Neoadjuvant chemotherapy endows CD9 with prognostic value that differs between tumor and stromal areas in patients with pancreatic cancer

BackgroundThe selective pressure imposed by chemotherapy creates a barrier to tumor eradication and an opportunity for metastasis and recurrence. As a newly discovered stemness marker of pancreatic ductal adenocarcinoma (PDAC), the impact of CD9 on tumor progression and patient''s prognosis remain controversial.MethodsA total of 179 and 211 PDAC patients who underwent surgical resection with or without neoadjuvant chemotherapy, respectively, were recruited for immunohistochemical analyses of CD9 expression in both tumor and stromal areas prior to statistical analyses to determine the prognostic impact and predictive accuracy of CD9.ResultsThe relationship between CD9 and prognostic indicators was not significant in the non‐neoadjuvant group. Nevertheless, CD9 expression in both tumor (T‐CD9) and stromal areas (S‐CD9) was significantly correlated with the clinicopathological features in the neoadjuvant group. High levels of T‐CD9 were significantly associated with worse OS (p = 0.005) and RFS (p = 0.007), while positive S‐CD9 showed the opposite results (OS: p = 0.024; RFS: p = 0.008). Cox regression analyses identified CD9 in both areas as an independent prognostic factor. The T&S‐CD9 risk‐level system was used to stratify patients with different survival levels. The combination of T&S‐CD9 risk level and TNM stage were accurate predictors of OS (C‐index: 0.676; AIC: 512.51) and RFS (C‐index: 0.680; AIC: 519.53). The calibration curve of the nomogram composed of the combined parameters showed excellent predictive consistency for 1‐year RFS. These results were verified using a validation cohort.ConclusionNeoadjuvant chemotherapy endows CD9 with a significant prognostic value that differs between tumor and stromal areas in patients with pancreatic cancer.     

Global Pattern and Trends in Penile Cancer Incidence: Population-Based Study

BackgroundPenile cancer is a relatively rare genital malignancy whose incidence and mortality are rising in many countries.ObjectiveThis study aims to assess the recent incidence and mortality patterns and incidence trends of penile cancer.MethodsThe age-standardized incidence and mortality rates (ASIR and ASMR, respectively) of penile cancer in 2020 were estimated from the Global Cancer Registries (GLOBOCAN) database. Incidence trends of penile cancer from 1973 to 2012 were assessed in 44 populations from 43 countries using the Cancer Incidence in Five Continents plus (CI5plus) and the Nordic Cancer Registries (NORDCAN) databases. Average annual percentage change was calculated to quantify trends in ASIR using joinpoint regression.ResultsGlobally, the estimated ASIR and ASMR of penile cancer were 0.80 (per 100,000) and 0.29 (per 100,000) in 2020, equating to 36,068 new cases and 13,211 deaths in 2020, respectively. There was no significant correlation between the ASIR (P=.05) or ASMR (P=.90) and Human Development Index. In addition, 15 countries saw increasing ASIR for penile cancer, 13 of which were from Europe (United Kingdom, Lithuania, Norway, Estonia, Finland, Sweden, Cyprus, Netherlands, Italy, Croatia, Slovakia, Russia, and the Czech), and 2 from Asia (China and Israel).ConclusionsAlthough the developing countries still bear the higher incidence and mortality of penile cancer, the incidence is on the rise in most European countries. To mitigate the disease burden resulting from penile cancer, measures to lower the risk for penile cancers, including improving penile hygiene and male human papillomavirus vaccination, may be warranted.     

