Gossypol Inhibits Non-small Cell Lung Cancer Cells Proliferation by Targeting EGFRL858R/T790M

Background: Overexpression of epidermal growth factor receptor (EGFR) has been reported to be implicated in the pathogenesis of non-small cell lung cancer (NSCLC). Several EGFR inhibitors have been used in clinical treatment of NSCLC, but the emergence of EGFRL858R/T790M resistant mutation has reduced the efficacy of the clinical used EGFR inhibitors. There is an urgent need to develop novel EGFRL858R/T790M inhibitors for better NSCLC treatment.Methods: By screening a natural product library, we have identified gossypol as a novel potent inhibitor targeting EGFRL858R/T790M. The activity of gossypol on NSCLC cells was evaluated by cell proliferation, cell apoptosis and cell migration assays. Kinase activity inhibition assay and molecular docking were used to study the inhibition mechanism of gossypol to EGFRL858R/T790M. Western blotting was performed to study the molecular mechanism of gossypol inhibiting the downstream pathways of EGFR.Results: Gossypol inhibited the cell proliferation and cell migration of NSCLC cells, and induced caspase-dependent cell apoptosis of NSCLC cells by upregulating the expression of pro-apoptotic protein BAD. Molecular docking revealed that gossypol could bind to the kinase domain of EGFRL858R/T790M with good binding affinity through hydrogen bonds and hydrophobic interactions. Gossypol inhibited the kinase activity of EGFRL858R/T790M with EC50 of 150.1 nM. Western blotting analysis demonstrated that gossypol inhibited the phosphorylation of EGFR and its downstream signal pathways in a dose-dependent manner.Conclusion: Gossypol inhibited cell proliferation and induced apoptosis of NSCLC cells by targeting EGFRL858R/T790M. Our findings provided a basis for developing novel EGFRL858R/T790M inhibitors for treatment of NSCLC

Reducing maternal infection after assisted vaginal birth in a diverse and deprived population

Postpartum maternal sepsis is a leading cause of maternal mortality and morbidity. A single dose of prophylactic antibiotics following assisted vaginal births has been shown to significantly reduce postpartum maternal infection in a landmark multicentre randomised controlled trial, which led to its national recommendation. This project aimed to improve the local implementation of prophylactic antibiotics following assisted vaginal births to reduce postnatal maternal infections. Using a prospectively collated birth register, data were collected retrospectively on prophylactic antibiotics administration and postnatal maternal infection rates after assisted vaginal births at the Sandwell and West Birmingham Hospitals National Health Service Trust in North-West Birmingham of the UK. The data were collected from routinely used electronic health records over three audit cycles (n=287) between 2020 and 2023. A mixed-method approach was used to improve the use of prophylactic antibiotics: (1) evidence-based journal clubs targeting doctors in training, (2) presentations of results after all three audit cycles at our and (3) expedited a formal change of local guidelines to support prophylactic antibiotics use. Prophylactic antibiotic administration increased from 13.2% (December 2021) to 90.7% (July 2023), associated with a reduction in maternal infection rates (18.2% when prophylaxis was given vs 22.2% when no prophylaxis was given). However, we observed a gradual increase in the overall postnatal maternal infection rates during the project period. Our repeat audit identified prophylactic antibiotics were regularly omitted after deliveries in labour ward rooms (59.3%), compared with 100% of those achieved in theatre. After further interventions, prophylactic antibiotics administration rates were comparable between these clinical areas (>90%) in 2023. Together, we have demonstrated a simple set of interventions that induced sustainable changes in practice. Further evaluation of other modifiable risk factors and infection rates following all deliveries is warranted in view of the gradual increase in the overall postnatal maternal infection rates

The effects of physical activity, fast-mimicking diet and psychological interventions on cancer survival: a systematic review and meta-analysis of randomized controlled trials

Background: Health professionals are often asked if non-pharmacological interventions prolong life. This review aims to evaluate the effects of physical activity, fast-mimicking diet (FMD) and psychological interventions on survival in all cancers. Methods: A systematic review and meta-analysis of randomized controlled trials (RCTs). Only RCTs of physical activity, FMD and psychological interventions (including counselling, cognitive and other psychotherapies) in cancer patients that reported survival outcomes were included. Data sources: CENTRAL, MEDLINE, Embase, CINAHL, APA PsycINFO, Web of Science, ICTRP and ClinicalTrials.gov from inception to January 2020 were searched without language restrictions. The protocol was prospectively registered at PROSPERO (CRD42019160944). Results: Thirty-one RCTs (9 on physical activity and 22 on psychological interventions) were included in the final analysis after evaluation of 60,207 records from our initial search. No eligible RCT on FMD was reported. RCTs on group psychological interventions (41.9%) and in patients with breast cancer (38.7%) were the most common. Most evaluated short-term interventions and in primary or adjuvant settings. Only one of 9 (11%) RCTs on physical activity and 8 of 22 (36%) RCTs on psychological interventions were associated with improved overall survival. Only group psychological interventions in breast cancer had adequate number of RCTs to allow a meta-analysis to be performed. It demonstrated a trend towards improved overall survival (HR -0.20, 95%CI -0.49 to 0.10), particularly in RCTs that evaluated long-term (>6 months) therapies (HR -0.29, 95%CI -0.59 to 0.01). Conclusion: Longer term interventions starting early in the patients’ care journey in primary and adjuvant settings have shown the most promise for improving survival. Better designed RCTs including survival outcomes are particularly needed in non-breast cancers

