Exome sequencing identifies ADGRG4 G-protein-coupled receptors gene as a novel cancer biomarker in ovarian cancer patients from North India.

Adhesion G protein-coupled receptor G4 (ADGRG4) is a G protein-coupled receptor (GPCR) that belongs to the adhesion family. Participation of ADGRG4 in cell adhesion and migration, signaling pathway activation, influence on angiogenesis, and modulation of immune responses are some of the possible ways through which it may contribute to oncogenesis. Conducting extensive omics studies poses budgetary challenges to small labs in peripheral areas, primarily due to restricted research funding and resource limitations. Here we propose a low-budget model for biomarker screening. A total of 11 ovarian cancer samples were sent for exome sequencing. Among various genes, ADGRG4 variants were present in all 11 samples and thus were chosen as a potential biomarker in the present population. However, the precise role of ADGRG4 in cancer is not fully understood. The present study aims to look at the association between the ADGRG4 gene variants and their risk of ovarian cancer in the North Indian region of Jammu and Kashmir, India. Overall, 235 individuals (115 cases and 120 healthy controls) were genotyped for the selected biomarker using Sanger sequencing. Logistic regression was used to assess the relationship between the variant and ovarian cancer. A statistically significant association was identified between the ADGRG4 variant rs5930932 polymorphism and the incidence of ovarian cancer among the study population. When corrected for age and BMI, the dominating OR of variant rs5930932 was 1.035 (1.003-1.069) under HWE patients (0.95) and controls (0.18), with a p-value of (0.03). According to the findings of the current investigation, the ADGRG4 gene variant rs5930932 increases the chance of developing ovarian cancer in the studied population.

Associations between telomere attrition, genetic variants in telomere maintenance genes, and non-small cell lung cancer risk in the Jammu and Kashmir population of North India.

BACKGROUND: Telomeres are repetitive DNA sequences located at the ends of chromosomes, playing a vital role in maintaining chromosomal integrity and stability. Dysregulation of telomeres has been implicated in the development of various cancers, including non-small cell lung cancer (NSCLC), which is the most common type of lung cancer. Genetic variations within telomere maintenance genes may influence the risk of developing NSCLC. The present study aimed to evaluate the genetic associations of select variants within telomere maintenance genes in a population from Jammu and Kashmir, North India, and to investigate the relationship between telomere length and NSCLC risk. METHODS: We employed the cost-effective and high-throughput MassARRAY MALDI-TOF platform to assess the genetic associations of select variants within telomere maintenance genes in a population from Jammu and Kashmir, North India. Additionally, we used TaqMan genotyping to validate our results. Furthermore, we investigated telomere length variation and its relation to NSCLC risk in the same population using dual-labeled fluorescence-based qPCR. RESULTS: Our findings revealed significant associations of TERT rs10069690 and POT1 rs10228682 with NSCLC risk (adjusted p-values = 0.019 and 0.002, respectively), while TERF2 rs251796 and rs2975843 showed no significant associations. The TaqMan genotyping validation further substantiated the associations of TERT rs10069690 and rs2242652 with NSCLC risk (adjusted p-values = 0.02 and 0.003, respectively). Our results also demonstrated significantly shorter telomere lengths in NSCLC patients compared to controls (p = 0.0004). CONCLUSION: This study highlights the crucial interplay between genetic variation in telomere maintenance genes, telomere attrition, and NSCLC risk in the Jammu and Kashmir population of North India. Our findings suggest that TERT and POT1 gene variants, along with telomere length, may serve as potential biomarkers and therapeutic targets for NSCLC in this population. Further research is warranted to elucidate the underlying mechanisms and to explore the potential clinical applications of these findings.

Genetic analysis of colorectal carcinoma using high throughput single nucleotide polymorphism genotyping technique within the population of Jammu and Kashmir.