Distinct histopathological phenotypes of severe alcoholic hepatitis suggest different mechanisms driving liver injury and failure

Intrahepatic neutrophil infiltration has been implicated in severe alcoholic hepatitis (SAH) pathogenesis; however, the mechanism underlying neutrophil-induced injury in SAH remains obscure. This translational study aims to describe the patterns of intrahepatic neutrophil infiltration and its involvement in SAH pathogenesis. Immunohistochemistry analyses of explanted livers identified two SAH phenotypes despite a similar clinical presentation, one with high intrahepatic neutrophils (Neu^hi), but low levels of CD8⁺ T cells, and vice versa. RNA-Seq analyses demonstrated that neutrophil cytosolic factor 1 (NCF1), a key factor in controlling neutrophilic ROS production, was upregulated and correlated with hepatic inflammation and disease progression. To study specifically the mechanisms related to Neu^hi in AH patients and liver injury, we used the mouse model of chronic-plus-binge ethanol feeding and found that myeloid-specific deletion of the Ncf1 gene abolished ethanol-induced hepatic inflammation and steatosis. RNA-Seq analysis and the data from experimental models revealed that neutrophilic NCF1-dependent ROS promoted alcoholic hepatitis (AH) by inhibiting AMP-activated protein kinase (a key regulator of lipid metabolism) and microRNA-223 (a key antiinflammatory and antifibrotic microRNA). In conclusion, two distinct histopathological phenotypes based on liver immune phenotyping are observed in SAH patients, suggesting a separate mechanism driving liver injury and/or failure in these patients.     

305例三阴乳腺癌患者的临床特征及预后因素分析

背景与目的:三阴乳腺癌(triple-negative breast cancer)指雌激素受体(estrogen receptor,ER)、孕激素受体(progesterone receptor,PR)和HER2/neu均无表达的乳腺癌,被认为是一种独立的临床病理类型,以侵袭性强、预后较差为主要特征的乳腺癌。本研究目的在于分析三阴乳腺癌的临床特征和影响预后的因素。方法:收集2000年1月至2004年12月中山大学肿瘤防治中心收治的经病理组织学证实、有完整随访资料的1280例可手术乳腺癌患者的临床资料,经病理学检查证实ER、PR和HER2/neu均为阴性的三阴乳腺癌305例(23.8%)。回顾性分析三阴乳腺癌患者的临床特征、复发及生存情况。结果:本组乳腺癌患者中有23.8%(305/1280)是三阴乳腺癌,多见于年轻患者,诊断时肿块较大、局部淋巴结阳性者较多,有乳腺癌家族史的患者较多。截止至2007年6月,三阴乳腺癌组患者中位随访时间为52个月(28～89个月),有234例患者出现复发及转移,94例已死亡。三阴乳腺癌组局部复发率与非三阴乳腺癌患者相比无显著性差异;但三阴乳腺癌患者远处转移发生率显著增高,主要表现肺转移(HR=4.41,P<0.001)和肝转移(HR=2.13,P=0.006)发生率高。生存分析显示,三阴乳腺癌患者的5年无病生存率和总生存率分别为73.7%和88.5%,均显著低于非三阴乳腺癌患者(80.8%和92.8%,P=0.025,P=0.010)。多因素分析显示,肿块大小和淋巴结状况是影响三阴乳腺癌预后的两个主要因素。结论:三阴乳腺癌在乳腺癌中占有约1/4的比例。这些患者往往年轻、有乳腺癌家族史、肿块较大、淋巴结阳性多。三阴乳腺癌容易出现肺转移和肝转移,这可能是导致三阴乳腺癌预后较差的重要原因。     

SB203580和WP631对照射后肺成纤维细胞内Smad通路信号转导的影响

背景与目的:放射性肺纤维化以成纤维细胞增殖和细胞外基质过度沉积为特征.转化生长因子β1 (transforming growth factor β1,TGFβ1)是放射性肺纤维化发生发展的"开关"性分子并被作为治疗的靶分子,因此阻断TGFβ1的信号转导可能减轻肺纤维化.本研究检测Smad通路抑制剂SB203580和WP631对照射后人肺成纤维细胞(human lung fibroblast, HLF)中信号转导的影响并探讨其效应.方法:将HLF用25μmol/L SB203580和5nmol/L WP631预处理后,再应用3 Gy 60co γ射线照射和10μg/L TGFβ1 刺激,通过凝胶阻滞电泳(electrophoretic mobility shift assay, EMSA)、免疫印迹、免疫组织化学及细胞周期流式细胞仪检测等方法检测转录因子SP1和AP1活性的变化、Smad3,4,7和p-Smad3 及Ⅰ型胶原和Ⅰ型组织纤溶酶原激活物抑制剂 (typeⅠplasminogen activator inhibitor,PAI-1)的表达变化及细胞周期的变化.结果:经3 Gy γ射线照射及TGFβ1 刺激后,与未经预处理的HLF相比,应用SB203580或WP631预处理的HLF出现G2-M 期阻滞,S期细胞显著减少.SB203580预处理可减少HLF中P21WAF1/CIP1和p-Smad3的表达,而WP631预处理可减少HLF表达PAI-1,抑制转录因子SP1和AP1的活化.结论:SB203580和WP631通过阻断TGFβ-Smad通路的信号转导,抑制γ射线和TGFβ1 作用所导致的HLF过度增殖和P21WAF1/CIP1及PAI-1表达增多.     

