Therapeutic Advances Research Articles

Identification of prognostic biomarkers in neuroblastoma using WGCNA and multi-omics analysis

BackgroundNeuroblastoma (NB) is one of the most frequent parenchymal tumors among children, with a high degree of heterogeneity and wide variation in clinical presentation. Despite significant therapeutic advances in recent years, long-term survival in high-risk patients remains low, emphasizing the urgent need to find new biomarkers and construct reliable prognostic models.MethodsIn this study, data from neuroblastoma samples in the ArrayExpress database were utilized to identify key gene modules and pivotal genes associated with NB prognosis by weighted gene co-expression network analysis (WGCNA). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis was performed using the DAVID database. Based on these hub genes, survival prognosis models were constructed and validated on an independent validation set in the Gene Expression Omnibus (GEO) database. Differences in biological functions and immune microenvironments and the sensitivity to pharmacological and immunotherapeutic treatments of patients in the high- and low-risk groups were examined by gene set enrichment analysis (GSEA) and immune infiltration analysis.ResultsWGCNA identified 14 gene modules and screened the module with the highest relevance to the International Neuroblastoma Staging System (INSS), containing 60 pivotal genes. GO and KEGG analyses demonstrated that these pivotal genes were mainly implicated in biological processes and signaling pathways including DNA replication, cell division, mitotic cell cycle, and cell cycle. Based on Lasso regression and COX regression analysis, a prognostic model containing DHFR, GMPS and E2F3 was constructed, and the RiskScore was significantly correlated with the 1-, 3- and 5-year survival of the patients. GSEA and immune infiltration analyses revealed significant differences in the levels of cell cycle-related pathways and immune cell infiltration between the high and low RiskScore groups. In particular, patients in the high-risk group are less likely to benefit from immunotherapy and may be better suited for treatment with drugs such as Oxaliplatin and Alpelisib.ConclusionThis research systematically identified biomarkers related to NB prognosis and developed a reliable prognostic model applying WGCNA and multiple bioinformatics methods. The model has important application value in predicting patients’ prognosis, evaluating drug sensitivity and immunotherapy effect, and provides new ideas and directions for precise treatment of neuroblastoma.

Glioma stem cells remodel immunotolerant microenvironment in GBM and are associated with therapeutic advancements.

Glioma is the most common primary tumor of the central nervous system (CNS). Glioblastoma (GBM) is incurable with current treatment strategies. Additionally, the treatment of recurrent GBM (rGBM) is often referred to as terminal treatment, necessitating hospice-level care and management. The presence of the blood-brain barrier (BBB) gives GBM a more challenging or "cold" tumor microenvironment (TME) than that of other cancers and gloma stem cells (GSCs) play an important role in the TME remodeling, occurrence, development and recurrence of giloma. In this review, our primary focus will be on discussing the following topics: niche-associated GSCs and macrophages, new theories regarding GSC and TME involving pyroptosis and ferroptosis in GBM, metabolic adaptations of GSCs, the influence of the cold environment in GBM on immunotherapy, potential strategies to transform the cold GBM TME into a hot one, and the advancement of GBM immunotherapy and GBM models.

Bioflavonoid Daidzein: Therapeutic Insights, Formulation Advances, and Future Directions.

Bioflavonoids, are a diverse group of phytonutrients that are widely distributed in fruits, vegetables, grains, teas, and certain medicinal herbs. They are characterized by their antioxidant properties and play essential roles in plant biology, such as providing color to fruits and flowers, protecting plants from environmental stresses. Daidzein, a bioflavonoid classified under natural products, is sourced from plants like soybeans and legumes. It exists in forms such as glycosides and aglycones, with equol and trihydroxy isoflavone being key metabolites formed by gut bacteria. Known for its wide-ranging therapeutic potential, daidzein has shown effects on cardiovascular health, cancer, diabetes, skin conditions, osteoporosis, and neurodegenerative disorders. Its mechanisms include interaction with estrogen receptors, antioxidative and anti-inflammatory properties, and modulation of apoptosis and cell cycles. Recent advances in formulation technologies aimed at enhancing daidzein's bioavailability and efficacy are critically evaluated, including nanoparticle-based delivery systems and encapsulation strategies. Researchers have developed advanced formulations like nanoparticles and liposomes to enhance daidzein's solubility, stability, bioavailability, and targeted delivery. Considered a promising nutraceutical, daidzein warrants further exploration into its molecular actions and safety profile to fully realize its clinical potential. This review offers a succinct overview encompassing therapeutic benefits, chemical characteristics, historical uses, toxicology insights, recent advancements in delivery systems, and future directions for daidzein research.

