Evidence-based medicine or statistically manipulated medicine? Are we slaves to the P-value?

First popularized almost a century ago in epidemiologic research by Ronald Fisher and Jerzy Neyman, the P-value has become perhaps the most misunderstood and even misused statistical value or descriptor. Indeed, modern clinical research has now come to be centered around and guided by an arbitrary P-value of <0.05 as a magical threshold for significance, so much so that experimental design, reporting of experimental findings, and interpretation and adoption of such findings have become largely dependent on this "significant" P-value. This has given rise to multiple biases in the overall body of biomedical literature that threatens the very validity of clinical research. Ultimately, a drive toward reporting a "significant" P-value (by various statistical manipulations) risks creating a falsely positive body of science, leading to (i) wasted resources in pursuing fruitless research and (ii) futile or even harmful policies/therapeutic recommendations. This article reviews the history of the P-value, the conceptual basis of P-value in the context of hypothesis testing and challenges in critically appraising clinical evidence vis-à-vis the P-value. This review is aimed at raising awareness of the pitfalls of this rigid observation of the threshold of statistical significance when evaluating clinical trials and to generate discussion regarding whether the scientific body needs a rethink about how we decide clinical significance.

Whole exome sequencing identifies novel variants of PIK3CA and validation of hotspot mutation by droplet digital PCR in breast cancer among Indian population.

BACKGROUND: Breast cancer (BC) is the most common malignancy with very high incidence and relatively high mortality in women. The PIK3CA gene plays a pivotal role in the pathogenicity of breast cancer. Despite this, the mutational status of all exons except exons 9 and 20 still remains unknown. METHODS: This study uses the whole exome sequencing (WES) based approach to identify somatic PIK3CA mutations in Indian BC cohorts. The resultant hotspot mutations were validated by droplet digital PCR (ddPCR). Further, molecular dynamics (MD) simulation was applied to elucidate the conformational and functional effects of hotspot position on PIK3CA protein. RESULTS: In our cohort, PIK3CA showed a 44.4% somatic mutation rate and was among the top mutated genes. The mutations of PIK3CA were confined in Exons 5, 9, 11, 18, and 20, whereas the maximum number of mutations lies within exons 9 and 20. A total of 9 variants were found in our study, of which 2 were novel mutations observed on exons 9 (p.H554L) and 11 (p.S629P). However, H1047R was the hotspot mutation at exon 20 (20%). In tumor tissues, there was a considerable difference between copy number of wild-type and H1047R mutant was detected by ddPCR. Significant structural and conformational changes were observed during MD simulation, induced due to point mutation at H1047R/L position. CONCLUSIONS: The current study provides a comprehensive view of novel as well as reported single nucleotide variants (SNVs) in PIK3CA gene associated with Indian breast cancer cases. The mutation status of H1047R/L could serve as a prognostic value in terms of selecting targeted therapy in BC.

Expression Profile, Molecular Association, and Clinical Significance of POLD4 in Glioblastoma.

The POLD4 gene encodes a subunit (δ4) of DNA polymerase delta, which is a key enzyme involved in DNA replication and repair. Recent studies have suggested that POLD4 plays a crucial role in developing certain cancers. However, there is a lack of knowledge regarding the role of POLD4 in the context of glioblastoma (GBM). Therefore, in this study we have used various cancer bioinformatics tools to explore the role of POLD4 in glioblastoma. Data from various sources were accessed to analyze POLD4 gene expression and estimate tumor-infiltrating immune cells in glioblastoma. Methylation data were retrieved using the MEXPRESS web browser and analyzed. UALCAN webserver was used to analyze the protein expression of POLD4. Gene correlation and pathway enrichment analysis were performed using cBioPortal and GSEA software, respectively. Afterward, survival analysis was performed. POLD4 was significantly upregulated in glioblastoma at both gene and protein levels in GBM, and ROC curve analysis revealed it as a potential biomarker in glioblastoma. GSEA analysis of TCGA-GBM pan-cancer study exhibited that POLD4 expression was associated with critical pathways, such as interferon-gamma response, G2M checkpoint, inflammatory response, E2F targets, EMT transition, and KRAS signaling pathways. Furthermore, POLD4 expression was positively correlated with DNA methylation at 3 CpG sites, including Cg16509978, with a Pearson correlation coefficient value of 0.398 (p-value ≤ 0.01), while the promoter region had a positive correlation but was not significant. In addition, POLD4 is significantly linked with poor OS, PFS, and DFS. We also found association of POLD4 expression with altered immune cell infiltration. In conclusion, POLD4 is significantly upregulated in glioblastoma and may be used as a potential diagnostic or prognostic biomarker for GBM patients. However, to establish the same a large cohort study is needed. Using TCGA data and various cancer bioinformatics tools mentioned above we observed very high level of gene and protein expression of POLD4 in glioblastoma patients. The expression of POLD4 was significantly correlated with inflammatory and oncogenic pathways and it also has a significant correlation with adverse outcome in patients with glioblastoma.

