Preparation, Characterization and In Vitro Biological Activities of New Diphenylsulphone Derived Schiff Base Ligands and Their Co(II) Complexes.

The present work describes the chemical preparation of Schiff bases derived from 4,4'-diaminodiphenyl sulfone (L1-L5) and their Co(II) metal complexes. The evaluation of antimicrobial and anticancer activities against MCF-7 cell line and human lung cancer cell line A-549 was performed. The aforementioned synthesized compounds are characterized by spectroscopic techniques and elemental analysis confirms successful synthesis. The results from the above analytical techniques revealed that the complexes are in an octahedral geometry. The antimicrobial activity of the synthesized Schiff base ligands and their metal complexes under study was carried out by using the agar well diffusion method. The ligand and complex interactions for biological targets were predicted using molecular docking and high binding affinities. Further, the anticancer properties of the synthesized compounds are performed against the MCF-7 cell line and human lung cancer cell line A-549 using adriamycin as the standard drug.

Molecular and Biochemical Therapeutic Strategies for Duchenne Muscular Dystrophy.

Significant progress has been achieved in understanding Duchenne muscular dystrophy (DMD) mechanisms and developing treatments to slow disease progression. This review article thoroughly assesses primary and secondary DMD therapies, focusing on innovative modalities. The primary therapy addresses the genetic abnormality causing DMD, specifically the absence or reduced expression of dystrophin. Gene replacement therapies, such as exon skipping, readthrough, and gene editing technologies, show promise in restoring dystrophin expression. Adeno-associated viruses (AAVs), a recent advancement in viral vector-based gene therapies, have shown encouraging results in preclinical and clinical studies. Secondary therapies aim to maintain muscle function and improve quality of life by mitigating DMD symptoms and complications. Glucocorticoid drugs like prednisone and deflazacort have proven effective in slowing disease progression and delaying loss of ambulation. Supportive treatments targeting calcium dysregulation, histone deacetylase, and redox imbalance are also crucial for preserving overall health and function. Additionally, the review includes a detailed table of ongoing and approved clinical trials for DMD, exploring various therapeutic approaches such as gene therapies, exon skipping drugs, utrophin modulators, anti-inflammatory agents, and novel compounds. This highlights the dynamic research field and ongoing efforts to develop effective DMD treatments.

TACE inhibition: a promising therapeutic intervention against AATF-mediated steatohepatitis to hepatocarcinogenesis.

Metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma (MASH-HCC) is a global clinical challenge for which there is a limited understanding of disease pathogenesis and a subsequent lack of therapeutic interventions. We previously identified that tumor necrosis factor-alpha (TNF-α) upregulated apoptosis antagonizing transcription factor (AATF) in MASH. Here, we investigated the effect of TNF-α converting enzyme (TACE) inhibition as a promising targeted therapy against AATF-mediated steatohepatitis to hepatocarcinogenesis. A preclinical murine model that recapitulates human MASH-HCC was used in the study. C57Bl/6 mice were fed with chow diet normal water (CD) or western diet sugar water (WD) along with a low dose of carbon tetrachloride (CCl4; 0.2 µL·g-1, weekly) for 24 weeks. TACE activity, TNF-α levels, and AATF expression were measured. The mice were treated with the TACE inhibitor Marimastat for 12 weeks, followed by analyses of liver injury, fibrosis, inflammation, and oncogenic signaling. In vitro experiments using stable clones of AATF control and AATF knockdown were also conducted. We found that AATF expression was upregulated in WD/CCl4 mice, which developed severe MASH at 12 weeks and advanced fibrosis with HCC at 24 weeks. WD/CCl4 mice showed increased TACE activity with reduced hepatic expression of sirtuin 1 (Sirt1) and tissue inhibitor of metalloproteinase 3 (Timp3). The involvement of the SIRT1/TIMP3/TACE axis was confirmed by the release of TNF-α, which upregulated AATF, a key molecular driver of MASH-HCC. Interestingly, TACE inhibition by Marimastat reduced liver injury, dyslipidemia, AATF expression, and oncogenic signaling, effectively preventing hepatocarcinogenesis. Furthermore, Marimastat inhibited the activation of JNK, ERK1/2, and AKT, which are key regulators of tumorigenesis in WD/CCl4 mice and in AATF control cells, but had no effect on AATF knockdown cells. This study shows that TACE inhibition prevents AATF-mediated inflammation, fibrosis, and oncogenesis in MASH-HCC, offering a potential target for therapeutic intervention.

