Project description:A new global pandemic of coronavirus disease 2019 (COVID-19) has resulted in high mortality and morbidity. Currently numerous drugs are under expedited investigations without well-established safety or efficacy data. Pharmacogenomics may allow individualization of these drugs thereby improving efficacy and safety. In this review, we summarized the pharmacogenomic literature available for COVID-19 drug therapies including hydroxychloroquine, chloroquine, azithromycin, remdesivir, favipiravir, ribavirin, lopinavir/ritonavir, darunavir/cobicistat, interferon beta-1b, tocilizumab, ruxolitinib, baricitinib, and corticosteroids. We searched PubMed, reviewed the Pharmacogenomics Knowledgebase (PharmGKB®) website, Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, the U.S. Food and Drug Administration (FDA) pharmacogenomics information in the product labeling, and the FDA pharmacogenomics association table. We found several drug-gene variant pairs that may alter the pharmacokinetics of hydroxychloroquine/chloroquine (CYP2C8, CYP2D6, SLCO1A2, and SLCO1B1); azithromycin (ABCB1); ribavirin (SLC29A1, SLC28A2, and SLC28A3); and lopinavir/ritonavir (SLCO1B1, ABCC2, CYP3A). We also identified other variants, that are associated with adverse effects, most notable in hydroxychloroquine/chloroquine (G6PD; hemolysis), ribavirin (ITPA; hemolysis), and interferon β -1b (IRF6; liver toxicity). We also describe the complexity of the risk for QT prolongation in this setting because of additive effects of combining more than one QT-prolonging drug (i.e., hydroxychloroquine/chloroquine and azithromycin), increased concentrations of the drugs due to genetic variants, along with the risk of also combining therapy with potent inhibitors. In conclusion, although direct evidence in COVID-19 patients is lacking, we identified potential actionable genetic markers in COVID-19 therapies. Clinical studies in COVID-19 patients are deemed warranted to assess potential roles of these markers.
Project description:Soft tissue sarcomas (STS) are heterogeneous rare malignancies comprising ~1% of all solid cancers in adults and including more than 70 histological and molecular subtypes with different pathological and clinical development characteristics. Over the last two decades, the increased knowledge of the new molecular and genomic mechanisms of different STS histotypes allowed for a reclassification of these tumors and consequently to the development of novel chemotherapeutic agents. Generally, surgery, in combination with radiotherapy only in selected cases of localized disease, represents the most common treatment of primary STS, whereas the principal treatment modality for locally advanced or metastatic disease is first-line chemotherapy. The principal treatment for the preponderance of STS patients is usually an anthracycline (epirubicin and doxorubicin) in monotherapy or in combination with other drug novel chemotherapeutic agents. However, survival for treated patients with metastatic disease is poor, and a 2-years survival rate is about 30%. In this scenario, Pharmacogenomics (PGx) biomarkers that can predict drug response play an important role in the improvement of molecular diagnostics in clinical routines and contribute to elucidating the genetic basis for the differences in treatment efficacy and toxicity among STS patients. This review focuses on recent insight in the PGx biomarkers that have been described to modulate responsiveness and toxicity parameters of conventional and new chemotherapeutics drugs in several STS histotypes.
Project description:High levels of HDL cholesterol (HDL-C) have traditionally been linked to lower incidence of cardiovascular disease, prompting the search for effective and safe HDL-C raising pharmaceutical agents. Although drugs such as niacin and fibrates represent established therapeutic approaches, HDL-C response to such therapies is variable and heritable, suggesting a role for pharmacogenomic determinants. Multiple genetic polymorphisms, located primarily in genes encoding lipoproteins, cholesteryl ester transfer protein, transporters and CYP450 proteins have been shown to associate with HDL-C drug response in vitro and in epidemiologic studies. However, few of the pharmacogenomic findings have been independently validated, precluding the development of clinical tools that can be used to predict HDL-C response and leaving the goal of personalized medicine to future efforts.
