Cell Therapy Strategies to Combat Immunosenescence.
Ontology highlight
ABSTRACT:
SUBMITTER: Stahl EC
PROVIDER: S-EPMC4879890 | biostudies-other | 2015
REPOSITORIES: biostudies-other
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Project description:"Drug resistance is an unavoidable consequence of the use of drugs; however, the emergence of multi-drug resistance can be managed by accurate diagnosis and tailor-made regimens."Antimicrobial resistance (AMR), is one of the most paramount health perils that has emerged in the 21st century. The global increase in drug-resistant strains of various bacterial pathogens prompted the World Health Organization (WHO) to develop a priority list of AMR pathogens. Mycobacterium tuberculosis (Mtb), an acid-fast bacillus that causes tuberculosis (TB), merits being one of the highest priority pathogens on this list since drug-resistant TB (DR-TB) accounts for ∼29% of deaths attributable to AMR. In recent years, funded collaborative efforts of researchers from academia, not-for-profit virtual R&D organizations and industry have resulted in the continuous growth of the TB drug discovery and development pipeline. This has so far led to the accelerated regulatory approval of bedaquiline and delamanid for the treatment of DR-TB. However, despite the availability of drug regimes, the current cure rate for multi-drug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) treatment regimens is 50% and 30%, respectively. It is to be noted that these regimens are administered over a long duration and have a serious side effect profile. Coupled with poor patient adherence, this has led to further acquisition of drug resistance and treatment failure. There is therefore an urgent need to develop new TB drugs with novel mechanism of actions (MoAs) and associated regimens.This Account recapitulates drug resistance in TB, existing challenges in addressing DR-TB, new drugs and regimens in development, and potential ways to treat DR-TB. We highlight our research aimed at identifying novel small molecule leads and associated targets against TB toward contributing to the global TB drug discovery and development pipeline. Our work mainly involves screening of various small molecule chemical libraries in phenotypic whole-cell based assays to identify hits for medicinal chemistry optimization, with attendant deconvolution of the MoA. We discuss the identification of small molecule chemotypes active against Mtb and subsequent structure-activity relationships (SAR) and MoA deconvolution studies. This is followed by a discussion on a chemical series identified by whole-cell cross-screening against Mtb, for which MoA deconvolution studies revealed a pathway that explained the lack of in vivo efficacy in a mouse model of TB and reiterated the importance of selecting an appropriate growth medium during phenotypic screening. We also discuss our efforts on drug repositioning toward addressing DR-TB. In the concluding section, we preview some promising future directions and the challenges inherent in advancing the drug pipeline to address DR-TB.
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Project description:The 2019-novel coronavirus disease (COVID-19) is caused by SARS-CoV-2 is transmitted from human to human has recently reported in China. Now COVID-19 has been spread all over the world and declared epidemics by WHO. It has caused a Public Health Emergency of International Concern. The elderly and people with underlying diseases are susceptible to infection and prone to serious outcomes, which may be associated with acute respiratory distress syndrome (ARDS) and cytokine storm. Due to the rapid increase of SARS-CoV-2 infections and unavailability of antiviral therapeutic agents, developing an effective SAR-CoV-2 vaccine is urgently required. SARS-CoV-2 which is genetically similar to SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) is an enveloped, single and positive-stranded RNA virus with a genome comprising 29,891 nucleotides, which encode the 12 putative open reading frames responsible for the synthesis of viral structural and nonstructural proteins which are very similar to SARS-CoV and MERS-CoV proteins. In this review we have summarized various vaccine candidates i.e., nucleotide, subunit and vector based as well as attenuated and inactivated forms, which have already been demonstrated their prophylactic efficacy against MERS-CoV and SARS-CoV, so these candidates could be used as a potential tool for the development of a safe and effective vaccine against SARS-CoV-2.
