鼠疫菌Pgm因子在阿拉善黄鼠体内的突变试验观察

用阿拉善黄鼠(Citellus alsachanicus)鼠疫疫源地的鼠疫菌Pgm~+和Pgm~-株,连续通过阿拉善黄鼠进行传代试验。在传代前后用阿拉善黄鼠测其毒力。Pgm~+株连续传代15代后未发现突变,其主要生化特性、抗原结构和毒力都没有发生改变。而含有0.1～0.3％Pgm~+鼠疫菌个体的Pgm~-株在连续传代5代后即突变为Pgm~+株,且毒力增强。但生化特性和抗原结构仍无改变。纯系Pgm~-株在连续传代8～11代后可突变为Pgm~+株,至20代仍未完全突变为Pgm~+,其他生化特性和抗原结构亦没有改变,但其毒力逐渐增强。作者分析鼠疫菌Pgm细胞突变与阿拉善黄鼠动物鼠疫流行和间歇有密切关系,这对研究该疫源地内鼠疫菌的保存机制及流行病学分析提供了参考资料。     

Immune evasion in HPV− head and neck precancer–cancer transition is driven by an aneuploid switch involving chromosome 9p loss

An aneuploid-immune paradox encompasses somatic copy-number alterations (SCNAs), unleashing a cytotoxic response in experimental precancer systems, while conversely being associated with immune suppression and cytotoxic-cell depletion in human tumors, especially head and neck cancer (HNSC). We present evidence from patient samples and cell lines that alterations in chromosome dosage contribute to an immune hot-to-cold switch during human papillomavirus-negative (HPV⁻) head and neck tumorigenesis. Overall SCNA (aneuploidy) level was associated with increased CD3⁺ and CD8⁺ T cell microenvironments in precancer (mostly CD3⁺, linked to trisomy and aneuploidy), but with T cell-deficient tumors. Early lesions with 9p21.3 loss were associated with depletion of cytotoxic T cell infiltration in TP53 mutant tumors; and with aneuploidy were associated with increased NK-cell infiltration. The strongest driver of cytotoxic T cell and Immune Score depletion in oral cancer was 9p-arm level loss, promoting profound decreases of pivotal IFN-γ-related chemokines (e.g., CXCL9) and pathway genes. Chromosome 9p21.3 deletion contributed mainly to cell-intrinsic senescence suppression, but deletion of the entire arm was necessary to diminish levels of cytokine, JAK-STAT, and Hallmark NF-κB pathways. Finally, 9p arm-level loss and JAK2-PD-L1 codeletion (at 9p24) were predictive markers of poor survival in recurrent HPV⁻ HNSC after anti–PD-1 therapy; likely amplified by independent aneuploidy-induced immune-cold microenvironments observed here. We hypothesize that 9p21.3 arm-loss expansion and epistatic interactions allow oral precancer cells to acquire properties to overcome a proimmunogenic aneuploid checkpoint, transform and invade. These findings enable distinct HNSC interception and precision-therapeutic approaches, concepts that may apply to other CN-driven neoplastic, immune or aneuploid diseases, and immunotherapies.

The genetic bases for predisposition, and neoplastic transformation, to cancer have been increasingly well described. However, it remains less clear how early, precancer cells employ these genetic alterations to acquire the characteristic features and properties (1) of malignant disease. For example, studies of the immune landscape led to breakthrough trials of programmed death-1 (PD-1) inhibitors for recurrent, metastatic head and neck squamous cell carcinoma (HNSC) therapy (2–4). This underscores the importance of immune modulation in these tumors, despite a still suboptimal overall response rate of less than 20% in advanced cancers. Immune response within tumors has been observed to be strongest at the earliest neoplastic stages, as reported recently in lung adenocarcinoma precursors (5). As such, new, immune-based strategies could be developed to reduce the high global burden of HNSC, by intercepting the most common precursor of the most common HNSC presentation: HPV⁻ oral squamous cell carcinomas (6–8).Studies of chromosome somatic copy-number (CN) alteration (SCNA) profiles have reported the impact of 3p14, 9p21, or 17p13 loss in molecular models of HNSC progression (9) and risk (10–15). Early studies reported that patients with oral precancers harboring 9p21 and/or 3p14 loss were at significantly greater cancer risk than those with retention at these loci (10, 16). A comprehensive, prospective validation study examined the relative contribution of six candidate chromosome-arm regions. 9p21 loss had the greatest influence on cancer risk (13). The mechanism underlying the association between CN and malignant transformation of precancers, however, is unclear (17–20). Studies of CN-altered neoplastic cells have shown that SCNAs can trigger a cytotoxic response in experimental precancer systems (21, 22) but, paradoxically, were associated with immune evasion (23) and suppression (24) in computational studies of naturally occurring human cancers. The latter, in melanoma, found that nonresponders to PD-1 and CTLA-4 blockade had higher CN alteration and loss burdens, which correlated with immunologically cold tumors, characterized by cytotoxic-cell, marker, and metric reductions, and suppressive microenvironment cell, network, and signal increases (23–26). This SCNA-cold association was particularly strong in our previous, pan-The Cancer Genome Atlas (TCGA) computational study in HNSC (23). These data point to a putative in vivo switch from immune hot-to-cold in the precancer–cancer transition, and raise the hypothesis that SCNAs in precursor lesions contribute to malignant transformation through genomic events and mechanisms that enable the acquisition of immune-suppressive, evasive properties. To test this hypothesis, we evaluated CN influence on immune profiles and outcomes in a large prospective oral precancer patient cohort, and HPV⁻ HNSC (tissue specimens and cell lines) and anti–PD-1–treated recurrent-disease cohorts.     

