EGFR Kinase Inhibiting Amino-enones for Breast Cancer; CADD Approach.

BACKGROUND: The Computer-Aided Drug Discovery (CADD) approach was used to develop a few Epidermal Growth Factor Receptor (EGFR) kinase inhibitors. EGFR kinase expression is highly associated with genomic instability, higher proliferation, lower hormone receptor levels, and HER2 over-expression. It is more common in breast cancer. Thus, EGFR Kinase is one of the main targets in discovering new cancer medicine. OBJECTIVE: To computationally validate some amides substituted ß-amino enones as EGFR inhibitors and to carry out associated in vitro anticancer agents. METHODS: We used tools such as molecular docking, MD simulations, DFT calculations, and ADMET predictions in silico to establish a preliminary SAR. In vitro, we used BT474 (ER+HER2+) and MCF-7 (ER-HER2) cell lines along with normal breast cell epithelial cells (MFC-10a) for anticancer studies and EGFR kinase inhibition assay studies. As the Reactive Oxygen Species (ROS) plays the main role in cancer development, we also analyzed the antioxidant potentials of these compounds. RESULTS: Among the family of eleven amides substituted (Z)-ß-amino enones (5a-k), compounds 5b, 5c, 5g, and 5h showed valuable in silico and in vitro bio-activity. Remarkably, the in-silico results almost coincided with in vitro study results. CONCLUSION: We recommend compounds 5b, 5c, 5g, and 5h for pre-clinical and clinical evaluation to establish them as future cancer therapeutics.

A Systematic Review of Mortality Rates Among Adult Acute Respiratory Distress Syndrome Patients Undergoing Extracorporeal Membrane Oxygenation Therapy.

Acute respiratory distress syndrome (ARDS) is a severe lung disease associated with a high mortality rate. Extracorporeal membrane oxygenation (ECMO) is a life-saving therapy for severe ARDS patients who do not respond to conventional treatments. Nevertheless, the optimal management of ARDS patients undergoing ECMO and their mortality rates remain subjects of controversy. Thus, this systematic review aims to assess mortality rates in ARDS patients on ECMO and identify associated factors. The review adhered to the Preferred Reporting Items for Systemic Review and Meta-Analysis (PRISMA) 2020 guidelines. A comprehensive literature search was conducted on PubMed, PubMed Central (PMC), Medline, and Embase. In accordance with our inclusion and exclusion criteria, filters, and key terms, we proceeded to screen the articles. After assessing the relevance of each article to our topic, further screening was carried out. Quality assessment of the articles was conducted, resulting in the inclusion of a total of 12 articles for the review. The primary outcome focused on mortality rates among ARDS patients undergoing ECMO. Secondary outcomes explored potential contributors to mortality, including patient age, underlying cause of ARDS, and Sequential Organ Failure Assessment (SOFA) scores at the initiation of ECMO. Mortality rates exhibited significant variation, ranging from 22% to 62.6%. Several factors emerged as potential predictors of mortality, encompassing patient age, comorbidities, complications during ECMO therapy, and treatment-related variables. This systematic review offers valuable insights into the intricate factors influencing mortality rates among ARDS patients on ECMO. A comprehension of these factors is essential to steer clinical practice and enhance patient outcomes. While ECMO serves as a restorative avenue for ARDS patients, future research is warranted to further elucidate these complex interactions and refine ECMO therapy protocols.

The Effects of Serotonin Receptor Type 7 Modulation on Bowel Sensitivity and Smooth Muscle Tone in Patients With Irritable Bowel Syndrome.

Irritable bowel syndrome (IBS) is a gut-brain disorder involving alterations in intestinal sensitivity and motility. Currently, IBS has no cure, and treatment focuses on the management of symptoms. The diverse, and sometimes contradictory, collections of symptoms reported across the different subtypes of IBS make treatment, as well as diagnosis, difficult for physicians. All subtypes of IBS have one symptom in common: abdominal pain caused by differences in the level of visceral sensitivity. Though current research on this topic is in its infancy, some researchers have proven, through experimental studies, that 5-hydroxytryptamine (serotonin) receptor type 7 (5-HT7) affects both visceral sensitivity and smooth muscle tone in the bowel. Therefore, this review will be discussing the future possibility of alleviating abdominal pain in patients with IBS and related disorders by modulating the 5-HT7 receptor.

Physical Therapy Interventions in Children With Cerebral Palsy: A Systematic Review.

