Human BUBR1 is a mitotic checkpoint kinase that monitors CENP-E functions at kinetochores and binds the cyclosome/APC.

Human cells express two kinases that are related to the yeast mitotic checkpoint kinase BUB1. hBUB1 and hBUBR1 bind to kinetochores where they are postulated to be components of the mitotic checkpoint that monitors kinetochore activities to determine if chromosomes have achieved alignment at the spindle equator (Jablonski, S.A., G.K.T. Chan, C.A. Cooke, W.C. Earnshaw, and T.J. Yen. 1998. Chromosoma. 107:386-396). In support of this, hBUB1 and the homologous mouse BUB1 have been shown to be important for the mitotic checkpoint (Cahill, D.P., C. Lengauer, J. Yu, G.J. Riggins, J.K. Willson, S.D. Markowitz, K.W. Kinzler, and B. Vogelstein. 1998. Nature. 392:300-303; Taylor, S.S., and F. McKeon. 1997. Cell. 89:727-735). We now demonstrate that hBUBR1 is also an essential component of the mitotic checkpoint. hBUBR1 is required by cells that are exposed to microtubule inhibitors to arrest in mitosis. Additionally, hBUBR1 is essential for normal mitotic progression as it prevents cells from prematurely entering anaphase. We establish that one of hBUBR1's checkpoint functions is to monitor kinetochore activities that depend on the kinetochore motor CENP-E. hBUBR1 is expressed throughout the cell cycle, but its kinase activity is detected after cells have entered mitosis. hBUBR1 kinase activity was rapidly stimulated when the spindle was disrupted in mitotic cells. Finally, hBUBR1 was associated with the cyclosome/anaphase-promoting complex (APC) in mitotically arrested cells but not in interphase cells. The combined data indicate that hBUBR1 can potentially provide two checkpoint functions by monitoring CENP-E-dependent activities at the kinetochore and regulating cyclosome/APC activity.     

酿酒酵母S期检查点通路上web2基因与rad53基因的位置关系

为探讨酿酒酵母(S.cerevisiae)S期检查点通路上,web2(wants E1A badly2,web2)基因与rad53基因的上下游位置及相互作用关系,利用羟基脲(hydroxyurea,HU)分别阻断web2突变株和野生株细胞的DNA合成.采用pHA- rad53质粒救助实验测定质粒源性Rad53蛋白是否能救助web2突变株对羟基脲的敏感性;Western印迹及免疫共沉淀反应检测Rad53蛋白表达及磷酸化.结果显示,pHA-rad53质粒可以救助web2突变株的存活;Western印迹检测到web2突变株内质粒源性Rad53蛋白表达增强而且至少Rad53部分蛋白为磷酸化蛋白.说明在HU作用下,过表达并磷酸化的质粒源性Rad53蛋白可以救助web2突变株的S期检查点功能缺陷,在酿酒酵母S期检查点通路上web2基因位于rad53基因上游,可能直接参与将检查点信号传递至Rad53蛋白.     

Radiation combines with immune checkpoint blockade to enhance T cell priming in a murine model of poorly immunogenic pancreatic cancer

Radiation has been a pillar of cancer therapy for decades. The effects of radiation on the anti-tumour immune response are variable across studies and have not been explicitly defined in poorly immunogenic tumour types. Here, we employed combination checkpoint blockade immunotherapy with stereotactic body radiation therapy and examined the effect on tumour growth and immune infiltrates in subcutaneous and orthotopic mouse models of pancreatic cancer. Although immune checkpoint blockade and radiation were ineffective alone, their combination produced a modest growth delay in both irradiated and non-irradiated tumours that corresponded with significant increases in CD8+ T cells, CD4+ T cells and tumour-specific T cells as identified by IFNγ ELISpot. We conclude that radiation enhances priming of tumour-specific T cells in poorly immunogenic tumours and that the frequency of these T cells can be further increased by combination with immune checkpoint blockade.     

Age‐dependent integrity of the meiotic spindle assembly checkpoint in females requires Aurora kinase B

A hallmark of advanced maternal age is a significant increase in meiotic chromosome segregation errors, resulting in early miscarriages and congenital disorders. These errors most frequently occur during meiosis I (MI). The spindle assembly checkpoint (SAC) prevents chromosome segregation errors by arresting the cell cycle until proper chromosome alignment is achieved. Unlike in mitosis, the SAC in oocytes is desensitized, allowing chromosome segregation in the presence of improperly aligned chromosomes. Whether SAC integrity further deteriorates with advancing maternal age, and if this decline contributes to increased segregation errors remains a fundamental question. In somatic cells, activation of the SAC depends upon Aurora kinase B (AURKB), which functions to monitor kinetochore–microtubule attachments and recruit SAC regulator proteins. In mice, oocyte‐specific deletion of AURKB (Aurkb cKO) results in an increased production of aneuploid metaphase II‐arrested eggs and premature age‐related infertility. Here, we aimed to understand the cause of the short reproductive lifespan and hypothesized that SAC integrity was compromised. In comparing oocytes from young and sexually mature Aurkb cKO females, we found that SAC integrity becomes compromised rapidly with maternal age. We show that the increased desensitization of the SAC is driven by reduced expression of MAD2, ZW10 and Securin proteins, key contributors to the SAC response pathway. The reduced expression of these proteins is the result of altered protein homeostasis, likely caused by the accumulation of reactive oxygen species. Taken together, our results demonstrate a novel function for AURKB in preserving the female reproductive lifespan possibly by protecting oocytes from oxidative stress.     