Bone marrow metastasis of testicular germ cell tumour: A rare case.

Germ cell tumour (GCT) is the most common testicular tumour that commonly presents as a painless mass. Bone marrow metastasis in cases of testicular GCT is rare; only few case reports are available till date in the literature. Here an adult male presented with an intra-abdominal mass in right iliac fossa with inguinal lymphadenopathy with a deranged kidney function test. Bone marrow (BM) aspirate smear revealed metastatic tumour cells, but BM-biopsy was unremarkable. High serum Beta - HCG (38286 mIU/L) pointed towards germ cell lesion. Lymph node biopsy along with immunomarkers confirmed metastatic foci from germ cell tumor and managed as per standard protocol. Rarely BM aspirate is seen positive for malignancy, while biopsy turns out to be negative. Secondly, BM metastasis of GCT should be considered while dealing with cases like this. Informed consent: This is certified that the informed consent has been obtained from the patient.

Cardioprotective and Antianginal Efficacy of Nicorandil: A Comprehensive Review.

ABSTRACT: Angina pectoris remains a significant burden despite advances in medical therapy and coronary revascularization. Many patients (up to 30%) with angina have normal coronary arteries, with coronary microvascular disease and/or coronary artery vasospasm being major drivers of the myocardial demand-supply mismatch. Even among patients revascularized for symptomatic epicardial coronary stenosis, recurrent angina remains highly prevalent. Medical therapy for angina currently centers around 2 disparate goals, viz secondary prevention of hard clinical outcomes and symptom control. Vasodilators, such as nitrates, have been first-line antianginal agents for decades, along with beta-blockers and calcium channel blockers. However, efficacy in symptoms control is heterogenous, depending on underlying mechanism(s) of angina in an individual patient, often necessitating multiple agents. Nicorandil (NCO) is an antianginal agent first discovered in the late 1970s with a uniquely dual mechanism of action. Like a typical nitrate, it mediates medium-large vessel vasodilation through nitric oxide. In addition, NCO has adenosine triphosphate (ATP)-dependent potassium channel agonist activity (K ATP ), mediating microvascular dilatation. Hence, it has proven effective in both coronary artery vasospasm and coronary microvascular disease, typically challenging patient populations. Moreover, emerging evidence suggests that cardiomyocyte protection against ischemia through ischemic preconditioning may be mediated through K ATP agonism. Finally, there is now fairly firm evidence in favor of NCO in terms of hard event reduction among patients with stable coronary artery disease, following myocardial infarction, and perhaps even among patients with congestive heart failure. This review aims to summarize the mechanism of action of NCO, its efficacy as an antianginal, and current evidence behind its impact on hard outcomes. Finally, we review other cardiac and emerging noncardiac indications for NCO use.

Neuroendocrine carcinoma of cervix and review literature.

INTRODUCTION: Neuroendocrine carcinoma of the cervix (NECC) is a rare variant of cervical cancer with poor prognosis and high mortality. Recurrence is seen with multi-organ metastasis including liver. CASE PRESENTATION: A 65 year old female presented with vaginal bleeding for the past one year. Cervical cancer screening and biopsy demonstrated poorly differentiated squamous carcinoma. Immunohistochemistry showed positive expression of chromogranin, synaptophysin, pancytokeratin, TTP1, and CEA and negative expression of p40 and estrogen receptors. An adenocarcinoma with neuroendocrine tumor was suggested. Hysterectomy with bilateral salpingo-oophrectomy was performed. This was followed by carboplatin and etoposide therapy to have clinical remission for a year. Then recurrence was observed to start same drugs again resulting in to partial improvement. It was followed by radiotherapy. The patient succumbed to death approximately after three months. CONCLUSION: A metastatic lesion in liver may be a case of Neuroendocrine tumor of cervix, a rare condition that can be easily missed on histopathological examination. More studies are required to establish a standard therapeutic protocol.