Progression-free survival estimation of docetaxel-based second-line treatment for advanced non-small cell lung cancer: a pooled analysis from 18 randomized control trials.

Background: Lung cancer is the foremost cause of cancer-related death globally, with non-small cell lung cancer (NSCLC) accounting for 85-90% of cases. Targeted therapy is the most essential therapeutic option for NSCLC, other common treatments include radiation therapy, surgery, chemotherapy, and immunotherapy. Objective: Our study objective was to estimate whether progression-free survival (PFS) is an outcome of NSCLC extracted from 18 randomized control trials (RCTs) with docetaxel as experimental group and antineoplastic agent, kinase inhibitor, and monoclonal antibodies as a control group. Methods: We selected relevant studies published between 2011 and 2022 using Google Scholar, PubMed, Scopus, Science Direct, and Cochrane Library. Advanced NSCLC, chemotherapy, RCT, docetaxel, and second-line treatment were the terms included in the search. A total of 9738 patients were evaluated from the 18 identified studies. We used the meta package of R Studio to perform the meta-analysis. Graphical funnel plots were used to evaluate publication bias visually. Results: Patients who underwent docetaxel-based therapy had a considerably longer PFS than those who got antineoplastic agents, kinase inhibitors, or monoclonal antibodies-based treatment. Patients in the standard treatment arm had a slightly longer PFS than those in the experimental therapy arm in the overall meta-analysis. Conclusion: Docetaxel outperformed monoclonal antibodies, antineoplastic agents, and kinase inhibitors in the second-line therapy of advanced NSCLC since PFS was extensively utilized.

Unveiling Silent Consequences: Impact of Pulmonary Tuberculosis on Lung Health and Functional Wellbeing after Treatment.

Background: Pulmonary tuberculosis (TB) remains a major public health issue in India, with high incidence and mortality. The current literature on post-TB sequelae functional defects focuses heavily on spirometry, with conflicting obstruction vs. restriction data, lacks advanced statistical analysis, and has insufficient data on diffusion limitation and functional impairment. Objective: This study aimed to thoroughly evaluate post-tubercular sequelae after treatment, assessing chest radiology, spirometry, diffusing capacity, and exercise capacity. Methods: A total of 85 patients were studied at a university teaching hospital in Mysuru. The data collected included characteristics, comorbidities, smoking history, and respiratory symptoms. The investigations included spirometry, DLCO, chest X-rays with scoring, and 6MWT. Results: Of the patients, 70% had abnormal X-rays post-treatment, correlating with reduced lung function. Additionally, 70% had impaired spirometry with obstructive/restrictive patterns, and 62.2% had reduced DLCO, with females at higher risk. Smoking increased the risk of sequelae. Conclusions: Most patients had residual radiological/lung function abnormalities post-treatment. Advanced analyses provide insights into obstructive vs. restrictive defects. Ongoing research should explore pathogenetic mechanisms and therapeutic modalities to minimize long-term post-TB disability.

Can soluble CD163 predict outcome of patients with acute respiratory distress from mechanical ventilation?: A pilot study.

PURPOSE: CD163 is a monocyte/macrophage-associated antigen which has recently been identified as a hemoglobin scavenger receptor and has also anti-inflammatory properties and an immunoregulatory role. This surface receptor undergoes ectodomain shedding upon an inflammatory stimulus, leading to increased fraction of soluble CD163 (sCD163). Hence, we hypothesized that the mechanical ventilation (MV) which is known to elicit inflammatory response may cause increased serum levels of sCD163 which can predict the outcome of patients from MV. SUBJECTS AND METHODS: Thirty patients with acute respiratory distress aged >18 years who required MV were enrolled for the study. Serum levels of sCD163 were estimated using quantitative immunometric sandwich enzyme immunoassay technique from 3 mL of the venous blood sample which was collected immediately and at 24 h after the patient was connected to MV. On the basis of the outcome of the patient from MV, they were divided into two groups; survivors and nonsurvivors. RESULTS: Out of the 30 patients, 18 patients survived and 12 patients expired. Serum levels of sCD163 were significantly increased in nonsurvivors when compared with survivors (P < 0.01) at 24 h after connecting to MV. sCD163 > 1020 ng/mL at 24 h of MV increases the probability of mortality by factor 6. An increase of sCD163 by 1 ng/mL significantly increases the relative probability of mortality by a factor of 1.0017 (95% confidence interval, 1.0004-1.0030, P = 0.0005). CONCLUSIONS: Elevated levels of sCD163 at 24 h of MV help in predicting the outcome of patients with acute respiratory failure from MV.

