Human Genetics to Identify Therapeutic Targets for NAFLD: Challenges and Opportunities.
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ABSTRACT:
SUBMITTER: Du X
PROVIDER: S-EPMC8688763 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Dispersal is one of the most important but least understood processes in plant ecology and evolutionary biology. Dispersal of seeds maintains and establishes populations, and pollen and seed dispersal are responsible for gene flow within and among populations. Traditional views of dispersal and gene flow assume models that are governed solely by geographic distance and do not account for variation in dispersal vector behavior in response to heterogenous landscapes. Landscape genetics integrates population genetics with Geographic Information Systems (GIS) to evaluate the effects of landscape features on gene flow patterns (effective dispersal). Surprisingly, relatively few landscape genetic studies have been conducted on plants. Plants present advantages because their populations are stationary, allowing more reliable estimates of the effects of landscape features on effective dispersal rates. On the other hand, plant dispersal is intrinsically complex because it depends on the habitat preferences of the plant and its pollen and seed dispersal vectors. We discuss strategies to assess the separate contributions of pollen and seed movement to effective dispersal and to delineate the effects of plant habitat quality from those of landscape features that affect vector behavior. Preliminary analyses of seed dispersal for three species indicate that isolation by landscape resistance is a better predictor of the rates and patterns of dispersal than geographic distance. Rates of effective dispersal are lower in areas of high plant habitat quality, which may be due to the effects of the shape of the dispersal kernel or to movement behaviors of biotic vectors. Landscape genetic studies in plants have the potential to provide novel insights into the process of gene flow among populations and to improve our understanding of the behavior of biotic and abiotic dispersal vectors in response to heterogeneous landscapes.
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Project description:High-throughput sequencing describes multiple alterations in individual tumors, but their functional relevance is often unclear. Clinic-close, individualized molecular model systems are required for functional validation and to identify therapeutic targets of high significance for each patient. Here, we establish a Cre-ERT2-loxP (causes recombination, estrogen receptor mutant T2, locus of X-over P1) based inducible RNAi- (ribonucleic acid interference) mediated gene silencing system in patient-derived xenograft (PDX) models of acute leukemias in vivo. Mimicking anti-cancer therapy in patients, gene inhibition is initiated in mice harboring orthotopic tumors. In fluorochrome guided, competitive in vivo trials, silencing of the apoptosis regulator MCL1 (myeloid cell leukemia sequence 1) correlates to pharmacological MCL1 inhibition in patients´ tumors, demonstrating the ability of the method to detect therapeutic vulnerabilities. The technique identifies a major tumor-maintaining potency of the MLL-AF4 (mixed lineage leukemia, ALL1-fused gene from chromosome 4) fusion, restricted to samples carrying the translocation. DUX4 (double homeobox 4) plays an essential role in patients' leukemias carrying the recently described DUX4-IGH (immunoglobulin heavy chain) translocation, while the downstream mediator DDIT4L (DNA-damage-inducible transcript 4 like) is identified as therapeutic vulnerability. By individualizing functional genomics in established tumors in vivo, our technique decisively complements the value chain of precision oncology. Being broadly applicable to tumors of all kinds, it will considerably reinforce personalizing anti-cancer treatment in the future.
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Project description:This article aims to summarize the current literature on genetic alterations related to tumors of the genitourinary tract. Novel associations have recently been reported between specific DNA alterations and genitourinary malignancies. The most common cause of chromosome 3p loss in clear cell renal cell carcinoma is a chromothripsis event, which concurrently generates a chromosome 5q gain. Specific patterns of clear cell renal cell carcinoma metastatic evolution have been uncovered. The first therapy targeting a specific molecular alteration has now been approved for urothelial carcinoma. Germline mutations in DNA damage repair genes and the transcription factor HOXB13 are associated with prostate cancer and may be targeted therapeutically. The genetic associations noted across different genitourinary cancers can inform potential screening approaches and guide novel targeted treatment strategies.
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Project description:Genome-wide association studies (GWAS) have been successful in identifying and confirming novel genetic variants that are associated with diverse HIV phenotypes. However, these studies have predominantly focused on European cohorts. HLA molecules have been consistently associated with HIV outcomes, some of which have been found to be population specific, underscoring the need for diversity in GWAS. Recently, there has been a concerted effort to address this gap that leads to health care (disease prevention, diagnosis, treatment) disparities with marginal improvement. As precision medicine becomes more utilized, non-European individuals will be more and more disadvantaged, as the genetic variants identified in genomic research based on European populations may not accurately reflect that of non-European individuals. Leveraging pre-existing, large, multiethnic cohorts, such as the UK Biobank, 23andMe, and the National Institute of Health's All of Us Research Program, can contribute in raising genomic research in non-European populations and ultimately lead to better health outcomes.