BACKGROUND: SNP genotyping has become increasingly more common place to understand the genetic basis of complex diseases like cancer. SNP-genotyping through MassARRAY™ is a cost-effective method to quantitatively analyse the variation of gene expression in multiple samples, making it a potential tool to identify the underlying causes of colorectal carcinogenesis. METHODS: In the present study, SNP genotyping was carried out using Agena MassARRAY™, which is a cost-effective, robust, and sensitive method to analyse multiple SNPs simultaneously. We analysed 7 genes in 492 samples (100 cases and 392 controls) associated with CRC within the population of Jammu and Kashmir. These SNPs were selected based on their association with multiple cancers in literature. RESULTS: This is the first study to explore these SNPs with colorectal cancer within the J&K population.7 SNPs with a call rate of 90% were selected for the study. Out of these, five SNPs rs2234593, rs1799966, rs2229080, rs8034191, rs1042522 were found to be significantly associated with the current study under the allelic model with an Odds Ratio OR = 2.981(1.731-5.136 at 95% CI); p value = 4.81E-05 for rs2234593,OR = 1.685(1.073-2.647 at 95% CI);; p value = 0.02292 for rs1799966, OR = 1.5 (1.1-2.3 at 95% CI), p value = 0.02 for rs2229080, OR = 1.699(1.035-2.791 at 95% CI); p value = 0.03521 for rs8034191, OR = 20.07 (11.26-35.75); p value = 1.84E-34 for rs1042522 respectively. CONCLUSION: This is the first study to find the relation of Genetic variants with the colorectal cancer within the studied population using high throughput MassARRAY™ technology. It is further anticipated that the variants should be evaluated in other population groups that may aid in understanding the genetic complexity and bridge the missing heritability.

Evaluation of 17 genetic variants in association with leukemia in the north Indian population using MassARRAY Sequenom.

Leukemia is a heterogeneous disorder, characterized by elevated proliferation of white blood cells. In this study, we explored the association of 17 genetic variants with leukemia patients in the Jammu and Kashmir region of north India. The variants were genotyped by using a high-throughput Agena MassARRAY platform in 758 individuals (166 cases and 592 controls). Of the 17 single-nucleotide polymorphisms (SNPs) studied, five SNPs were showing significant association with the high risk of leukemia in the north Indian population, which includes rs10069690 of telomere reverse transcriptase (TERT) with OR = 0.34 (95% CI, 0.20-0.58; p = .0008), rs2972392 (​​​PSCA) with OR 1.86 (95% CI, 1.04-3.81; p = .035), rs4986764 (BRIP1) with OR 1.34 (95% CI, 1.00-1.80; p = .04), rs6990097 (TNKS) with OR 1.81 (95% CI, 1.2-2.6; p = .001) and rs12190287 (TCF21) with OR 2.87 (95% CI, 1.72-4.7; p = .0001) by allelic association using Plink and analyzed by SPSS. This is the first study to explore these variants with leukemia in the studied population.

MassARRAY-based single nucleotide polymorphism analysis in breast cancer of north Indian population.

BACKGROUND: Breast Cancer (BC) is associated with inherited gene mutations. High throughput genotyping of BC samples has led to the identification and characterization of biomarkers for the diagnosis of BC. The most common genetic variants studied are SNPs (Single Nucleotide Polymorphisms) that determine susceptibility to an array of diseases thus serving as a potential tool for identifying the underlying causes of breast carcinogenesis. METHODS: SNP genotyping employing the Agena MassARRAY offers a robust, sensitive, cost-effective method to assess multiple SNPs and samples simultaneously. In this present study, we analyzed 15 SNPs of 14 genes in 550 samples (150 cases and 400 controls). We identified four SNPs of genes TCF21, SLC19A1, DCC, and ERCC1 showing significant association with BC in the population under study. RESULTS: The SNPs were rs12190287 (TCF21) having OR 1.713 (1.08-2.716 at 95% CI) p-value 0.022 (dominant), rs1051266 (SLC19A1) having OR 3.461 (2.136-5.609 at 95% CI) p-value 0.000000466 (dominant), rs2229080 (DCC) having OR 0.6867 (0.5123-0.9205 at 95% CI) p-value 0.0116 (allelic) and rs2298881 (ERCC1) having OR 0.669 (0.46-0.973 at 95% CI), p-value 0.035 (additive) respectively. The in-silico analysis was further used to fortify the above findings. CONCLUSION: It is further anticipated that the variants should be evaluated in other population groups that may aid in understanding the genetic complexity and bridge the missing heritability.