Structural changes in the organs of the lymphoid system in terms of induced carcinogenesis

Colorectal cancer is the third most common cancer in the world. Despite recent therapeutic advances, it causes more than 500,000 deaths each year. The immune system plays a crucial role in protecting the body from cancer. However, cancer cells are able to evade immune detection and destruction. For example, they can downregulate antigen expression, produce immunosuppressive molecules, or recruit immune cells that perform regulatory or inhibitory functions. Understanding the complex interactions between the immune system and carcinogenesis is crucial for developing effective cancer treatments. The study aimed to determine the morphological changes in the thymus, spleen, and lymph nodes under N,N-dimethylhydrazine-induced carcinogenesis. The study was performed on 77 male outbred albino rats weighing 190-230 g, kept in standard vivarium conditions. Colon adenocarcinoma was modeled by administration of N,N-dimethylhydrazine hydrochloride for 30 weeks. To study the peculiarities of morphological and functional changes in lymphoid organs in the dynamics of colon tumor lesions, animals were withdrawn from the experiment every 30 days. Paraffin sections of the thymus, spleen, and lymph nodes 5-6 μm thick were made on a rotary microtome and stained with hematoxylin and eosin. The experimental investigation unveiled the character and extent of histological alterations within the lymphoid system organs under conditions of N,N-dimethylhydrazine-induced colon adenocarcinomatosis. As the experiment progressed, there was a noticeable escalation in the severity of detrimental and degenerative modifications observed in the thymus, spleen, and lymph nodes. These modifications were evident in the disruption of blood circulation within the examined organs, leading to vascular wall impairment and hemorrhaging, the disarray of morphofunctional elements and the development of fibrosis. Given the significant role played by the thymus, spleen, and lymph nodes in regulating carcinogenesis and maintaining immune balance, it is extremely important to delve into understanding the changes in their structure and function. Obtained results indicate that carcinogenesis is accompanied by pronounced morphological changes in the structural components of the lymphoid system organs, the degree of which increases in direct proportion to the duration of exposure to the oncogenic factor.

Date palm: a potential nutraceutical and phytomedicine in most frequent aging associated diseases

AbstractSenescence, often known as ageing, is a condition of decline that shows itself as a decrease in fertility and survival at older ages. Ageing theory suggests that ageing evolves as a function of life history optimization or because of mutation pressure, depending on the degree of externally imposed mortality and shocks to fertility. An important key factor to many aging-related disorders (ARDs), such as hypertension, myocardial infarction, atherosclerosis, osteoporosis, cancer, and neurodegenerative diseases like Alzheimer’s and Parkinson’s disease, is ageing, a process influenced by countless biological and genetic pathways. While there have been significant advancements in therapeutics for age-related disorders, nutritional therapy, encasing various products from natural sources is recommended for durable and fruitful treatment. Numerous health advantages of the date palm, Phoenix dactylifera, have been well-documented. These include antioxidant, anti-inflammatory, cardioprotective, and neuroprotective activity. Phytochemical analysis of date palm demonstrates a lot of beneficial nutraceuticals that can ameliorate ARDs like polyphenols, phytosterols, carotenoids, flavonoids, terpenoids, fatty acids, carbohydrates, vitamins, and amino acids etc. The major signaling and molecular pathways by which these phytoconstituents exert their anti-ageing effects include terminating inflammation by blocking the release in of IL-6, TNF-α and clearance of Aβ plaques for neurodegenerative diseases; blocking ACE-II and HMG-CoA for cardio-protection; regulating RANK, p38MAPK-Runx2 pathways, and insulin-growth factor-1 (IGF-1) for osteoporosis. However, research on the benefits of date palm is still lacking. The purpose of this review is to shed light on the various biological activities of date palm in ARDs and to explore its remedial mechanisms.