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Project description:Solute carrier (SLC) transporters - a family of more than 300 membrane-bound proteins that facilitate the transport of a wide array of substrates across biological membranes - have important roles in physiological processes ranging from the cellular uptake of nutrients to the absorption of drugs and other xenobiotics. Several classes of marketed drugs target well-known SLC transporters, such as neurotransmitter transporters, and human genetic studies have provided powerful insight into the roles of more-recently characterized SLC transporters in both rare and common diseases, indicating a wealth of new therapeutic opportunities. This Review summarizes knowledge on the roles of SLC transporters in human disease, describes strategies to target such transporters, and highlights current and investigational drugs that modulate SLC transporters, as well as promising drug targets.
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Project description:Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), is a growing cause of liver cirrhosis and liver cancer worldwide because of the global increases in obesity, dyslipidemia, hypertension, and type 2 diabetes mellitus. Contrary to the advancements in therapies for viral hepatitis, effective treatments remain unestablished for patients with NAFLD. NAFLD, including NASH, is characterized by steatosis, inflammation, hepatic necrosis, and fibrosis. Despite our understanding of its pathophysiology, there are currently no effective treatments for NAFLD. In this review, we provide an update on the known pathophysiological mechanisms involved in the development of NAFLD and the role of hepatic stellate cells, and summarize the potential therapeutic agents, including natural products, for NAFLD.
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Project description:Mesenchymal stromal cells (MSCs) have been the subject of clinical trials for more than a generation, and the outcomes of advanced clinical trials have fallen short of expectations raised by encouraging pre-clinical animal data in a wide array of disease models. In this Perspective, important biological and pharmacological disparities in pre-clinical research and human translational studies are highlighted, and analyses of clinical trial failures and recent successes provide a rational pathway to MSC regulatory approval and deployment for disorders with unmet medical needs.
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Project description:Background:Many genetic tests are now available due to evolution by the Human Genome Project. However, the growing use of genetic testing and screening may not only lead to improvements in public health and health promotion, but also trigger grave ethical, legal, and societal concerns. The involvement of community healthcare providers is expected in the future because they have direct contact with the residents through their health programs. The aims of the current study were to clarify how public health nurses perceive the relationship between genetics and professional duties and to identify opportunities and challenges of integrating genetics education into their professional duties. Methods:In 2017, data were collected through a focus group interview. Content related to the 'presence or absence of health consultation related to genetic issues as part of actual job duties' and 'training for handling genetic-related health consultations' was extracted. Entire sentences were coded and categorized based on similar semantic content. Results:Public health nurses had difficulties in recognizing genetic issues in public health activities. In some cases, genetic contents were included in conversation and consultation with the general public. Through the professional education and experiences, public health nurses needed specialized education, post-graduation studies and mentoring about genetics. Conclusions:Public health nurses whose professional duties do not directly relate to genetics were exposed to genetics-related episodes on a regular basis without their awareness. The provision of accurate information and knowledge related to genetics by public health nurses would also provide an opportunity for clients to be informed about their latent genetic risks. Hence, there is a need for practical resources, the establishment of collaboration networks, and the development of professional organizations for public health nurses.
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Project description:The metabolic syndrome and neuropathy are common conditions, especially in the elderly, that are associated with significant morbidity. Furthermore, the metabolic syndrome is reaching epidemic proportions across the world. Current evidence supports the association of the metabolic syndrome and its individual components with neuropathy. Several clinical trials have demonstrated that treating hyperglycemia, a component of the metabolic syndrome, has a significant effect on reducing the incidence of neuropathy in those with type 1 diabetes. However, glucose control has only a marginal effect on preventing neuropathy in those with type 2 diabetes, suggesting that other factors may be driving nerve injury in these patients. Emerging evidence supports the metabolic syndrome as including risk factors for neuropathy. Interventions exist for treatment of all of the metabolic syndrome components, but only glucose control has strong evidence to support its use and is widely employed. Our understanding of the biology of metabolic nerve injury has rapidly expanded over the past several years. Mechanisms of injury include fatty deposition in nerves, extracellular protein glycation, mitochondrial dysfunction, and oxidative stress. Additionally, the activation of counter-regulatory signaling pathways leads to chronic metabolic inflammation. Medications that target these signaling pathways are being used for a variety of diseases and are intriguing therapeutic agents for future neuropathy clinical trials. As we move forward, we need to expand our understanding of the association between the metabolic syndrome and neuropathy by addressing limitations of previous studies. Just as importantly, we must continue to investigate the pathophysiology of metabolically induced nerve injury.
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