心血管病高危与非高危人群的生存质量比较:倾向评分匹配分析

目的探究心血管病高危与非高危人群生存质量差异。方法采用2015-2017年国家心血管病高危人群早期筛查与综合干预项目江苏省项目点调查数据,对调查对象进行问卷调查和体格检查,运用倾向评分匹配分析(PSM)方法,按照1∶1匹配心血管病高危组与非高危组间性别和年龄,采用多重线性回归模型分析心血管病高危对生存质量[欧洲五维度健康量表(EQ-5D)]得分及其中的直观相似尺度(EQ-VAS)评分的影响。结果调查对象40 243(高危组20 839,非高危组19 404)人,倾向评分匹配后得到调查对象31 605(高危组15 948,非高危组15 657)人,EQ-5D指数得分0.97±0.07,EQ-VAS评分79.83±9.36,高危组行动能力、自理能力、日常生活能力和疼痛/不适报告有困难率高于非高危组(1.9%比1.0%、0.6%比0.3%、1.5%比0.8%、16.8%比15.7%,均P<0.05);高危组与非高危组焦虑/不适报告有困难率差异无统计学意义(4.5%比4.4%,P=0.785);女性、高龄、不在婚、初中及以下学历、不吸烟、不饮酒、肥胖、患有高血压、患有血脂异常的调查对象EQ-5D指数得分和EQ-VAS评分低于不在此状态或不患有此疾病人群(P<0.05),家庭年收入≤5万元、患有糖尿病的调查对象EQ-VAS评分低于不在此状态或不患有此疾病人群(P<0.001);多因素线性回归分析显示,调整基本情况和主要慢性病情况后,高危组EQ-VAS评分降低(β=-0.054, 95 CI-1.264^-0.766,P<0.001)。结论高危组人群的EQ-VAS评分低,应关注心血管病高危人群的生存质量。     

Clinical scale isolation of T cell-depleted CD56+ donor lymphocytes in children

We present a clinical scale method for immunomagnetic separation of CD56+ donor natural killer cells for adoptive immunotherapy of pediatric leukemias after allogeneic transplantation. This time-saving and partially automated procedure employed CD56+ selection followed by CD3+ depletion, resulting in a median purity of 98.6% NK cells and a four-log depletion of T cells. The enriched NK cells demonstrated high cytotoxic activity against K562 target cells and fresh leukemic blasts with low HLA class I expression, which could be further enhanced by IL-2 stimulation. Lysis of NK-insensitive leukemic cells with high HLA class I expression could also be demonstrated via ADCC. Due to the high degree of T cell depletion, alloreactive proliferation in mixed lymphocyte cultures and response to T cell-specific mitogen stimulation was profoundly decreased. Our results suggest that, even in the case of mismatched donors, infusions of donor NK cells with extremely low T cell content may be a promising treatment option for leukemic minimal residual disease after allogeneic transplantation without risk of inducing severe GVHD.     