MassARRAY analysis of twelve cancer related SNPs in esophageal squamous cell carcinoma in J&K, India.

BACKGROUND: MassARRAY (Agena Bioscience™) combines competitive PCR with MALDI-TOF mass spectrometry (MS) analysis that gives highly accurate, sensitive, and high-throughput methods for the quantitative analysis of variation of gene expression in multiple samples. SNPs (Single Nucleotide Polymorphisms) have a very high potential of discovering disease-gene relationships. SNP-genotyping through MassARRAY is not only a cost-effective genotyping method but also provides a platform to validate variants observed through a high-throughput Next-generation sequencing (NGS). METHODS: In the present study, we have incorporated the use of matrix-assisted laser desorption/ionization-time of flight, mass spectrometry (MALDI-TOF) as a tool for differentiating genotypes based on the mass of variant. We have performed multiplex PCR and genotyped 12 SNPs in 758 samples (166 cases and 592 controls). The 12 studied SNPs were chosen with a rationale for their association with multiple cancers in literature. RESULTS: This is the first study to explore these SNPs with esophageal cancer within the J&K population. Out of 12 SNPs, two SNPs rs12190287 of TCF21 and rs10046 of CYP19A1 were significantly associated with esophageal cancer with Odds Ratio (OR) 1.412 (1.09-1.8 at 95% CI, p = 0.008) and 1.54 (1.21-2.072 at 95% CI, p = 0.0007) within the population of Jammu and Kashmir. CONCLUSION: We explored 12 SNPs that were found to be associated with multiple cancers in literature with esophageal cancer within the population of J&K. This is the first study to find the relation of these SNPs with ESCC within the studied population. This study explores the relation of genetic and environmental factors with the ESCC susceptibility.

Probability distributions of extinction times, species richness, and immigration and extinction rates in neutral ecological models.

In community ecology, neutral models make the assumption that species are equivalent, such that species abundances differ only because of demographic stochasticity. Despite their ecological simplicity, neutral models have been found to give reasonable descriptions of expected patterns of biodiversity in communities with many species. Such patterns include the expected total number of species and species-abundance distributions describing the expected number of species in different abundance classes. However, the expected patterns represent only the central tendencies of the full distributions of possible outcomes. Thus, ecological inferences and conclusions based only on expected patterns are incomplete, and may be misleading. Here, we address this issue for the spatially implicit neutral model, by using classic results from birth-death processes to derive (1) the probability distribution of extinction time of a species with given abundance for the metacommunity; (2) the probability distributions of total species richness and number of species with given abundance for both the metacommunity and local community; and (3) the probability distributions of the average immigration and extinction rates in the local community, across different values of total species richness. We illustrate the utility of these probability distributions in providing greater ecological insight via statistical inference. Firstly, we show that under the neutral metacommunity model, there is only 2.65×10-9 probability that the age of a common tree species in the Amazon is  ≤ 3  × 108 yr, which is approximately the oldest estimated age of the first angiosperm. Thus, species ages from the model are unrealistically high. Secondly, for a tree community in a 50 ha plot at Barro Colorado Island in Panama, we show that the spatially implicit model can be fitted to observed species richness and an independent estimate of the immigration parameter, with the fitted model predicting a species-abundance distribution close to the observed distribution. Our results complement those using sampling formulae that specify the multivariate probability distribution of species abundances from neutral models.

