A DNA vaccine expressing an optimized secreted FAPα induces enhanced anti-tumor activity by altering the tumor microenvironment in a murine model of breast cancer

Cancer-associated fibroblasts (CAFs), major components of the tumor microenvironment (TME), promote tumor growth and metastasis and inhibit the anti-tumor immune response. We previously constructed a DNA vaccine expressing human FAPα, which is highly expressed by CAFs, to target these cells in the TME, and observed limited anti-tumor effects in the 4T1 breast cancer model. When the treatment time was delayed until tumor nodes formed, the anti-tumor effect of the vaccine completely disappeared. In this study, to improve the safety and efficacy, we constructed a new FAPα-targeted vaccine containing only the extracellular domain of human FAPα with a tissue plasminogen activator signal sequence for enhanced antigen secretion and immunogenicity. The number of CAFs was more effectively reduced by CD8⁺ T cells induced by the new vaccine. This resulted in decreases in CCL2 and CXCL12 expression, leading to a significant decrease in the ratio of myeloid-derived suppressor cells in the TME. Moreover, when mice were treated after the establishment of tumors, the vaccine could still delay tumor growth. To facilitate the future application of the vaccine in clinical trials, we further optimized the gene codons and reduced the homology between the vaccine and the original sequence, which may be convenient for evaluating the vaccine distribution in the human body. These results indicated that the new FAPα-targeted vaccine expressing an optimized secreted human FAPα induced enhanced anti-tumor activity by reducing the number of FAPα⁺ CAFs and enhancing the recruitment of effector T cells in the 4T1 tumor model mice.     

Genetic and epigenetic alterations of the EGFR and mutually independent association with BRCA1, MGMT,and RASSF1A methylations in Vietnamese lung adenocarcinomas

Genetic and epigenetic alterations importantly contribute to the pathogenesis of lung cancer. In the study, we measured the frequency and distribution of molecular abnormalities of EGFR as well as the aberrant promoter methylations of BRCA1, MGMT, MLH1, and RASSF1A in Vietnamese lung adenocarcinomas. We investigated the association between genetic and epigenetic alteration, and between each abnormality with clinicopathologic parameters. Somatic EGFR mutation that was found in 49/139 (35.3%) lung adenocarcinomas showed a significant association with young age, female gender, and non-smokers. EGFR overexpression was identified in 82 tumors (59.0%) and statistical relationships with EGFR or BRCA1 methylation but not EGFR mutation. In addition, EGFR, BRCA1, MGMT, MLH1, and RASSF1A methylations were found in 33 (23.7%), 41 (29.5%), 46 (33.1%), 28 (20.1%), and 41 (29.5%) cases of a total of 139 lung adenocarcinomas, respectively. The RASSF1A methylation was found to be linked to the smoking habit. Methylations in MGMT and RASSF1A were also found to correlate with metastasis status. Furthermore, the distribution of EGFR mutation and that of BRCA1, MGMT or RASSF1A methylation were significantly exclusive in lung adenocarcinomas. The main finding of our study demonstrate that epigenetic abnormalities might play a critical role for the lung tumorigenesis in patients with smoking history and metastasis, and partly affect the predictive value of EGFR mutations through blocking expression due to promoter EGFR hypermethylation. Mutually exclusive distribution of genetic and epigenetic alterations reflects differently biological characteristics in the etiology of lung adenocarcinomas.     

我国血吸虫对吡喹酮抗药性研究之概要

血吸虫病是一种严重危害人类健康、影响社会经济发展的重大传染病,为全球公共卫生负担和危害最严重的被忽视的热带病之一。吡喹酮是20世纪70年代研制出的一种高效、低毒、价廉的广谱抗蠕虫口服药,为世界卫生组织（WHO）推荐的抗血吸虫的首选药物。吡喹酮在血吸虫病流行区现场大规模反复使用已超过40年,血吸虫是否会对吡喹酮产生抗药性引起国际社会极大担忧,为学术界关注的热点科学问题。针对血吸虫病防治中这一重大需求,自1996年起, 在国家科技支撑计划、国家自然科学基金、江苏省自然科学基金等项目基金资助下,我们在血吸虫病流行区现场和实验室,对血吸虫在吡喹酮药物的压力是否会产生抗药性、抗性虫株的生物学特性、抗性的检测、吡喹酮抗性的交叉抗药性及抗药性的预防和控制等科学问题进行较为系统的研究,本文就其研究及其意义作一概述。     

Synthesis of 13C-labeled parabens from isotopically enriched phenols using the Houben–Hoesch reaction

Parabens are antimicrobial additives found in a wide array of consumer products. However, the halogenated compounds formed from parabens during wastewater disinfection are a potential environmental concern. In order to identify these transformation products and investigate their mechanism of formation, a synthetic route to ethyl parabens labeled with the stable isotope carbon-13 at specific positions within the benzene ring was developed. This efficient two-step procedure starts from commercially available ¹³C-labeled phenols and involves (1) initial acylation of the phenol via a Houben–Hoesch reaction with trichloroacetonitrile followed by (2) a modified haloform reaction of the resulting trichloromethyl ketone to afford the corresponding ¹³C-labeled ethyl parabens in 65%–80% overall yield. The scope of the modified haloform reaction was also investigated, allowing for the synthesis of other parabens derived from primary or secondary alcohols, including ¹³C- and deuterium-labeled esters. In addition, 4-hydroxybenzoic acid can be formed directly from the common trichloromethyl ketone intermediate upon treatment with lithium hydroxide. This protocol complements existing methods for preparing ¹³C-labeled paraben derivatives and offers the specific advantages of exhibiting complete regioselectivity in the Houben–Hoesch reaction (to form the para-disubstituted product) and avoiding the need for protecting groups in the modified haloform reaction that forms the paraben esters.     

