Mebendazole prevents distant organ metastases in part by decreasing ITGß4 expression and cancer stemness.

Breast cancer is the most diagnosed cancer among women. Approximately 15-20% of all breast cancers are highly invasive triple-negative breast cancer (TNBC) and lack estrogen, progesterone, and ERBB2 receptors. TNBC is challenging to treat due to its aggressive nature with far fewer targeted therapies than other breast cancer subtypes. Current treatments for patients with TNBC consist of cytotoxic chemotherapies, surgery, radiation, and in some instances PARP inhibitors and immunotherapy. To advance current therapeutics, we repurposed mebendazole (MBZ), an orally available FDA-approved anthelmintic that has shown preclinical efficacy for cancers. MBZ has low toxicity in humans and efficacy in multiple cancer models including breast cancer, glioblastoma multiforme, medulloblastoma, colon cancer, pancreatic and thyroid cancer. MBZ was well-tolerated in a phase I clinical trial of adults recently diagnosed with glioma. We determined that the half-maximal inhibitory concentration (IC50) of MBZ in four breast cancer cell lines is well within the range reported for other types of cancer. MBZ reduced TNBC cell proliferation, induced apoptosis, and caused G2/M cell cycle arrest. MBZ reduced the size of primary tumors and prevented lung and liver metastases. In addition, we uncovered a novel mechanism of action for MBZ. We found that MBZ reduces integrin ß4 (ITGß4) expression and cancer stem cell properties. ITGß4 has previously been implicated in promoting "cancer stemness," which may contribute to the efficacy of MBZ. Collectively, our results contribute to a growing body of evidence suggesting that MBZ should be considered as a therapeutic to slow tumor progression and prevent metastasis.

Biallelic TMEM251 variants in patients with severe skeletal dysplasia and extreme short stature.

Skeletal dysplasias are a heterogeneous group of disorders ranging from mild to lethal skeletal defects. We investigated two unrelated families with individuals presenting with a severe skeletal disorder. In family NMD02, affected individuals had a dysostosis multiplex-like skeletal dysplasia and severe short stature (<-8.5 SD). They manifested increasingly coarse facial features, protruding abdomens, and progressive skeletal changes, reminiscent of mucopolysaccharidosis. The patients gradually lost mobility and the two oldest affected individuals died in their twenties. The affected child in family ID01 had coarse facial features and severe skeletal dysplasia with clinical features similar to mucopolysaccharidosis. She had short stature, craniosynostosis, kyphoscoliosis, and hip-joint subluxation. She died at the age of 5 years. Whole-exome sequencing identified two homozygous variants c.133C>T; p.(Arg45Trp) and c.215dupA; p.(Tyr72Ter), respectively, in the two families, affecting an evolutionary conserved gene TMEM251 (NM_001098621.1). Immunofluorescence and confocal studies using human osteosarcoma cells indicated that TMEM251 is localized to the Golgi complex. However, p.Arg45Trp mutant TMEM251 protein was targeted less efficiently and the localization was punctate. Tmem251 knockdown by small interfering RNA induced dedifferentiation of rat primary chondrocytes. Our work implicates TMEM251 in the pathogenesis of a novel disorder and suggests its potential function in chondrocyte differentiation.

The Hidden Threat: Endocrine Disruptors and Their Impact on Insulin Resistance.

