Hepatobiliary infection after transjugular intrahepatic portosystemic shunt creation in patients with prior biliary intervention: A multi-institution retrospective study.

PURPOSE: To estimate the risk of hepatobiliary infection, including endoTIPSitis, liver abscesses, and cholangitis, after transjugular intrahepatic portosystemic shunt (TIPS) creation in patients with prior biliary intervention. MATERIALS AND METHODS: This multi-institution, retrospective study identified 76 patients (n=48 males; mean age 54.9; mean model for end stage liver disease score=13.2; n=45 for ascites and n=23 for varices; n=31 with prior liver transplantation) among 2,130 undergoing TIPS (3.6%) who had prior biliary intervention (n=19 bilioenteric anastomoses, n=35 sphincterotomies, n=28 internal plastic stents, n=4 internal metal stents, and n=6 percutaneous biliary drains). The baseline risk of post-TIPS hepatobiliary infection was estimated from a control group of 1,202 TIPS procedures in patients without prior biliary intervention. RESULTS: Eleven of 76 patients (14.5%) developed hepatobiliary infection after TIPS, including 7 with endoTIPSitis, 4 with hepatic abscesses, and 2 with cholangitis. The 30-day risk of infection was 10.9% (95% CI=3.5-17.8%), significantly higher than the 0.4% risk (95% CI=0.1-0.8%) observed in patients without prior biliary intervention (hazard ratio (HR)=25.56, 95% CI=8.36-78.13, p<0.001). All types of biliary intervention were associated with increased risk of infection, with bilioenteric anastomoses conferring the highest risk. Paradoxically, among patients with prior biliary intervention, use of post-procedural antibiotic prophylaxis was associated with an increased infection risk (HR=19.85; 95% CI=2.44-161.50; p=0.005). Microbial culture data showed high rates of Enterococcus, Klebsiella, and Candida species. CONCLUSIONS: Prior biliary intervention was associated with a 10.9% risk of hepatobiliary infection, including endoTIPSitis, liver abscess, and cholangitis, within 30 days after TIPS creation.

Remdesivir-Induced Bradycardia.

Remdesivir, a viral RNA-dependent RNA polymerase inhibitor, found extensive use in coronavirus disease 2019-infected patients because it curbs the viral load expansion. Among patients hospitalized as a result of lower respiratory tract infection, remdesivir proved to improve recovery time; however, remdesivir also can induce significant cytotoxic effects on cardiac myocytes. In this narrative review, we discuss the pathophysiological mechanism of remdesivir-induced bradycardia and diagnostic and management strategies for these patients. We conclude that further research is necessary to understand better the mechanism of bradycardia in coronavirus disease 2019 patients with or without cardiovascular disorder treated with remdesivir.

Exploring Sorafenib and Simvastatin Combination for Ferroptosis-Induced Cancer Treatment: Cytotoxicity Screening, In Vivo Efficacy, and Safety Assessment.

Ferroptosis, a pathway dependent on oxygen and iron catalysts, holds promise as a therapeutic approach for cancer treatment due to its manageable regulation, direct control, and immunogenic properties. The sensitivity of cancer cells to ferroptosis induction varies based on their metabolic, genetic, and signalling pathways, prompting the use of combination therapy. In this study, we conducted a screening of drug combinations, including sorafenib (SOR) with simvastatin (SIM), phenethyl isothiocyanate, and trigonelline, in MDA-MB-231, A549, and HeLa cells to assess their cytotoxicity. The SOR-SIM combination exhibited a synergistic effect in MDA-MB-231, A549, and HeLa cells, with calculated CI values of ~ 0.66, 0.53, and 0.59, respectively. Furthermore, co-treatment with ferrostatin-1 resulted in a concentration-dependent increase in the IC50 values. Additionally, SOR + SIM demonstrated a significant reduction in GSH levels, an increase in MDA levels, and mitochondrial membrane depolarization across all three cell lines, indicating their ferroptosis inducing potential. In-vivo studies showed a significant reduction in tumor volume by 3.53-, 2.55-, and 1.47-fold compared to control, SIM, and SOR, respectively. Toxicity assessments revealed insignificant changes in biomarker levels and no observable deformations in isolated organs, except for erythrocyte shrinkage and membrane scrambling effects caused by the SOR + SIM combination. Overall, our findings highlight the potential of the SOR + SIM combination as an effective strategy for cancer treatment, emphasizing the importance of further research in targeted drug delivery systems to ensure its safety.

