Aspartate transcarbamoylase (ATC) is the first committed step in de novo pyrimidine biosynthesis in eukaryotes and plants. A potent transition state analog of human ATCase (PALA) has previously been assessed in clinical trials for the treatment of cancer, but was ultimately unsuccessful. Additionally, inhibition of this pathway has been proposed to be a target to suppress cell proliferation in E. coli, the malarial parasite and tuberculosis. In this manuscript we screened a 70-member library of ATC inhibitors developed against the malarial and tubercular ATCases for inhibitors of the human ATC. Four compounds showed low nanomolar inhibition (IC
In China, spouses of patients with advanced cancer have reported experiencing psychological distress. However, little attention has been paid to the positive psychological health trajectories of these caregivers, particularly regarding their resilience and the factors influencing its development over time. To examine the trajectories of resilience in Chinese spousal caregivers over a nine-month post-treatment period and to identify the basic characteristics associated with these trajectory patterns. This was a longitudinal, observational study conducted in mainland Chinese between January 2022 and May 2024. A total of 306 spouses of patients receiving cancer treatment were recruited from five local hospitals. Data was collected in four waves: within one month of initial treatment, and then at three-, six-, and nine-month intervals post-treatment. Socio-demographic questionnaires, the Connor-Davidson Resilience Scale, and the Beliefs in Chinese Familism Scale were used to collect data. Growth mixture modeling was employed to determine the various trajectories of resilience, followed by logistic regression analysis to examine the associated factors to predict types of trajectories. Growth mixture modeling showed two distinct trajectories of resilience were identified: an increased group (N = 78, 25.5%) and a stable group (N = 228, 74.5%). The increased group began with a low baseline level (intercept = 46.713) and showed a slight increase over time (slope = 7.505, p < 0.001), while the stable group had a moderate baseline level (intercept = 56.565) and remained stable over time (slope = 0.068, p > 0.05). Those in the stable group were more likely to be female, and to have achieved a middle school level of education, a lower family income, and greater Chinese familism at baseline than those in the increased group. Our findings underscore the importance of tracking the trajectories of resilience and predictors of trajectory patterns among spouses caring for patients with advanced cancer within a specific cultural context. Healthcare providers should provide tailored interventions to enhance resilience in spousal caregivers, considering the trajectory patterns of mental health change.
Clostridium difficile (C.difficile) is an exclusively anaerobic, spore-forming, and Gram-positive pathogen that is the most common cause of nosocomial diarrhea and is becoming increasingly prevalent in the community. Because C. difficile is strictly anaerobic, spores that can survive for months in the external environment contribute to the persistence and diffusion of C. difficile within the healthcare environment and community. Antimicrobial therapy disrupts the natural intestinal flora, allowing spores to develop into propagules that colonize the colon and produce toxins, thus leading to antibiotic-associated diarrhea and pseudomembranous enteritis. However, there is no licensed vaccine to prevent Clostridium difficile infection (CDI). In this study, a multi-epitope vaccine was designed using modern computer methods. Two target proteins, CdeC, affecting spore germination, and fliD, affecting propagule colonization, were chosen to construct the vaccine so that it could simultaneously induce the immune response against two different forms (spore and propagule) of C. difficile. We obtained the protein sequences from the National Center for Biotechnology Information (NCBI) database. After the layers of filtration, 5 cytotoxic T-cell lymphocyte (CTL) epitopes, 5 helper T lymphocyte (HTL) epitopes, and 7 B-cell linear epitopes were finally selected for vaccine construction. Then, to enhance the immunogenicity of the designed vaccine, an adjuvant was added to construct the vaccine. The Prabi and RaptorX servers were used to predict the vaccine's two- and three-dimensional (3D) structures, respectively. Additionally, we refined and validated the structures of the vaccine construct. Molecular docking and molecular dynamics (MD) simulation were performed to check the interaction model of the vaccine-Toll-like receptor (TLR) complexes, vaccine-major histocompatibility complex (MHC) complexes, and vaccine-B-cell receptor (BCR) complex. Furthermore, immune stimulation, population coverage, and in silico molecular cloning were also conducted. The foregoing findings suggest that the final formulated vaccine is promising against the pathogen, but more researchers are needed to verify it.