High performance asymmetric supercapacitor based on vertical nanowire arrays of a novel Ni@Co-Fe LDH core@shell as negative and Ni(OH)2 as positive electrode.

An efficient synthesis of the electrode material with abundant active sites is imperative for obtaining a flexible supercapacitor with excellent electrochemical performance. Herein, a novel flexible Ni@Co-Fe LDH core-shell nanowires supercapacitor negative electrode is synthesized using polycarbonate membrane on a copper substrate via an electrochemical deposition technique. The synthesized battery-type negative electrode exhibits remarkable specific capacitance of 1289 F g-1 at 1 A g-1 and excellent cycling stability with 76.66% capacitive retention after 5000 cycles. Furthermore, the Ni(OH)2//Ni@Co-Fe LDH nanowires based asymmetric supercapacitor exhibits excellent cycling stability of 90.49% after 1000 cycles with a highest energy density of 68 Wh kg-1 at 0.38 KW kg-1, and a good energy density of 31.8 Wh kg-1 is still attained at a high power density of 6 KW kg-1. For practical demonstration, a white LED of 3.3 V is lit by using two asymmetrical supercapacitor devices connected in series. The device offers a favorable and effective pathway for advanced energy storage.

Differential sensitivity of gastric and small intestinal muscles to inducible knockdown of anoctamin 1 and the effects on gastrointestinal motility.

KEY POINTS: Electrical pacemaking in gastrointestinal muscles is generated by specialized interstitial cells of Cajal that produce the patterns of contractions required for peristalsis and segmentation in the gut. The calcium-activated chloride conductance anoctamin-1 (Ano1) has been shown to be responsible for the generation of pacemaker activity in GI muscles, but this conclusion is established from studies of juvenile animals in which effects of reduced Ano1 on gastric emptying and motor patterns could not be evaluated. Knocking down Ano1 expression using Cre/LoxP technology caused dramatic changes in in gastric motor activity, with disrupted slow waves, abnormal phasic contractions and delayed gastric emptying; modest changes were noted in the small intestine. Comparison of the effects of Ano1 antagonists on muscles from juvenile and adult small intestinal muscles suggests that conductances in addition to Ano1 may develop with age and contribute to pacemaker activity. ABSTRACT: Interstitial cells of Cajal (ICC) generate slow waves and transduce neurotransmitter signals in the gastrointestinal (GI) tract, facilitating normal motility patterns. ICC express a Ca2+ -activated Cl- conductance (CaCC), and constitutive knockout of the channel protein anoctamin-1 leads to loss of slow waves in gastric and intestinal muscles. These knockout experiments were performed on juvenile mice. However, additional experiments demonstrated significant differences in the sensitivity of gastric and intestinal muscles to antagonists of anoctamin-1 channels. Furthermore, the significance of anoctamin-1 and the electrical and mechanical behaviours facilitated by this conductance have not been evaluated on the motor behaviours of adult animals. Cre/loxP technology was used to generate cell-specific knockdowns of anoctamin-1 in ICC (KitCreERT2/+ ;Ano1tm2jrr/+ ) in GI muscles. The recombination efficiency of KitCreERT was evaluated with an eGFP reporter, molecular techniques and immunohistochemistry. Electrical and contractile experiments were used to examine the consequences of anoctamin-1 knockdown on pacemaker activity, mechanical responses, gastric motility patterns, gastric emptying and GI transit. Reduced anoctamin-1 caused loss of gastric, but not intestinal slow waves. Irregular spike complexes developed in gastric muscles, leading to uncoordinated antral contractions, delayed gastric emptying and increased total GI transit time. Slow waves in intestinal muscles of juvenile mice were more sensitive to anoctamin-1 antagonists than slow waves in adult muscles. The low susceptibility to anoctamin-1 knockdown and weak efficacy of anoctamin-1 antagonists in inhibiting slow waves in adult small intestinal muscles suggest that a conductance in addition to anoctamin-1 may develop in small intestinal ICC with ageing and contribute to pacemaker activity.