Paradox of complex diversity: Challenges in the diagnosis and management of bacterial keratitis

Bacterial keratitis continues to be one of the leading causes of corneal blindness in the developed as well as the developing world, despite swift progress since the dawn of the “anti-biotic era”. Although, we have expeditiously developed our understanding about the different causative organisms and associated pathology leading to keratitis, extensive gaps in knowledge continue to dampen the efforts required for early and accurate diagnosis, and management in these patients, resulting in poor clinical outcomes. The ability of the causative bacteria to subdue the therapeutic challenge stems from their large genome encoding complex regulatory networks, variety of unique virulence factors, and rapid secretion of tissue damaging proteases and toxins.In this review article, we provide an overview of the established diagnostic techniques and therapeutics for keratitis caused by various bacteria. We extensively report the recent in-roads through novel tools for accurately diagnosing mono- and poly-bacterial corneal infections. Furthermore, we outline the recent progress by our groups and others in understanding the sub-cellular genomic changes that lead to antibiotic resistance in these organisms. Finally, we discuss in detail, the novel therapies and drug delivery systems in development for the efficacious management of bacterial keratitis.     

Survival and Outcomes of Newly Diagnosed Multiple Myeloma Patients Stratified by Transplant Status 2007-2018: Retrospective Analysis from the Canadian Myeloma Research Group Database

BackgroundConsiderable progress has been made in therapeutic options for multiple myeloma (MM). Understanding the current landscape of MM treatment options and associated outcomes in the real world is important in providing key insights into clinical and knowledge gaps which could be targeted for further optimization.MethodsThe Canadian Myeloma Research Group Database (CMRG-DB) is a prospectively maintained disease-specific database with >7000 patients. The objective of this study was to describe the trends in the treatment landscape and outcomes including early mortality, time to next treatment, and overall survival (OS) in each line of treatment stratified by autologous stem cell transplant (ASCT) receipt among newly-diagnosed MM patients in Canada between 2007 and 2018.ResultsA total of 5154 patients were identified among which 3030 patients (58.8%) received an upfront ASCT and 2124 (41.2%) did not. At diagnosis, the median age was 64 years and 58.6% were males. Bortezomib and lenalidomide were most frequently used (>50%) in first and second-line treatment respectively among both the ASCT and non-ASCT cohort. The median OS was 122.0 months (95% Cl 115.0-135.0 months) and 54.3 months (95% CI 50.8-58.8 months) for the ASCT and non-ASCT cohort respectively with an incremental decrease in OS in each subsequent line of treatment.ConclusionWe present the largest study to date in the Canadian landscape showing the characteristics, therapy usage, and outcomes among MM patients. This information will be critical in benchmarking current outcomes and provide key insight into areas of unmet needs and gaps for improvement of MM patients nationally.     

Challenges facing HIV-positive persons who use drugs and their families in Vietnam

It is hypothesized that persons who use drugs (PWUD) in Vietnam who are also HIV-positive may face additional challenges in psychosocial outcomes, and these challenges may extend to their family members. In this study, we examined depressive symptoms, stigma, social support, and caregiver burden of HIV-positive PWUD and their family members, compared to the outcomes of HIV-negative PWUD and their family members. Baseline, 3-month, and 6-month assessment data were gathered from 83 PWUD and 83 family members recruited from four communes in Phú Th? Province, Vietnam. For PWUD, although we observed a general decline in overall stigma over time for both groups, HIV-positive PWUD consistently reported significantly higher overall stigma for all three periods. Depressive symptoms among family members in both groups declined over time; however, family members of HIV-positive PWUD reported higher depressive symptoms across all three periods. In addition, family members of HIV-positive PWUD reported lower levels of tangible support across all three periods. Caregiver burden among family members of HIV-positive PWUD increased significantly over time, whereas the reported burden among family members of HIV-negative PWUD remained relatively unchanged. The findings highlight the need for future interventions for PWUD and family members, with targeted and culturally specific strategies to focus on the importance of addressing additional stigma experienced by PWUD who are HIV-positive. Such challenges may have direct negative impact on their family members' depressive symptoms, tangible support, and caregiver burden.     

新型冠状病毒肺炎免疫治疗药物托珠单抗的作用机制及安全性风险分析

目的分析托珠单抗的安全性风险,为临床合理用药提供参考。方法对世界卫生组织药品不良反应监测数据库、我国药品不良反应监测数据库、国内文献数据库中的不良反应报告情况及国外药监机构风险控制措施等相关资料进行整理与分析。结果应重视托珠单抗临床使用中可能发生的肝功能异常、皮肤损害、过敏反应、胃肠道损害、感染、血液系统损害等不良反应。结论托珠单抗临床使用中,应加强对严重感染及肝功能损害等严重不良反应的安全性监测,促进药品的临床合理使用。