40例原发性胃肠道弥漫大B细胞淋巴瘤临床特征、细胞来源与预后分析

背景与目的:原发性胃肠道弥漫大B细胞淋巴瘤(primary gastrointestinal diffuse large B-cell lymphoma,PGI-DLBCL)的发病部位及其临床表现与胃肠道其它肿瘤性疾病难以鉴别,误诊率较高,且其标准治疗的方法仍未确定。本研究旨在分析PGI-DLBCL的临床特征、肿瘤细胞来源及预后,并探讨有效的联合治疗方法。方法:分析我院1998～2007年诊治的40例PGI-DLBCL,应用Kaplan-Meier法、log-rank检验和Cox回归模型对其临床资料和实验室检测结果进行生存分析及单因素和多因素预后分析。通过免疫组化染色分析34例患者的肿瘤细胞来源。治疗方法包括联合化疗、手术 联合化疗及放疗、单纯手术等,联合化疗方案为CHOP及CHOP样方案。结果:40例PGI-DLBCL患者中,年龄10～89岁中位年龄56.5岁,男女比例1.86∶1,胃与肠道的发病比率为1.05∶1。预后分析可追访病例38例中,死亡12例(31.6%),3年和5年生存率均为64.7%。9例多部位发病的患者中,8例(88.9%)在3年内死亡。9例(26.5%)肿瘤细胞来源于生发中心(germinal center,GC),25例(73.5%)来源于非生发中心(non-germinal center,non-GC)。单因素预后分析发现肿瘤细胞来源、国际预后指数(international prognosis index,IPI)、B症状对生存率的影响有显著性(P<0.05)。Cox多因素预后分析显示血清乳酸脱氢酶(LDH)升高组患者的死亡风险是LDH正常组的2.87倍。结论:PGI-DLBCL发病以中年男性为主,多部位发病是该类患者死亡的重要原因。肿瘤细胞来源、IPI、B症状对预测患者生存和指导治疗有重要作用,其中初诊时血清LDH水平升高是本组患者的独立预后因素。     

大剂量甲氨蝶呤静脉给药时间对淋巴瘤患者脑脊液中药物浓度的影响

背景与目的:甲氨蝶呤(methotrexate,MTX)在脑脊液中高于最小有效治疗浓度是治疗中枢淋巴瘤的必要条件,目前尚不明确大剂量MTX(high doseMTX,HD-MTX)静脉给药时间对MTX穿透血脑屏障的影响.本研究探索HD-MTX静脉不同给药时间对脑脊液中MTX浓度的影响,以获得更好的中枢淋巴瘤防治效果并尽可能减少MTX外周毒性.方法:34例非霍奇金淋巴瘤患者分别接受MTX 1～3g/m2 6 h持续静脉给药或24 h持续静脉给药,其中17例交替使用两种给药方法;采用高效液相色谱法检测MTX停药0 h、24 h、48 h的MTX血清浓度,及停药0 h后脑脊液中MTX浓度;比较两组血中和脑脊液中MTX浓度以及毒性反应,并对影响MTX浓度的因素进行相关分析.结果:给药结束时6 h给药组的MTX血清浓度显著高于24 h给药组:自身对照结果6 h给药组的脑脊液中MTX浓度为0.70 Ixmol/L,明显高于24 h给药组的0.49 Ixmol/L(校正值,P=0.044).MTX的脑脊液浓度与血清浓度呈正相关,中枢侵犯患者脑脊液MTX浓度显著高于无中枢侵犯的患者.自身对照结果6 h组和24 h组Ⅱ～Ⅳ度粘膜炎的发生率分别15.4%和37.8%.Ⅲ～Ⅳ度骨髓抑制的发生率分别为46.2%和67.6%.结论:在提高MTX的中枢浓度和降低外周毒性方面,HD-MTX 6 h给药方案优于24 h给药方案.     