Association of newly identified genetic variant rs2853677 of TERT with non-small cell lung cancer and leukemia in population of Jammu and Kashmir, India.

BACKGROUND: Telomere genetics has recently been emerged as an important field in molecular oncology. Various genome-wide association studies in different population groups have revealed that polymorphisms in Telomere maintenance gene (TERT) gene located on 5p15.33 is associated with susceptibility to leukemia and lung cancer risk. However, association of TERT with leukemia and lung cancer risk in north Indian population groups is still unknown. This study observed the association between genetic variant rs2853677 of TERT and leukemia and lung cancer in the state of Jammu and Kashmir, India. METHODS: A total of 781 subjects, out of which 381 cases (203 leukemic patients and 178 non-small cell lung cancer patients NSCLC) and 400 healthy controls were recruited for the study. Genetic variant rs2853677of TERT was detected using the real-time and Taqman Chemistry. Hardy-Weinberg Equilibrium was assessed using the chi square test. The allele and genotype- specific risks were estimated as odds ratio with 95% confidence interval. RESULTS: We observed that variant rs2853677 was strongly associated with lung cancer and leukemia risk with an odds ratio (OR) =1.8 (1.03-3.2 at 95% CI); p value (adjusted) = 0.03; odds ratio (OR) =2.9 (1.4-5.5.at 95% CI); p value (adjusted) = 0.002, respectively. CONCLUSION: The results of this study suggested that rs2853677 of TERT signifies association in multiple cancers and suggests that it can become potential marker for diagnosis of non-small cell lung cancer and leukemia. The study will provide an insight in understanding the genetic etiology and highlights the role of telomere-associated pathways in non-small cell lung cancer and leukemia. However, it would be quite interesting to explore the contribution of this variant in other cancers as well.

Investigation of the Potential of Nanoparticles as a New Drug Delivery System for Endodontic Treatment: An In Vitro Study.

Background: Endodontic treatment involves the removal of infected dental pulp and subsequent disinfection of the root canal system. The effectiveness of drug delivery systems in root canal disinfection is critical for successful treatment outcomes. This in vitro study explores the potential of nanoparticles as a novel drug delivery system for endodontic treatment. Materials and Methods: Nanoparticles were synthesized using a biocompatible polymer and loaded with an antimicrobial agent. A total of 60 extracted human teeth were prepared to create standardized root canal infections. The teeth were randomly divided into three experimental groups: (1) conventional irrigation, (2) nanoparticle irrigation, and (3) control (no irrigation). The root canals in each group were irrigated with their respective solutions for 5 minutes. After treatment, microbial samples were collected from the root canals and cultured for colony-forming unit (CFU) analysis. The depth of penetration of nanoparticles into dentinal tubules was assessed using scanning electron microscopy (SEM). Results: The conventional irrigation group showed a reduction in microbial load from an average of 7.8 × 10^5 CFU/mL (SD ± 1.2 × 10^5) to 3.4 × 10^4 CFU/mL (SD ± 7.9 × 10^3) (P < 0.001). In contrast, the nanoparticle irrigation group exhibited a more significant reduction, with a decrease in CFU to 1.2 × 10^3 CFU/mL (SD ± 4.2 × 10^2) (P < 0.001). SEM analysis revealed deep penetration of nanoparticles into dentinal tubules, reaching an average depth of 150 µm. Conclusion: Nanoparticles loaded with antimicrobial agents demonstrated superior efficacy in reducing microbial load within root canals compared to conventional irrigation. Their ability to penetrate dentinal tubules suggests their potential as an innovative drug delivery system for endodontic treatment. Further research and clinical trials are warranted to validate these promising in vitro results and assess the safety and efficacy of nanoparticles in clinical practice.