免疫系统中编程性细胞死亡的分子机制

免疫系统中编程性细胞死亡的分子机制郑德先（中国医学科学院基础医学研究所医学分子生物学国家重点实验室,血液学研究所实验血液学国家重点实验室）免疫细胞从其前体细胞发育成熟到抗原应答反应过程中,始终伴随着编程性细胞死亡（ｐｒｏｇｒａｍｍｅｄｃｅｌｌｄｅａｔｈ,ＰＣＤ）或细胞凋亡（ａｐｏｐｔｏｓｉｓ）。没有免疫细胞的编程性死亡,机体就没有健全的免疫防御体系。     

帕博利珠单抗联合培美曲塞和卡铂治疗晚期非鳞状非小细胞肺癌的疗效及对肿瘤标志物和细胞免疫功能的影响

摘要 目的：探讨卡铂和培美曲塞联合帕博利珠单抗治疗对晚期非鳞状非小细胞肺癌（NSCLC）细胞免疫功能和肿瘤标志物的影响。方法：选取2018年10月~2021年2月期间徐州医科大学附属医院收治的78例晚期非鳞状NSCLC患者,按照随机数字表法分为对照组（n=39,接受培美曲塞联合卡铂治疗）和联合组（n=39,在对照组的基础上接受帕博利珠单抗治疗）。对比两组疗效、肿瘤标志物水平、细胞免疫功能指标、不良反应发生情况。结果：联合组的客观缓解率、疾病控制率均高于对照组（P<0.05）。两组不良反应发生率对比无差异（P>0.05）。治疗后,两组癌胚抗原（CEA）、细胞角蛋白19片段（CYFRA21-1）、糖类抗原125（CA125）水平下降,且联合组低于对照组（P<0.05）。治疗后,两组CD3⁺、CD4⁺、CD4⁺/CD8⁺下降,但联合组高于对照组（P<0.05）;治疗后,两组CD8⁺升高,但联合组低于对照组（P<0.05）。结论：帕博利珠单抗联合培美曲塞和卡铂治疗晚期非鳞状NSCLC,可有效控制疾病进展,改善患者免疫功能,降低CEA、CYFRA21-1、CA125水平。     

免疫增强型肠内营养对老年重症肺炎患者营养状态、肺功能及体液免疫指标的影响

摘要 目的：探讨免疫增强型肠内营养对老年重症肺炎（SP）患者营养状态、肺功能及体液免疫指标的影响。方法：选取我院2021年1月至2023年1月104例老年SP患者作为研究对象,按随机抽签法随机分为对照组和观察组各52例,对照组采用常规肠内营养支持,观察组采用免疫增强型肠内营养支持。比较两组组患者症状及体征恢复时间,治疗前后的病情严重程度、肺炎严重指数、肺功能、营养状态、体液免疫指标。结果：观察组发热、咳嗽、肺部啰音、X线阴影消失时间短于对照组（P＜0.05）;治疗后观察组急性生理与慢性健康评估（APACHE Ⅱ）评分低于对照组（P＜0.05）;治疗后观察组肺炎危险分级优于对照组（P＜0.05）;治疗后观察组总蛋白（TP）、前白蛋白（PA）、白蛋白（ALB）、转铁蛋白（TRF）水平高于对照组（P＜0.05）;治疗后观察组肺动态顺应性（Cdyn）高于对照组,气道阻力（R）低于对照组（P＜0.05）;治疗后观察组免疫球蛋白A（IgA）、免疫球蛋白M（IgM）、免疫球蛋白G（IgG）、补体C3、补体C4水平高于对照组（P＜0.05）。结论：免疫增强型肠内营养支持能加速老年SP患者临床症状及体征缓解,改善其病情、肺炎严重程度及肺功能,提升患者的免疫能力和营养水平,有一定临床应用价值。     

丝氨酸蛋白酶抑制剂(SERPIN)家族相关基因在结肠腺癌中预后模型的建立及应用

应用生物信息学方法,构建结肠腺癌(COAD)丝氨酸蛋白酶抑制剂(SERPIN)家族相关基因预后模型。从TCGA数据库和GEO数据库下载结肠腺癌(COAD)转录组和临床数据,根据数据中SERPINs家族基因的表达量对COAD患者进行一致性聚类分析;将数据随机均分为训练集(Train)组和验证集(Test)组,基于两个亚型的差异基因,利用Train组进行COX回归和Lasso回归构建预后模型,根据模型风险评分中位值将样本分为高、低风险两组,绘制高低风险组患者生存曲线;通过ROC曲线评价模型预测能力;利用Test组数据验证模型;构建列线图,评估患者生存率模型预测值与实际值的一致性;并利用利用ESTIMATE算法和CIBERSORT算法评估风险评分和肿瘤微环境(TME)以及免疫浸润的相关性。通过34个SERPIN基因确定了两个亚型,基于2个亚型筛选出了436个预后相关分型差异基因,通过Lasso回归确定出了11个预后相关基因参与风险模型的构建,根据模型评分区分的高低风险组具有明显的生存差异,列线图可以准确预测1、3和5年生存率。肿瘤微环境分析和免疫浸润分析显示高风险评分组患者免疫活性差。SERPIN家族相关基因构建的风险评分模型能够预测COAD的预后,有利于进一步指导临床对COAD的诊治,提高患者生存率。     

肿瘤治疗中免疫检查点抑制剂相关的感染并发症

近年来,免疫检查点抑制剂(immune checkpoint inhibitors,ICI)作为肿瘤免疫治疗的重要方法之一受到了广泛关注.针对细胞毒性T淋巴细胞抗原4、程序性死亡受体1和程序性死亡配体1的ICI,其临床应用为黑色素瘤和其他肿瘤的治疗带来了希望.目前没有证据表明ICI会直接增加感染的风险,但因免疫功能上调...