Enhancing RNA-lipid nanoparticle delivery: Organ- and cell-specificity and barcoding strategies

Recent advancements in RNA therapeutics highlight the critical need for precision gene delivery systems that target specific organs and cells. Lipid nanoparticles (LNPs) have emerged as key vectors in delivering mRNA and siRNA, offering protection against enzymatic degradation, enabling targeted delivery and cellular uptake, and facilitating RNA cargo release into the cytosol. This review discusses the development and optimization of organ- and cell-specific LNPs, focusing on their design, mechanisms of action, and therapeutic applications. We explore innovations such as DNA/RNA barcoding, which facilitates high-throughput screening and precise adjustments in formulations. We address major challenges, including improving endosomal escape, minimizing off-target effects, and enhancing delivery efficiencies. Notable clinical trials and recent FDA approvals illustrate the practical applications and future potential of LNP-based RNA therapies. Our findings suggest that while considerable progress has been made, continued research is essential to resolve existing limitations and bridge the gap between preclinical and clinical evaluation of the safety and efficacy of RNA therapeutics. This review highlights the dynamic progress in LNP research. It outlines a roadmap for future advancements in RNA-based precision medicine.

Exosome-mediated delivery of siRNA molecules in cancer therapy: triumphs and challenges.

The discovery of novel and innovative therapeutic strategies for cancer treatment and management remains a major global challenge. Exosomes are endogenous nanoscale extracellular vesicles that have garnered increasing attention as innovative vehicles for advanced drug delivery and targeted therapy. The attractive physicochemical and biological properties of exosomes, including increased permeability, biocompatibility, extended half-life in circulation, reduced toxicity and immunogenicity, and multiple functionalization strategies, have made them preferred drug delivery vehicles in cancer and other diseases. Small interfering RNAs (siRNAs) are remarkably able to target any known gene: an attribute harnessed to knock down cancer-associated genes as a viable strategy in cancer management. Extensive research on exosome-mediated delivery of siRNAs for targeting diverse types of cancer has yielded promising results for anticancer therapy, with some formulations progressing through clinical trials. This review catalogs recent advances in exosome-mediated siRNA delivery in several types of cancer, including the manifold benefits and minimal drawbacks of such innovative delivery systems. Additionally, we have highlighted the potential of plant-derived exosomes as innovative drug delivery systems for cancer treatment, offering numerous advantages such as biocompatibility, scalability, and reduced toxicity compared to traditional methods. These exosomes, with their unique characteristics and potential for effective siRNA delivery, represent a significant advancement in nanomedicine and cancer therapeutics. Further exploration of their manufacturing processes and biological mechanisms could significantly advance natural medicine and enhance the efficacy of exosome-based therapies.

Structural Basis for Monoclonal Antibody Therapy for Transthyretin Amyloidosis.

The disease of transthyretin (TTR) amyloidosis (ATTR) has been known since the 1960s, and during the past 60 or so years, there has been a sustained period of steady discoveries that have led to the current model of ATTR pathogenesis. More recent research has achieved major advances in both diagnostics and therapeutics for ATTR, which are having a significant impact on ATTR patients today. Aiding these recent achievements has been the remarkable ability of cryo-electron microscopy (EM) to determine high-resolution structures of amyloid fibrils obtained from individual patients. Here, we will examine the cryo-EM structures of transthyretin amyloid fibrils to explore the structural basis of the two monoclonal antibody therapies for ATTR that are in clinical trials, ALXN-2220 and Coramitug, as well as to point out potential applications of this approach to other systemic amyloid diseases.

Exploring Chemical Space to Identify Partial Binders Against hMPV Nucleocapsid Protein.