Project description:The exponential expansion of genomic data coupled with the lack of appropriate clinical categorization of the variants is posing a major challenge to conventional medications for many common and rare diseases. To narrow this gap and achieve the goals of personalized medicine, a collaborative effort should be made to characterize the genomic variants functionally and clinically with a massive global genomic sequencing of "healthy" subjects from several ethnicities. Familial-based clustered diseases with homogenous genetic backgrounds are amongst the most beneficial tools to help address this challenge. This review will discuss the diagnosis, management, and clinical monitoring of familial hypercholesterolemia patients from a wide angle to cover both the genetic mutations underlying the phenotype, and the pharmacogenomic traits unveiled by the conventional and novel therapeutic approaches. Achieving a drug-related interactive genomic map will potentially benefit populations at risk across the globe who suffer from dyslipidemia.
Project description:The drug pipeline for the treatment of inflammatory bowel disease (IBD) has dramatically expanded over the last two decades, and it is expected to further grow in the upcoming years with the introduction of new agents with different mechanisms of action. However, such an increase of therapeutic options needs to be paralleled with an appropriate development of research to help physicians in the decision-making process when choosing which drug to prescribe. On the population level, comparative effectiveness research (CER) is intended to explore and identify relevant differences-in terms of both efficacy and safety outcomes-amongst different therapeutic regimens and/or strategies, in order to find the correct placement for each treatment in the therapeutic algorithm. CER revolves around three cornerstones: network meta-analyses, head-to-head trials and real-world studies, each of which has specific pros and cons, and can therefore offer answers to different questions. In this review, we aim to provide an overview on the methodological features specific to each of these research approaches, as well as to illustrate the main findings coming from CER on IBD target therapies (i.e., biologics and small molecules) and to discuss their appropriate interpretation.
Project description:The frequency of fibrosing Crohn's disease (CD) is significant, with approximately 40% of CD patients with ileal disease developing clinically apparent strictures throughout their lifetime. Although strictures may be subdivided into fibrotic, inflammatory, or mixed forms, despite immunosuppressive therapy in CD patients in the form of steroids or immunomodulators, the frequency of fibrostenosing complications has still remained significant. A vast number of genetic and epigenetic variables are thought to contribute to fibrostenosing disease, including those that affect cytokine biology, and therefore highlight the complexity of disease, but also shed light on targetable pathways. Exclusively targeting fibrosis may be difficult, however, because of the relatively slow evolution of fibrosis in CD, and the potential adverse effects of inhibiting pathways involved in tissue repair and mucosal healing. Acknowledging these caveats, cytokine-targeted therapy has become the mainstay of treatment for many inflammatory conditions and is being evaluated for fibrotic disorders. The question of whether anti-cytokine therapy will prove useful for intestinal fibrosis is, therefore, acutely relevant. This review will highlight some of the current therapeutics targeting cytokines involved in fibrosis.
Project description:Background This study examines longitudinal bio-psychological dynamics and their interplay in IBD patients undergoing conventional and biological therapies. Methods Fifty IBD participants (24 UC, 26 CD) in clinical remission were followed for 12 months. Complete longitudinal datasets, biological samples, validated scores of psychological status were collected monthly for analysis of association. Microbiome analysis was performed to identify microbial dynamics and signatures. Patients were grouped on disease phenotype (CD, UC) and mode of treatment (biological therapies, non-biological treatment). General linear models, mixed models, cluster analysis, and analyses of variance were used to examine the longitudinal trends of the variables and their associations over time. Results were corrected for multiple testing. Results Results substantiated different interactions between biological therapy and longitudinal trends of inflammatory biomarkers in remission CD and UC patients as well as significant differences between CD and UC patients in their psychological measures during clinical remission, with UC patients having inferior condition compared to CD. A significant reduction in microbial diversity in CD patients compared to UC was identified. Results characterized considerable differences in longitudinal microbial profile between those taking and not taking biological treatment in UC patients, but not in CD patients. Conclusion A different trajectory of interdependence was identified between psychological state, sleep, and microbial dynamics with mode of treatment when compared between CD and UC patients. Further studies should investigate the causal relationships between bio-psychological factors for improved treatment purposes.
