Retinoid X Receptor agonists as selective modulators of the immune system for the treatment of cancer.

Upon heterodimerizing with other nuclear receptors, retinoid X receptors (RXR) act as ligand-dependent transcription factors, regulating transcription of critical signaling pathways that impact numerous hallmarks of cancer. By controlling both inflammation and immune responses, ligands that activate RXR can modulate the tumor microenvironment. Several small molecule agonists of these essential receptors have been synthesized. Historically, RXR agonists were tested for inhibition of growth in cancer cells, but more recent drug discovery programs screen new molecules for inhibition of inflammation or activation of immune cells. Bexarotene is the first successful example of an effective therapeutic that molecularly targets RXR; this drug was approved to treat cutaneous T cell lymphoma and is still used as a standard of care treatment for this disease. No additional RXR agonists have yet achieved FDA approval, but several promising novel compounds are being developed. In this review, we provide an overview of the multiple mechanisms by which RXR signaling regulates inflammation and tumor immunity. We also discuss the potential of RXR-dependent immune cell modulation for the treatment or prevention of cancer and concomitant challenges and opportunities.

Covariates of Knowledge, Attitude, Practice, and Burdens among the Caregivers of Hypertensive Patients.

Caregivers of hypertensive patients play a significant role in ensuring adequate patient care and lowering the risk of hypertension-relatedcomplications. Caregivers are ideal study subjects for identifying gaps in hypertension management. Our study aimed to assess the knowledge, attitude, and practice (KAP) of hypertensive patients' caregivers, to identify their extent of involvement in patients' care, and to assess their care-related attributes. A descriptive cross-sectional study was conducted from August 2020 to February 2021 in the eight largest tertiary care medical college hospitals and all eight divisions of Bangladesh, with 949 caregivers enrolled. Data were collected using a pretested interviewer-administered questionnaire through snowball sampling and analyzed using a one-way ANOVA, independent-sample T-test, and chi-square test. Among the 949 interviewed caregivers, 541 (57.0%) were female, and 479 (50.5%) were aged 18 to 25 years. The percentage scores regarding overall knowledge, attitude, and practice of the caregivers were 54.83 ± 17.95, 47.95 ± 24.05, and 61.26 ± 17.50, respectively. Caregivers' education, history of hypertension, residence, age, relationship with the patient, occupation, and caregiving duration were significantly associated with the KAP scores. In addition, factors such as relationship with the patient, age, educational status, occupation, residence, and caregiving duration/day had significant correlations with all types of burden. Findings of this study suggest the necessity for awareness programs for the caregivers of hypertensive patients to diminish the gap in their KAP and improve their mental and physical health.

Association between comorbidity and health-related quality of life in a hypertensive population: a hospital-based study in Bangladesh.

BACKGROUND: Hypertension is a known risk factor for several chronic conditions including diabetes and cardiovascular diseases. However, little is known about its impact on Health-related quality of life (HRQoL) in the context of Bangladesh. This study aimed to evaluate the association of hypertension on HRQoL among Bangladeshi patients corresponding to the socio-demographic condition, comorbid conditions, treatment, and health outcomes. METHODS: A hospital based cross-sectional study was conducted using a pre-tested structured questionnaire among patients with hypertension in 22 tertiary medical college hospitals in Bangladesh. The study recruited male and female hypertensive patients of age ≥18 years between July 2020 to February 2021 using consecutive sampling methods. Health related quality of life was measured using the widely-used index of EQ-5D that considers 243 different health-related attributes and uses a scale in which 0 indicates a health state equivalent to death and 1 indicates perfect health status. The five dimensions of the quality index included mobility, self-care, usual activities, pain or discomfort, and anxiety or depression. Ordered logit regression and linear regression models were used to estimate the predictors of comorbidity and HRQoL. RESULTS: Of the 1,912 hypertensive patients, 56.2% were female, 86.5% were married, 70.7% were either overweight or obese, 67.6% had a family history of hypertension, and 85.5% were on anti-hypertensive medication. Among the individuals with comorbidities, 47.6% had diabetes, 32.3% were obese, 16.2% had heart disease, 15% were visually impaired, and 13.8% were suffering from psychological diseases. HRQoL was found to be inversely proportional to the number of comorbidities. The most frequent comorbidities of diabetes and obesity showed the highest EQ- 5D mean utilities of 0.59 and 0.64, respectively. CONCLUSIONS: Prevalent comorbidities, diabetes and obesity were found to be the significant underlying causes of declining HRQoL. It is recommended that the comorbidities should be adequately addressed for better HRQoL. Special attention should be given to address mental health issues of patients with hypertension.

