Project description:Photothermal-radiotherapy (PT-RT) is an effective strategy for relieving hypoxia-related radiotherapy resistance and inducing tumor-specific cell apoptosis/necrosis. Nevertheless, limited tissue penetration of near-infrared (NIR) laser and the serious side effects of high-dose radiation severely hinder its applications for deep tumors. An interventional photothermal-brachytherapy (IPT-BT) technology is proposed here for the internal site-specific treatment of deep tumors. This technology utilizes a kind of biodegradable honeycomb-like gold nanoparticles (HGNs) acting as both internal photothermal agents and radiosensitizers. A high tumor inhibition rate of 96.6% is achieved in SW1990 orthotopic pancreatic tumor-bearing mice by HGNs-mediated IPT-BT synergistic therapy. Interestingly, this approach effectively causes double-stranded DNA damage and improves the oxygen supply and the penetration of nanoparticles inside the tumor. Therefore, it is believed that this strategy may open up a new avenue for PT-RT synergistic therapy of deep malignant tumors and has a significant impact on the future clinical translation.
Project description:Around 1.6 million people lost their life to Tuberculosis in 2021 according to WHO estimates. Although an intensive treatment plan exists against the causal agent, Mycobacterium Tuberculosis, evolution of multi-drug resistant strains of the pathogen puts a large number of global populations at risk. Vaccine which can induce long-term protection is still in the making with many candidates currently in different phases of clinical trials. The COVID-19 pandemic has further aggravated the adversities by affecting early TB diagnosis and treatment. Yet, WHO remains adamant on its "End TB" strategy and aims to substantially reduce TB incidence and deaths by the year 2035. Such an ambitious goal would require a multi-sectoral approach which would greatly benefit from the latest computational advancements. To highlight the progress of these tools against TB, through this review, we summarize recent studies which have used advanced computational tools and algorithms for-early TB diagnosis, anti-mycobacterium drug discovery and in the designing of the next-generation of TB vaccines. At the end, we give an insight on other computational tools and Machine Learning approaches which have successfully been applied in biomedical research and discuss their prospects and applications against TB.
Project description:BackgroundTraditional lipoarabinomannan tests have limited sensitivity in HIV-negative individuals. Our aims were to compare chemiluminescence-based LAM (AIMLAM) and other diagnostic modalities in HIV-negative patients and to explore whether lymphocyte counts impact the sensitivity and costs of AIMLAM.MethodsThis is a prospective, cross-sectional, diagnostic accuracy study. Participants underwent testing with sputum acid-fast bacilli, sputum culture, GeneXpert, and AIMLAM. Their diagnostic efficiency and cost-effectiveness alone or under different lymphocyte count categories was evaluated.ResultsUsing MRS as a reference, the sensitivities of different diagnostic methods were as follows: sputum smear 27.43%, sputum culture 45.13%, GeneXpert 74.34%, and AIMLAM 71.68%. Patients with lymphocyte counts <0.8 × 109/L were significantly more likely to have a positive AIMLAM result (OR = 9.431, 95% CI: 2.659-33.447, P = 0.001). The sensitivity of AIMLAM in patients with lymphocyte counts <0.8 × 109/L reached 93.02%. The overall cost of AIMLAM to detect a positive TB case was $129.82, lower than sputum culture ($136.10) and GeneXpert ($180.27). For patients with lymphocyte counts <0.8 × 109/L, the cost of AIMLAM was further reduced to $67.84 (a 47.74% decrease), which was lower than GeneXpert ($111.65) and sputum culture ($94.28).ConclusionAIMLAM showed promising diagnostic performance in HIV-negative patients. Stratifying patients using lymphocyte cell counting lifted the sensitivity and lowered the cost of LAM, offering a novel diagnostic strategy for tuberculosis in resource-limited settings.
Project description:TB is now the leading, global cause of death due to a single infectious microbe. To achieve the End TB vision of reducing TB by 90% by 2035 we will need new interventions. The objectives of this manuscript are to summarize the status of the clinical TB vaccine pipeline; to assess the challenges facing the TB development field; and to discuss some of the key strategies being embraced by the field to overcome these challenges. Currently, 8 of the 13 vaccines in clinical development are subunit vaccines; 6 of these contain or express either Ag85A or Ag85B proteins. A major challenge to TB vaccine development is the lack of diversity in both the antigens included in TB vaccines, and the immune responses elicited by TB vaccine candidates. Both will need to be expanded to maximise the potential for developing a successful candidate by 2025. Current research efforts are focused on broadening both antigen selection and the range of vaccine-mediated immune responses. Previous and ongoing TB vaccine efficacy trials have built capacity, generated high quality data on TB incidence and prevalence, and provided insight into immune correlates of risk of TB disease. These gains will enable the design of better TB vaccines and, importantly, move these vaccines into efficacy trials more rapidly and at a lower cost than was possible for previous TB vaccine candidates.
