Gut microbiome in cancer immunotherapy: Current trends, translational challenges and future possibilities.

Gut microbiota is regarded as a crucial regulator of the immune system. Healthy gut microbiota plays a specialized role in host xenobiotics, nutrition, drug metabolism, regulation of the structural integrity of the gut mucosal barrier, defense against infections, and immunomodulation. It is now understood that any imbalance in gut microbiota composition from that present in a healthy state is linked to genetic susceptibility to a number of metabolic disorders, including diabetes, autoimmunity, and cancer. Recent research has suggested that immunotherapy can treat many different cancer types with fewer side effects and better ability to eradicate tumors than conventional chemotherapy or radiotherapy. However, a significant number of patients eventually develop immunotherapy resistance. A strong correlation was observed between the composition of the gut microbiome and the effectiveness of treatment by examining the variations between populations that responded to immunotherapy and those that did not. Therefore, we suggest that modulating the microbiome could be a potential adjuvant therapy for cancer immunotherapy and that the architecture of the gut microbiota may be helpful in explaining the variation in treatment response. Herein, we focus on recent research on the interactions among the gut microbiome, host immunity, and cancer immunotherapy. In addition, we highlighted the clinical manifestations, future opportunities, and limitations of microbiome manipulation in cancer immunotherapy.

Lynch Syndrome and MSI-H Cancers: From Mechanisms to "Off-The-Shelf" Cancer Vaccines.

Defective DNA mismatch repair (dMMR) is associated with many cancer types including colon, gastric, endometrial, ovarian, hepatobiliary tract, urinary tract, brain and skin cancers. Lynch syndrome - a hereditary cause of dMMR - confers increased lifetime risk of malignancy in different organs and tissues. These Lynch syndrome pathogenic alleles are widely present in humans at a 1:320 population frequency of a single allele and associated with an up to 80% risk of developing microsatellite unstable cancer (microsatellite instability - high, or MSI-H). Advanced MSI-H tumors can be effectively treated with checkpoint inhibitors (CPI), however, that has led to response rates of only 30-60% despite their high tumor mutational burden and favorable immune gene signatures in the tumor microenvironment (TME). We and others have characterized a subset of MSI-H associated highly recurrent frameshift mutations that yield shared immunogenic neoantigens. These frameshifts might serve as targets for off-the-shelf cancer vaccine designs. In this review we discuss the current state of research around MSI-H cancer vaccine development, its application to MSI-H and Lynch syndrome cancer patients and the utility of MSI-H as a biomarker for CPI therapy. We also summarize the tumor intrinsic mechanisms underlying the high occurrence rates of certain frameshifts in MSI-H. Finally, we provide an overview of pivotal clinical trials investigating MSI-H as a biomarker for CPI therapy and MSI-H vaccines. Overall, this review aims to inform the development of novel research paradigms and therapeutics.

Mendelian disease research in the Plain populations of Lancaster County, Pennsylvania.

Founder populations have long contributed to our knowledge of rare disease genes and phenotypes. From the pioneering work of Dr. Victor McKusick to today, research in these groups has shed light on rare recessive phenotypes, expanded the clinical spectrum of disease, and facilitated disease gene identification. Current clinical and research studies in these special groups augment the wealth of knowledge already gained, provide new insights into emerging problems such as variant interpretation and reduced penetrance, and contribute to the development of novel therapies for rare genetic diseases. Clinical developments over the past 30 years have altered the fundamental relationship with the Lancaster Plain communities: research has become more collaborative, and the knowledge imparted by these studies is now being harnessed to provide cutting-edge translational medicine to the very community of vulnerable individuals who need it most.

Defective Autophagy and Mitophagy in Alzheimer's Disease: Mechanisms and Translational Implications.

The main histopathology of Alzheimer's disease (AD) is featured by the extracellular accumulation of amyloid-ß (Aß) plaques and intracellular tau neurofibrillary tangles (NFT) in the brain, which is likely to result from co-pathogenic interactions among multiple factors, e.g., aging or genes. The link between defective autophagy/mitophagy and AD pathologies is still under investigation and not fully established. In this review, we consider how AD is associated with impaired autophagy and mitophagy, and how these impact pathological hallmarks as well as the potential mechanisms. This complicated interplay between autophagy or mitophagy and histopathology in AD suggests that targeting autophagy or mitophagy probably is a promising anti-AD drug candidate. Finally, we review the implications of some new insights for induction of autophagy or mitophagy as the new therapeutic way that targets processes upstream of both NFT and Aß plaques, and hence stops the neurodegenerative course in AD.

Opportunities and challenges in translational science.

The mission of translational science is to bring predictivity and efficiency to the development and dissemination of interventions that improve human health. Ten years ago this year, the National Center for Advancing Translational Sciences was founded to embody, conduct, and support this new discipline. The Center's first decade has brought substantial progress across a broad range of translational areas, from diagnostic and drug development to clinical trials to implementation science to education. The origins of the translational science and advances to this point are reviewed here and allow the establishment of an ambitious future research agenda for the field.

Application of Machine Learning in Translational Medicine: Current Status and Future Opportunities.

The exponential increase in our ability to harness multi-dimensional biological and clinical data from experimental to real-world settings has transformed pharmaceutical research and development in recent years, with increasing applications of artificial intelligence (AI) and machine learning (ML). Patient-centered iterative forward and reverse translation is at the heart of precision medicine discovery and development across the continuum from target validation to optimization of pharmacotherapy. Integration of advanced analytics into the practice of Translational Medicine is now a fundamental enabler to fully exploit information contained in diverse sources of big data sets such as "omics" data, as illustrated by deep characterizations of the genome, transcriptome, proteome, metabolome, microbiome, and exposome. In this commentary, we provide an overview of ML applications in drug discovery and development, aligned with the three strategic pillars of Translational Medicine (target, patient, dose) and offer perspectives on their potential to transform the science and practice of the discipline. Opportunities for integrating ML approaches into the discipline of Pharmacometrics are discussed and will revolutionize the practice of model-informed drug discovery and development. Finally, we posit that joint efforts of Clinical Pharmacology, Bioinformatics, and Biomarker Technology experts are vital in cross-functional team settings to realize the promise of AI/ML-enabled Translational and Precision Medicine.

The role of small extracellular vesicles in cerebral and myocardial ischemia-Molecular signals, treatment targets, and future clinical translation.

The heart and the brain mutually interact with each other, forming a functional axis that is disturbed under conditions of ischemia. Stem cell-derived extracellular vesicles (EVs) show great potential for the treatment of ischemic stroke and myocardial infarction. Due to heart-brain interactions, therapeutic actions of EVs in the brain and the heart cannot be regarded in an isolated way. Effects in each of the two organs reciprocally influence the outcome of the other. Stem cell-derived EVs modulate a large number of signaling pathways in both tissues. Upon ischemia, EVs prevent delayed injury, promote angiogenesis, enhance parenchymal remodeling, and enable functional tissue recovery. The therapeutic effects greatly depend on EV cargos, among which are noncoding RNAs like microRNAs (miRNAs) and proteins, which modulate cell signaling in a differential way that not always corresponds to each other in the two tissues. Interestingly, the same miRNA or protein localized in EVs can modulate different signaling pathways in the ischemic heart and brain, which may have diverse consequences for disease outcomes. Paying careful attention to unveiling these underlying mechanisms may provide new insights into tissue remodeling processes and identify targets for ischemic stroke and myocardial infarction therapies. Some of these mechanisms are discussed in this concise review, and consequences for the clinical translation of EVs are presented.