Project description:Hepatitis C virus (HCV) is a major global health problem with high morbidity and mortality. About 185 million people are living with HCV, of which 80% are living in low and middle income countries. With the development of new highly effective treatments for HCV, it is considered that the eradication of HCV may only be one step away. The major problem with new treatment options is its high price. The price of sofosbuvir-based treatment for one patient in the United States is US$85000-110000, while the actual production cost of a 12 wk direct-acting antiviral regimen is less than US$250. Another major hindrance in HCV eradication is the lack of quality management of blood transfusion screens. Due to the lack of HCV screening, 75% of people in the United States with HCV infection are unaware of their positive HCV status. The control of massive HCV pandemic will require a significant financial investment, political will, and support from medical, pharmaceutical, and civil organizations around the globe.
Project description:BackgroundThere are few long-term mortality prediction studies after acute aortic dissection (AAD) Type A and none were performed using new models such as neural networks (NN) or support vector machines (SVM) which may show a higher discriminatory potency than standard multivariable models.MethodsWe used 32 risk factors identified by Literature search and previously assessed in short-term outcome investigations. Models were trained (50%) and validated (50%) on 2 random samples from a consecutive 235-patient cohort. NN were run only on patients with complete data for all included variables (N = 211); SVM on the overall group. Discrimination was assessed by receiver operating characteristic area under the curve (AUC) and Gini's coefficients along with classification performance.ResultsThere were 84 deaths (36%) occurring at 564 +/- 48 days (95%CI from 470 to 658 days). Patients with complete variables had a slightly lower death rate (60 of 211, 28%). NN classified 44 of 60 (73%) dead patients and 147 of 151 (97%) long-term survivors using 5 covariates: immediate post-operative chronic renal failure, circulatory arrest time, the type of surgery on ascending aorta plus hemi-arch, extracorporeal circulation time and the presence of Marfan habitus. Global accuracies of training and validation NN were excellent with AUC respectively 0.871 and 0.870 but classification errors were high among patients who died. Training SVM, using a larger number of covariates, showed no false negative or false positive cases among 118 randomly selected patients (error = 0%, AUC 1.0) whereas validation SVM, among 117 patients, provided 5 false negative and 11 false positive cases (error = 22%, AUC 0.821, p < 0.01 versus NN results). An html file was produced to adopt and manipulate the selected parameters for practical predictive purposes.ConclusionsBoth NN and SVM accurately selected a few operative and immediate post-operative factors and the Marfan habitus as long-term mortality predictors in AAD Type A. Although these factors were not new per se, their combination may be used in practice to index death risk post-operatively with good accuracy.
Project description:Caspases are an evolutionary conserved family of cysteine-dependent proteases that are involved in many vital cellular processes including apoptosis, proliferation, differentiation and inflammatory response. Dysregulation of caspase-mediated apoptosis and inflammation has been linked to the pathogenesis of various diseases such as inflammatory diseases, neurological disorders, metabolic diseases, and cancer. Multiple caspase inhibitors have been designed and synthesized as a potential therapeutic tool for the treatment of cell death-related pathologies. However, only a few have progressed to clinical trials because of the consistent challenges faced amongst the different types of caspase inhibitors used for the treatment of the various pathologies, namely an inadequate efficacy, poor target specificity, or adverse side effects. Importantly, a large proportion of this failure lies in the lack of understanding various caspase functions. To overcome the current challenges, further studies on understanding caspase function in a disease model is a fundamental requirement to effectively develop their inhibitors as a treatment for the different pathologies. Therefore, the present review focuses on the descriptive properties and characteristics of caspase inhibitors known to date, and their therapeutic application in animal and clinical studies. In addition, a brief discussion on the achievements, and current challenges faced, are presented in support to providing more perspectives for further development of successful therapeutic caspase inhibitors for various diseases.