Human metapneumovirus (hMPV) has gained prominence in recent times as the predominant etiological agent of acute respiratory tract infections. This virus targets children, the elderly, and individuals with compromised immune systems. Given the protracted duration of hMPV transmission, it is probable that the majority of children will have acquired the virus by the age of 5. In individuals with compromised immune systems, recurrence of hMPV infection is possible. As hMPV matures, it remains latent from the time of acquisition. The genome of hMPV encompasses a pivotal protein referred to as the nucleocapsid protein (N). This protein assumes the form of a left-handed helical nucleocapsid, enveloping the viral RNA genome. The primary function of this structure is to protect nucleases, rendering it a potentially promising target for therapeutic advancements. The present study employs a methodology that involves structure-based virtual screening, followed by molecular dynamics simulation at a 250-ns time scale, to identify potential natural molecules or their derivatives from the ZINC Database. These molecules are investigated for their binding properties against the hMPV nucleoprotein. Based on an evaluation of the docking score, binding site interaction, and molecular dynamics studies, it has been found that two naturally occurring molecules, namely M1 (ZINC85629735) and M3 (ZINC85569125), have shown notable docking scores of -9.6and -10.7 kcal/mol, acceptable RMSD, RMSF, Rg, and soon calculated from molecular dynamics trajectory associated with MMGBSA binding energy of -81.94 and -99.63 kcal/mol, respectively. These molecules have shown the highest binding affinity towardnucleocapsid protein and demonstrated promising attributes as potential binders against hMPV.

Real-World Primary Resistance to First-Line Immune-Based Combinations in Patients with Advanced Renal Cell Carcinoma (ARON-1).

Therapeutic advancements based on immuno-oncology combinations have revolutionized the management of patients with renal cell carcinoma. However, patients who have progressive disease as the best response, "primary refractory" (Pref), face dismal outcomes. Our multicenter retrospective real-world study aims to assess the prevalence and clinicopathological characteristics of Pref patients. This study collected data from 72 centers across 22 countries (1709 patients), involving patients aged ≥18 years with metastatic clear cell renal cell carcinoma. All patients were treated with first-line immune-oncology combinations. Data included patient demographics, histology, metastatic sites, and treatment responses. Radiological assessments followed Response Evaluation Criteria in Solid Tumors version 1.1. Statistical analyses employed Kaplan-Meier method, Cox proportional hazard models, logistic regression, and the receiver operating characteristic curve. In our study, the Pref rate was 19%. Nivolumab/ipilimumab showed the highest Pref rate (27%), while pembrolizumab/lenvatinib exhibited the lowest (10%). Primary refactory patients demonstrated significantly lower median overall survival (7.6 months) compared with non-Pref patients (55.7 months), p < 0.001. At the multivariate analysis, nephrectomy, sarcomatoid de-differentiation, intermediate/poor International Metastatic RCC Database Consortium risk, and bone and brain metastases emerged as significant predictors of overall survival for Pref patients with renal cell carcinoma. Logistic regression showed a significant relationship between liver metastases, intermediate/poor International Metastatic RCC Database Consortium risk, and no surgery and an increased risk of Pref. This study presents limitations, mainly because of its retrospective design. The ARON-1 study provides valuable insights into Pref patients, emphasizing the challenges of this precociously resistant subgroup. Identified predictors could guide risk stratification, aiding clinicians in tailored therapeutic approaches.

Development of Amphotericin B Decorated Gold Nanoparticles as a Promising Antileishmanial Nanoconjugate.

Leishmaniasis, attributed to the protozoan parasite Leishmania, manifests in diverse clinical forms, including cutaneous, mucocutaneous, and visceral leishmaniasis; VL constitutes a significant global health menace. Prevalent in tropical and subtropical regions, this affliction disproportionately impacts individuals below the poverty threshold, transmitted through the bite of female sandflies. Existing treatments, such as pentavalent antimony, miltefosine, and Amphotericin B, exhibit limitations. Despite the emergence of liposomal Amphotericin B (AmBisome) as a promising antileishmanial agent, its utility is impeded by adverse effects, elevated production expenses, and cytotoxicity. To address these challenges, our investigation introduces a potential remedy─a citrate-coated gold Amphotericin B nanoparticle formulation. Characterized using dynamic light scattering and transmission electron microscopy, this pioneering formulation exhibited efficacy against L. donovani Ag83 promastigotes as demonstrated by MTT cell viability testing. Evaluating internal reactive oxygen species (ROS) levels and dual staining with acridine orange and ethidium bromide unveiled its consequential impact on cell death. Significantly, our study discloses this novel nanoformulation's unprecedented inhibition of the trypanothione reductase enzyme. The findings posit the citrate-coated gold Amphotericin B nanoformulation as a promising and targeted antileishmanial agent, representing potential advancements in leishmaniasis therapeutics.