Cerebral palsy is a group of disorders affecting individuals already from birth. It enormously impacts an individual's physical and emotional life and can bring many challenges to the individual, caregivers, and families. Therefore, it is crucial to investigate interventions that could improve various symptoms in children with cerebral palsy. Our systematic review intends to assess the effect of different exercise and physical therapy interventions in children with cerebral palsy. We used three databases for our article search: PubMed, Medical Literature Analysis and Retrieval System Online (MEDLINE), and PubMed Central (PMC). The combined number of papers found in all databases was 65,412. We then applied our inclusion and exclusion criteria, filters, key terms, and Medical Subheadings (MeSH). After applying our quality assessment tools, we included nine papers in our systematic review. The studies included in our review used various interventions to assess for improvement in symptoms in individuals with cerebral palsy. Interventions included stretching and resistance exercises, horse riding, biking, core stability exercises, slackline training, a home exercise program using an online tool, sit-to-stand exercise program, and functional training. Many studies have shown that interventions improved symptoms like balance, coordination, gait, and cardiovascular endurance in cerebral palsy. This review suggests that some of the included interventions have great potential to improve the symptoms of cerebral palsy and, therefore, can be a great addition to existing training and rehabilitation programs. Given that studies included a relatively small number of participants and were conducted over a short time, more research with a more significant number of participants over a longer time is necessary.

Estrogen's Tissue-Specific Regulation of the SLC26A6 Anion Transporter Reveal a Phenotype of Kidney Stone Disease in Estrogen-Deficient Females: A Systematic Review.

Kidney stone formation is an intricate process that involves a disruption in the interplay of the multiple organs and systems involved in regulating the concentration of specific ions in the body. Women who have gone through menopause are susceptible to kidney stone disease. This systematic review aims to investigate the potential influence of estrogen on kidney function and oxalate homeostasis, notably through the anion transporter SLC26A6 (also known as putative anion transporter 1 or PAT1) in females. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 checklist, a systematic search of online databases included Pubmed, ScienceDirect Journals, and Ingenta Connect Journals. Predetermined criteria to include and exclude papers, gathering articles published between 2012 and 2022, were determined. After a thorough analysis, eight articles (three cohorts, one case-control, one in vivo, one in vitro, and two cross-sectional studies) were identified for the final quality assessment review.  The eight selected and quality-assessed articles provided evidence of a directly proportional connection between estrogen and kidney function. A correlation between serum estrogen levels and the development of kidney stone disease was confirmed. Administration of ß-estradiol was shown to effectively inhibit the function of the anion transporter PAT1 in a tissue-specific manner. In the case of the kidney, estrogen was observed to down-regulate PAT1, which led to a reduction in oxalate transporting activity and, consequently, a decrease in kidney stone formation. Consensus suggests that serum estrogen levels and optimal kidney functioning are interrelated. Furthermore, analysis of the quality-assessed articles and a comprehensive literature review revealed estrogen's tissue-specific regulation of the PAT1 anion transporter aids in maintaining kidney function and anion homeostasis. Additional research is needed to solidify estrogen's role in kidney stone disease to determine its therapeutic value in clinical practice.

Comparing the Safety and Efficacy of Proton Pump Inhibitors and Histamine-2 Receptor Antagonists in the Management of Patients With Peptic Ulcer Disease: A Systematic Review.

Peptic ulcer disease (PUD) refers to the occurrence of an open erosion in the inner lining of the stomach, duodenum, or sometimes lower esophagus. Treatments like proton pump inhibitors (PPIs) or histamine 2 receptor antagonists (H2RAs) are available on the market to efficiently treat the break in the mucosal lining. However, there is little evidence about the effects of the medication on the type and location of the ulcer and the epigastric pain caused by disintegration and increased acidity in the stomach. Given the above, we conducted a systematic review comparing the safety and efficacy of PPIs and H2RAs in various ulcer locations (gastric, duodenal, and pre-pyloric) and the effect of prolonging the treatment with the same medication or changing into a drug from another class in treatment-resistant ulcers. We employed major research literature databases and search engines such as PubMed, Medical Literature Analysis and Retrieval System Online (MEDLINE), Science Direct, and Google Scholar to find relevant articles. After a thorough screening, a quality check using various tools, and applying filters that suited our eligibility criteria, we identified eight articles, of which five were random clinical trials (RCTs), two review articles, and one meta-analysis. This study compares the different side effects of PPIs and H2RAs. Most studies concluded that omeprazole is superior in healing ulcers and bringing pain relief and that patients resistant to H2RAs can be treated better when switched to a PPI. This study also discusses the adverse effects of chronic use, such as diarrhea, constipation, headaches, and gastrointestinal infections. Patients on long-term PPI therapy are required to take calcium supplements to prevent the risk of fractures in older adults. Regarding long-term outcomes, PPIs remain the mainstay of treatment for peptic ulcer disease, based on the papers we reviewed.