Project description:Type 2 diabetes is one of the major causes of mortality with rapidly increasing prevalence. Pharmacological treatment is the first recommended approach after failure in lifestyle changes. However, a significant number of patients shows-or develops along time and disease progression-drug resistance. In addition, not all type 2 diabetic patients have the same responsiveness to drug treatment. Despite the presence of nongenetic factors (hepatic, renal, and intestinal), most of such variability is due to genetic causes. Pharmacogenomics studies have described association between single nucleotide variations and drug resistance, even though there are still conflicting results. To date, the most reliable approach to investigate allelic variants is Next-Generation Sequencing that allows the simultaneous analysis, on a genome-wide scale, of nucleotide variants and gene expression. Here, we review the relationship between drug responsiveness and polymorphisms in genes involved in drug metabolism (CYP2C9) and insulin signaling (ABCC8, KCNJ11, and PPARG). We also highlight the advancements in sequencing technologies that to date enable researchers to perform comprehensive pharmacogenomics studies. The identification of allelic variants associated with drug resistance will constitute a solid basis to establish tailored therapeutic approaches in the treatment of type 2 diabetes.
Project description:Pharmacogenomics is an emerging field in oncology, one that could provide valuable input on identifying patients with inherent risk of toxicity, thus allowing for treatment tailoring and personalization on the basis of the clinical and genetic characteristics of a patient. Cardiotoxicity is a well-known side effect of anthracyclines and anti-HER2 agents, although at a much lower incidence for the latter. Data on single-nucleotide polymorphisms related to cardiotoxicity are emerging but are still scarce, mostly being of retrospective character and heterogeneous. A literature review was performed, aiming to describe current knowledge in pharmacogenomics and prediction of cardiotoxicity related to breast cancer systemic therapies and radiotherapies. Most available data regard genes encoding various enzymes related to anthracycline metabolism and HER2 polymorphisms. The available data are presented, together with the challenges and open questions in the field.
Project description:BACKGROUND:Although anti-tumor necrosis factor (TNF) agents are effective in patients with inflammatory bowel disease (IBD), many patients either do not respond to anti-TNF treatment or lose response over time. The aim of this study was to determine factors associated with response to anti-TNF therapy in IBD. METHODS:Patients with Crohn's disease (CD) or ulcerative colitis who had consented to participate in a genetics registry and been treated with anti-TNF agents were evaluated retrospectively and categorized as primary nonresponders or secondary nonresponders. We evaluated clinical, serological, and genetic characteristics associated with primary nonresponse or time to loss of response to anti-TNF agents. RESULTS:We included 314 CD (51 [16.2%] primary nonresponders and 179 [57.0%] secondary nonresponders) and 145 subjects with ulcerative colitis (43 [29.7%] primary nonresponders and 74 [51.0%] secondary nonresponders). Colonic involvement (P = 0.017; odds ratio = 8.0) and anti-TNF monotherapy (P = 0.017; odds ratio = 4.9) were associated in a multivariate analysis with primary nonresponse to anti-TNF agents in CD. In addition, higher anti-nuclear cytoplasmic antibody levels (P = 0.019; hazard ratio = 1.01) in CD, anti-nuclear cytoplasmic antibody positivity (P = 0.038; hazard ratio = 1.6) in ulcerative colitis, and a positive family history of IBD (P = 0.044; hazard ratio = 1.3) in all patients with IBD were associated with time to loss of response to anti-TNF agents. Furthermore, various known IBD susceptibility single-nucleotide polymorphisms and additional variants in immune-mediated genes were shown to be associated with primary nonresponse or time to loss of response. CONCLUSIONS:Our results may help to optimize the use of anti-TNF agents in clinical practice and position these therapies appropriately as clinicians strive for a more personalized approach to managing IBD.