Glial Malignancies.

Gliomas comprise a diverse spectrum of related tumor subtypes with varying biological and molecular features and clinical outcomes. Advances in detailed genetic and epigenetic characterizations along with an appreciation that subtypes associated with developmental origins, including brain location and patient age, have shifted glioma classification from the historical reliance on histopathological features to updated categories incorporating molecular signatures and spatiotemporal incidence. Within a subtype, individual gliomas show cellular heterogeneity, generally containing subpopulations resembling different types of normal glial and progenitor cells. In addition to tumor-autonomous mechanisms of aberrant growth regulation driven by genetic mutations and signaling between tumor cells, interactions with the tumor microenvironment, including neurons, astrocytes, oligodendrocyte precursor cells, and the immune microenvironment play important roles in driving glioma growth and influencing response to treatment. The emerging understanding of the complex contributions of normal brain to glioma growth represents new opportunities for therapeutic advances.

Investigation of effect of complexing agent and processing method on solubility of Efonidipine

Nanosponges are versatile carriers due to their exceptional capability to improve the solubility of poorly water-soluble drugs, taste masking and enhancement of stability. This study investigates potential of nanosponges, prepared by crosslinking β-cyclodextrin with diphenyl carbonate in 1:4 ratio for enhancing solubility of Efonidipine. Nanosponges were characterized in terms of particle size. Phase solubility studies and solution state interaction studies were employed to understand the nature and strength of drug: nanosponge complexation. Complexes were prepared by kneading method and spray drying. Saturation solubility, in vitro dissolution studies and molecular modeling studies were performed. Complexes were characterized by differential scanning calorimetry (DSC), infrared spectroscopy, X ray powder diffraction (XRPD) and scanning electron microscopy. Phase solubility studies revealed 1:2 complexation between drug and carriers. Saturation solubility studies showed significant solubility increase with both beta CD and nanosponges. The increase was higher in case of spray dried complexes in all media. An 18 fold increase was observed in case of spray dried complexes in distilled water. DSC and PXRD confirmed amorphization of drug in the complexes. Thus solubility enhancement of EFD could be attributed to complexation and amorphization. Molecular modeling studies revealed the mode of entrapment of efonidipine in the carriers. In conclusion the versatility of nanosponges in encapsulating both hydrophilic and hydrophobic drug molecules holds immense promise for personalized medicine and targeted therapy, ultimately leading to improved patient outcomes. Moreover, the study introduces the efficacy of spray drying as a scalable and practical approach to maximize the solubility-enhancing benefits of nanosponges. This research highlights the potential of nanosponges to overcome a fundamental challenge in pharmaceuticals, opening new avenues for drug delivery and therapeutic advancement. Keywords: Nanosponges, β -cyclodextrin, inclusion complexes, solubility enhancement, molecular modelling

Understanding Amyotrophic Lateral Sclerosis: Pathophysiology, Diagnosis, and Therapeutic Advances.

This review offers an in-depth examination of amyotrophic lateral sclerosis (ALS), addressing its epidemiology, pathophysiology, clinical presentation, diagnostic techniques, and current as well as emerging treatments. The purpose is to condense key findings and illustrate the complexity of ALS, which is shaped by both genetic and environmental influences. We reviewed the literature to discuss recent advancements in understanding molecular mechanisms such as protein misfolding, mitochondrial dysfunction, oxidative stress, and axonal transport defects, which are critical for identifying potential therapeutic targets. Significant progress has been made in refining diagnostic criteria and identifying biomarkers, leading to earlier and more precise diagnoses. Although current drug treatments provide some benefits, there is a clear need for more effective therapies. Emerging treatments, such as gene therapy and stem cell therapy, show potential in modifying disease progression and improving the quality of life for ALS patients. The review emphasizes the importance of continued research to address challenges such as disease variability and the limited effectiveness of existing treatments. Future research should concentrate on further exploring the molecular foundations of ALS and developing new therapeutic approaches. The implications for clinical practice include ensuring the accessibility of new treatments and that healthcare systems are equipped to support ongoing research and patient care.