Probiotic Formulations: A Patent Landscaping Using the Text Mining Approach.

The outstanding research outcomes and registrations of myriads of probiotic strains have flooded the health market with various innovative probiotic-based products and their patents. The study of patented formulations of probiotics can give an overall insight into its existing application. A landscaping review of patents for probiotic-based preparations is presented in the current work. The patent search was performed over commercially available patent databased and analysis tool-PatSeer Pro®. Search strings containing words "Formulation" and "Composition" resulted in more than 3700 patents. Landscaping review of 400 + patents from the last 20 years (2000-2020) was performed using the Text-Mining approach. Text-Mining helped to identify 19 technological clusters which represent these patents. These clusters include the patents of probiotic preparations on animal feed, human food, cosmetics, antimicrobial, antidiabetic, arthritis, etc. A review of this massive number of patents unveiled many exciting preparations. Probiotic-based innovative products for depression, diabetes, Parkinson's, tumor, acne, and animal husbandry are reviewed comprehensively. The present work also unravels a few new-flanged products like probiotic layered condoms, products for acute alcoholism, and traditional Chinese medicine with probiotics. The patent landscape of probiotic-based preparations has presented a whole scenario of probiotic-based preparations. It has also revealed many unexplored areas where innovation can be excelled.

A Narrative Review of the Pathophysiology and Treatment of Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a genetic autosomal dominant disorder of the heart muscle that is characterized by left ventricular hypertrophy and sudden cardiac death. It is the most common inherited cardiac disease. HCM is defined by sarcomeric mutations that result in fibrosis of the heart, affecting contraction. In most cases, clinical presentations can range from asymptomatic to systolic and diastolic ventricular dysfunction, arrhythmias, and sudden cardiac death. Some histopathologic features typical of the disease are changes in myocyte disarray and myocardial fibrosis. Mutations in the ß-myosin heavy chain and myosin-binding protein C have been identified as the cause of the disease. The goals of pharmacological therapy as well as nonpharmacological therapy are to alleviate the symptoms and to prevent sudden cardiac death. Anatomical defects are treated primarily by surgical intervention, whereas other issues such as hypercontractility are treated with pharmacotherapy. In this article, we review the pathophysiology and treatment options for HCM.

Efficient farnesylation of an extended C-terminal C(x)3X sequence motif expands the scope of the prenylated proteome.

Protein prenylation is a post-translational modification that has been most commonly associated with enabling protein trafficking to and interaction with cellular membranes. In this process, an isoprenoid group is attached to a cysteine near the C terminus of a substrate protein by protein farnesyltransferase (FTase) or protein geranylgeranyltransferase type I or II (GGTase-I and GGTase-II). FTase and GGTase-I have long been proposed to specifically recognize a four-amino acid CAAX C-terminal sequence within their substrates. Surprisingly, genetic screening reveals that yeast FTase can modify sequences longer than the canonical CAAX sequence, specifically C(x)3X sequences with four amino acids downstream of the cysteine. Biochemical and cell-based studies using both peptide and protein substrates reveal that mammalian FTase orthologs can also prenylate C(x)3X sequences. As the search to identify physiologically relevant C(x)3X proteins begins, this new prenylation motif nearly doubles the number of proteins within the yeast and human proteomes that can be explored as potential FTase substrates. This work expands our understanding of prenylation's impact within the proteome, establishes the biologically relevant reactivity possible with this new motif, and opens new frontiers in determining the impact of non-canonically prenylated proteins on cell function.

Rhabdomyolysis Secondary to Clenbuterol Use and Exercise.