AATF inhibition exerts antiangiogenic effects against human hepatocellular carcinoma.

Background and aims: Angiogenesis is a key factor in the growth and metastasis of hepatic tumors and thus a potential therapeutic target in hepatocellular carcinoma (HCC). In this study, we aim to identify the key role of apoptosis antagonizing transcription factor (AATF) in tumor angiogenesis and its underlying mechanisms in HCC. Methods: HCC tissues were analyzed for AATF expression by qRT-PCR and immunohistochemistry. Stable clones of control and AATF knockdown (KD) were established in human HCC cells. The effect of AATF inhibition on the angiogenic processes was determined by proliferation, invasion, migration, chick chorioallantoic membrane (CAM) assay, zymography, and immunoblotting techniques. Results: We identified high levels of AATF in human HCC tissues compared to adjacent normal liver tissues, and the expression was found to be correlated with the stages and tumor grades of HCC. Inhibiting AATF in QGY-7703 cells resulted in higher levels of pigment epithelium-derived factor (PEDF) than controls due to decreased matric metalloproteinase activity. Conditioned media from AATF KD cells inhibited the proliferation, migration, and invasion of human umbilical vein endothelial cells as well as the vascularization of the chick chorioallantoic membrane. Furthermore, the VEGF-mediated downstream signaling pathway responsible for endothelial cell survival and vascular permeability, cell proliferation, and migration favoring angiogenesis was suppressed by AATF inhibition. Notably, PEDF inhibition effectively reversed the anti-angiogenic effect of AATF KD. Conclusion: Our study reports the first evidence that the therapeutic strategy based on the inhibition of AATF to disrupt tumor angiogenesis may serve as a promising approach for HCC treatment.

Redefining the polypill: pros and cons in cardiovascular precision medicine.

Polypill is a multi-drug formulation in a single pill intended to simplify the drug regimen and reduce medication-induced adverse effects. The most common multidrug combinations in a polypill are used to treat cardiovascular diseases and are targeted against key modifiable risk factors such as hypertension and hyperlipidemia. These contain blood-pressure lowering agents, statins, and anti-platelet agents usually in a fixed dose. Polypills can be an affordable therapeutic intervention for treating high-risk patients, as these are proven to increase patients' adherence to medication and improve clinical outcomes. Over the previous years, randomized clinical trials of several polypills have yielded contradictory findings, raising skepticism regarding their widespread use in primary disease prevention. Here, we have reviewed the concept of polypills, the evidence-based strengths, the limitations of this polypharmacy intervention strategy, and discussed future directions for their use in the primary and secondary preventive management of cardiovascular diseases and associated risk factors.

The Validity of the ROX Index and APACHE II in Predicting Early, Late, and Non-Responses to Non-Invasive Ventilation in Patients with COVID-19 in a Low-Resource Setting.