Correlates of improved outcomes in patients with COVID-19 treated in US emergency departments

BackgroundThe COVID-19 pandemic was managed in part by the rapid development of vaccines, diagnostics, and therapeutics including antiviral agents and advances in emergency airway and ventilatory management. The impact of these therapeutic advances on clinically pertinent metrics of emergency care have not been well-studied. MethodsWe abstracted data from emergency department (ED) visits made to 21 US health systems during the first two years of the pandemic, from February 1, 2020 to January 31, 2022. These health systems were participants in the NIH-supported COVID EHR Cohort, in which the University of Wisconsin served as the coordinating site. Limited patient-level data files were submitted monthly. Data elements included demographic and clinical variables, as well as standard measures of ED outcomes including 72-h returns, 72-h returns leading to readmission, and in-hospital mortality. Multivariable models were fitted to identify correlates of each of the dependent variables. A test for trend was used to detect changes in outcomes over time. ResultsDuring the two-year period, 150,357 individuals aged 18 years or older visited the ED. The median age was 45.4 years (IQR 27), 58.1 % were female, 49 % were White, 18.3 % Hispanic/Latino, and 45 % were publicly insured or uninsured. The prevalence of 72-h ED returns, readmissions, and in-hospital mortality significantly declined across the two-year period. SARS-CoV-2 vaccination was associated with reduced ED returns and mortality. Therapeutic agents were associated with increased mortality risk but were likely confounded by unmeasured covariates. ConclusionsOperational and clinical outcomes of ED-based treatment of individuals with COVID-19 improved in the first two years of the pandemic. This improvement is likely multifactorial and includes the development and deployment of SARS-CoV-2-specific vaccines, therapeutic agents, and improved healthcare delivery in the ED and elsewhere addressing management of airway and ventilatory status, as well as increased innate immunity in the general population.

Recurrence rates and risk factors in obscure gastrointestinal bleeding.

To determine the recurrence rate and identify risk factors for recurrence following diagnostic and therapeutic interventions using CE and balloon-assisted endoscopyin patients with OGIB. A retrospective cohort study at Gifu University Hospital analyzed CE procedures for patients with OGIB from 2008 to 2022. Patients underwent CE with subsequent treatments based on the findings. Statistical analyses, including Kaplan-Meier and Cox proportional hazards models, were used to estimate cumulative recurrence rates and identify recurrence risk factors. Out of 417 patients, 65.2% had positive CE findings, leading to therapeutic interventions in 16.3% of cases. The cumulative recurrence rates at 12, 24, and 36 months were 4.3%, 9.0%, and 13.9%, respectively. Liver cirrhosis (hazard rate: 4.15, 95% confidence interval 1.88-9.18, p < 0.01) was identified as a significant risk factor for recurrence. A significant recurrence rate in OGIB patients, with liver cirrhosis being a major risk factor. Despite diagnostic and therapeutic advances, a comprehensive approach including careful follow-up and consideration of risk factors is essential for management.

Current Advances in Diagnosis, Therapeutics, and Surgical Interventions for the Management of Refractory Gastroesophageal Reflux Disease (GERD): An Update.

Gastroesophageal reflux disease (GERD) is a chronic illness characterized by complications arising from the reflux of stomach contents, which significantly lower the quality of life, increase morbidity, and increase medical expenses associated with treating the condition. The main goal of treatment in GERD is symptomatic relief, relapse prevention, and healing of erosive esophagitis. The treatment mainly involves lifestyle changes to control acid production and proton pump inhibitors (PPIs) as the first line of treatment. Endoscopic interventions or anti-reflux surgery may be beneficial in relieving symptoms in people whose symptoms are triggered by reflux. In this review, we discuss the pathophysiology and newer diagnostic and treatment modalities including available surgical management options to manage refractory GERD.