BACKGROUND: The literature regarding rhabdomyolysis secondary to illicit drug use is sparse. Clenbuterol is a bronchodilator approved for veterinary use, which in high doses can increase protein deposition and lipolysis similarly to anabolic steroids, and is thereby abused for bodybuilding and weight loss effects. Clenbuterol has previously been described in case reports to be cardiotoxic, with patient presentations similar to overdoses of sympathomimetic substances, but reports of rhabdomyolysis are limited to a single case series in horses. CASE REPORT: We report the first case of rhabdomyolysis secondary to clenbuterol in a human. Our patient used clenbuterol for muscle-building effects in addition to exercise for multiple days prior to presentation. The patient's chief complaint at Emergency Department (ED) presentation was discolored urine. Workup for rhabdomyolysis was initiated, and an initial creatine kinase was measured at 122,933 units/L. Our patient's rhabdomyolysis was successfully treated with supportive therapy, and the patient was eventually discharged to home with no identifiable disability. The patient's kidney function remained at baseline, and no acute kidney injury was experienced secondary to rhabdomyolysis. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Patients presenting to the ED may have been unintentionally exposed through cutting of illicit substances or through intentional use in bodybuilding. Clenbuterol has well-described cardiotoxic effects, and we report the additional toxicity of rhabdomyolysis with its use.

Barriers to adopting intracorporeal anastomosis in colorectal procedures amongst Australian general surgeons.

INTRODUCTION: Minimally invasive colonic anastomosis can be performed intracorporeally or extracorporeally with laparoscopic or robotic assistance. In colorectal surgery, choosing the optimal approach is still controversial. Mainly, the debate involves balancing the potential benefits of intracorporeal anastomosis (ICA) with increased technical difficultly with the more straightforward and widely accepted extracorporeal anastomosis (ECA). Both techniques require different skill sets, and this study aims to identify barriers that prevent adoption of ICA. METHODS: A 31-point questionnaire survey was distributed through the General Surgeons Australia (GSA) platform of active general surgeon in Australia. It was open for 2 months between July and August 2023. Statistical analysis was completed using descriptive analysis and logistic regression. RESULTS: Forty-three general surgeons completed the survey. ECA was the most performed and preferred surgical technique. It was identified that increased operative time is the biggest barrier to completing ICA followed by lack of training and no perceived benefit with ICA. Patient comorbidities did not result in choosing ICA over ECA; however, surgeons with less experience and volume in colorectal surgery were more likely complete ECA in operations with increased technical difficulty. CONCLUSION: Although ECA is the go-to technique for many Australian general surgeons, it is evident that they may be overlooking the benefits offered by ICA. Further training is required to improve operative times and confidence in the technique. Ongoing research, audits of existing techniques, and updated training will assist surgeons becoming acquainted with the latest evidence and to offer the best care to their patients.

A Metabolic Axis of Immune Intractability.

Immune cells in the tumor niche robustly influence disease progression. Remarkably, in cancer, developmental pathways are reenacted. Many parallels between immune regulation of embryonic development and immune regulation of tumor progression can be drawn, with evidence clearly supporting an immune-suppressive microenvironment in both situations. In these ecosystems, metabolic and bioenergetic circuits guide and regulate immune cell differentiation, plasticity, and functional properties of suppressive and inflammatory immune subsets. As such, there is an emerging pattern of intersection across the dynamic process of ontogeny and the ever-evolving tumor neighborhood. In this article, we focus on the convergence of immune programming during ontogeny and in the tumor microenvironment. Exemplifying dysregulation of Hedgehog (Hh) activity, a key player during ontogeny, we highlight a critical convergence of these fields and the metabolic axis of the nutrient sensing hexosamine biosynthetic pathway (HBP) that integrates glucose, glutamine, amino acids, acetyl CoA, and uridine-5'-triphosphate (UTP), culminating in the synthesis of UDP-GlcNAc, a metabolite that functions as a metabolic and bioenergetic sensor. We discuss an emerging pattern of immune regulation, orchestrated by O-GlcNAcylation of key transcriptional regulators, spurring suppressive activity of dysfunctional immune cells in the tumor microenvironment.