Association of Physical Activity with the Prevention and Treatment of Depression During the Postpartum Period: A Narrative Review.

The benefits of physical activity during pregnancy or postpartum are auspicious, especially in preventing and treating postpartum depression. This review aimed to examine the relationship between exercise and postpartum depression in terms of prevention and treatment. The goals were to determine if exercise alone is sufficient for this purpose and to attract attention to the kind, intensity, and duration needed to achieve this purpose. A literature review was conducted in PubMed, PubMed Central, MEDLINE, and Cochrane libraries. The search terms were "physical activity," "postpartum depression," "postnatal depression," and "exercise." Physical activity can be a preventative measure and a treatment aid for pregnant or postpartum women with depressive disorders. However, the exercise protocol should include a support/wellness program to achieve better and more remarkable results.

Understanding the Role of the Gut Microbiome in Diabetes and Therapeutics Targeting Leaky Gut: A Systematic Review.

The gut microbiota has been studied and continues to be a developing area in the pathognomic development of metabolic diseases like diabetes. Treatment with diet changes, the addition of supplements like prebiotics/probiotics, and the impact of fecal microbial transplantation can be correlated to targeting changes in dysbiosis. Understanding the impacts of various anti-hyperglycemic agents such as metformin and the implications of post-bariatric surgery on the gut microbiota diversity has emerged. These areas of study are crucial to understanding the pathognomic aspects of diabetes disease progression at the microbial level of metabolic and inflammatory mechanisms, which may give more insight into focusing on the role of diet prebiotic/probiotic supplements as potential forms of prospective management in diabetes and the development of more agents that target gut microbiota, which harbors low-grade inflammation. Intestinal dysbiosis was consistently observed in the mechanism of gut microbial change in diabetic individuals, contributing to reduced insulin sensitivity and poor glycemic control. This systematic review was carried out using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 checklist. We performed a literature search using the PubMed, Google Scholar and Science Direct databases in accordance with the eligibility criteria and ultimately selected 14 articles for final analysis. The Scale for the Assessment of Narrative Review Articles (SANRA) and the PRISMA 2020 checklist were used to assess the quality of selected articles for cross-sectional studies, traditional literature reviews, and systematic reviews, respectively. We collected papers from 2012 to 2022 for this review. We gathered articles from databases, such as this study, which show there is a strong connection between microbiota and diabetes that appears to exist. The objective is to assess and identify any dietary and therapeutic agents that may alter the microbiota and potentially target and modulate insulin sensitivity. This review article will discuss the pathophysiological effects of gut microbiota in diabetes management and the impact of various gut biodiversity therapeutics that can aid in reversing insulin sensitivity.

Inflammatory Bowel Sugar Disease: A Pause From New Pharmacological Agents and an Embrace of Natural Therapy.

Inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis, are immune-mediated chronic inflammatory diseases that target the gastrointestinal tract and other distant organs. The incidence of IBDs has been rising and is more prevailing in Western communities. The etiology has been vague, but different theories include environmental factors that elicit an uncontrolled immune response, which damages internal organs. Treatment of either Crohn's disease or ulcerative colitis has witnessed significant advances; however, pharmacological drugs' side effects limit their use. Research about microbiota and its influence on IBDs has gained fame, and multiple studies correlate microbiota diversity positively with IBD treatment. Many factors contribute to the microbiota's health, including different diets, antibiotics, prebiotics, probiotics, synbiotics, and postbiotics. Specific immune responses lie behind the pathogenesis of IBDs and microbiota dysbiosis, and different studies have postulated new ways to control this abnormal response. Physical activity, sun exposure, efficient sleep, intermittent fasting, and supplementation of probiotics and vitamins are natural ways that help modulate this immune response, do not cost money as IBD pharmacological drugs, and do not come with deleterious side effects that are sometimes more harmful than IBDs. Our article proposes a comprehensive natural approach that can benefit IBD patients enormously. This approach does not replace the medications currently used in treating IBDs. The suggested approach can be used in combination with medications and might aid in reducing the doses of those medications.

Comparison of the Clinical Efficacy, Safety, and Postoperative Outcomes Between Peroral Esophageal Myotomy and Laparoscopic Heller's Myotomy With Fundoplication: A Systematic Review.