The use of the Ratio of Oxygen Saturation (ROX) index to predict the success of high-flow nasal oxygenation (HFNO) is well established. The ROX can also predict the need for intubation, mortality, and is easier to calculate compared with APACHE II. In this prospective study, the primary aim is to compare the ROX (easily administered in resource limited setting) to APACHE II for clinically relevant outcomes such as mortality and the need for intubation. Our secondary aim was to identify thresholds for the ROX index in predicting outcomes such as the length of ICU stay and failure of non-invasive respiratory support therapies and to assess the effectiveness of using the ROX (day 1 at admission, day 2, and day 3) versus Acute physiology and chronic health evaluation (APACHE) II scores (at admission) in patients with Coronavirus Disease 2019 (COVID-19) pneumonia and Acute Respiratory Distress Syndrome (ARDS) to predict early, late, and non-responders. After screening 208 intensive care unit patients, a total of 118 COVID-19 patients were enrolled, who were categorized into early (n = 38), late (n = 34), and non-responders (n = 46). Multinomial logistic regression, receiver operating characteristic (ROC), Multivariate Cox regression, and Kaplan-Meier analysis were conducted. Multinomial logistic regressions between late and early responders and between non- and early responders were associated with reduced risk of treatment failures. ROC analysis for early vs. late responders showed that APACHE II on admission had the largest area under the curve (0.847), followed by the ROX index on admission (0.843). For responders vs. non-responders, we found that the ROX index on admission had a slightly better AUC than APACHE II on admission (0.759 vs. 0.751). A higher ROX index on admission [HR (95% CI): 0.29 (0.13-0.52)] and on day 2 [HR (95% CI): 0.55 (0.34-0.89)] were associated with a reduced risk of treatment failure. The ROX index can be used as an independent predictor of early response and mortality outcomes to HFNO and NIV in COVID-19 pneumonia, especially in low-resource settings, and is non-inferior to APACHE II.

Substantiation of a clopidogrel metabolism-associated gene (CYP2C19) variation among healthy individuals.

BACKGROUND: It is essential to investigate the prevalence of CYP2C19 alleles that affect drug metabolism. This study measures the allelic and genotypic frequencies of CYP2C19 loss-of-function (LoF) alleles CYP2C19∗2, CYP2C19∗3, and gain-of-function (GoF) alleles CYP2C19∗17 in the general population. METHODOLOGY: The study involved 300 healthy subjects between the ages of 18 and 85 recruited by simple random sampling. Allele-specific touchdown PCR was employed to identify the various alleles. The genotype and allele frequencies were calculated and checked for Hardy-Weinberg equilibrium. The phenotypic prediction of ultra-rapid metabolizer (UM = ∗17/∗17), extensive metabolizer (EM = ∗1/∗17, ∗1/∗1), intermediate metabolizer (IM = ∗1/∗2, ∗1/∗3, ∗2/∗17) and poor metabolizer (PM = ∗2/∗2, ∗2/∗3, ∗3/∗3) was made based on their genotype. RESULTS: The allele frequency of CYP2C19∗2, CYP2C19∗3, and CYP2C19∗17 was 0.365, 0.0033, and 0.18, respectively. The IM phenotype predominated with an overall frequency of 46.67%, including 101 subjects with ∗1/∗2, two subjects with ∗1/∗3, and 37 subjects with ∗2/∗17 genotype. This was followed by EM phenotype with an overall frequency of 35%, including 35 subjects with ∗1/∗17 and 70 subjects with ∗1/∗1 genotype. PM phenotype had an overall frequency of 12.67%, including 38 subjects with ∗2/∗2 genotype, and UM phenotype had an overall frequency of 5.67%, including 17 subjects with ∗17/∗17 genotype. CONCLUSION: Given the high allelic frequency of PM in the study population, a pre-treatment test to identify the individual's genotype may be recommended to decide the dosage, monitor the drug response, and avoid adverse drug reactions.

Online practical assessment in biochemistry designed on Bloom's taxonomy to assess the student's competency: Prior exposure of the students to online tools beneficial.

