肺癌发病及骨转移相关因素分析

目的:探讨肺癌发病的可能相关因素。方法:选择87例确诊为肺癌的患者,收集患者的一般资料,临床信息以及诊断和治疗信息,其中伴骨转移者39例。结果:发病年龄平均67.8岁;6例(35.3%)女性患者为吸烟者,58例(97.7%)男性患者有吸烟史。女性吸烟人数及吸烟量增多;咳嗽为最常见的症状;病理组织学男性患者多为鳞癌,女性腺癌多见;Ⅲ和Ⅳ期明显多于Ⅰ期和Ⅱ期。虽然外科手术治疗后可以提高患者生存时间,接受外科手术患者仍较少。骨转移与性别、年龄和放化疗与否无关,与病理类型有关。结论:年龄、吸烟与肺癌发病密切相关,多数患者就诊时为中晚期,多只能接受姑息治疗,早期诊断及其重要。腺癌患者需警惕骨转移。     

3,5-Dialkoxypyridine analogues of bedaquiline are potent antituberculosis agents with minimal inhibition of the hERG channel

Bedaquiline is a new drug of the diarylquinoline class that has proven to be clinically effective against drug-resistant tuberculosis, but has a cardiac liability (prolongation of the QT interval) due to its potent inhibition of the cardiac potassium channel protein hERG. Bedaquiline is highly lipophilic and has an extremely long terminal half-life, so has the potential for more-than-desired accumulation in tissues during the relatively long treatment durations required to cure TB. The present work is part of a program that seeks to identify a diarylquinoline that is as potent as bedaquiline against Mycobacterium tuberculosis, with lower lipophilicity, higher clearance, and lower risk for QT prolongation. Previous work led to the identification of compounds with greatly-reduced lipophilicity compounds that retain good anti-tubercular activity in vitro and in mouse models of TB, but has not addressed the hERG blockade. We now present compounds where the C-unit naphthalene is replaced by a 3,5-dialkoxy-4-pyridyl, demonstrate more potent in vitro and in vivo anti-tubercular activity, with greatly attenuated hERG blockade. Two examples of this series are in preclinical development.     

SKAP2 Modular Organization Differently Recognizes SRC Kinases Depending on Their Activation Status and Localization

Dimerization of SRC kinase adaptor phosphoprotein 2 (SKAP2) induces an increase of binding for most SRC kinases suggesting a fine-tuning with transphosphorylation for kinase activation. This work addresses the molecular basis of SKAP2-mediated SRC kinase regulation through the lens of their interaction capacities. By combining a luciferase complementation assay and extensive site-directed mutagenesis, we demonstrated that SKAP2 interacts with SRC kinases through a modular organization depending both on their phosphorylation-dependent activation and subcellular localization. SKAP2 contains three interacting modules consisting in the dimerization domain, the SRC homology 3 (SH3) domain, and the second interdomain located between the Pleckstrin homology and the SH3 domains. Functionally, the dimerization domain is necessary and sufficient to bind to most activated and myristyl SRC kinases. In contrast, the three modules are necessary to bind SRC kinases at their steady state. The Pleckstrin homology and SH3 domains of SKAP2 as well as tyrosines located in the interdomains modulate these interactions. Analysis of mutants of the SRC kinase family member hematopoietic cell kinase supports this model and shows the role of two residues, Y390 and K7, on its degradation following activation. In this article, we show that a modular architecture of SKAP2 drives its interaction with SRC kinases, with the binding capacity of each module depending on both their localization and phosphorylation state activation. This work opens new perspectives on the molecular mechanisms of SRC kinases activation, which could have significant therapeutic impact.     

血培养阳性脓毒症病原体监测及相关指标分析

目的：观察血培养阳性脓毒症检出菌的变迁规律,探讨与其预后相关的因素。方法：总结2010 年至2013 年我院呼吸内科血 培养阳性脓毒症136 株检出菌及相关指标,并将其分为两组：一组为治愈及好转组,二组为未愈及死亡组,使用统计软件进行单 因素分析,筛选出可能与脓毒症预后相关的因素。结果：主要以凝固酶阴性葡萄球菌(CNS)为首,其次为大肠埃希氏菌,发现耐亚 胺培南大肠埃希菌株一例,其耐药率为2.9%;两组间进行比较,对年龄、性别、基础疾病包括心血管病、脑血管病后遗症、糖尿病、 恶性肿瘤在内、住院前是否应用抗生素、发热程度、是否存在肺部感染及低白蛋白血症进行单因素分析,肺部感染情况P<0.05,有 统计学意义,可认为其与脓毒症的预后相关,其余指标P 均>0.05,尚不能认为其与脓毒症预后相关。结论：革兰阳性球菌是血培 养阳性脓毒症的主要致病菌;肺部感染情况与脓毒症的预后相关。     

Glutamate-stimulated activation of DNA synthesis via mitogen-activated protein kinase in primary astrocytes: involvement of protein kinase C and related adhesion focal tyrosine kinase