Upcycling of surgical facemasks into carbon based thin film electrode for supercapacitor technology.

Polypropylene (PP), a commonly used plastic, is used for making the outer layers of a surgical face mask. In 2020, around 3 billion surgical face masks were disposed into the environment, causing a huge threat to wildlife, aquatic life, and ecosystems. In this work, we have reported the sulfonation technique for stabilizing the surgical face masks and their conversion into carbon nanoparticles for application as a supercapacitor electrode. The electrode is fabricated by preparing a slurry paste of carbon nanoparticles and pasting it on a conductive wearable fabric. To investigate the performance of the carbon thin film electrode, electrochemical techniques are employed. The Cyclic Voltammetry (CV) analysis performed at different scan rates in a 6 molar KOH electrolyte reveals that the carbon thin film acts as a positive electrode. At 4 A g-1, the electrode shows a specific capacitance of 366.22 F g-1 and 100% retention of specific capacitance for 8000 cycles. A two-electrode asymmetric device is fabricated using carbon thin film as the positive electrode, NiO thin film as the negative electrode, and a KOH separator between two electrodes. The device shows a specific capacitance of 113.73 F g-1 at 1.3 A g-1 and glows a red LED for 6 min. This work is a step towards upcycling the waste produced from surgical face masks used during the COVID-19 pandemic and its application for energy storage.

Genetic analysis of polymorphism rs10937405 of TP63 gene in breast and ovarian cancer patients of North Indian Cohort.

Introduction: Ovarian and breast cancers are highly prevalent in the population of Jammu and Kashmir (J&K). However, case-control association studies on breast and ovarian cancers are lacking in this population. Moreover, no case-control study is available on variant rs10937405 of TP63 in breast and ovarian cancers. Thus, we designed to replicate the cancer susceptible variant rs10937405 of TP63 in ovarian and breast cancers in the population of J&K because the TP63 gene act as a tumor suppressor gene and was previously associated with various cancers. Materials and Methods: This case-control association study conducted at the Shri Mata Vaishno Devi University, includes 150 breast, 150 ovarian cancer cases, and 210 healthy controls (age and sex-matched). Variant rs10937405 of the TP63 gene was determined by the TaqMan assay. Hardy-Weinberg equilibrium for the variant was assessed using the Chi-square test. The allele and genotype-specific risks were estimated by odds ratios (ORs) with 95% confidence intervals (CI). Results: In this study, variant rs10937405 of TP63 gene did not show any risk with ovarian and breast cancer with (P-value = 0.70) having OR 0.94, (0.69-1.28 at 95% CI) and (P-value = 0.16) having OR 0.80, (0.59-1.10). Discussion: Our results indicate that the variant rs10937405 of the TP63 gene did not impart any risk of breast and ovarian cancer in the population of J&K. Our results indicate that a larger sample size is needed for further statistical validation. As the study was for a particular variant, it warrants the analysis of other variants of this gene.

Cisplatin-based combination therapy for cancer.

Cisplatin, that is, cis-diamminedichloroplatinum is a coordinate compound that is mainly preferred as prior treatment against several solid tumors and malignancies like ovaries, head and neck, testicular, and lung cancers because of its anticancer activity. Cisplatin binds at the N7 position of purine and forms adducts, leading to altered activity of DNA that triggers apoptosis. DNA damage is followed by several signaling pathways like induced oxidative stress, upregulated p53, mitogen-activated protein kinase (MAPK), and Jun N-terminal kinases (JNK) or Akt pathways along with induced apoptosis. Additionally, cisplatin treatment comes with few disadvantages such as toxic effects, that is, hepatotoxicity, cardiotoxicity, neurotoxicity, etc., and drug resistance. Furthermore, to overcome cisplatin resistance and toxicological effects, combination drug therapy has been considered. The aim of the review is to focus on the molecular mechanism of action of cisplatin and combination drug therapy to reduce the side effects in cancer therapy.

