The prevalence of multidrug-resistant (MDR) ESKAPE pathogens, including Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa, represents a critical global public health challenge. In response, mRNA vaccines offer an adaptable and scalable platform for immunotherapy against ESKAPE pathogens by encoding specific antigens that stimulate B-cell-driven antibody production and CD8
Abstract The epithelial-to-mesenchymal transition (EMT) is a vital control point in metastatic breast cancer (MBC). TWIST1, SNAIL1, SLUG, and ZEB1, as key EMT-inducing transcription factors (EMT-TFs), are involved in MBC through different signaling cascades. This updated meta-analysis was conducted to assess the correlation between the expression of EMT-TFs and prognostic value in MBC patients. A total of 3,218 MBC patients from fourteen eligible studies were evaluated. The pooled hazard ratios (HR) for EMT-TFs suggested that high EMT-TF expression was significantly associated with poor prognosis in MBC patients (HRs = 1.72; 95% confidence intervals (CIs) = 1.53–1.93; P = 0.001). In addition, the overexpression of SLUG was the most impactful on the risk of MBC compared with TWIST1 and SNAIL1, which sponsored fixed models. Strikingly, the increased risk of MBC was less associated with ZEB1 expression. However, the EMT-TF expression levels significantly increased the risk of MBC in the Asian population (HR = 2.11, 95% CI = 1.70–2.62) without any publication bias (t = 1.70, P = 0.11). These findings suggest that the overexpression of potentially TWIST1, SNAIL1 and especially SLUG play a key role in the aggregation of MBC treatment as well as in the improvement of follow-up plans in Asian MBC patients.
Monkeypox (Mpox) is a growing public health concern, with complex interactions within host systems contributing to its impact. This study employs multi-omics approaches to uncover therapeutic targets and potential drug repurposing opportunities to better understand Mpox's molecular pathogenesis. We developed an in silico host-pathogen interaction (HPI) network and applied weighted gene co-expression network analysis (WGCNA) to explore interactions between Mpox and host proteins. Subtype-specific host-pathogen protein-protein interaction networks were constructed, and key modules from the HPI and WGCNA were integrated to identify significant host proteins. To predict upstream signaling pathways and transcription factors, we used eXpression2Kinases and ChIP-X Enrichment Analysis. The multi-Steiner trees method was applied to compare our findings with those from FDA-approved antiviral drugs. Analysis of 55 differentially expressed genes in Mpox infection revealed 11 kinases and 15 transcription factors as key regulators. We identified 16 potential drug targets, categorized into 8 proviral genes (ESR2, ERK1, ERK2, P38, JNK1, CDK4, GSK3B, STAT3) designated for inhibition, and 8 antiviral genes (IKKA, HDAC1, HIPK2, TF65, CSK21, HIPK2, ESR2, GSK3B) designated for activation. Proviral genes are involved in the AKT, Wnt, and STAT3 pathways, while antiviral genes impact the AP-1, NF-κB, apoptosis, and IFN pathways. Promising FDA-approved candidates were identified, including kinase inhibitors, steroid hormone receptor agonists, STAT3 inhibitors, and notably Niclosamide. This study enhances our understanding of Mpox by identifying key therapeutic targets and potential repurposable drugs, providing a valuable framework for developing new treatments.
Abstract BRAF and NRAS are the most reported mutations associated to melanomagenesis. The lack of accurate diagnostic markers in response to therapeutic treatment in BRAF/NRAS-driven melanomagenesis is one of the main challenges in melanoma personalized therapy. In order to assess the diagnostic value of phosphatidylserine-specific phospholipase A1-alpha (PLA1A), a potent lysophospholipid mediating the production of lysophosphatidylserine, PLA1A mRNA and serum levels were compared in subjects with malignant melanoma (n = 18), primary melanoma (n = 13), and healthy subjects (n = 10). Additionally, the correlation between histopathological subtypes of BRAF/NRAS-mutated melanoma and PLA1A was analyzed. PLA1A expression was significantly increased during melanogenesis and positively correlated to disease severity and histopathological markers of metastatic melanoma. PLA1A mRNA and serum levels were significantly higher in patients with BRAF-mutated melanoma compared to the patients with NRAS-mutated melanoma. Notably, PLA1A can be used as a diagnostic marker for an efficient discrimination between naïve melanoma samples and advanced melanoma samples (sensitivity 91%, specificity 57%, and AUC 0.99), as well as BRAF-mutated melanoma samples (sensitivity 62%, specificity 61%, and AUC 0.75). Our findings suggest that PLA1A can be considered as a potential diagnostic marker for advanced and BRAF-mutated melanoma.
To discover vulnerabilities associated with dermokine (DMKN) as a new trigger of the epithelial-mesenchymal transition (EMT) -driven melanoma, we undertook a genome-wide genetic screening using transgenic. Here, we showed that DMKN expression could be constitutively increased in human malignant melanoma (MM) and that this correlates with poor overall survival in melanoma patients, especially in BRAF-mutated MM samples. Furthermore, in vitro , knockdown of DMKN inhibited the cell proliferation, migration, invasion, and apoptosis of MM cancer cells by the activation of ERK/MAPK signaling pathways and regulator of STAT3 in downstream molecular. By interrogating the in vitro melanoma dataset and characterization of advanced melanoma samples, we found that DMKN downregulated the EMT-like transcriptional program by disrupting EMT cortical actin, increasing the expression of epithelial markers, and decreasing the expression of mesenchymal markers. In addition, whole exome sequencing was presented with p.E69D and p.V91A DMKN mutations as a novel somatic loss of function mutations in those patients. Moreover, our purposeful proof-of-principle modeled the interaction of ERK with p.E69D and p.V91A DMKN mutations in the ERK-MAPK kinas signaling that may be naturally associated with triggering the EMT during melanomagenesis. Altogether, these findings provide preclinical evidence for the role of DMKN in shaping the EMT-like melanoma phenotype and introduced DMKN as a new exceptional responder for personalized MM therapy.
Background/Aim: Gastro-esophageal reflux has been suggested to be associated with several pulmonary complications such as asthma, and post-transplant bronchiolitis obliterans (BO). Pepsin or bile salts in the sputum is shown to be an optimal molecular marker of gastric contents macro/micro aspiration. In this study, we investigated sputum pepsin as a marker of micro-aspiration in sulfur mustard (SM) exposed cases compared to healthy controls. Materials and Methods: In a case controlled study, 26 cases with BO and 12 matched healthy controls were recruited and all cases were symptomatic and their exposure to SM was previously documented during Iran-Iraq conflict. Pepsin levels in sputum and total bile acids were measured using enzymatic assay. The severity of respiratory disorder was categorized based upon the spirometric values. Result: The average concentration of pepsin in sputum was higher in the case group (0.29 ± 0.23) compared with healthy subjects (0.13 ± 0.07; P ± 0.003). Moreover, the average concentration of bile acids in the sputum cases was not significantly different in comparison to the controls (P = 0.5). Conclusion: Higher pepsin concentrations in sputum of SM exposed patients compared with healthy control subjects indicate the occurrence of significantly more gastric micro-aspiration in SM exposed patients.
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