Acute myeloid leukemia: novel mutations and their clinical implications.

Acute myeloid leukemia (AML) is a heterogenous and challenging hematological malignancy with suboptimal outcomes. The implications of advanced technologies in the genetic characterization of AML have enhanced the understanding of individualized patient risk, which has also led to the development of new therapeutic strategies. A comprehensive study of novel mutations is essential to moderate the complicacies in patient management and achieve optimal outcomes in AML. In this review, we summarized the clinical relevance of important novel mutations, including TET2, ETV6, SATB1, EZH2, PTPN11, and U2AF1, which impact the prognosis of AML. TET2 mutation can lead to DNA hypermethylation, and gene fusion, and mutation in ETV6 disrupts hematopoietic transcription machinery, SATB1 downregulation aggravates the disease, and EZH2 mutation confers resistance to chemotherapy. PTPN11 mutation influences the RAS-MAPK signaling pathway, and U2AF1 alters the splicing of downstream mRNA. The systemic influence of these mutations has adverse consequences. Therefore, extensive research on novel mutations and their mechanism of action in the pathogenesis of AML is vital. This study lays out the perspective of expanding the apprehension about AML and novel drug targets. The combination of advanced genetic techniques, risk stratification, ongoing improvements, and innovations in treatment strategy will undoubtedly lead to improved survival outcomes in AML.

Unraveling the therapeutic potential of natural products in the prevention and treatment of leukemia.

Leukemia is a heterogeneous group of hematological malignancies distinguished by differentiation blockage and uncontrolled proliferation of myeloid or lymphoid progenitor cells in the bone marrow (BM) and peripheral blood (PB). There are various types of leukemia in which intensive chemotherapy regimens or hematopoietic stem cell transplantation (HSCT) are now the most common treatments associated with severe side effects and multi-drug resistance in leukemia cells. Therefore, it is crucial to develop novel therapeutic approaches with adequate therapeutic efficacy and selectively eliminate leukemic cells to improve the consequences of leukemia. Medicinal plants have been utilized for ages to treat multiple disorders due to their diverse bioactive compounds. Plant-derived products have been used as therapeutic medication to prevent and treat many types of cancer. Over the last two decades, 50 % of all anticancer drugs approved worldwide are from natural products and their derivatives. Therefore this study aims to review natural products such as polyphenols, alkaloids, terpenoids, nitrogen-containing, and organosulfur compounds as antileukemic agents. Current investigations have identified natural products efficiently destroy leukemia cells through diverse mechanisms of action by inhibiting proliferation, reactive oxygen species production, inducing cell cycle arrest, and apoptosis in both in vitro, in vivo, and clinical studies. Current investigations have identified natural products as suitable promising chemotherapeutic and chemopreventive agents. It played an essential role in drug development and emerged as a possible source of biologically active metabolites for therapeutic interventions, especially in leukemia. DATA AVAILABILITY: Data will be made available on request.

Demethylation of CADM1 and SOCS1 using capsaicin in cervical cancer cell line.