A next generation sequencing (NGS) analysis to reveal genomic and proteomic mutation landscapes of SARS-CoV-2 in South Asia.

Counts for SARS-CoV-2 associated infections and fatalities are on the rise globally even in regions which contained the spread momentarily. The pattern of infections has been found to be controlled by the distinctive selection pressures exerted by fluctuating environmental nature and hosts. A total of 410 whole-genome sequences submitted by the South Asian countries were retrieved from the GISAID database and analyzed to assess the impact and pattern of mutations in this region. Most common and frequent mutations in the South Asian countries are 241C > T, 3037C > T, 14408C > T, and 23403A > G and about 85% SNPs are localized in ORF1ab, spike protein, and nucleocapsid. Among the identified mutations, the proportion of missense type (54.17%) was highest, followed by the synonymous (41.66%) and the non-coding types (4.17%). While analyzing transmission source in terms of geolocation, the largest clustered group from the South Asian countries was based on the G-clade (D614G) (81.7%; 335/410 samples), tracing the inception and transmission of SARS-CoV-2 infections in the South Asian countries from European regions. Phylogenetic analysis also revealed that the South Asian strains are highly related to the South American and European strains. We found that G-clade mutations are more prevalent (96.19%) in the samples of Bangladesh which were also prevalent in the European isolates. Surprisingly, one missense mutation (1163A > T) in ORF1ab gene became dominant only in Bangladesh (78.8%), which led to debates regarding effects on the pathogenicity and transmissibility of the virus. Overall, the findings of this study highlight the frequently mutated SARS-CoV-2 variants among the COVID-19 patients in the South Asian countries which might ease containment of the disease in this region through investigating the virulence reducing factors as the identified mutations are strongly correlated with low infection and mortality rate.

Evaluation of the susceptibility and fatality of lung cancer patients towards the COVID-19 infection: A systemic approach through analyzing the ACE2, CXCL10 and their co-expressed genes.

Coronavirus disease-2019 (COVID-19) is a recent world pandemic disease that is caused by a newly discovered strain of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS- CoV-2). Patients with comorbidities are most vulnerable to this disease. Therefore, cancer patients are reported to be more susceptible to COVID-19 infection, particularly lung cancer patients. To evaluate the probable reasons behind the excessive susceptibility and fatality of lung cancer patients to COVID-19 infection, we targeted the two most crucial agents, Angiotensin-converting enzyme 2 (ACE2) and C-X-C motif 10 (CXCL10). ACE2 is a receptor protein that plays a vital role in the entry of SARS-CoV-2 into the host cell and CXCL10 is a cytokine mainly responsible for the lung cell damage involving in a cytokine storm. By using the UALCAN and GEPIA2 databases, we observed that ACE2 and CXCL10 are mostly overexpressed in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). We then identified the functional significance of ACE2 and CXCL10 in lung cancer development by determining the genetic alteration frequency in their amino acid sequences using the cBioPortal web portal. Lastly, we did the pathological assessment of targeted genes using the PANTHER database. Here, we found that ACE2 and CXCL10 along with their commonly co-expressed genes are involved respectively in the binding activity and immune responses in case of lung cancer and COVID-19 infection. Finally, based on this systemic analysis, we concluded that ACE2 and CXCL10 are two possible biomarkers responsible for the higher susceptibility and fatality of lung cancer patients towards the COVID-19.

