Dual inhibition of the TrkA and JAK2 pathways using entrectinib and pacritinib suppresses the growth and metastasis of HER2-positive and triple-negative breast cancers.

HER2-positive and triple-negative breast cancers (TNBC) are difficult to treat and associated with poor prognosis. Despite showing initial response, HER2-positive breast cancers often acquire resistance to HER2-targeted therapies, and TNBC lack effective therapies. To overcome these clinical challenges, we evaluated the therapeutic utility of co-targeting TrkA and JAK2/STAT3 pathways in these breast cancer subtypes. Here, we report the novel combination of FDA-approved TrkA inhibitors (Entrectinib or Larotrectinib) and JAK2 inhibitors (Pacritinib or Ruxolitinib) synergistically inhibited in vitro growth of HER2-positive breast cancer cells and TNBC cells. The Entrectinib-Pacritinib combination inhibited the breast cancer stem cell subpopulation, reduced expression of stemness genes, SOX2 and MYC, and induced apoptosis. The Entrectinib-Pacritinib combination suppressed orthotopic growth of HER2-positive Trastuzumab-refractory breast cancer xenografts and basal patient-derived xenograft (PDXs), reduced tumoral SOX2 and MYC, and induced apoptosis in both mouse models. The Entrectinib-Pacritinib combination inhibited overall metastatic burden, and brain and bone metastases of intracardially inoculated TNBC cells without toxicity. Together, our results demonstrate for the first time that co-inhibition of TrkA and JAK2 synergistically suppresses breast cancer growth and metastasis, thereby providing preclinical evidence that supports future clinical evaluations.

Orthostatic Hypotension in Benign Prostatic Hyperplasia Patients and Its Association With Alpha-1 Antagonist Use: A Comprehensive Literature Review.

Orthostatic hypotension (OH) is frequently observed in benign prostatic hyperplasia (BPH) patients undergoing alpha-1 adrenergic antagonist (A1AA) therapy. While previous studies have acknowledged the prevalence of OH in BPH patients on A1AAs, limited data exist on ranking the safety of different A1AAs. This comprehensive review explores the underlying mechanisms of OH, examines numerous factors influencing its development, and provides insights into effective treatment strategies such as hydration, gradual postural changes, leg exercises, compression stockings, and tilt-table training for BPH management. The review highlights the significance of individualized care, interdisciplinary collaboration, and further research to optimize A1AA treatment, improve patient outcomes, and enhance quality of life.

Chronic hypoxia is associated with transcriptomic reprogramming and increased genomic instability in cancer cells.

Hypoxia afflicts the microenvironment of solid tumors fueling malignancy. We investigated the impact of long hypoxia exposure on transcriptional remodeling, tumor mutational burden (TMB), and genomic instability of cancer cells that were grouped based on their inherent sensitivity or resistance to hypoxia. A hypoxia score was used as a metric to distinguish between the most hypoxia-sensitive (hypoxia high (HH)), and most resistant (hypoxia low (HL)) cancer cells. By applying whole exome sequencing and microarray analysis, we showed that the HH group was indeed more sensitive to hypoxia, having significantly higher TMB (p = 0.03) and copy number losses (p = 0.03), as well as a trend of higher transcriptional response. Globally cells adapted by decreasing expression of genes involved in metabolism, proliferation, and protein maturation, and increasing alternative splicing. They accumulated mutations, especially frameshift insertions, and harbored increased copy number alterations, indicating increased genomic instability. Cells showing highest TMB simultaneously experienced a significant downregulation of DNA replication and repair and chromosomal maintenance pathways. A sixteen-gene common response to chronic hypoxia was put forth, including genes regulating angiogenesis and proliferation. Our findings show that chronic hypoxia enables survival of tumor cells by metabolic reprogramming, modulating proliferation, and increasing genomic instability. They additionally highlight key adaptive pathways that can potentially be targeted to prevent cancer cells residing in chronically hypoxic tumor areas from thriving.

p53 reactivating small molecule PRIMA­1MET/APR­246 regulates genomic instability in MDA­MB­231 cells.

Pharmacological reactivation of tumor­suppressor protein p53 has acted as a promising strategy for more than 50% of human cancers that carry a non­functional mutant p53 (mutp53). p53 plays a critical role in preserving genomic integrity and DNA fidelity through numerous biological processes, including cell cycle arrest, DNA repair, senescence and apoptosis. By contrast, non­functional mutp53 compromises the aforementioned genome stabilizing mechanisms through gain of function, thereby increasing genomic instability in human cancers. Restoring the functional activity of p53 using both genetic and pharmacological approaches has gained prominence in targeting p53­mutated tumors. Thus, the present study aimed to investigate the reactivation of p53 in DNA repair mechanisms and the maintenance of genomic stability using PRIMA­1MET/APR­246 small molecules, in both MDA­MB­231 and MCF­7 breast cancer cell lines, which carry mutp53 and wild­type p53, respectively. Results of the present study revealed that reactivation of p53 through APR­246 led to an increase in the functional activity of DNA repair. Prolonged treatment of MDA­MB­231 cells with APR­246 in the presence of cisplatin led to a reduction in mutational accumulation, compared with cells treated with cisplatin alone. These findings demonstrated that APR­246 may act as a promising small molecule to control the genomic instability in p53­mutated tumors.