Cervical cancer is one of the leading causes of women's mortality in developing countries. The prevalence of cervical cancer is higher in developing countries like India and continents like Africa. Hyper-methylation of tumor suppressor genes through human papillomavirus (HPV) infection is known to be one of the major causes of cervical cancer. The promoter hypermethylation of the cell adhesion molecule 1 (CADM1) and suppressor of cytokine signalling (SOCS1) genes due to DNMT1 overexpression leads to their epigenetic silencing followed by gene repression causing cervical cancer. In silico study on the inhibition effect of capsaicin on DNMT1 was simulated by different servers. The binding energy was observed to be -7.8 kcal/mol. In vitro studies on the effect of capsaicin on aberrant methylation of CADM1 and SOCS1 were performed on the adenocarcinoma cervical cancer cell line, HeLa. The IC50 of capsaicin was observed to be 160 µM through crystal violet assay. DNA methylation of the CADM1 and SOCS1 was analyzed by methylation-specific PCR along with their reversal using capsaicin (20 µM) by treating the cells for 72 h and 6 days. In silico results suggested that capsaicin has an inhibitory effect on DNMT1, which regulates DNA methylation leading to the hypermethylation of CADM1 and SOCS1 genes. The in vitro studies suggested that hypermethylation leads to the inhibition of CADM1 and SOCS1 expression, which could be reversed using capsaicin with visible changes in methylation-specific and unmethylation-specific bands in MS-PCR, respectively. The present study shows the reversal of methylation of CADM1 and SOCS1 after 72 h which showed a further increase in case of 6 days of treatment using 20 µM capsaicin, which makes capsaicin a potent candidate for causing demethylation of CADM1 and SOCS1 genes that may lead to the reactivation of the downregulated gene.

Elucidations of Molecular Mechanism and Mechanistic Effects of Environmental Toxicants in Neurological Disorders.

Due to rising environmental and global public health concerns associated with environmental contamination, human populations are continually being exposed to environmental toxicants, including physical chemical mutagens widespread in our environment causing adverse consequences and inducing a variety of neurological disorders in humans. Physical mutagens comprise ionizing and non-ionizing radiation, such as UV rays, IR rays, X-rays, which produces a broad spectrum of neuronal destruction, including neuroinflammation, genetic instability, enhanced oxidative stress driving mitochondrial damage in the human neuronal antecedent cells, cognitive impairment due to alterations in neuronal function, especially in synaptic plasticity, neurogenesis repression, modifications in mature neuronal networks drives to enhanced neurodegenerative risk. Chemical Mutagens including alkylating agents (EMS, NM, MMS, and NTG), Hydroxylamine, nitrous acid, sodium azide, halouracils are the major toxic mutagen in our environment and have been associated with neurological disorders. These chemical mutagens create dimers of pyrimidine that cause DNA damage that leads to ROS generation producing mutations, chromosomal abnormalities, genotoxicity which leads to increased neurodegenerative risk. The toxicity of four heavy metal including Cd, As, Pb, Hg is mostly responsible for complicated neurological disorders in humans. Cadmium exposure can enhance the permeability of the BBB and penetrate the brain, driving brain intracellular accumulation, cellular dysfunction, and cerebral edema. Arsenic exerts its toxic effect by induction of ROS production in neuronal cells. In this review, we summarize the molecular mechanism and mechanistic effects of mutagens in the environment and their role in multiple neurological disorders.

Presence of entry receptors and viral markers suggest a low level of placental replication of hepatitis B virus in a proportion of pregnant women infected with chronic hepatitis B.

The transplacental route of vertical transmission of Hepatitis B Virus (HBV) has been known for over a decade. Here we present evidence which suggest HBV can replicate in placenta. Forty-one HBsAg positive and 10 control pregnant women were enrolled in the study after obtaining informed consent. HBV positives were further divided in the High Viral Load (HVL) Group and Low Viral Load (LVL) Group according to INASL guidelines 2018. The Presence of the HBV DNA and expression of NTCP in the placenta was analyzed by qPCR/RT-qPCR and/or immunohistochemistry (IHC). The presence of cccDNA was assessed using Digital Droplet PCR while the presence of pre-genomic (pg) RNA was assessed through qRT-PCR and sequencing. The presence of HBeAg and HBcAg in the placenta was assessed by IHC. Immunostaining of NTCP, HBeAg and HBcAg on trophoblasts along with the presence of total HBV DNA, cccDNA and pgRNA indicated, that these cells are not only susceptible to HBV infection but may also support viral replication. This is further supported by the finding that trophoblasts of the several HBeAg seronegative samples harbored the HBeAg. Although, we did not find any correlation in NTCP expression and viral markers with viral load indicates placental replication may not aping hepatocytes. The presence of the HBV receptor, NTCP along with the presence of cccDNA, pgRNA, and HBeAg in placenta of HBV infected females without circulating HBeAg suggest that placenta act as a replication host.

Potential Therapeutic Role of Mesenchymal-Derived Stem Cells as an Alternative Therapy to Combat COVID-19 through Cytokines Storm.