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Project description:Background and objective: The use of suboptimal weight loss strategies in order to reach specific weight ranges as observed in combat sport disciplines can give rise to severe health problems. However, particular aspects regarding management of weight category comparing three sport disciplines remain to be investigated. Therefore, the aim of the present study was to obtain information regarding the weight loss strategies that competitors performed before a tournament. Materials and Methods: This article describes the most common dietary-nutritional strategies used by 140 national university male competitors of judo (n = 52), karate (n = 40) and taekwondo (n = 48) in order to achieve a specific weight, according to the rapid weight loss questionnaire (RWLQ) and the EAT-27 questionnaire. Results: Around 50% of participants were not involved in a weight loss process. Among the remaining participants, we considered three periods for weight reduction: less than 1 week (35% in judo, 8% in karate and 19% in taekwondo), less than 1 month (17% in judo, 15% in karate and 26% in taekwondo) and more than 1 month (0% in judo, 5% in karate and 21% in taekwondo). Severe fasting, focused on food/water restriction, was the most commonly used strategy, being more frequent in judo players. Light weight judo practitioners generally lost 2-5 kg before the contest. One third of participants avoided carbohydrate consumption when performing food restriction. Finally, individuals that reduced weight in the last week seemed to develop an unhealthy psychological relationship with food. Conclusion: All these aspects could be particularly relevant, providing information regarding how competitors manage basic nutritional concepts that guide dieting strategies. This information is relevant to prepare future educational interventions in the area of nutrition for competitors, coaches and technical staff.
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Project description:OBJECTIVE: To determine the cost effectiveness of selected malaria control interventions in the context of reaching the millennium development goals for malaria. DESIGN: Generalised cost effectiveness analysis. DATA SOURCES: Efficacy data came from the literature and authors' calculations supported by expert opinion. Quantities for resource inputs came from the literature and from expert opinion; prices came from the WHO-CHOICE database. METHODS: Costs were assessed in year 2000 international dollars, and effects were assessed as disability adjusted life years averted by a 10 year implementation programme. Analysis was restricted to sub-Saharan regions where the most deadly form of malaria, Plasmodium falciparum, is most prevalent. The impact on population health for various interventions, and their combinations, was evaluated at selected coverage levels by using a state-transition model. Sensitivity analysis was done for age weights and discounting. RESULTS: High coverage with artemisinin based combination treatments was found to be the most cost effective strategy for control of malaria in most countries in sub-Saharan Africa. CONCLUSIONS: A much larger infusion of resources than those currently available is needed to make headway in the fight to roll back malaria. On cost effectiveness grounds, in most areas in sub-Saharan Africa greater coverage with highly effective combination treatments should be the cornerstone of malaria control. However, treatment alone can achieve less than half the total benefit obtainable through a combination of interventions-scaling up the use of impregnated mosquito nets or indoor spraying with insecticides is also critical. Intermittent presumptive treatment of pregnant women can bring a small but important additional health gain at relatively low cost.
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Project description:Aging is associated with immune dysfunction, especially T-cell defects, which result in increased susceptibility to various diseases. Previous studies showed that T cells from aged mice express multiple inhibitory receptors, providing evidence of the relationship between T-cell exhaustion and T-cell senescence. In this study, we showed that T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT), a novel co-inhibitory receptor, was upregulated in CD8+ T cells of elderly adults. Aged TIGIT+ CD8+ T cells expressed high levels of other inhibitory receptors including PD-1 and exhibited features of exhaustion such as downregulation of the key costimulatory receptor CD28, representative intrinsic transcriptional regulation, low production of cytokines, and high susceptibility to apoptosis. Importantly, their functional defects associated with aging were reversed by TIGIT knockdown. CD226 downregulation on aged TIGIT+ CD8+ T cells is likely involved in TIGIT-mediated negative immune suppression. Collectively, our findings indicated that TIGIT acts as a critical immune regulator during aging, providing a strong rationale for targeting TIGIT to improve dysfunction related to immune system aging.
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