Glutamate is the major excitatory neurotransmitter in the CNS. Although its role in neurons has been studied extensively, little is known about its function in astrocytes. We studied the effects of glutamate on signaling pathways in primary astrocytes. We found that the tyrosine kinase related adhesion focal tyrosine kinase (RAFTK) is tyrosine phosphorylated in response to glutamate in a time- and dose-dependent manner. This phosphorylation was pertussis toxin (PTX) sensitive and could be attenuated by the depletion of Ca2+ from intracellular stores. RAFTK tyrosine phosphorylation was mediated primarily by class I/II metabotropic glutamate receptors and depends on protein kinase C (PKC) activation. Glutamate treatment of primary astrocytes also results in a significant increase in the activity of the mitogen-activated protein kinases [extracellular signal-related kinases 1/2 (ERK1/2)]. Like RAFTK phosphorylation, ERK1/2 activation is PTX sensitive and can be attenuated by the depletion of intracellular Ca2+ and by PKC inhibition, suggesting that RAFTK might mediate the glutamate-dependent activation of ERK1/2. Furthermore, we demonstrated that glutamate stimulation of primary astrocytes leads to a significant increase in DNA synthesis. Glutamate-stimulated DNA synthesis is PTX sensitive and can be inhibited by the MAP kinase kinase inhibitor PD98059, suggesting that in primary astrocytes, glutamate might signal via RAFTK and MAP kinase to promote DNA synthesis and cell proliferation.     

Treatment-resistant schizophrenia and DAT and SERT polymorphisms

One fifth to one third of all patients diagnosed with schizophrenia are resistant to drug treatment, which makes it a major clinical challenge. Genetic studies have focused on the association between treatment resistant schizophrenia (TRS) and a number of candidate genes, including serotonin and dopamine system genes. We explored associations between carefully characterized TRS and DAT–VNTR, SERT-PR and SERT-in2 polymorphisms. There were 173 patients enrolled in the study that were clinically evaluated using Positive and Negative Syndrome Scale and Clinical Global Impressions Scales and divided into two groups based on treatment resistance (92 patients in TRS group). Patients with a combination of SERT-in2 ll and DAT 9/10, 9/11, 9/9 and 6/6 genotypes were more likely to have TRS, compared to those with 10/10 or 10/12 genotype (OR = 5.1; 95% CI = 1.6–16.8). In the group of patients with DAT 10/10 or 10/12 genotype, those who also shared SERT-in2 ls or ss genotype were more likely to have TRS, compared to ll genotype carriers (OR = 2.7; 95% CI = 1.0–7.0). The model in which interaction between SERT-in2 and DAT polymorphisms is linked to TRS can possibly explain contradictory previous results regarding role of DAT and SERT in TRS, but further research is needed.     

基底节区脑梗塞的神经心理学和听觉事件相关诱发电位的研究

目的：了解基底节区脑梗塞（BGRI）患者发病后记忆力和视空间能力的状况,分析BGRI是否对认知功能产生影响及其特点。方法：通过对21名初发的单侧单灶BGRI及21位年龄、性别、受教育程度相匹配的基本健康志愿者分别进行Rey复杂图形检查（Rey）,临床记忆量表（CMS）、Hospital Anxiety-Depression Scale（HAD）,美国国立卫生研究院卒中量表（NIHSS）、牛津残障量表（OHS）、Barthel指数（BI）及听觉事件相关诱发电位（AERP）的检查。结果：病例组的焦虑及抑郁分值,具有极显著的统计学意义;AERP检查反应时较对照组长,具有显著的统计学意义;在临床记忆量表中,病例组图像自由回忆分测验的量表分和记忆商（MQ）较差,与对照组相比有显著统计学意义。病例组Rey检查中临摹得分、即刻回忆得分和延迟回忆得分与对照组比较无显著性差异。结论：单侧单灶的基底节区脑梗塞可以对执行功能、记忆能力以及情绪造成影响：对视空间功能的影响不大.     

Influences of related retroviruses on lymphocyte functions

Abstract The human immunodeficiency virus (HIV-1) is known to be profoundly immunosuppressive [Spickett and Dalgleish (1988) Clin. Exp. Immunol. 71, 1]. In this communication, we have studied the influences of HIV-1 (BH10), HIV-2 (LAV-2) and STLV-3 on B and T cells from healthy volunteers. B lymphocytes were found to differentiate into immunoglobulin secreting cells in response to stimulation by proteins of HIV-1 and LAV-2, but not by STLV-3. This response was obtained at protein concentrations of 0.05-0.005 μg/ml and was T cell dependent. IgM secretion was induced only by HIV-1 in the EBV-transformed B cell line SKW 6.4. At higher concentrations all three retroviral preparations had inhibitory influences on functions of B as well as T lymphocytes. B cell differentiation was maximally inhibited by HIV-1 and LAV-2 when these proteins were added concurrently to cultures with the polyclonal B cell activators pokeweed mitogen or Epstein-Barr virus. Tetanus antigen-specific T cell lymphoproliferation was inhibited by all retroviral proteins. These findings suggest that related retroviruses differ in their capacity to influence normal immune responses.