The association between Insulin resistance, a global health issue, and endocrine disruptors (EDCs), chemicals interfering with the endocrine system, has sparked concern in the scientific community. This article provides a comprehensive review of the existing literature regarding the intricate relationship between EDCs and insulin resistance. Phthalates, commonly found in consumer products, are well-established EDCs with documented effects on insulin-signaling pathways and metabolic processes. Epidemiological studies have connected phthalate exposure to an increased risk of type 2 diabetes mellitus (T2DM). Perfluoroalkyl substances (PFAS), persistent synthetic compounds, have shown inconsistent associations with T2DM in epidemiological research. However, studies suggest that PFAS may influence insulin resistance and overall metabolic health, with varying effects depending on specific PFAS molecules and study populations. Bisphenol A (BPA), found in plastics and resins, has emerged as a concern for glucose regulation and insulin resistance. Research has linked BPA exposure to T2DM, altered insulin release, obesity, and changes in the mass and function of insulin-secreting ß-cells. Triclosan, an antibacterial agent in personal care products, exhibits gender-specific associations with T2DM risk. It may impact gut microbiota, thyroid hormones, obesity, and inflammation, raising concerns about its effects on metabolic health. Furthermore, environmental EDCs like polycyclic aromatic hydrocarbons, pesticides, and heavy metals have demonstrated associations with T2DM, insulin resistance, hypertension, and obesity. Occupational exposure to specific pesticides and heavy metals has been linked to metabolic abnormalities.

The Role of Artificial Intelligence in Prediction, Risk Stratification, and Personalized Treatment Planning for Congenital Heart Diseases.

This narrative review delves into the potential of artificial intelligence (AI) in predicting, stratifying risk, and personalizing treatment planning for congenital heart disease (CHD). CHD is a complex condition that affects individuals across various age groups. The review highlights the challenges in predicting risks, planning treatments, and prognosticating long-term outcomes due to CHD's multifaceted nature, limited data, ethical concerns, and individual variabilities. AI, with its ability to analyze extensive data sets, presents a promising solution. The review emphasizes the need for larger, diverse datasets, the integration of various data sources, and the analysis of longitudinal data. Prospective validation in real-world clinical settings, interpretability, and the importance of human clinical expertise are also underscored. The ethical considerations surrounding privacy, consent, bias, monitoring, and human oversight are examined. AI's implications include improved patient outcomes, cost-effectiveness, and real-time decision support. The review aims to provide a comprehensive understanding of AI's potential for revolutionizing CHD management and highlights the significance of collaboration and transparency to address challenges and limitations.

blaOXA, blaSHV-, and blaTEM- extended-spectrum ß-lactamases in Gram-negative strains from burn patients in Lahore, Pakistan.

INTRODUCTION: Gram-negative bacterial pathogens are associated with complications of post-burn infections that showed significant association with different genotypic variants of extended-spectrum ß-lactamases. In this study, we aimed to determine the distribution of ESBL gene variants among bacterial pathogens from post-burn infections. METHODOLOGY: Cephalosporin-resistant isolates were collected from Jinnah Burn and Reconstructive Surgery Centre, Lahore. Phenotypic testing: double-disk synergy test, combination disk test, multiplex PCR for blaOXA, blaTEM, and blaSHV genes were performed. RESULTS: Of the 53.5% cephalosporin-resistant isolates, 50.7% were community-acquired and 49.3% were nosocomial pathogens. Seventy-two percent of post-burn infections were found in males (p-value = 0.92, OR = 1.04). The age of burn victims ranged from 4 to 85 years (mean = 28.9, SD = 15.6). Pseudomonas aeruginosa was most predominant at a rate of 49%. There were 83.3% multidrug-resistant isolates, which showed susceptibility to meropenem, imipenem, and amikacin in 28.7%, 25.3%, and 26% respectively. In phenotypic tests 16% ESBLs detected by the DDST and 14% confirmed by the CDT. Molecular detection proved effective for the detection of 79.7% blaTEM, 37.7% blaOXA, and 18.8% blaSHV isolates. blaTEM genes were confirmed in 18.1% CDT-positive isolates, with 62.6% diagnostic accuracy (95% CI = 54.7-70) and 88% specificity (95% CI = 80.4-93.4). CONCLUSIONS: The antimicrobial resistance associated with the ESBL-producing Pseudomonas spp. and Enterobacteriaceae is becoming a challenge for the treatment and survival of burn patients. The high rate blaTEM, blaOXA, and blaSHV genes confirm the need to improve the management of burn patients in order to prevent post-burn infections.