Online assessments are needed during the prevailing pandemic situation to continue educational activities while ensuring safety. After conducting the online practical assessment (OPrA) in Biochemistry, we analyzed the students' responses. The blueprint of the OPrA was prepared by the faculty, referring to the various levels and domains of Bloom's taxonomy. Four components were chosen for the online assessment: digital spotters, enumerating the steps of objective structured practical examination, interpretation of quantitative estimation, and case discussion. Each faculty assessed about 12-13 students in separate breakout rooms over 15-20 min on all four components. Feedback on the conduct of the examination was collected from the students and faculty anonymously and analyzed. Out of the 200 students who attended the online assessment, only one scored less than 50%, majority of them scored between 71% and 90%. Under the individual exercises, the average score of students in "Spotters" was 9.8 out of 10; in "OSPE," 8.7 out of 10; in "Quantitative experiments," 15.2 out of 20 and in "Case discussion," 22.4 out of 30. Around 20% had previous experience attending the OPrA. They differed in their opinion from the rest of the students on five aspects; time allotted for the assessment (p value = 0.02, χ2  = 5.07), students using unfair means during the online viva (p value = 0.02, χ2  = 5.57), their computing skills (p value = 0.001, χ2  = 19.82), their performance (p value = 0.001, χ2  = 8.84), and overall conduct of the examination (p value = 0.001, χ2  = 15.55). OPrA tools may be designed referring to Bloom's taxonomy, and prior exposure to the online tools may benefit the students.

Pectin/PVA and pectin-MgO/PVA films: Preparation, characterization and biodegradation studies.

There is a great demand to replace non-renewable materials with eco-friendly renewable materials for many applications in recent times. In the present study, such an attempt was made to substitute synthetic polymer-based films used for food packaging applications with films prepared out of renewable materials derived from waste. The pectin/polyvinyl alcohol (PP) and pectin-MgO/polyvinyl alcohol (PMP) films were prepared and characterized to ascertain their suitability for packaging applications. To improve the mechanical strength and thermal stability of films, MgO nanoparticles were incorporated in situ into the polymer matrix. The pectin used in the study was extracted from citrus fruit peel. The prepared nanocomposite films were evaluated for physico-mechanical properties, water contact angle, thermal stability, crystallinity, morphology, compositional purity and biodegradability. The elongation at break for PP film was 42.24% and for PMP film it was 39.18%. Also, the ultimate modulus in terms of MPa for PP film was 6.8 and for PMP it was 7.9. So, it was found that PMP films have better ductility and modulus than PP films due to the presence of MgO nanoparticles. The spectral studies confirmed the compositional purity of the prepared films. The biodegradation studies revealed that both films could be degraded at ambient conditions at appreciable time span, suggesting them to be a better choice as an environmentally friendly food packaging material.

Circulatory Serum Krebs von Den Lungen-6 and Surfactant Protein-D Concentrations Predict Interstitial Lung Disease Progression and Mortality.

There is a need for biomarkers to predict outcomes, including mortality, in interstitial lung disease (ILD). Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D) are associated with lung damage and fibrosis in all ILDs and are related to important clinical outcomes. Though these two biomarkers have been associated with ILD outcomes, there are no studies that have evaluated their predictive potential in combination. This study aims to determine whether KL-6 and SP-D are linked to poor disease outcomes and mortality. Additionally, we plan to examine whether changes in KL-6 and SP-D concentrations correspond with changes in lung function and whether serial measurements improve their predictive potential to identify disease progression and mortality. Forty-four patients with ILD participated in a prospective 6-month longitudinal observational study. ILD patients who succumbed had the highest KL-6 levels (3990.4 U/mL (3490.0-4467.6)) and highest SP-D levels (256.1 ng/mL (217.9-260.0)), followed by those who deteriorated: KL-6 levels 1357.0 U/mL (822.6-1543.4) and SP-D levels 191.2 ng/mL (152.8-210.5). The generalized linear model (GLM) analysis demonstrated that changes in forced vital capacity (FVC), diffusing capacity of lungs for carbon monoxide (DLCO), forced expiratory volume in 1 s (FEV1), and partial pressure of arterial oxygen (PaO2) were correlated to changes in KL6 (p = 0.016, 0.014, 0.027, 0.047) and SP-D (p = 0.008, 0.012, 0.046, 0.020), respectively. KL-6 (odds ratio (OR): 2.87 (1.06-7.79)) and SPD (OR: 1.76 (1.05-2.97)) were independent predictors of disease progression, and KL-6 (hazard ratio (HR): 3.70 (1.46-9.41)) and SPD (HR: 2.58 (1.01-6.59)) were independent predictors of death by Cox regression analysis. Combined biomarkers (KL6 + SPD + CT + FVC) had the strongest ability to predict disease progression (AUC: 0.797) and death (AUC: 0.961), on ROC analysis. Elevated KL-6 and SPD levels are vital biomarkers for predicting the severity, progression, and outcomes of ILD. High baseline levels or an increase in levels over a six-month follow-up despite treatment indicate a poor prognosis. Combining KL6 and SPD with conventional measures yields a more potent prognostic indicator. Clinical studies are needed to test additional interventions, and future research will determine if this combined biomarker benefits different ethnicities globally.