Impact of follow-up visits on disease outcome in Chinese systemic lupus erythematosus

The objective of this study is to determine whether the frequency of visits would affect disease activity and disease damage in patients with systemic lupus erythematosus (SLE). We recruited 147 patients who met the 1997 American College of Rheumatology (ACR) criteria for SLE. Patients were divided into three groups based on follow-up frequency: ≤ 6 visits/year (group 1), 6–12 visits/year (group 2), and > 12 visits/year (group 3). Disease activity and organ damage were evaluated using the SLE disease activity index (SLEDAI) and Systemic Lupus International Collaborative Clinics (SLICC)/ACR criteria, respectively. Data on disease features, patient characteristics, and treatment were retrospectively reviewed. We found that the SLICC score was significantly lower in patients with > 12 visits/year (P = 0.008), while the SLEDAI score showed no significant difference. The age at symptom onset (32.68 ± 13.53) and the age at SLE diagnosis (33.32 ± 13.81) in group 3 were significantly older than those in the other two groups. In univariate regression analysis, the frequency of visits, the age at symptom onset, and the age at SLE diagnosis were found to be associated with the SLICC scores. Visit frequency has no impact on SLE disease activity, but may be associated with less disease damage, an important outcome.     

Effects of Deviant Child Behavior on Parental Alcohol Consumption: Stress-Induced Drinking in Parents of ADHD Children

Distress and ad lib alcohol consumption after interactions with child confederates were investigated in parents of children with externalizing disorders—attention-deficit hyperactivity disorder (ADHD), conduct disorder (CD), or oppositional defiant disorder (ODD). Sixty subjects interacted with boys trained to act like either normal children or children with ADHD/CD/ODD. Interactions with deviant confederates resulted in feelings of inadequacy and produced negative affect but had no effect on alcohol consumption. Post hoc analyses showed that parents with a family history of alcohol problems (FH+) showed increased drinking after interaction with a deviant confederate, compared with FH+ parents who interacted with the normal confederate. FH- parents showed the opposite pattern of results. (Am J Addict 1998; 7:103–114)     

Detection of left ventricular dysfunction after acute myocardial infarction: comparison of clinical, echocardiographic, and neurohormonal methods.

OBJECTIVE--The SAVE study showed that captopril improves mortality in patients with left ventricular dysfunction after myocardial infarction and that this benefit occurred even in patients with no clinically overt heart failure. On the basis of this, it seems important to identify correctly which patients have left ventricular dysfunction after a myocardial infarction. The objective was to compare various methods of identifying patients with left ventricular dysfunction (left ventricular ejection fraction, LVEF, < or = 40%) after acute myocardial infarction. The methods compared were echocardiography (quantitative and qualitative visual assessment), clinical evaluation (subjective assessment and three clinical score methods), and measurement of plasma concentrations of cardiac natriuretic peptide hormones (atrial and brain natriuretic peptides, ANP and BNP). DESIGN--Cross sectional study of left ventricular function in patients two to eight days after acute myocardial infarction. SETTING--Coronary care unit of a teaching hospital. PATIENTS--75 survivors of a recent myocardial infarction aged 40 to 88 with no history of cardiac failure and without cardiogenic shock at the time of entry to the study. MAIN OUTCOME MEASURES--Sensitivities and specificities of the various methods of detecting left ventricular dysfunction were calculated by comparing them with a cross sectional echocardiographic algorithm for LVEF. RESULTS--Clinical impression was poor at identifying LVEF < 40% (sensitivity 46%). Clinical scoring improved this figure somewhat (modified Peel index sensitivity 64%). Qualitative visual assessment echocardiography was a more sensitive method (sensitivity 82%) for detecting LVEF < 40%. Plasma BNP concentration was also a sensitive measure for detecting left ventricular dysfunction (sensitivity 84%) but plasma ANP concentration was much poorer (sensitivity 64%). CONCLUSION--Left ventricular dysfunction is easily and reliably detected by echocardiographic measurement of LVEF and also by a quick qualitative echocardiographic assessment but is likely to be missed by clinical assessment alone. High concentrations of plasma BNP maybe another useful indicator of left ventricular dysfunction, particularly in hospitals where not all patients can be screened by echocardiography or radionuclide ventriculography after myocardial infarction.     

