotection of early phase of hydrogen peroxide preconditioning against apoptosis induced by oxidative stress

Our previous studies have demonstrated that preconditioning with hydrogen peroxide (H₂O₂) activated the JAK-STAT pathway that played an important role in the cytoprotection, and inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) mediated the late phase of cytoprotection induced by high concentration of H₂O₂ after preconditioning. Here we sought to identify the downstream targets of the JAK-STAT axis that mediated H₂O₂ preconditioning and the expression of iNOS and COX-2 in the early phase of H₂O₂ preconditioning. It was shown that (1) Preconditioning with H₂O₂ at 100 μmol/L for 90 min in PC12 cells induced significant expression of iNOS and COX-2. (2) Pretreatment with the iNOS inhibitor AG (10 μmol/L) or the COX-2 inhibitor NS-398 (10 μmol/L) respectively 20 min before H₂O₂ preconditioning not only inhibits the increased expression of iNOS or COX-2 but also abrogates the protective effects of H₂O₂ preconditioning against apoptosis induced by oxidative stress. (3) Pretreatment with the JAK inhibitor AG-490 (10 μmol/L) 20 min before H₂O₂ preconditioning obviously inhibits the up-regulation of iNOS or COX-2 induced by H₂O₂ preconditioning. These results suggested that JAK-STAT pathway modulates the roles of iNOS and COX-2 in the cytoprotection of early phase of H₂O₂ preconditioning.     

The CFP10/ESAT6 complex of Mycobacterium tuberculosis may function as a regulator of macrophage cell death at different stages of tuberculosis infection

Tuberculosis is a human disease caused by infection with Mycobacterium tuberculosis. M. tuberculosis (Mtb) is a facultative intracellular pathogen. The alveolar macrophages provide a critical niche for the intracellular pathogen. It has been shown that virulent strains mycobacteria (Mtb-H37Rv, Mycobacterium bovis) induce less apoptosis in host macrophage than avirulent mycobacteria strains (Bacillus Calmette-Guérin, H37Ra). Comparative genomics analysis has revealed that the region of difference (RD1) of M. tuberculosis is absent from all strains of Bacillus Calmette-Guérin (BCG). On the contrary, it presents in all virulent strains of M. tuberculosis and M. bovis. The culture filtrate protein 10 (CFP10) and early secretory antigenic target protein 6 (ESAT6) are encoded by RD1 genes Rv3874 and Rv3875, respectively. Recent studies indicated that the CFP10 and ESAT6 played an important role in M. tuberculosis virulence. It has been shown that incorporation of the RD1 region into BCG to restore the expression of CFP10 and ESAT6 leads to increasing the virulence and immunogenicity of bacterium. On the contrary, deletion of the genes encoding CFP10 and ESAT6 from the virulent M. bovis strain results in attenuation of virulence. Meanwhile, several studies showed that CFP10 and ESAT6 could inhibit and/or promote the production of tumor necrosis factor α (TNF-α) from macrophages. Furthermore, TNF-α can induce apoptosis and necrosis of infected macrophages in tuberculosis. Considering above results, we hypothesize that the CFP10 and ESAT6 may be involved in the virulence of Mycobacterium through modulating macrophage cell death.     

Computer-assisted three-dimensional reconstruction of the fetal pancreas including the supplying arteries according to immunohistochemistry of pancreatic polypeptide

Purpose  

Computer-assisted three-dimensional reconstruction of the fetal human pancreas was prepared to reconsider topographical relation between the dorsal/ventral anlagen and the vascular supply.     

外科重症监护病房术后行机械通气病人的疼痛强度评估方法研究

[目的]了解外科重症监护病房(SICU)术后机械通气清醒病人的疼痛情况及评估方法.[方法]采用方便抽样方法,应用行为疼痛量表(BPS)和数字疼痛强度量表(NRS)对北京市某三级甲等医院SICU 95 例术后行机械通气清醒病人进行疼痛强度测评.[结果]BPS分值为(5.83±1.82)分、NRS为(5.98±2.55)分.不同性别、文化程度病人BPS和NRS疼痛强度比较,差异无统计学意义(P>0.05).年龄与BPS和NRS的疼痛强度呈负相关(r值分别为-0.215和-0.302).应用和没有应用镇痛泵病人BPS及NRS疼痛分值比较差异无统计学意义.BPS评分与NRS评分存在正相关(r=0.613,P<0.001).[结论]术后病人普遍存在疼痛,BPS用于机械通气病人疼痛的评估是可靠有效的.