Medical health systems continue to be challenged due to newly emerging COVID-19, and there is an urgent need for alternative approaches for treatment. An increasing number of clinical observations indicate cytokine storms to be associated with COVID-19 severity and also to be a significant cause of death among COVID-19 patients. Cytokine storm involves the extensive proliferative and hyperactive activity of T and macrophage cells and the overproduction of pro-inflammatory cytokines. Stem cells are the type of cell having self-renewal properties and giving rise to differentiated cells. Currently, stem cell therapy is an exciting and promising therapeutic approach that can treat several diseases that were considered incurable in the past. It may be possible to develop novel methods to treat various diseases by identifying stem cells' growth and differentiation factors. Treatment with mesenchymal stem cells (MSCs) in medicine is anticipated to be highly effective. The present review article is organized to put forward the positive arguments and implications in support of mesenchymal stem cell therapy as an alternative therapy to cytokine storms, to combat COVID-19. Using the immunomodulatory potential of the MSCs, it is possible to fight against COVID-19 and counterbalance the cytokine storm.

Comprehensive mutations analyses of FTO (fat mass and obesity-associated gene) and their effects on FTO's substrate binding implicated in obesity.

An excessive amount of fat deposition in the body leads to obesity which is a complex disease and poses a generic threat to human health. It increases the risk of various other diseases like diabetes, cardiovascular disease, and multiple types of cancer. Genomic studies have shown that the expression of the fat mass obesity (FTO) gene was highly altered and identified as one of the key biomarkers for obesity. This study has been undertaken to investigate the mutational profile of the FTO gene and elucidates its effect on the protein structure and function. Harmful effects of various missense mutations were predicted using different independent tools and it was observed that all mutations were highly pathogenic. Molecular dynamics (MD) simulations were performed to study the structure and function of FTO protein upon different mutations and it was found that mutations decreased the structure stability and affected protein conformation. Furthermore, a protein residue network analysis suggested that the mutations affected the overall residues bonding and topology. Finally, molecular docking coupled with MD simulation suggested that mutations affected FTO substrate binding by changing the protein-ligand affinity. Hence, the results of this finding would help in an in-depth understanding of the molecular biology of the FTO gene and its variants and lead to the development of effective therapeutics against associated diseases and disorders.

Fractional Flow Reserve Cardio-Oncology Effects on Inpatient Mortality, Length of Stay, and Cost Based on Malignancy Type: Machine Learning Supported Nationally Representative Case-Control Study of 30 Million Hospitalizations.

Background and Objectives: There are no nationally representative studies of mortality and cost effectiveness for fractional flow reserve (FFR) guided percutaneous coronary interventions (PCI) in patients with cancer. Our study aims to show how this patient population may benefit from FFR-guided PCI. Materials and Methods: Propensity score matched analysis and backward propagation neural network machine learning supported multivariable regression was performed for inpatient mortality in this case-control study of the 2016 National Inpatient Sample (NIS). Regression results were adjusted for age, race, income, geographic region, metastases, mortality risk, and the likelihood of undergoing FFR versus non-FFR PCI. All analyses were adjusted for the complex survey design to produce nationally representative estimates. Results: Of the 30,195,722 hospitalized patients meeting criteria, 3.37% of the PCIs performed included FFR. In propensity score adjusted multivariable regression, FFR versus non-FFR PCI significantly reduced inpatient mortality (OR 0.47, 95%CI 0.35−0.63; p < 0.001) and length of stay (LOS) (in days; beta −0.23, 95%CI −0.37−−0.09; p = 0.001) while increasing cost (in USD; beta $5708.63, 95%CI, 3042.70−8374.57; p < 0.001), without significantly increasing complications overall. FFR versus non-FFR PCI did not specifically change cancer patients' inpatient mortality, LOS, or cost. However, FFR versus non-FFR PCI significantly increased inpatient mortality for Hodgkin's lymphoma (OR 52.48, 95%CI 7.16−384.53; p < 0.001) and rectal cancer (OR 24.38, 95%CI 2.24−265.73; p = 0.009). Conclusions: FFR-guided PCI may be safely utilized in patients with cancer as it does not significantly increase inpatient mortality, complications, and LOS. These findings support the need for an increased utilization of FFR-guided PCI and further studies to evaluate its long-term impact.