Bioinformatic Tools for the Identification of MicroRNAs Regulating the Transcription Factors in Patients with ß-Thalassemia.

ß-thalassemia is a significant health issue worldwide, with approximately 7% of the world's population having defective hemoglobin genes. MicroRNAs (miRNAs) are short noncoding RNAs regulating gene expression at the post-transcriptional level by targeting multiple gene transcripts. The levels of fetal hemoglobin (HbF) can be increased by regulating the expression of the γ-globin gene using the suppressive effects of miRNAs on several transcription factors such as MYB, BCL11A, GATA1, and KLF. An early step in discovering miRNA:mRNA target interactions is the computational prediction of miRNA targets that can be later validated with wet-lab investigations. This review highlights some commonly employed computational tools such as miRBase, Target scan, DIANA-microT-CDS, miRwalk, miRDB, and micro-TarBase that can be used to predict miRNA targets. Upon comparing the miRNA target prediction tools, 4 main aspects of the miRNA:mRNA target interaction are shown to include a few common features on which most target prediction is based: conservation sites, seed match, free energy, and site accessibility. Understanding these prediction tools' usage will help users select the appropriate tool and interpret the results accurately. This review will, therefore, be helpful to peers to quickly choose a list of the best miRNAs associated with HbF induction. Researchers will obtain significant results using these bioinformatics tools to establish a new important concept in managing ß-thalassemia and delivering therapeutic strategies for improving their quality of life.

Impact of Acute Exacerbation and Its Phenotypes on the Clinical Outcomes of Chronic Obstructive Pulmonary Disease in Hospitalized Patients: A Cross-Sectional Study.

Acute exacerbations of COPD (AECOPD) are clinically significant events having therapeutic and prognostic consequences. However, there is a lot of variation in its clinical manifestations described by phenotypes. The phenotypes of AECOPD were categorized in this study based on pathology and exposure. In our cross-sectional study, conducted between 1 January 2016 to 31 December 2020, the patients were categorized into six groups based on pathology: non-bacterial and non-eosinophilic; bacterial; eosinophilic; bacterial infection with eosinophilia; pneumonia; and bronchiectasis. Further, four groups were classified based on exposure to tobacco smoke (TS), biomass smoke (BMS), both, or no exposure. Cox proportional-hazards regression analyses were performed to assess hazard ratios, and Kaplan-Meier analysis was performed to assess survival, which was then compared using the log-rank test. The odds ratio (OR) and independent predictors of ward admission type and length of hospital stay were assessed using binomial logistic regression analyses. Of the 2236 subjects, 2194 were selected. The median age of the cohort was 67.0 (60.0 to 74.0) and 75.2% were males. Mortality rates were higher in females than in males (6.2% vs. 2.3%). AECOPD-B (bacterial infection) subjects [HR 95% CI 6.42 (3.06-13.46)], followed by AECOPD-P (pneumonia) subjects [HR (95% CI: 4.33 (2.01-9.30)], were at higher mortality risk and had a more extended hospital stay (6.0 (4.0 to 9.5) days; 6.0 (4.0 to 10.0). Subjects with TS and BMS-AECOPD [HR 95% CI 7.24 (1.53-34.29)], followed by BMS-AECOPD [HR 95% CI 5.28 (2.46-11.35)], had higher mortality risk. Different phenotypes have different impacts on AECOPD clinical outcomes. A better understanding of AECOPD phenotypes could contribute to developing an algorithm for the precise management of different phenotypes.

Trends in the Bacterial Prevalence and Antibiotic Resistance Patterns in the Acute Exacerbation of Chronic Obstructive Pulmonary Disease in Hospitalized Patients in South India.