Project description:Ochratoxin-A (OTA) is a mycotoxin with possibly carcinogenic and nephrotoxic effects in humans and animals. OTA is often found as a contaminant in agricultural commodities. The aim of the present work was to evaluate OTA-degrading and detoxifying potential of Cupriavidus basilensis ŐR16 strain. In vivo administration of OTA in CD1 male mice (1 or 10 mg/kg body weight for 72 hours or 0.5 mg/kg body weight for 21 days) resulted in significant elevation of OTA levels in the blood, histopathological alterations- and transcriptional changes in OTA-dependent genes (annexinA2, clusterin, sulphotransferase and gadd45 and gadd153) in the renal cortex. These OTA-induced changes were not seen in animals that have been treated with culture supernatants in which OTA was incubated with Cupriavidus basilensis ŐR16 strain for 5 days. HPLC and ELISA methods identified ochratoxin α as the major metabolite of OTA in Cupriavidus basilensis ŐR16 cultures, which is not toxic in vivo. This study has demonstrated that Cupriavidus basilensis ŐR16 efficiently degrade OTA without producing toxic adventitious metabolites.
Project description:Mycobacterium tuberculosis remains the leading cause of death attributed to a single infectious organism. Bacillus Calmette-Guerin (BCG), the standard vaccine against M. tuberculosis, is thought to prevent only 5% of all vaccine-preventable deaths due to tuberculosis, thus an alternative vaccine is required. One of the principal barriers to vaccine development against M. tuberculosis is the complexity of the immune response to infection, with uncertainty as to what constitutes an immunological correlate of protection. In this paper, we seek to give an overview of the immunology of M. tuberculosis infection, and by doing so, investigate possible targets of vaccine development. This encompasses the innate, adaptive, mucosal and humoral immune systems. Though MVA85A did not improve protection compared with BCG alone in a large-scale clinical trial, the correlates of protection this has revealed, in addition to promising results from candidate such as VPM1002, M72/ASO1E and H56:IC31 point to a brighter future in the field of TB vaccine development.
Project description:Zearalenone (hereafter referred to as ZEA) is a nonsteroidal estrogenic mycotoxin produced by several Fusarium spp. on cereal grains. ZEA is one of the most hazardous natural endocrine disrupting chemicals (EDC) which induces hyper estrogenic responses in mammals. This can result in reproductive disorders in farm animals as well as in humans. Consequently, detoxification strategies for contaminated crops are crucial for food safety. In this study we have developed a bacterial based detoxification system using a non-pathogen Rhodococcus pyridinivorans K408 strain. Following 5 days treatment of ZEA with R. pyridinivorans K408 strain HPLC analyses showed an 87.21% ZEA-degradation efficiency of the bacterial enzyme systems. In another approach, the strain biotransformation ability has also been confirmed by a bioluminescent version of the yeast estrogen screening system (BLYES), which detected an 81.75% of biodegradability of ZEA, in a good agreement with the chemical analyses. Furthermore, the capacity of R. pyridinivorans to eliminate the estrogenic effects of ZEA was tested by using an immature uterotrophic assay. Prepubertal female rats were treated with vehicle (olive oil), 17?-estradiol, ZEA (0.1-1-5-10 mg/kg body weight) and LB broth containing 500 mg/l ZEA that has already been incubated with or without Rhodococcus pyridinivorans K408 strain. Uterine weights were measured and the mRNA level changes relating to apelin, aquaporin 5, complement component 2, and calbindin-3 genes were measured by qRT-PCR. These genes represent the major pathways that are affected by estromimetic compounds. Zearalenone feeding significantly increased the uterus weight in a dose dependent manner and at the same time upregulated complement component 2 and calbindin-3 expression as well as decreased apelin and aquaporin 5 mRNA levels comparable to that seen in 17?-estradiol exposed rats. In contrast, LB broth in which ZEA was incubated with Rhodococcus pyridinivorans K408 prior to the feeding did not display any estrogenic effect neither on uterine weight nor on the expression of estrogen-regulated genes. Consequently, the identification of Rhodococcus pyridinivorans K408 strain in ZEA biodegradation proved to be a very efficient biological tool that is able to eliminate the complete estrogenic effects of ZEA. It is also remarkable that this biotransformation pathway of ZEA did not result in any residual estrogenic effects.
Project description:In a Perspective, Gavin Churchyard and Sue Swindells discuss the importance of strategies to target latent tuberculosis infection in high risk populations and thus disrupt a reservoir for new infections in high burden countries.
Project description:The recent release of COVID-19 spike glycoprotein allows detailed analysis of the structural features that are required for stabilizing the infective form of its quaternary assembly. Trying to disassemble the trimeric structure of COVID-19 spike glycoprotein, we analyzed single protomer surfaces searching for concave moieties that are located at the three protomer-protomer interfaces. The presence of some druggable pockets at these interfaces suggested that some of the available drugs in Drug Bank could destabilize the quaternary spike glycoprotein formation by binding to these pockets, therefore interfering with COVID-19 life cycle. The approach we propose here can be an additional strategy to fight against the deadly virus. Ligands of COVID-19 spike glycoprotein that we have predicted in the present computational investigation, might be the basis for new experimental studies in vitro and in vivo.