The role of investigative molecular toxicology in early stage drug development

Molecular toxicology, the application of molecular biology principles and technologies to preclinical safety assessment, represents a key tool for understanding mechanisms of toxicity and assessing the risks associated with specific toxicities. The application of gene expression markers to early stage preclinical safety assessment has the potential to impact pipelines in two main areas: lead optimisation and issue management. Lead optimisation focuses on deprioritising leads with significant, development-limiting toxicological liabilities while advancing those compounds with the greatest chance of successfully navigating the gauntlet of preclinical and clinical safety studies. Issue management utilises mechanistic toxicology studies to position non-development-limiting findings prior to the onset of Good Laboratory Practice studies in full development, and can help to identify and validate gene expression markers predictive of adverse events to avoid issues in second-generation projects. In this review, the authors describe the application of molecular toxicology to a standard pharmaceutical testing funnel, provide examples of the successful application of gene expression markers, and discuss the potential for future impact in several broad categories of clinically relevant toxicity.     

鞘脂激活蛋白C抑制LNCaP细胞雄激素受体降解的研究

目的:探讨Saposin C对LNCaP细胞雄激素受体(AR)蛋白降解的影响。方法:通过转染实验,将Saposin C、TAT-Saposin C真核表达载体转染至LNCaP细胞,MTS检测Saposin C对LNCaP细胞增殖的影响,Western blot检测Saposin C对AR蛋白水平的影响及其在细胞中降解的调节作用。结果:Saposin C抑制LNCaP细胞AR蛋白的降解,上调胞内AR蛋白水平,促进LNCaP细胞增殖。结论:Saposin C增强AR蛋白的稳定性抑制其在细胞中的降解。     

PBL教学法在生物化学与分子生物学实验教学中的应用

在临床本科生物化学与分子生物学实验教学中,尝试使用问题式教学法（PBL）进行实验教学改革,采用问卷调查的形式获取信息。调查分析结果表明,问题式教学法能够激发学生的学习兴趣,提高学生分析和解决问题的能力,对于提高学生的综合能力,促进实验教学改革,全面提高实验教学质量有着重要意义。     

Integrating gene expression profiling into NCCN high-risk cutaneous squamous cell carcinoma management recommendations: impact on patient management

Abstract

Objective: To integrate gene expression profiling into the management of high-risk cutaneous squamous cell carcinoma (cSCC) within the National Comprehensive Cancer Network (NCCN) guidelines to improve risk-aligned management recommendations.

Methods: A cohort of 300 NCCN-defined high-risk cSCC patients, along with the American Joint Committee on Cancer (AJCC) T stage, Brigham and Women’s Hospital (BWH) T stage, and known patient outcomes were analyzed. Risk classifications using a validated 40-gene expression profile (40-GEP) test and T stage were applied to NCCN patient management guidelines. Risk-directed patient management recommendations within the NCCN guidelines framework were aligned based on risk for metastasis.

Results: Of the 300 NCCN high-risk cSCC patients, 159 (53.0%) were 40-GEP Class 1 and AJCC T1-T2, and 173 (57.7%) were Class 1 and BWH T1-2a, indicating low risk for metastasis and, thereby, suggesting low management intensity. The 40-GEP integration suggested high intensity management for only 24 (8.0%) patients (all Class 2B), and moderate intensity management for the remainder of the cohort.

Conclusions: The 40-GEP test can be integrated within existing NCCN guideline recommendations for managing cSCC patients to help refine risk-directed management decisions. Integration of the 40-GEP test would allow >50% of this NCCN-defined high-risk cohort to be managed with the lowest intensity recommendations within the broad NCCN guidelines. High intensity management was deemed risk-appropriate for a small subpopulation (8.0%). This study demonstrates that the 40-GEP test, in combination with T stage, has clinical utility to impact patient management decisions in NCCN high-risk cSCC for improving risk-aligned management within the NCCN guidelines framework.     

Periodic patterns in Rodentia: Development and evolution

Mammalian periodic pigment patterns, such as spots and stripes, have long interested mathematicians and biologists because they arise from non‐random developmental processes that are programmed to be spatially constrained, and can therefore be used as a model to understand how organized morphological structures develop. Despite such interest, the developmental and molecular processes underlying their formation remain poorly understood. Here, we argue that Arvicanthines, a clade of African rodents that naturally evolved a remarkable array of coat patterns, represent a tractable model system in which to dissect the mechanistic basis of pigment pattern formation. Indeed, we review recent insights into the process of stripe formation that were obtained using an Arvicanthine species, the African striped mouse (Rhabdomys pumilio), and discuss how these rodents can be used to probe deeply into our understanding of the factors that specify and implement positional information in the skin. By combining naturally evolved pigment pattern variation in rodents with classic and novel experimental approaches, we can substantially advance our understanding of the processes by which spatial patterns of cell differentiation are established during embryogenesis, a fundamental question in developmental biology.     

The Institut Pasteur attic dwellers: their origins,their paths to discovery

Although this volume is dedicated to honoring François Jacob, I would like my contribution to broaden the context by recalling the background within which the scientists of those times operated. The specific scientific accomplishments of Jacob will certainly be covered by the other contributors who collaborated with him. My handful of recollections presented here largely as vignettes is intended to give the reader a feeling for the elements, many social, that shaped the generation of scientists that included such central figures, Jacob, Lwoff, Monod. It is the tale of a generation trying to express its creativity in a world caught up in war, irrational values and unforgivable inhumanity. Even this limited account is a great story bringing us important lessons for thought.