Enhancing anti-cancer potential by delivering synergistic drug combinations via phenylboronic acid modified PLGA nanoparticles through ferroptosis-based therapy.

In this study, we investigated the potential of the sorafenib (SOR) and simvastatin (SIM) combination to induce ferroptosis-mediated cancer therapy. To enhance targeted drug delivery, we encapsulated the SOR + SIM combination within 4-carboxy phenylboronic acid (CPBA) modified PLGA nanoparticles (CPBA-PLGA(SOR + SIM)-NPs). The developed CPBA-PLGA(SOR + SIM)-NPs exhibited a spherical shape with a size of 213.1 ± 10.9 nm, a PDI of 0.22 ± 0.03, and a Z-potential of -22.9 ± 3.2 mV. Notably, these nanoparticles displayed faster drug release at acidic pH compared to physiological pH. In cellular experiments, CPBA-PLGA(SOR + SIM)-NPs demonstrated remarkable improvements, leading to a 2.51, 2.69, and 2.61-fold decrease in IC50 compared to SOR alone, and a 7.50, 16.71, and 5.11-fold decrease in IC50 compared to SIM alone in MDA-MB-231, A549, and HeLa cells, respectively. Furthermore, CPBA-PLGA(SOR + SIM)-NPs triggered a reduction in glutathione (GSH) levels, an increase in malondialdehyde (MDA) levels, and mitochondrial membrane depolarization in all three cell lines. Pharmacokinetic evaluation revealed a 2.50- and 2.63-fold increase in AUC0-∞, as well as a 1.53- and 2.46-fold increase in mean residence time (MRT) for SOR and SIM, respectively, compared to the free drug groups. Notably, the CPBA-PLGA(SOR + SIM)-NPs group exhibited significant reduction in tumor volume, approximately 9.17, 2.45, and 1.63-fold lower than the control, SOR + SIM, and PLGA(SOR + SIM)-NPs groups, respectively. Histological examination and biomarker analysis showed no significant differences compared to the control group, suggesting the biocompatibility of the developed particles for in-vivo applications. Altogether, our findings demonstrate that CPBA-PLGA(SOR + SIM)-NPs hold tremendous potential as an efficient drug delivery system for inducing ferroptosis, providing a promising therapeutic option for cancer treatment.

3D visualization systems improve operator efficiency during difficult laparoscopic cholecystectomy: a retrospective blinded review of surgical videos.

BACKGROUND: 3D visualization systems in laparoscopic surgery have been proposed to improve manual task handling compared to 2D, however, few studies have compared the intra-operative efficacy in laparoscopic cholecystectomy (LC). The aim of this study is to determine if there is a benefit in intra-operative efficiency when using a 3D visualization system in difficult LC compared to traditional 2D visualization systems. METHODS: Retrospective analysis of 'difficult' LCs (Grades 3 or 4) was completed. The assessor was blinded as all cases were recorded and viewed in 2D only. Variables collected included time to complete steps, missed hook diathermy attempts, failed grasp attempts, missed clip attempts and preparation steps for intra-operative cholangiogram (IOC). Multiple linear regression was undertaken for time variables, Poisson regression or negative binomial regression was completed for continuous variables. RESULTS: Fifty-two operative videos of 'difficult' LC were reviewed. 3D systems were associated with reduced operative times, although this was not statistically significant (CI: -2.93-14.93, P-value = 0.183). Dissection of the anterior fold to achieve the critical view of safety was significantly faster by 3.55 min (CI: 1.215-9.206, P-value = 0.002), and with considerably fewer errors when using 3D systems. Fewer IOC preparation errors were observed with a 3D system compared with a 2D system. CONCLUSIONS: 3D systems appear to enhance operator efficiency, allowing faster completion of critical steps with fewer errors. This pilot study underscores the utility of video annotation for intra-operative assessment and suggests that, in larger multi-centre studies, 3D systems may demonstrate superior intra-operative efficiency over 2D systems during a 'difficult' LC.