Vascular endothelial growth factor restores delayed tumor progression in tumors depleted of macrophages

Genetic depletion of macrophages in Polyoma Middle T oncoprotein (PyMT)‐induced mammary tumors in mice delayed the angiogenic switch and the progression to malignancy. To determine whether vascular endothelial growth factor A (VEGF‐A) produced by tumor‐associated macrophages regulated the onset of the angiogenic switch, a genetic approach was used to restore expression of VEGF‐A into tumors at the benign stages. This stimulated formation of a high‐density vessel network and in macrophage‐depleted mice, was followed by accelerated tumor progression. The expression of VEGF‐A led to a massive infiltration into the tumor of leukocytes that were mostly macrophages. This study suggests that macrophage‐produced VEGF regulates malignant progression through stimulating tumor angiogenesis, leukocytic infiltration and tumor cell invasion

Barriers and shortcomings in access to cardiovascular management and prevention for familial hypercholesterolemia during the COVID-19 pandemic

Familial hypercholesterolemia (FH) is a hereditary condition caused by mutations in the lipid pathway. The goal in managing FH is to reduce circulating low-density lipoprotein cholesterol and, therefore, reduce the risk of developing atherosclerotic cardiovascular disease (ASCVD). Because FH patients were considered high risk groups due to an increased susceptible for contracting COVID-19 infection, we hypothesized whether the effects of the pandemic hindered access to cardiovascular care. In this review, we conducted a literature search in databases Pubmed/Medline and ScienceDirect. We included a comprehensive analysis of findings from articles in English related and summarized the effects of the pandemic on cardiovascular care through direct and indirect effects. During the COVID-19 pandemic, FH patients presented with worse outcomes and prognosis, especially those that have suffered from early ASCVD. This caused avoidance in seeking care due to fear of transmission. The pandemic severely impacted consultations with lipidologists and cardiologists, causing a decline in lipid profile evaluations. Low socioeconomic communities and ethnic minorities were hit the hardest with job displacements and lacked healthcare coverage respectively, leading to treatment nonadherence. Lock-down restrictions promoted sedentary lifestyles and intake of fatty meals, but it is unclear whether these factors attenuated cardiovascular risk in FH. To prevent early atherogenesis in FH patients, universal screening programs, telemedicine, and lifestyle interventions are important recommendations that could improve outcomes in FH patients. However, the need to research in depth on the disproportionate impact within different subgroups should be the forefront of FH research

Non-Small Cell Lung Cancer Cells Expressing CD44 Are Enriched for Stem Cell-Like Properties

Background: The cancer stem cell theory hypothesizes that cancers are perpetuated by cancer stem cells (CSC) or tumor initiating cells (TIC) possessing self-renewal and other stem cell-like properties while differentiated non-stem/initiating cells have a finite life span. To investigate whether the hypothesis is applicable to lung cancer, identification of lung CSC and demonstration of these capacities is essential. Methodology/Principal Finding: The expression profiles of five stem cell markers (CD34, CD44, CD133, BMI1 and OCT4) were screened by flow cytometry in 10 lung cancer cell lines. CD44 was further investigated by testing for in vitro and in vivo tumorigenecity. Formation of spheroid bodies and in vivo tumor initiation ability were demonstrated in CD44+ cells of 4 cell lines. Serial in vivo tumor transplantability in nude mice was demonstrated using H1299 cell line. The primary xenografts initiated from CD44+ cells consisted of mixed CD44+ and CD44- cells in similar ratio as the parental H1299 cell line, supporting in vivo differentiation. Semi-quantitative Real-Time PCR (RT-PCR) showed that both freshly sorted CD44+ and CD44+ cells derived from CD44+-initiated tumors expressed the pluripotency genes OCT4/POU5F1, NANOG, SOX2. These stemness markers were not expressed by CD44- cells. Furthermore, freshly sorted CD44+ cells were more resistant to cisplatin treatment with lower apoptosis levels than CD44- cells. Immunohistochemical analysis of 141 resected non-small cell lung cancers showed tumor cell expression of CD44 in 50.4% of tumors while no CD34, and CD133 expression was observed in tumor cells. CD44 expression was associated with squamous cell carcinoma but unexpectedly, a longer survival was observed in CD44-expressing adenocarcinomas. Conclusion/Significance: Overall, our results demonstrated that stem cell-like properties are enriched in CD44-expressing subpopulations of some lung cancer cell lines. Further investigation is required to clarify the role of CD44 in tumor cell renewal and cancer propagation in the in vivo environment.© 2010 Leung et al.published_or_final_versio