Identification of putative drug targets in Vancomycin-resistant Staphylococcus aureus (VRSA) using computer aided protein data analysis.

Vancomycin-resistant Staphylococcus aureus (VRSA) is a Gram-positive, facultative aerobic bacterium which is evolved from the extensive exposure of Vancomycin to Methicillin resistant S. aureus (MRSA) that had become the most common cause of hospital and community-acquired infections. Due to the emergence of different antibiotic resistance strains, there is an exigency to develop novel drug targets to address the provocation of multidrug-resistant bacteria. In this study, in-silico genome subtraction methodology was used to design potential and pathogen specific drug targets against VRSA. Our study divulged 1987 proteins from the proteome of 34,549 proteins, which have no homologues in human genome after sequential analysis through CD-HIT and BLASTp. The high stringency analysis of the remaining proteins against database of essential genes (DEG) resulted in 169 proteins which are essential for S. aureus. Metabolic pathway analysis of human host and pathogen by KAAS at the KEGG server sorted out 19 proteins involved in unique metabolic pathways. 26 human non-homologous membrane-bound essential proteins including 4 which were also involved in unique metabolic pathway were deduced through PSORTb, CELLO v.2.5, ngLOC. Functional classification of uncharacterized proteins through SVMprot derived 7 human non-homologous membrane-bound hypothetical essential proteins. Study of potential drug target against Drug Bank revealed pbpA-penicillin-binding protein 1 and hypothetical protein MQW_01796 as the best drug target candidate. 2D structure was predicted by PRED-TMBB, 3D structure and functional analysis was also performed. Protein-protein interaction network of potential drug target proteins was analyzed by using STRING. The identified drug targets are expected to have great potential for designing novel drugs against VRSA infections and further screening of the compounds against these new targets may result in the discovery of novel therapeutic compounds that can be effective against Vancomycin resistant S. aureus.

Functional and Structural Consequences of Damaging Single Nucleotide Polymorphisms in Human Prostate Cancer Predisposition Gene RNASEL.

A commonly diagnosed cancer, prostate cancer (PrCa), is being regulated by the gene RNASEL previously known as PRCA1 codes for ribonuclease L which is an integral part of interferon regulated system that mediates antiviral and antiproliferative role of the interferons. Both somatic and germline mutations have been implicated to cause prostate cancer. With an array of available Single Nucleotide Polymorphism data on dbSNP this study is designed to sort out functional SNPs in RNASEL by implementing different authentic computational tools such as SIFT, PolyPhen, SNPs&GO, Fathmm, ConSurf, UTRScan, PDBsum, Tm-Align, I-Mutant, and Project HOPE for functional and structural assessment, solvent accessibility, molecular dynamics, and energy minimization study. Among 794 RNASEL SNP entries 124 SNPs were found nonsynonymous from which SIFT predicted 13 nsSNPs as nontolerable whereas PolyPhen-2 predicted 28. SNPs found on the 3' and 5' UTR were also assessed. By analyzing six tools having different perspectives an aggregate result was produced where nine nsSNPs were found to be most likely to exert deleterious effect. 3D models of mutated proteins were generated to determine the functional and structural effect of the mutations on ribonuclease L. The initial findings were reinforced by the results from I-Mutant and Project HOPE as these tools predicted significant structural and functional instability of the mutated proteins. Expasy-ProSit tool defined the mutations to be situated in the functional domains of the protein. Considering previous analysis this study revealed a conclusive result deducing the available SNP data on the database by identifying the most damaging three nsSNP rs151296858 (G59S), rs145415894 (A276V), and rs35896902 (R592H). As such studies involving polymorphisms of RNASEL were none to be found, the results of the current study would certainly be helpful in future prospects concerning prostate cancer in males.