Temperature, cardiovascular mortality, and the role of hypertension and renin-angiotensin-aldosterone axis in seasonal adversity: a narrative review.

Environmental temperature is now well known to have a U-shaped relationship with cardiovascular (CV) and all-cause mortality. Both heat and cold above and below an optimum temperature, respectively, are associated with adverse outcomes. However, cold in general and moderate cold specifically is predominantly responsible for much of temperature-attributable adversity. Importantly, hypertension-the most important CV risk factor-has seasonal variation such that BP is significantly higher in winter. Besides worsening BP control in established hypertensives, cold-induced BP increase also contributes to long-term BP variability among normotensive and pre-hypertensive patients, also a known CV risk factor. Disappointingly, despite the now well-stablished impact of temperature on BP and on CV mortality separately, direct linkage between seasonal BP change and CV outcomes remains preliminary. Proving or disproving this link is of immense clinical and public health importance because if seasonal BP variation contributes to seasonal adversity, this should be a modifiable risk. Mechanistically, existing evidence strongly suggests a central role of the sympathetic nervous system (SNS), and secondarily, the renin-angiotensin-aldosterone axis (RAAS) in mediating cold-induced BP increase. Though numerous other inflammatory, metabolic, and vascular perturbations likely also contribute, these may also well be secondary to cold-induced SNS/RAAS activation. This review aims to summarize the current evidence linking temperature, BP and CV outcomes. We also examine underlying mechanisms especially in regard to the SNS/RAAS axis, and highlight possible mitigation measures for clinicians.

A Case of Neuroparacoccidioidomycosis in Houston, Texas.

Paracoccidioidomycosis is a systemic fungal disease caused by the dimorphic Paracoccidioides species endemic to South America. Infection classically presents with pulmonary, mucosal, or reticuloendothelial involvement, though other organs can be involved. Central nervous system involvement is rare, and almost universally reported within the endemic area for the fungus. We present a 60-year-old Brazilian male who complained of occipital headache, ataxia, dysmetria, and dysarthria for two months, diagnosed with neuroparacoccidioidomycosis in Houston, Texas. The patient had a cerebellar mass and a left pulmonary spiculated apical mass suspicious for a lung metastatic malignancy and a preliminary histological report consistent with invasive cryptococcosis. The patient's work and travel history were paramount in achieving the final diagnosis.

Premorbid echocardiography and risk of hospitalization in COVID-19.

BACKGROUND: COVID-19 has caused a global pandemic unprecedented in a century. Though primarily a respiratory illness, cardiovascular risk factors predict adverse outcomes. We aimed to investigate the role of baseline echocardiographic abnormalities in further refining risk in addition to clinical risk factors. METHODS: Adults with COVID-19 positive RT-PCR test across St Luke's University Health Network between March 1st 2020-October 31st 2020 were identified. Those with trans-thoracic echocardiography (TTE) within 15-180 days preceding COVID-19 positivity were selected, excluding severe valvular disease, acute cardiac event between TTE and COVID-19, or asymptomatic patients positive on screening. Demographic, clinical, and echocardiographic variables were manually extracted from patients' EHR and compared between groups stratified by disease severity. Logistic regression was used to identify independent predictors of hospitalization. RESULTS: 192 patients met inclusion criteria. 87 (45.3%) required hospitalization, 34 (17.7%) suffered severe disease (need for ICU care/mechanical ventilation/in-hospital death). Age, co-morbidities, and several echocardiographic abnormalities were more prevalent in those with moderate-severe disease than in mild disease, with notable exceptions of systolic/diastolic dysfunction. On multivariate analysis, age (OR 1.039, 95% CI 1.011-1.067), coronary artery disease (OR 4.184, 95% CI 1.451-12.063), COPD (OR 6.886, 95% CI 1.396-33.959) and left atrial diameter ≥ 4.0 cm (OR 2.379, 95% CI 1.031-5.493) predicted need for hospitalization. Model showed excellent discrimination (ROC AUC 0.809, 95% CI 0.746-0.873). CONCLUSIONS: Baseline left atrial enlargement is an independent risk factor for risk of hospitalization among patients with COVID-19. When available, baseline LA enlargement may identify patients for (1) closer outpatient follow up, and (2) counseling vaccine-hesitancy.