Abstract Purpose It is generally believed that Carbapenem-resistant Enterobacteriaceae (CRE) colonization is primarily responsible for subsequent systemic infection in humans. In China, the specific situation of CRE colonization and subsequent systemic infection in hospitalized patients necessitates further exploration. Methods We retrospectively analyzed data of intestinal CRE colonization inpatients at Xiangya Hospital, Central South University, regarding demography, clinical and pathogenic characteristics, treatment, and outcome. A risk prediction model for subsequent CRE infection was established and externally validated. Results In total, 839 intestinal CRE colonization samples from inpatients were included. Finally, 317 cases of intestinal CRE colonization were enrolled, 25.9% of whom developed systemic infections. The subsequent CRE infection rates of CRKP and CREC were 27.0% and 32.3%, respectively. The incidence of subsequent CRE infection in the respiratory medicine department, hematology department, and intensive care unit (ICU) was 26.7%, 21.8%, and 45.0%, respectively. Taking probiotics and the combined oral and intravenous administration of antibiotics were the protective factors for the subsequent infection of intestinal CRE colonization, while liver disease, agranulocytosis ≥ 7 days, hypoproteinemia, invasive respiratory assisted ventilation, history of surgery/trauma in the past 3 months, and use of antifungal drugs were the independent risk factors. Conclusions CRE infection after intestinal CRE colonization in inpatients can significantly prolong the length of hospital stay and increase total medical costs. The CRE infection group exhibited poor efficacy and high mortality. Thus, the established risk prediction model for intestinal infection after CRE colonization in hospitalized patients has a good prediction efficacy for high-risk departments.
Background . The study aimed to investigate whether endogenous H 2 S pathway was involved in high-salt-stimulated mitochondria-related vascular endothelial cell (VEC) apoptosis. Methods . Cultured human umbilical vein endothelial cells (HUVECs) were used in the study. H 2 S content in the supernatant was detected. Western blot was used to detect expression of cystathionine gamma-lyase (CSE), cleaved-caspase-3, and mitochondrial and cytosolic cytochrome c (cytc). Fluorescent probes were used to quantitatively detect superoxide anion generation and measure the in situ superoxide anion generation in HUVEC. Mitochondrial membrane pore opening, mitochondrial membrane potential, and caspase-9 activities were measured. The cell apoptosis was detected by cell death ELISA and TdT-mediated dUTP nick end labeling (TUNEL) methods. Results . High-salt treatment downregulated the endogenous VEC H 2 S/CSE pathway, in association with increased generation of oxygen free radicals, decreased mitochondrial membrane potential, enhanced the opening of mitochondrial membrane permeability transition pore and leakage of mitochondrial cytc, activated cytoplasmic caspase-9 and caspase-3 and subsequently induced VEC apoptosis. However, supplementation of H 2 S donor markedly inhibited VEC oxidative stress and mitochondria-related VEC apoptosis induced by high salt. Conclusion . H 2 S/CSE pathway is an important endogenous defensive system in endothelial cells antagonizing high-salt insult. The protective mechanisms for VEC damage might involve inhibiting oxidative stress and protecting mitochondrial injury.
The greatest cause of cancer-related fatalities globally is colorectal cancer (CRC). Targeted therapies like panitumumab are revolutionizing its treatment. Our study focuses on the impact of KRAS and NRAS genotypes on the efficacy of panitumumab and also on the significance of tumor location (colon vs. rectum) in treatment outcomes. We selected a specific clinical trial (NCT00364013) for further statistical analysis. Our work adds to what has already been learned by showing that KRAS and NRAS genotypes are important for how well panitumumab works to treat CRC. Meanwhile, the P-value of 0.49 demonstrated that, in contrast to what we had previously believed, the tumor site had no significant impact on progression-free survival outcomes. Our research highlights the critical role of genotyping in personalized CRC therapy and raises questions about the established opinion that tumor location impacts therapy outcomes significantly. These findings may help CRC management move toward a more genotype-centric approach, optimizing therapies and reducing expenses. Nevertheless, future studies with more significant cohorts would be needed to confirm these findings, given the larger sample size.