Contamination of heavy metals in poultry eggs: a study presenting relation between heavy metals in feed intake and eggs.

This study aims to quantify heavy metals (Ni, Pb, Zn, Mn, Cr, Cu and Se) in eggs obtained from poultry farms and backyard raised hens by comparing the concentration of metals in their feed intake. Overall, 90 samples of egg and 12 samples of poultry feed (6 each with food and water) were collected from 3 different poultry farms and backyards located in peri-urban areas of Lahore. A di-acid digestion method was adopted for digestion, after which digested samples were analyzed under atomic absorption spectrophotometer. Results showed that the concentration of Pb, Cr and Se in egg white (Pb = 0.6578, Cr = 0.18 and Se = 0.2161), egg yolk (Pb = 0.7011, Cr = 0.2617 and Se = 0.2656), feed (Pb = 2.585, Cr = 1.3039 and Se = 0.9411) and water (Pb = 0.5483, Cr = 0.1006 and Se = 0.3461) were above permissible limits in both poultry farms (study group 1) and backyards (study group 2). The concentration of metals such as Pb, Mn, Cr, Cu and Se in poultry farms eggs were higher than backyard hen eggs, which may be due to the intake of contaminated feed. So, the current study concluded that the higher concentration of metals in eggs has a positive correlation with the intake of feed contaminated with heavy metals.

Potential druggable proteins and chimeric vaccine construct prioritization against Brucella melitensis from species core genome data.

The Brucella melitensis chronic infection and drug resistance emerged as a severe health problem in humans and domestic cattle. The pathogens fast genome sequences availability fetched the possibility to address novel therapeutics targets in a rationale way. We acquired the core genes set from 56 B. melitensis publically available complete genome sequences. A stringent bioinformatics layout of comparative genomics and reverse vaccinology was followed to identify potential druggable proteins and multi-epitope vaccine constructs from core genes. The 23 proteins were shortlisted as novel druggable targets based on their role in pathogen-specific metabolic pathways, non-homologous to human and human gut microbiome proteins and their druggability potential. Furthermore, potential chimeric vaccine constructs were generated from lead T and B-cell overlapped epitopes in combination with immune enhancer adjuvants and linkers sequences. The molecular docking and MD simulation analyses ensured stable molecular interaction of a finally prioritized vaccine construct with human immune cells receptors.

The In Silico Characterization of a Salicylic Acid Analogue Coding Gene Clusters in Selected Pseudomonas fluorescens Strains.

BACKGROUND: The microbial genome sequences provide solid in silico framework for interpretation of their drug-like chemical scaffolds biosynthetic potentials. Pseudomonas fluorescens strains are metabolically versatile and producing therapeutically important natural products. OBJECTIVES: The key objective of the present study was to mine the publically available data of P. fluorescens strains genomes for putative drug-like metabolites identification. MATERIALS AND METHODS: We implemented the computational biology resources of AntiSMASH and BAGEL3 for the secondary metabolites prediction from P. fluorescens strains genome sequences. The predicted secondary metabolites were evaluated using drug discovery chemoinformatics resources, like Drugbank database search and molecular docking inspection. RESULTS: The analyses unveiled a wide array of chemical scaffolds biosynthesis in different P. fluorescens strains. Subsequently, the drug-like potential evaluation of these metabolites identified few strains, including P. fluorescens PT14, P. fluorescens A5O6, and P. fluorescens FW300-N2E3 that harbor the biosynthetic gene clusters for salicylic acid-like metabolite biosynthesis. The molecular docking inspection of this metabolite against human cyclooxygenase and aldo-keto reductase targets revealed its feasible inhibitory potentials like other salicylate compounds. CONCLUSION: The computational biology and drug discovery analyses identified different gene clusters in P. fluorescens genomes coding for salicylic acid-like chemotypes biosynthesis. These gene clusters may worthy to target through metabolic engineering for the massive production of salicylates-like chemical scaffolds from microbial resources.

Evaluating the Oncogenic and Tumor Suppressor Role of XPO5 in Different Tissue Tumor Types

The miRNAs nuclear export protein XPO5 has been previously studied in several individual malignancies. In our recent study we have demonstrated that excess levels of XPO5 enhanced the proliferation of prostate cancer cells. Similarly, there are studies to support the inhibitory role of XPO5 in cancers. In order to evaluate discrepancies in the expression levels of XPO5 in differential tumor types, we quantified the expression of XPO5 using gene expression RNA-seq data for several tumor types which were independently confirmed by immunohistochemistry in multiple organs cancer tissue microarray (TMAs) experiment. We found that while some tumors (Breast, Bladder, Lymph-node, Lung, Esophagus and Ovary) showed higher differences between normal and malignant tumors in XPO5 expression, there were tissues (Kidney and Brain) that have a significantly lower XPO5 expression in malignant tumors. We further studies these observations of overexpression and down-regulation of XPO5 in breast and kidney cancer cell lines and found that XPO5 might have a dual role in promoting or inhibiting tumor growth in different cancer tissue types.

Giant Benign Prostatic Hyperplasia in a Pakistani Patient.

"Giant hyperplasia" of the prostate is a rare pathology of the prostate gland. We report one such case, in which a successful retropubic prostatectomy was performed on an elderly male patient in Pakistan. The weight of the resected prostate was 700 g, which is the eighth largest prostate with benign prostatic hyperplasia reported.