串联质谱分析干血滤纸片中酰基肉碱质控

目的：串联质谱技术是近几年应用于临床检验的新技术,具有特异性强、灵敏度高,一次试验可检测数十种物质的优点。本文通过对近4年的质控结果进行分析,探讨影响检测结果的因素及应对措施。方法：美国CDC每年提供4批酰基肉碱质控干血滤纸片,酰基肉碱检测方法为取直径为3mm的质控干血滤纸片放入96孔聚丙烯板,经含酰基肉碱内标的甲醇萃取,盐酸正丁醇衍生后,进行串联质谱检测。分析本实验室质控结果与美国CDC检测结果的偏差及其他实验室质控结果（169个实验室的均值）与美国CDC检测结果的偏差之间的差异。结果：本实验室每次质控结果所有酰基肉碱均在美国CDC检测结果95％可信区间内,且每一批结果的临床评价与美国CDC质控临床评价完全一致。本实验室质控结果与美国CDC检测结果的偏差与其他实验室质控结果与美国CDC检测结果的偏差比较,无显著差异,丙酰基肉碱差异显著（Z=-2．638,P〈0．005）,戊二酰基肉碱差异亦显著（Z=-2．482,P〈0．005）。结论：本实验室酰基肉碱质控结果,达到美国CDC的质控要求,丙酰基肉碱检测值偏高,其阳性判断切割值设定也相应增高,而戊二酰基肉碱检测值偏低,其阳性判断切割值设定也相应降低。     

Synergistic integration of metal nanoclusters and biomolecules as hybrid systems for therapeutic applications

Therapeutic nanoparticles are designed to enhance efficacy, real-time monitoring, targeting accuracy, biocompatibility, biodegradability, safety, and the synergy of diagnosis and treatment of diseases by leveraging the unique physicochemical and biological properties of well-developed bio-nanomaterials. Recently, bio-inspired metal nanoclusters (NCs) consisting of several to roughly dozens of atoms (<2 nm) have attracted increasing research interest, owing to their ultrafine size, tunable fluorescent capability, good biocompatibility, variable metallic composition, and extensive surface bio-functionalization. Hybrid core–shell nanostructures that effectively incorporate unique fluorescent inorganic moieties with various biomolecules, such as proteins (enzymes, antigens, and antibodies), DNA, and specific cells, create fluorescently visualized molecular nanoparticle. The resultant nanoparticles possess combinatorial properties and synergistic efficacy, such as simplicity, active bio-responsiveness, improved applicability, and low cost, for combination therapy, such as accurate targeting, bioimaging, and enhanced therapeutic and biocatalytic effects. In contrast to larger nanoparticles, bio-inspired metal NCs allow rapid renal clearance and better pharmacokinetics in biological systems. Notably, advances in nanoscience, interfacial chemistry, and biotechnologies have further spurred researchers to explore bio-inspired metal NCs for therapeutic purposes. The current review presents a comprehensive and timely overview of various metal NCs for various therapeutic applications, with a special emphasis on the design rationale behind the use of biomolecules/cells as the main scaffolds. In the different hybrid platform, we summarize the current challenges and emerging perspectives, which are expected to offer in-depth insight into the rational design of bio-inspired metal NCs for personalized treatment and clinical translation.Key words: Metal nanoclusters, Biomolecule, Nanoparticles, Hybrid system, Synergistic properties, Fluorescence, Bioprobe, Therapy