Achalasia, a neurodegenerative disease caused by the progressive destruction of ganglion cells in the myenteric plexus, is accompanied by incomplete relaxation of the lower esophageal sphincter. Laparoscopic Heller's myotomy (LHM) coupled with fundoplication has been the gold standard procedure for achalasia. Peroral esophageal myotomy (POEM) has recently gained popularity as it is minimally invasive, has fewer adverse events, and has excellent short-term outcomes. So, we aimed to compare the clinical efficacy, safety, and postoperative outcomes between LHM and POEM. We did a systematic review by following the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines for 2020 and exploring research databases such as PUBMED and PMC Central, Google Scholar, and Research Gate. After appropriate screenings, articles relevant to the review were scrutinized based on the eligibility criteria. Quality assessment tools such as the Newcastle-Ottawa Scale (NOS) and the assessment of multiple systematic reviews (AMSTAR) were used to finalize the articles. A total of 11 articles (seven observational studies, two RCTs, and two systematic reviews) were included in the review after a quality check. The study included 2127 patients, classified into 981 for POEM and 1146 for LHM, who had undergone treatment for achalasia. Most of the studies had a follow-up of ≤ two years. Comparing efficacy, POEM had similar results to LHM in terms of Eckardt scores. However, abnormal DeMeester scores were found in POEM. Adverse events were significantly higher in LHM when compared to POEM in terms of safety. Peroral esophageal myotomy also stood out as having a shorter procedure time, a shorter hospital stay, and lesser odds of being a clinical failure. As for postoperative outcomes, despite treatment with proton pump inhibitors, LHM was more effective in preventing the development of esophagitis compared to POEM due to partial fundoplication. Postoperative reflux and the development of esophagitis remain certain with POEM and need to be followed up with more studies with longer follow-ups. However, POEM still stands as a better choice compared to LHM in terms of efficacy and safety.

VEXAS syndrome with progression of MDS to MDS/MPN overlap syndrome.

VEXAS (vacuoles, E1 enzyme, X linked, autoinflammatory, somatic) syndrome is a novel inflammatory syndrome that was first described in December 2020. Patients with VEXAS syndrome have a somatic mutation in the UBA1 gene, inflammatory conditions and usually haematological conditions. Haematological conditions reported in patients with VEXAS syndrome include myelodysplastic syndrome (MDS), clonal cytopenia of undetermined significance, plasma cell neoplasm including multiple myeloma/monoclonal gammopathy of undetermined significance, haemophagocytic lymphohistiocytosis and monoclonal B-cell lymphocytosis. Here we describe a patient with VEXAS syndrome who had a progression of MDS to MDS/myeloproliferative neoplasm overlap syndrome. The ocular findings so far reported in these patients include episcleritis, uveitis, blepharitis and orbital cellulitis. Here we report retinal detachment as a clinical feature of VEXAS syndrome. This finding has a significant implication in patient management as it warrants higher vigilance for this sight-threatening complication.

Progress in Alternative Strategies to Combat Antimicrobial Resistance: Focus on Antibiotics.

Antibiotic resistance, and, in a broader perspective, antimicrobial resistance (AMR), continues to evolve and spread beyond all boundaries. As a result, infectious diseases have become more challenging or even impossible to treat, leading to an increase in morbidity and mortality. Despite the failure of conventional, traditional antimicrobial therapy, in the past two decades, no novel class of antibiotics has been introduced. Consequently, several novel alternative strategies to combat these (multi-) drug-resistant infectious microorganisms have been identified. The purpose of this review is to gather and consider the strategies that are being applied or proposed as potential alternatives to traditional antibiotics. These strategies include combination therapy, techniques that target the enzymes or proteins responsible for antimicrobial resistance, resistant bacteria, drug delivery systems, physicochemical methods, and unconventional techniques, including the CRISPR-Cas system. These alternative strategies may have the potential to change the treatment of multi-drug-resistant pathogens in human clinical settings.

A ten-year retrospective analysis of nocardiosis in a tertiary care center of South-coastal India.