Project description:Aortic dissection (AD) is a life-threatening disease and the detailed mechanism remains unclear. Thus, proper animal models are urgently required to better understand its pathogenesis. Our current study aims to establish a reliable, time and cost-effective mouse AD model. To conduct the meta-analysis, we searched PubMed for related studies up to 2021 and statistical analysis was conducted using Review Manager 5.4. For the animal experiment, 6-week-old male ApoE-/- mice were given β-aminopropionitrile (BAPN) at a concentration of 1 g/L for 3 weeks before being infused with saline, 1000 ng/kg/min or 2500 ng/kg/min angiotensin II (AngII) via osmotic mini pumps for 2 or 4 weeks. To determine the presence of AD, we performed B-ultrasonography, hematoxylin and eosin (H&E) staining, and van Gieson staining. The result of the meta-analysis showed that the use of BAPN and more than 2000 ng/kg/min AngII can increase the rate of AD formation, whereas administrating Ang II for more than 28 days has no significant effect on the rate of AD formation when compared with the less than 14 days group. In the present study, mice treated with BAPN combined with 2500 ng/kg/min AngII for 2 weeks (12/20) had a significantly higher AD formation rate than mice treated with BAPN combined with 1000 ng/kg/min Ang II for 4 weeks (2/10), and had a similar model formation rate compared with the mice treated withβ-aminopropionitrile combined with 2500 ng/kg/min AngII for 4 weeks (6/10). There were 3 mice (3/10) and 6 mice (6/20) who died in the group treated with β-aminopropionitrile combined with 2500 ng/kg/min AngII for 4 weeks and 2 weeks respectively, and only one mouse (1/10) died in the group treated with β-aminopropionitrile combined with 1000 ng/kg/min AngII for 4 weeks. In 6-week-old male ApoE-/- mice that received with 1 g/L BAPN in the drinking water for 3 weeks along with 2500 ng/kg/min AngII infusion via osmotic mini pumps for 2 weeks, the highest model formation rate and relative lower cumulative mortality were noted.
Project description:Zika virus (ZIKV) is a mosquito-borne flavivirus that spread throughout the American continent in 2015 causing considerable worldwide social and health alarm due to its association with ocular lesions and microcephaly in newborns, and Guillain-Barré syndrome (GBS) cases in adults. Nowadays, no licensed vaccines or antivirals are available against ZIKV, and thus, in this very short time, the scientific community has conducted enormous efforts to develop vaccines and antivirals. So that, different platforms (purified inactivated and live attenuated viruses, DNA and RNA nucleic acid based candidates, virus-like particles, subunit elements, and recombinant viruses) have been evaluated as vaccine candidates. Overall, these vaccines have shown the induction of vigorous humoral and cellular responses, the decrease of viremia and viral RNA levels in natural target organs, the prevention of vertical and sexual transmission, as well as that of ZIKV-associated malformations, and the protection of experimental animal models. Some of these vaccine candidates have already been assayed in clinical trials. Likewise, the search for antivirals have also been the focus of recent investigations, with dozens of compounds tested in cell culture and a few in animal models. Both direct acting antivirals (DAAs), directed to viral structural proteins and enzymes, and host acting antivirals (HAAs), directed to cellular factors affecting all steps of the viral life cycle (binding, entry, fusion, transcription, translation, replication, maturation, and egress), have been evaluated. It is expected that this huge collaborative effort will produce affordable and effective therapeutic and prophylactic tools to combat ZIKV and other related still unknown or nowadays neglected flaviviruses. Here, a comprehensive overview of the advances made in the development of therapeutic measures against ZIKV and the questions that still have to be faced are summarized.
Project description:Immunity against Mycobacterium tuberculosis (Mtb) is highly complex, and the outcome of the infection depends on the role of several immune mediators with particular temporal dynamics on the host microenvironment. Autophagy is a central homeostatic mechanism that plays a role on immunity against intracellular pathogens, including Mtb. Enhanced autophagy in macrophages mediates elimination of intracellular Mtb through lytic and antimicrobial properties only found in autolysosomes. Additionally, it has been demonstrated that standard anti-tuberculosis chemotherapy depends on host autophagy to coordinate successful antimicrobial responses to mycobacteria. Notably, autophagy constitutes an anti-inflammatory mechanism that protects against endomembrane damage triggered by several endogenous components or infectious agents and precludes excessive inflammation. It has also been reported that autophagy can be modulated by cytokines and other immunological signals. Most of the studies on autophagy as a defense mechanism against Mycobacterium have been performed using murine models or human cell lines. However, very limited information exists about the autophagic response in cells from tuberculosis patients. Herein, we review studies that face the autophagy process in tuberculosis patients as a component of the immune response of the human host against an intracellular microorganism such as Mtb. Interestingly, these findings might contribute to recognize new targets for the development of novel therapeutic tools to combat Mtb. Actually, either as a potential successful vaccine or a complementary immunotherapy, efforts are needed to further elucidate the role of autophagy during the immune response of the human host, which will allow to achieve protective and therapeutic benefits in human tuberculosis.