Unravelling the molecular mechanism of mutagenic factors impacting human health.

Environmental mutagens are chemical and physical substances in the environment that has a potential to induce a wide range of mutations and generate multiple physiological, biochemical, and genetic modifications in humans. Most mutagens are having genotoxic effects on the following generation through germ cells. The influence of germinal mutations on health will be determined by their frequency, nature, and the mechanisms that keep a specific mutation in the population. Early prenatal lethal mutations have less public health consequences than genetic illnesses linked with long-term medical and social difficulties. Physical and chemical mutagens are common mutagens found in the environment. These two environmental mutagens have been associated with multiple neurological disorders and carcinogenesis in humans. Thus in this study, we aim to unravel the molecular mechanism of physical mutagens (UV rays, X-rays, gamma rays), chemical mutagens (dimethyl sulfate (DMS), bisphenol A (BPA), polycyclic aromatic hydrocarbons (PAHs), 5-chlorocytosine (5ClC)), and several heavy metals (Ar, Pb, Al, Hg, Cd, Cr) implicated in DNA damage, carcinogenesis, chromosomal abnormalities, and oxidative stress which leads to multiple disorders and impacting human health. Biological tests for mutagen detection are crucial; therefore, we also discuss several approaches (Ames test and Mutatox test) to estimate mutagenic factors in the environment. The potential risks of environmental mutagens impacting humans require a deeper basic knowledge of human genetics as well as ongoing research on humans, animals, and their tissues and fluids.

Nanoparticles Mediated Target-specific Drug Delivery in Prostate Cancer: An In-depth Review.

Nanotechnology has been extensively exploited for its enormous therapeutic and diagnostic potential in the management of multiple disorders. It employs nanomaterials as drug carriers with enhanced efficacy and limited side effects on normal tissues. A lot of nanomaterials have been studied and produced, imminently reforming the treatment and diagnostics of numerous malignancies, including cancer. The purpose of the present study is to explore the role of nanotechnology-based devices/therapies that have a vital function in the therapeutics and diagnostics of cancer with potential impact at three levels: early detection, tumor imaging, and drug delivery methods. Concentrating on cancer, promising nanotechnology-based approaches have been planned to satisfy the need for targeted specificity of traditional agents of chemotherapeutics, in addition to early recognition of malignant and precancerous lesions. Prostate cancer is the fifth most wellknown cancer worldwide and the second most usually detected cancer in men. Therefore, there is a crucial need to improve therapeutic prospects for the diagnosis and treatment of prostate cancer via the exploitation of the potential of nanomaterials for cell-targeted specificity and improved primary diagnosis of precancerous tumors. The present review, therefore, focuses on summarizing all prospective applications of nanotechnology in the prognosis and diagnosis of prostate cancer, which would further help researchers to elucidate a more potent therapeutic approach for the better management of prostate cancer in the days ahead.

Computational investigation reveals that the mutant strains of SARS-CoV2 have differential structural and binding properties.

BACKGROUND AND OBJECTIVES: Remarkable infectivity of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV2) is due to the rapid emergence of various strains which enable the virus to ruling the world. Over the course of SARS-CoV2 pandemic, the scientific communities worldwide are responding to newly emerging genetic variants. However, mechanism behind the persistent infection of these variants is still not known due to the paucity of study of these variants at molecular level. In this scenario, computational methods have immense utility in understanding the molecular and functional properties of different variants. METHODS: The various mutants (MTs) of SpikeS1 receptor binding domain (RBD) of highly infectious SARS-CoV2 strains were manifested and elucidated the protein structure and binding strength using molecular dynamics (MD) simulation and protein-protein docking approaches. RESULTS: MD simulation study showed that all MTs exhibited stable structures with altered functional properties. Furthermore, the binding strength of different MTs along with WT (wildtype) was revealed that MTs showed differential binding affinities to host protein with high binding strength exhibited by V367F and V483A MTs. CONCLUSION: Hence, this study shed light on the molecular basis of infection caused by different variants of SARS-CoV2, which might play an important role in to cease the transmission and pathogenesis of virus and also implicate in rational designing of a specific drug.