Genetic and environmental control of host-gut microbiota interactions

Genetics provides a potentially powerful approach to dissect host-gut microbiota interactions. Toward this end, we profiled gut microbiota using 16s rRNA gene sequencing in a panel of 110 diverse inbred strains of mice. This panel has previously been studied for a wide range of metabolic traits and can be used for high-resolution association mapping. Using a SNP-based approach with a linear mixed model, we estimated the heritability of microbiota composition. We conclude that, in a controlled environment, the genetic background accounts for a substantial fraction of abundance of most common microbiota. The mice were previously studied for response to a high-fat, high-sucrose diet, and we hypothesized that the dietary response was determined in part by gut microbiota composition. We tested this using a cross-fostering strategy in which a strain showing a modest response, SWR, was seeded with microbiota from a strain showing a strong response, A×B19. Consistent with a role of microbiota in dietary response, the cross-fostered SWR pups exhibited a significantly increased response in weight gain. To examine specific microbiota contributing to the response, we identified various genera whose abundance correlated with dietary response. Among these, we chose Akkermansia muciniphila, a common anaerobe previously associated with metabolic effects. When administered to strain A×B19 by gavage, the dietary response was significantly blunted for obesity, plasma lipids, and insulin resistance. In an effort to further understand host-microbiota interactions, we mapped loci controlling microbiota composition and prioritized candidate genes. Our publicly available data provide a resource for future studies.Studies carried out over the last decade have revealed that gut microbiota contribute to a variety of common disorders, including obesity and diabetes (Musso et al. 2011), colitis (Devkota et al. 2012), atherosclerosis (Wang et al. 2011), rheumatoid arthritis (Vaahtovuo et al. 2008), and cancer (Yoshimoto et al. 2013). The evidence for metabolic interactions is particularly strong, as a large body of data now supports the conclusion that gut microbiota influence the energy harvest from dietary components, particularly complex carbohydrates, and that metabolites such as the short-chain fatty acids produced by gut bacteria can perturb metabolic traits, including adiposity and insulin resistance (Turnbaugh et al. 2006, 2009; Backhed et al. 2007; Wen et al. 2008; Ridaura et al. 2013). Gut microbiota communities are assembled each generation, influenced by maternal seeding, environmental factors, host genetics, and age, resulting in substantial variations in composition among individuals in human populations (Eckburg et al. 2005; Costello et al. 2009; Human Microbiome Project Consortium 2012; Goodrich et al. 2014). Most experimental studies of host-gut microbiota interactions have employed large perturbations, such as comparisons of germ-free versus conventional mice, and the significance of common variations in gut microbiota composition for disease susceptibility is still poorly understood. Furthermore, while studies with germ-free mice have clearly implicated microbiota in clinically relevant traits, it has proven difficult to identify the responsible taxa of bacteria.We now report a population-based analysis of host-gut microbiota interactions in the mouse. One of the issues we explore is the role of host genetics. Although some evidence is consistent with significant heritability of gut microbiota composition, the extent to which the host controls microbiota composition under controlled environmental conditions is unclear. We also examined the role of common variations in gut microbiota in metabolic traits such as obesity and insulin resistance and mapped loci contributing to the abundance of certain microbiota. We performed our study using a resource termed the Hybrid Mouse Diversity Panel (HMDP), consisting of about 100 inbred strains of mice that have been either sequenced or subjected to high-density genotyping (Bennett et al. 2010). The resource has several advantages for genetic analysis as compared to traditional genetic crosses. First, it allows high-resolution mapping by association rather than linkage analysis, and it has now been used for the identification of a number of novel genes underlying complex traits (Farber et al. 2011; Lavinsky et al. 2015; Parks et al. 2015; Rau et al. 2015). Second, since the strains are permanent, the data from separate studies can be integrated, allowing the development of large, publicly available databases of physiological and molecular traits relevant to a variety of clinical disorders (systems.genetics.ucla.edu and phenome.jax.org). Third, the panel is ideal for examining gene-by-environment interactions, since it is possible to examine individuals of a particular genotype under a variety of conditions (Orozco et al. 2012; Parks et al. 2013).     

厄贝沙坦联合氨氯地平对糖尿病高血压合并高尿酸血症患者降压及降尿酸疗效的Meta分析

目的评价厄贝沙坦联合氨氯地平对糖尿病高血压合并高尿酸血症患者控制血压及血尿酸的效果。方法检索"中国知网""万方数据库""维普数据库"2012年1月至2017年7月的文献,查找厄贝沙坦联合氨氯地平治疗糖尿病高血压合并高尿酸血症患者的随机对照试验的中文文献。提取相关数据并应用Stata13.0软件进行Meta分析。结果共纳入10篇中文文献,共有糖尿病高血压合并高尿酸血症患者1029例,其中联合用药组有477例,厄贝沙坦组244例,氨氯地平组308例。经6个月治疗后,联合用药组的收缩压及尿酸水平均低于单独用药组(均差异有统计学意义,P0.05)。结论厄贝沙坦联合氨氯地平对糖尿病高血压合并高尿酸血症患者的血压及尿酸控制效果是高于单独用药的。