Exacerbation due to antimicrobial-drug-resistant bacteria among chronic obstructive pulmonary disease (AECOPD) patients contributes to mortality and morbidity. We examined the prevalence of the bacterial organisms and trends in drug resistance in AECOPD. In this retrospective study, between January 2016 to December 2020, among 3027 AECOPD patients, 432 (14.3%) had bacteria isolated. The regression and generalized estimating equations (GEE) were used for trends in the resistance patterns over five years, adjusting for age, gender, and comorbidities. Klebsiella pneumoniae (32.4%), Pseudomonas aeruginosa (17.8%), Acinetobacter baumannii (14.4%), Escherichia coli (10.4%), and Staphylococcus aureus (2.5%) were common. We observed high levels of drug resistance in AECOPD patients admitted to ICU (87.8%) and non-ICU (86.5%). A Cox proportional hazard analysis, observed infection with Acinetobacter baumannii and female sex as independent predictors of mortality. Acinetobacter baumannii had 2.64 (95% confidence interval (CI): 1.08−6.43) higher odds of death, compared to Klebsiella pneumoniae. Females had 2.89 (95% CI: 1.47−5.70) higher odds of death, compared to males. A high proportion of bacterial AECOPD was due to drug-resistant bacteria. An increasing trend in drug resistance was observed among females.

Chemopreventive and Anticancer Property of Selenoproteins in Obese Breast Cancer.

Obesity is a significant risk factor for various cancers including breast cancer resulting in an increased risk of recurrence as well as morbidity and mortality. Extensive studies on various pathways have been successful in establishing a biological relationship between obesity and breast cancer. The molecular classification of breast cancer includes five groups each having different responses to treatment. Increased levels of inflammatory cytokines seen in obese conditions drive the pro-proliferative pathways, such as the influx of macrophages, angiogenesis, and antiapoptotic pathways. Increased peripheral aromatization of androgens by aromatase increases the circulating estrogen levels which are also responsible for the association of obesity with breast cancer. Also, increased oxidative stress due to chronic low-grade inflammation in obese women plays an important role in carcinogenesis. Despite the availability of safe and effective treatment options for breast cancer, obese women are at increased risk of adverse outcomes including treatment-related toxicities. In the recent decade, selenium compounds have gained substantial interest as chemopreventive and anticancer agents. The chemical derivatives of selenium include inorganic and organic compounds that exhibit pro-oxidant properties and alter cellular redox homeostasis. They target more than one metabolic pathway by thiol modifications, induction of reactive oxygen species, and chromatin modifications to exert their chemopreventive and anticancer activities. The primary functional effectors of selenium that play a significant role in human homeostasis are selenoproteins like glutathione peroxidase, thioredoxin reductase, iodothyronine deiodinases, and selenoprotein P. Selenoproteins play a significant role in adipose tissue physiology by modulating preadipocyte proliferation and adipogenic differentiation. They correlate negatively with body mass index resulting in increased oxidative stress that may lead to carcinogenesis in obese individuals. Methylseleninic acid effectively suppresses aromatase activation thus reducing the estrogen levels and acting as a breast cancer chemopreventive agent. Adipose-derived inflammatory mediators influence the selenium metabolites and affect the proliferation and metastatic properties of cancer cells. Recently selenium nanoparticles have shown potent anticancer activity which may lead to a major breakthrough in the management of cancers caused due to multiple pathways. In this review, we discuss the possible role of selenoproteins as chemopreventive and an anticancer agent in obese breast cancer.

Understanding the Emerging Link Between Circadian Rhythm, Nrf2 Pathway, and Breast Cancer to Overcome Drug Resistance.