Innovative Fusion of Probiotics and Mouth Fresheners: Investigating Unaltered Growth, Microscopic Analysis, and Mucoadhesive Strength.

Since ancient times, mouth fresheners in many different forms have been used throughout the world. Traditional knowledge describes the health benefits of mouth fresheners, and contemporary science is now investigating their benefits. Claims have been made that mouth fresheners not only improve digestion but also promote oral health. Similar, but in a more profound sense, probiotics offer astounding advantages in treating many disorders. In certain cases, probiotics also offer prophylactic effects. Numerous benefits for dental health are being studied for B. coagulans (MB-BCM9) and B. subtilis (MB-BSM12). In this current study, a probiotic and a mouth freshener were combined to ameliorate the impacts of both. The oral residence of probiotics was enhanced by employing mucoadhesive polymers. Numerous compositions were developed and evaluated for the unaltered growth of probiotics, along with other evaluations like microscopy, in vitro mucoadhesive strength, and stability studies. Xanthan gum and hydroxypropyl methylcellulose were used in the development of mucoadhesive probiotic powder by employing the lyophilization technique. More than five hours of residence time were observed in the in vitro study with goat oral mucosa. The enumeration study validated the label claims of MB-BCM9 and MB-BSM12. It also concluded that none of the components of the formulation had a detrimental effect on probiotics. In essence, the present work discloses the novel and stable formulation of a probiotic-based mouth freshener.

Shedding light on weight loss: A narrative review of medications for treating obesity.

Obesity and overweight are the major risk factors for numerous chronic diseases, including cardiovascular diseases such as heart disease and stroke, which are the leading causes of death worldwide. The prevalence of obesity has dramatically risen in both developed and developing countries, making it a significant public health concern and a global crisis. Despite lifestyle modifications being the first-line treatment, the high risk of relapse has led to a growing interest in non-invasive pharmacotherapeutic interventions to achieve and maintain weight loss and reverse the growth of the obesity epidemic. Cardiovascular diseases and cancer account for the highest mortality rates among other comorbidities associated with obesity and overweight. Excess and abnormally deposited adipose tissue secretes various inflammatory mediators, leading to cardiovascular diseases and cancers. Weight loss of 5-10% significantly reduces cardiometabolic risk. Medications currently approved in the USA for long-term management of obesity are orlistat, naltrexone, bupropion, phentermine/topiramate, and Glucagon Like Peptide-1 (GLP-1) agonists such as liraglutide and semaglutide. The benefit-to-risk of medications, comorbidities, and individual responses should guide the treatment decisions. The article provides a comprehensive overview and discussion of several weight loss medications used previously and currently, including their efficacy, mechanisms of action, and side effects.

Vitiligo non-responding lesions to narrow band UVB have intriguing cellular and molecular abnormalities that may prevent epidermal repigmentation.

We have discovered that human vitiligo patients treated with narrow-band UVB (NBUVB) demonstrated localized resistance to repigmentation in skin sites characterized by distinct cellular and molecular pathways. Using immunostaining studies, discovery-stage RNA-Seq analysis, and confirmatory in situ hybridization, we analyzed paired biopsies collected from vitiligo lesions that did not repigment after 6 months of NBUVB treatment (non-responding) and compared them with repigmented (responding) lesions from the same patient. Non-responding lesions exhibited acanthotic epidermis, had low number of total, proliferative, and differentiated melanocyte (MC) populations, and increased number of senescent keratinocytes (KCs) and of cytotoxic CD8+ T cells as compared with responding lesions. The abnormal response in the non-responding lesions was driven by a dysregulated cAMP pathway and of upstream activator PDE4B, and of WNT/ß-catenin repigmentation pathway. Vitiligo-responding lesions expressed high levels of WNT10B ligand, a molecule that may prevent epidermal senescence induced by NBUVB, and that in cultured melanoblasts prevented the pro-melanogenic effect of α-MSH. Understanding the pathways that govern lack of NBUVB-induced vitiligo repigmentation has a great promise in guiding the development of new therapeutic strategies for vitiligo.