Nocardiosis is an uncommon life-threatening infection caused by Nocardia spp. This study aimed to review the distribution of risk factors, clinical characteristics, microbiological findings, treatment and outcome of patients diagnosed with nocardiosis. This study was a retrospective case record review of all nocardiosis cases that were diagnosed at our tertiary care hospital from January 2008 to December 2019. A total of 48 patients with a mean age of 52.2±16.28 years were included. Out of which forty one (85%) were diagnosed as pulmonary nocardiosis and seven (14.6%) as disseminated disease. Chronic lung disease 25 (52.1%), long term steroid use 22 (45.8%) followed by diabetes mellitus 11 (22.9%) were common predisposing factors. The common symptoms were fever (87.5%), cough (79.2%) and breathlessness (52.1%). The most frequent radiologic finding included consolidation in 38 (79.1%), cavitation with thickened wall in 2 (4.1%), reticulonodular shadows in 2 (4.1%), and unilateral pleural effusion in 5 (10.4%). Nocardia otitidiscaviarum (22.9%) was frequently isolated from cultures. Resistance to trimethoprim-sulfamethoxazole (TMP-SMX) was observed in 21% cases. Mortality was noted in 6 (12.5%) patients and all were with pulmonary involvement. The percentage of death among those with and without pulmonary tuberculosis was 33.3% and 5% respectively. Patients affected by pulmonary nocardiosis with previous history of pulmonary tuberculosis showed significant association with poor outcome (p-value=0.05). In conclusion, nocardiosis mainly affects patients with structural lung disease or immunocompromised hosts with adverse outcome. Awareness of this infection is crucial for a clinician, and any suspicion should lead to make an early diagnosis and choose an appropriate empirical treatment to improve the outcome in this population.

RECK and TIMP-2 mediate inhibition of MMP-2 and MMP-9 by Annona muricata.

Up-regulation of MMP-2 and MMP-9 plays a significant role in promoting cancer progression by degrading the components of the extracellular matrix, thereby enhancing the migration of tumor cells. Although the antiproliferative and apoptotic effect of Annona muricata is well established, its effect on MMP-2 and MMP-9, a major target in several types of cancers, has not been studied. Powdered samples of various parts of A. muricata like fruit, stem, seed, and twig extracted using aqueous methanol showed significant dose-dependent inhibition of MMP-2 and MMP-9 in a highly metastatic fibrosarcoma cell line, HT1080. Additionally, these extracts also up-regulated the expression of several endogenous inhibitors of MMP-2 and MMP-9 like REversion-inducing Cysteine-rich protein with Kazal motifs (RECK) and Tissue Inhibitor of Metalloproteinase- 2 (TIMP-2). Furthermore, primary cells developed from tumor tissues obtained from patients not exposed to chemotherapy, also exhibited similar results. Remarkably, the inhibition of MMP-2 and MMP-9 observed was tumor specific, with the A. muricata fruit extract showing only 2% inhibition in cells obtained from normal tissues, when compared to 60% inhibition observed in cells obtained from tumor samples. The present study elucidates a novel mechanism by which A. muricata extracts selectively exhibit their anti-cancer activity in tumor cells by down-regulating MMP-2 and MMP-9 that are important biomarkers in cancer.

Occupational health and metabolic risk factors: A pilot intervention for transport workers.

OBJECTIVES: Heavy vehicle transport workers have a high risk of obesity and obesity-related disorders including cardiovascular disease and diabetes. Sedentary nature of their work makes a healthy work and lifestyle balance difficult to achieve. Educational interventions that promote behavioral changes have been shown to be effective in various group settings. The aims of this study were to determine the prevalence of metabolic risk factors among a population of urban bus drivers; to deliver a 3-month educational intervention specifically tailored for the workplace environment of transport workers; and to evaluate the efficacy of the intervention through quantitative measurements and qualitative feedback. MATERIAL AND METHODS: Thirty-three bus drivers from depots in south Queensland were recruited for the study. Baseline metabolic data were collected through anthropometric measurements, blood collection and diet/lifestyle questionnaires. Metabolic risk factors that were analyzed included: waist circumference, blood pressure, fasting glucose, blood triglycerides and high density lipoprotein cholesterol (HDL-C). Three interactive seminars were delivered over a 3-month period. At the end of the period, data collection was repeated. RESULTS: At the commencement of the study, 35% of the participants exhibited ≥ 3 of the metabolic risk factors that characterize metabolic syndrome. This is higher than the reported prevalence in the general Australian population (22.1%). A total 21 of the 33 participants remained committed to the intervention and provided pre and post intervention data. Of these, 28% (N = 6) showed a decrease in one or more of the risk factors associated with metabolic syndrome. There was a significant increase in the average HDL-C after the intervention. Qualitative feedback indicated that the workers benefited from the program, especially regarding their awareness of the risks associated with their profession. CONCLUSIONS: This pilot study demonstrates that lifestyle education seminars specifically tailored for the workplace can have an impact on the health behaviors of transport workers.