The levels of different molecules in the cell are rhythmically cycled by the molecular clock present at the cellular level. The circadian rhythm is closely linked to the metabolic processes in the cells by an underlying mechanism whose intricacies need to be thoroughly investigated. Nevertheless, Nrf2 has been identified as an essential bridge between the circadian clock and cellular metabolism and is activated by the by-product of cellular metabolism like hydrogen peroxide. Once activated it binds to the specific DNA segments and increases the transcription of several genes that play a crucial role in the normal functioning of the cell. The central clock located in the suprachiasmatic nucleus of the anterior hypothalamus synchronizes the timekeeping in the peripheral tissues by integrating the light-dark input from the environment. Several studies have demonstrated the role of circadian rhythm as an effective tumor suppressor. Tumor development is triggered by the stimulation or disruption of signaling pathways at the cellular level as a result of the interaction between cells and environmental stimuli. Oxidative stress is one such external stimulus that disturbs the prooxidant/antioxidant equilibrium due to the loss of control over signaling pathways which destroy the bio-molecules. Altered Nrf2 expression and impaired redox balance are associated with various cancers suggesting that Nrf2 targeting may be used as a novel therapeutic approach for treating cancers. On the other hand, Nrf2 has also been shown to enhance the resistance of cancer cells to chemotherapeutic agents. We believe that maximum efficacy with minimum side effects for any particular therapy can be achieved if the treatment strategy regulates the circadian rhythm. In this review, we discuss the various molecular mechanisms interlinking the circadian rhythm with the Nrf2 pathway and contributing to breast cancer pathogenesis, we also talk about how these two pathways work in close association with the cell cycle which is another oscillatory system, and whether this interplay can be exploited to overcome drug resistance during chemotherapy.

Impact of experiential learning among medical undergraduates: A randomized controlled trial.

BACKGROUND: Experiential learning sessions as a teaching aid have been applied early in the medical undergraduate curriculum to improve the knowledge and inculcate research interest. We compared the ability of 1st-year medical undergraduates to answer the molecular biology questions among those who had attended the experiential learning sessions of molecular biology techniques versus those who did not attend. SUBJECTS AND METHODS: A randomized controlled trial was carried out with 200 1st-year medical undergraduates, among whom 69 students were selected by simple random sampling for the demonstration of the molecular biology techniques, such as isolation of genomic DNA, polymerase chain reaction, cell culture techniques, western blotting, and high-performance liquid chromatography for 1-week duration. Student's feedback was collected on a five-point Likert sc ale at the end of the session to understand how they agree or disagree with a particular statement. The content validity rate (CVR) and content validity index (CVI) of the questionnaire were determined, and its internal consistency was examined by Cronbach's alpha. The internal assessment marks of these students, valued by faculty who were blinded to their training sessions, were compared with the rest of the 131 students by independent t-test to know the outcome of these experiential learning sessions. RESULTS: On CVR and CVI assessment, all the questions scored more than 0.70 and 0.85, respectively. Cronbach's alpha for the whole questionnaire was 0.85. Student's feedback indicated that these sessions did complement the cognitive skills acquired for these techniques. We also found a statistically significant improvement (P = 0.006) in the examination performance between the students who attended versus those who did not attend the experiential learning sessions. CONCLUSION: Experiential learning, through demonstration and hands-on experience, enhance d the learning of molecular biology techniques among 1st-year medical undergraduates.

Screening of school children for blood lead levels and attempts to reduce them by nonpharmacological means in a coastal city of India.

CONTEXT: Lead is a major health hazard, especially in children. Impact of lead poisoning on our society is not known. Effectiveness of environmental interventions in reducing blood lead levels is not exactly known, though the Center for Disease Control and Prevention strongly advocates use of such means. AIMS: We aimed at screening school children for blood lead levels (BLLs) and reducing the BLLs of children with preliminary BLL> 20 microg/dL by environmental intervention and intensive education. MATERIALS AND METHODS: To assess the extent of lead poisoning, a screening of 106 children was done, which showed that children belonging to a particular government primary school had higher BLLs. A second screening program of 87 children conducted in that school showed that only 19% had BLL < 10 microg/dL; whereas 44% had BLL between 10 and 20 microg/dL, and 37% had BLL> 20 microg/dL. Thirty-eight children having BLL> 20 microg/dL were selected from the two screening programs. After removing all potential sources of lead from their environment and educating them about the ways to prevent exposure to lead, follow-up of their BLLs was carried out at an interval of 6 months for a period of 1 year. STATISTICAL ANALYSIS: Values of the different follow-up studies were compared using repeated-measure ANOVA. RESULTS: Our results showed that there was a significant (P < 0.0001) reduction in the BLLs in the first and second follow-up studies. CONCLUSIONS: The study is a proof of the concept that a decline in the BLLs can be achieved by intense education and avoiding the potential environmental sources of lead.