Aortoesophageal fistula with hemorrhagic shock successfully treated with resuscitative endovascular balloon occlusion of the aorta

BackgroundAortoesophageal fistula (AEF) is a rare cause of upper gastrointestinal hemorrhage. Despite diagnostic and therapeutic advances, the mortality rate in AEF patients remains high because of its fulminant course, even with maximal intensive care. Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a resuscitation technique to control life-threatening bleeding. It has become an important modality in the management of life-threatening, traumatic or non-traumatic, arterial bleeding. However, it’s use in hemorrhagic shock caused by cancer has rarely been reported.Case presentationA 51-year-old woman with a history of esophageal cancer presented to our emergency department with hematemesis. Computed tomography was performed because of a strong suspicion of hemorrhagic shock. With a diagnosis of AEF due to esophageal cancer, emergency thoracic endovascular aortic repair was performed while the bleeding was controlled using REBOA. Staged elective esophageal reconstruction was successfully performed.ConclusionsHemostasis is crucial in patients who present with suspected hemorrhagic shock attributable to AEF. The timely implementation of REBOA has shown promise and potential effectiveness in such cases.

Targeting stress induction of GRP78 by cardiac glycoside oleandrin dually suppresses cancer and COVID-19

BackgroundDespite recent therapeutic advances, combating cancer resistance remains a formidable challenge. The 78-kilodalton glucose-regulated protein (GRP78), a key stress-inducible endoplasmic reticulum (ER) chaperone, plays a crucial role in both cancer cell survival and stress adaptation. GRP78 is also upregulated during SARS-CoV-2 infection and acts as a critical host factor. Recently, we discovered cardiac glycosides (CGs) as novel suppressors of GRP78 stress induction through a high-throughput screen of clinically relevant compound libraries. This study aims to test the possibility that agents capable of blocking stress induction of GRP78 could dually suppress cancer and COVID-19.ResultsHere we report that oleandrin (OLN), is the most potent among the CGs in inhibiting acute stress induction of total GRP78, which also results in reduced cell surface and nuclear forms of GRP78 in stressed cells. The inhibition of stress induction of GRP78 is at the post-transcriptional level, independent of protein degradation and autophagy and may involve translational control as OLN blocks stress-induced loading of ribosomes onto GRP78 mRNAs. Moreover, the human Na+/K+-ATPase α3 isoform is critical for OLN suppression of GRP78 stress induction. OLN, in nanomolar range, enhances apoptosis, sensitizes colorectal cancer cells to chemotherapeutic agents, and reduces the viability of patient-derived colon cancer organoids. Likewise, OLN, suppresses GRP78 expression and impedes tumor growth in an orthotopic breast cancer xenograft model. Furthermore, OLN blocks infection by SARS-CoV-2 and its variants and enhances existing anti-viral therapies. Notably, GRP78 overexpression mitigates OLN-mediated cancer cell apoptotic onset and suppression of virus release.ConclusionOur findings validate GRP78 as a target of OLN anti-cancer and anti-viral activities. These proof-of-principle studies support further investigation of OLN as a readily accessible compound to dually combat cancer and COVID-19.

Anti-Müllerian hormone type II receptor protein expression in non-small cell lung cancer and the effect of AMH/AMHR2 signaling on cancer cell proliferation.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide despite advances in cancer therapeutics. In several gynecological cancers, anti-Müllerian hormone receptor type 2 (AMHR2) mediates AMH-induced growth inhibition and is expressed at high levels. Furthermore, 5%-8% of NSCLCs exhibit high AMHR2 expression, suggesting that AMH may inhibit the progression of some lung cancers. However, the clinical relevance of AMHR2 expression and its role in lung cancer is not fully clarified. Immunostaining was performed on 79 surgical specimens of NSCLC. The Cancer Genome Atlas RNA-seq data for lung adenocarcinoma were analyzed, and gene ontology and gene set enrichment analyses were performed. In cellular experiments, AMHR2-overexpressing NSCLC cell lines were established, and the role of the AMH-AMHR2 pathway in cell proliferation with recombinant human AMH protein treatment was examined. A total of 13 cases (16.5%) were positive for immunostaining in lung adenocarcinoma tissues; no positive signals were detected in lung squamous carcinoma tissues. Gene expression variation analysis using The Cancer Genome Atlas data showed that the expression of genes related to the cell cycle was downregulated in the AMHR2-high group. Cellular experiments showed that activation of the AMH-AMHR2 pathway suppressed cell proliferation. In lung adenocarcinoma tissues with high expression of AMHR2, activation of the AMH-AMHR2 pathway may suppress cell proliferation.