Pyrimidine nucleotides are essential for a wide variety of cellular processes and are synthesized either via a salvage pathway or through de novo biosynthesis. The latter is particularly important in proliferating cells, such as infectious diseases and cancer cells. Aspartate transcarbamoylase (ATCase) catalyzes the first committed and rate‐limiting step in the de novo pyrimidine biosynthesis pathway, making it an attractive therapeutic target for various diseases. This review summarizes the development of a series of allosteric ATCase inhibitors, advancing them as potential candidates for malarial, tuberculosis and cancer therapies. Furthermore, it explores the potential for these compounds to be expanded into drugs targeting neglected tropical diseases, antimicrobial‐resistant infections caused by the ESKAPE pathogens, and their possible application as herbicides. We identify the likely equivalent allosteric pocket in these systems and perform a structure and sequence‐based analysis of the resides comprising it, providing a rationale for continued exploration of this compound series as both specific and broad‐range inhibitors. The review concludes by emphasizing the importance of continued research into ATCase inhibitors, given their potential broad applicability in treating diverse diseases to enhance both human health and agricultural practices.
Cancer is the second-most lethal global disease, as per health reports, and is responsible for around 70% of deaths in low- and middle-income countries. Endometrial cancer is one of the emerging malignancies and has been predicted as a public health challenge for the future. Insulin resistance, obesity, and diabetes mellitus are the key metabolic factors that promote risks for the development of endometrial cancer. Various signaling pathways and associated genes are involved in the genesis of endometrial cancer, and any mutation or deletion in such related factors leads to the induction of endometrial cancer. The conventional way of drug delivery has been used for ages but is associated with poor management of cancer due to non-targeting of the endometrial cancer cells, low efficacy of the therapy, and toxicity issues as well. In this context, nanocarrier-based therapy for the management of endometrial cancer is an effective alternate choice that overcomes the problems associated with conventional therapy. In this review article, we highlighted the nanocarrier-based targeting of endometrial cancer, with a special focus on targeting various metabolic signaling pathways. Furthermore, the future perspectives of nanocarrier-based targeting of metabolic pathways in endometrial cancer were also underpinned. It is concluded that targeting metabolic signaling pathways in endometrial cancer via nanocarrier scaffolds is the future of pharmaceutical design for the significant management and treatment of endometrial cancer.
It is generally believed that Carbapenem-resistant Enterobacterales (CRE) colonization is primarily responsible for systemic infection in humans. However, there is no consensus on whether decolonization should be recommended in clinical practice. In China, the specific situation of CRE colonization and consequent systemic infection in hospitalized patients necessitates further exploration. We conducted a cohort study and analyzed various clinical characteristics of inpatients with intestinal CRE colonization. A risk prediction model for consequent CRE infection was established and externally validated. Our prediction model is freely available online at https://creinfection.shinyapps.io/dynnomapp/ . 839 intestinal CRE colonization samples from inpatients were included. 317 cases of intestinal CRE colonization were enrolled, 25.9% of whom developed systemic infections. The consequent CRE infection rates of Klebsiella pneumoniae and Escherichia coli were 27.0% and 32.3%. The departments at high risk for subsequent CRE infection were respiratory medicine, hematology, and intensive care unit. Secondary infection after intestinal CRE colonization in inpatients can significantly prolong the length of hospital stay (26 days vs. 33 days, P < 0.001), increase the total medical cost (144735.34¥ vs. 281852.34¥, P < 0.001), and has poor (85.11% vs. 52.44%, P < 0.001) efficacy and high mortality (5.96% vs. 18.29%, P = 0.001). Our study makes a significant contribution to comprehensively specify CRE infection, because these results can facilitate early identification of high-risk hospitalized patients, timely implementation to decolonize treatment interventions, ultimately achieve the goal of CRE nosocomial infection prevention and control.
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)