A Comparison of Three-Dimensional Visualization Systems and Two-Dimensional Visualization Systems During Laparoscopic Cholecystectomy: A Narrative Review.

Background: Laparoscopic cholecystectomy is a common procedure for the definitive treatment for cholecystitis and symptomatic cholelithiasis. One advancement in minimally invasive surgery has been the development of three-dimensional (3D) visualization systems to provide stereopsis. It is yet to be determined whether this innovation is beneficial to the surgeon or simply just a gimmick. This narrative review aims to answer the following research question, what is the impact of 3D visualization systems on surgical efficiency compared with two-dimensional visualization systems in laparoscopic cholecystectomy? Methods: Through a broad literature search it was determined that operative time and intraoperative errors have been used in published research to assess intraoperative efficiency. Results: Studies published to date have used operative time, intraoperative errors, and intraoperative bleeding as current measures for intraoperative efficiency. Previous meta-analysis have shown a slight improvement in operative time for 3D visualization systems; however, subsequent randomized control trials have not shown a significant difference in operative time. Reporting of intraoperative errors has been quite subjective and a difference between visualisation modality has not been shown. Conclusion: 3D visualization systems have shown a minor improvement in operative time compared with traditional laparoscopic systems and it is unlikely to be of any clinical significance. Studies that measure intraoperative error vary greatly in what they report, and which assessment tool is used. Across existing literature, studies do not control for surgeon's experience, elective/emergent cases, and grade of gallbladder/difficulty. Further research is required, using novel tools for assessment in laparoscopic cholecystectomy to determine intraoperative differences through objective and quantitative variables.

From the inside out: understanding the gut-heart connection.

The gut microbiome was first termed as 'Animalcules' by Antonie van Leeuwenhoek in the 17th century. The diverse composition and complex interactions of gut microbes are essential for good human health. They play a crucial role in inflammation, which by itself leads to the development of cardiovascular diseases. Although the mechanisms are not fully understood, it has been studied that the gut microbiota produce several bioactive metabolites impacting cardiovascular health mainly through TMAO pathway, SCFA pathway and bile acid pathway. Moreover, studies have found that using dietary interventions like high fiber diet and probiotics to re-establish a healthy equilibrium show promising results on improving cardiovascular health and thus, could be potentially used for prevention and management of cardiovascular diseases.

Herbal Medicine- A Friend or a Foe of Cardiovascular Disease.

BACKGROUND: Herbal remedies are used by 80% of the Asian population in primary health care as per WHO. According to current research, the herbal medicine market was valued at nearly USD 166 billion in 2021 and is expected to reach approximately USD 348 billion by 2028. Increased incidence of chronic conditions such as diabetes, asthma, coronary artery disease, osteoarthritis, has fueled the growing interest in traditional herbal and plant-derived treatments among researchers. In addition, rural communities in developing nations have renewed interest in herbal treatments due to lower cost and easy availability. OBJECTIVE: Aim of the paper is to highlight the role of five of more commonly used herbal medicines that are Ginkgo biloba, Garlic, Flaxseed, Ginseng, Salvia miltiorrhiza in cardiovascular disorders. METHODS: A PubMed search was done using the keywords Herbal Medicine, Ginkgo biloba, Garlic, Flaxseed, Ginseng, Salvia miltiorrhiza. Articles which were available for free access were utilized. No formula inclusion or exclusion criteria was followed. A total of 42 papers were included for the study. CONCLUSION: Although there have been encouraging outcomes with the use of these herbal medications, many of these products are poorly monitored and are yet to be studied in detail regarding their adverse effects. Moreover, these medicinal products are known to interact with various drugs. To compete with the expanding pharmaceutical industry, more medicinally helpful herbal items must be used and scientifically validated.

Clinical Characteristics and Predictors of Mortality in Obese African-Americans with COVID-19: a Single-Center Retrospective Study.