Molecular-docking study of malaria drug target enzyme transketolase in Plasmodium falciparum 3D7 portends the novel approach to its treatment.

BACKGROUND: Malaria has been a major life threatening mosquito borne disease from long since. Unavailability of any effective vaccine and recent emergence of multi drug resistant strains of malaria pathogen Plasmodium falciparum continues to cause persistent deaths in the tropical and sub-tropical region. As a result, demands for new targets for more effective anti-malarial drugs are escalating. Transketolase is an enzyme of the pentose phosphate pathway; a novel pathway which is involved in energy generation and nucleic acid synthesis. Moreover, significant difference in homology between Plasmodium falciparum transketolase (Pftk) and human (Homo sapiens) transketolase makes it a suitable candidate for drug therapy. Our present study is aimed to predict the 3D structure of Plasmodium falciparum transketolase and design an inhibitor against it. RESULTS: The primary and secondary structural features of the protein is calculated by ProtParam and SOPMA respectively which revealed the protein is composed of 43.3 % alpha helix and 33.04 % random coils along with 15.62 % extended strands, 8.04 % beta turns. The three dimensional structure of the transketolase is constructed using homology modeling tool MODELLAR utilizing several available transketolase structures as templates. The structure is then subjected to deep optimization and validated by structure validation tools PROCHECK, VERIFY 3D, ERRAT, QMEAN. The predicted model scored 0.74 for global model reliability in PROCHECK analysis, which ensures the quality of the model. According to VERIFY 3D the predicted model scored 0.77 which determines good environmental profile along with ERRAT score of 78.313 which is below 95 % rejection limit. Protein-protein and residue-residue interaction networks are generated by STRING and RING server respectively. CASTp server was used to analyze active sites and His 109, Asn 108 and His 515 are found to be more positive site to dock the substrate, in addition molecular docking simulation with Autodock vina determined the estimated free energy of molecular binding was of -6.6 kcal/mol for most favorable binding of 6'-Methyl-Thiamin Diphosphate. CONCLUSION: This predicted structure of Pftk will serve first hand in the future development of effective Pftk inhibitors with potential anti-malarial activity. However, this is a preliminary study of designing an inhibitor against Plasmodium falciparum 3D7; the results await justification by in vitro and in vivo experimentations.

Highly conserved regions in Ebola virus RNA dependent RNA polymerase may be act as a universal novel peptide vaccine target: a computational approach.

PURPOSE: Ebola virus (EBOV) is such kind of virus which is responsible for 23,825 cases and 9675 deaths worldwide only in 2014 and with an average diseases fatality rate between 25 % and 90 %. Although, medical technology has tried to handle the problems, there is no Food and Drug Administration (FDA)-approved therapeutics or vaccines available for the prevention, post exposure, or treatment of Ebola virus disease (EVD). METHODS: In the present study, we used the immunoinformatics approach to design a potential epitope-based vaccine against the RNA-dependent RNA polymerase-L of EBOV. BioEdit v7.2.3 sequence alignment editor, Jalview v2 and CLC Sequence Viewer v7.0.2 were used for the initial sequence analysis for securing the conservancy from the sequences. Later the Immune Epitope Database and Analysis Resource (IEDB-AR) was used for the identification of T-cell and B-cellepitopes associated with type I and II major histocompatibility complex molecules analysis. Finally, the population coverage analysis was employed. RESULTS: The core epitope "FRYEFTAPF" was found to be the most potential one, with 100 % conservancy among all the strains of EBOV. It also interacted with both type I and II major histocompatibility complex molecules and is considered as nonallergenic in nature. Finally, with impressive cumulative population coverage of 99.87 % for the both MHC-I and MHC-II class throughout the world population was found for the proposed epitope. CONCLUSION: To end, the projected peptide gave us a solid stand to propose for vaccine consideration and that might be experimented for its potency in eliciting immunity through humoral and cell mediated immune responses in vitro and in vivo.