BACKGROUND: This study aims to add to the body of evidence linking obesity as an established risk factor for COVID-19 infection and also look at predictors of mortality for COVID-19 in the African-Americans (AA) population. METHODS: A retrospective cohort study of patients with confirmed COVID-19 infection was done in a community hospital in New York City. The cohort was divided into two groups, with the non-obese group having a BMI < 30 kg/m2 and the obese group with a BMI ≥ 30 kg/m2. Clinical predictors of mortality were assessed using multivariate regression analysis. RESULTS: Among the 469 (AA) patients included in the study, 56.3% (n = 264) had a BMI < 30 kg/m2 and 43.7% (n = 205) had a BMI ≥ 30 kg/m2. Most common comorbidities were hypertension (n = 304, 64.8%), diabetes (n = 200, 42.6%), and dyslipidemia (n = 74, 15.8%). Cough, fever/chills, and shortness of breath had a higher percentage of occurring in the obese group (67.8 vs. 55.7%, p = 0.008; 58.0 vs. 46.2%, p = 0.011; 72.2 vs. 59.8%, p = 0.005, respectively). In-hospital mortality (41.5 vs. 25.4%, p < 0.001) and mechanical ventilation rates (34.6 vs. 22.7%, p = 0.004) were also greater for the obese group. Advanced age (p = 0.034), elevated sodium levels (p = 0.04), and elevated levels of AST (0.012) were associated with an increase in likelihood of in-hospital mortality in obese group. CONCLUSIONS: Our results show that having a BMI that is ≥ 30 kg/m2 is a significant risk factor in COVID-19 morbidity and mortality. These results highlight the need for caution when managing obese individuals.

PRMT-1 and p120-Catenin as EMT Mediators in Osimertinib Resistance in NSCLC.

Osimertinib, an irreversible tyrosine kinase inhibitor, is a first-line therapy in EGFR-mutant NSCLC patients. Prolonged treatment with Osimertinib leads to resistance due to an acquired C797S mutation in the EGFR domain and other mechanisms, such as epithelial-mesenchymal transition (EMT). In this study, we investigated the role of PRMT-1 and p120-catenin in mediating Osimertinib resistance (OR) through EMT. These studies found upregulation of gene and protein expression of PRMT-1, p120-catenin and Kaiso factor. Knockdown of p120-catenin using siRNA increased OR efficacy by 45% as compared to cells treated with mock siRNA and OR. After 24 h of transfection, the percentage wound closure in cells transfected with p120-catenin siRNA was 26.2%. However, in mock siRNA-treated cells the wound closure was 7.4%, showing its involvement in EMT. We also found high levels of p120-catenin expressed in 30% of smokers as compared to 5.5% and 0% of non-smokers and quit-smokers (respectively) suggesting that smoking may influence p120-catenin expression in NSCLC patients. These results suggest that biomarkers such as PRMT-1 may mediate EMT by methylating Twist-1 and increasing p120-catenin expression, which causes transcriptional activation of genes associated with Kaiso factor to promote EMT in Osimertinib-resistant cells.

Disturbed Sleep is Not Good for the Heart: A Narrative Review.

Sleep-related breathing disorders, including obstructive sleep apnea (OSA) and central sleep apnea (CSA), have a major impact on cardiovascular function. It has shown an association with hypertension, coronary artery disease, cardiac arrhythmias, sudden cardiac death, and congestive heart failure (CHF). This review focuses on highlighting the relationship between sleep apnea and CHF. We discuss the underlying pathophysiology, which involves the mechanical, neurohormonal, and inflammatory mechanisms; in addition, the similarities and differentiating clinical features of OSA in patients with CHF and without CHF. We have also discussed several treatment strategies, including weight loss, continuous positive airway pressure (CPAP), supplemental oxygen therapy, theophylline, acetazolamide, mandibular advancement device, and hypoglossal nerve stimulation (HGNS). We conclude that since there are several overlapping clinical features in patients with OSA with Heart Failure (HF) and without HF, early detection and treatment are crucial to decrease the risk of HF, coronary artery disease, and stroke.