Feminizing adrenocortical oncocytoma presenting as precocious puberty: a case report and literature review.

OBJECTIVES: Feminizing adrenal tumors are rare in childhood. We present a case of a special category of adrenal tumor, an oncocytoma, causing isosexual peripheral precocity. CASE PRESENTATION: A 4-year old girl presented with breast development and menstrual bleeding over a period of 3-4 months. Her SMR staging was breast stage 4, pubic hair stage 3. Her bone age was advanced (6 year 10 months), stimulated LH 0.7 IU/L, estradiol 206 pmol/L and DHEAS >27.1 micromol/L. CT scan revealed a right adrenal mass with features of atypical adrenal adenoma. Laparoscopic adrenalectomy was done and histopathology revealed oncocytoma. Lin-Weiss-Bisceglia criteria classified it as likely benign, borne out till a 2 year follow up. CONCLUSIONS: Adrenal oncocytoma can be a cause of isosexual peripheral precocity in a young girl. Recognition and correct classification of this histological variant, which is more often benign, is important for prognostication and choice of therapy after surgery.

Role of Electrochemical Techniques for Photovoltaic and Supercapacitor Applications.

Electrochemistry forms the base of large-scale production of various materials, encompassing numerous applications in metallurgical engineering, chemical engineering, electrical engineering, and material science. This field is important for energy harvesting applications, especially supercapacitors (SCs) and photovoltaic (PV) devices. This review examines various electrochemical techniques employed to fabricate and characterize PV devices and SCs. Fabricating these energy harvesting devices is carried out by electrochemical methods, including electroreduction, electrocoagulation, sol-gel process, hydrothermal growth, spray pyrolysis, template-assisted growth, and electrodeposition. The characterization techniques used are cyclic voltammetry, electrochemical impedance spectroscopy, photoelectrochemical characterization, galvanostatic charge-discharge, and I-V curve. A study on different recently reported materials is also presented to analyze their performance in various energy harvesting applications regarding their efficiency, fill factor, power density, and energy density. In addition, a comparative study of electrochemical fabrication techniques with others (including physical vapor deposition, mechanical milling, laser ablation, and centrifugal spinning) has been conducted. The various challenges of electrochemistry in PVs and SCs are also highlighted. This review also emphasizes the future perspectives of electrochemistry in energy harvesting applications.

Astrocytes regulate vascular endothelial responses to simulated deep space radiation in a human organ-on-a-chip model.

Central nervous system (CNS) damage by galactic cosmic ray radiation is a major health risk for human deep space exploration. Simulated galactic cosmic rays or their components, especially high Z-high energy particles such as 56Fe ions, cause neurodegeneration and neuroinflammation in rodent models. CNS damage can be partially mediated by the blood-brain barrier, which regulates systemic interactions between CNS and the rest of the body. Astrocytes are major cellular regulators of blood-brain barrier permeability that also modulate neuroinflammation and neuronal health. However, astrocyte roles in regulating CNS and blood-brain barrier responses to space radiation remain little understood, especially in human tissue analogs. In this work, we used a novel high-throughput human organ-on-a-chip system to evaluate blood-brain barrier impairments and astrocyte functions 1-7 days after exposure to 600 MeV/n 56Fe particles and simplified simulated galactic cosmic rays. We show that simulated deep space radiation causes vascular permeability, oxidative stress, inflammation and delayed astrocyte activation in a pattern resembling CNS responses to brain injury. Furthermore, our results indicate that astrocytes have a dual role in regulating radiation responses: they exacerbate blood-brain barrier permeability acutely after irradiation, followed by switching to a more protective phenotype by reducing oxidative stress and pro-inflammatory cytokine and chemokine secretion during the subacute stage.

REV3L single nucleotide variants lead to increased susceptibility towards non-small cell lung cancer in the population of Jammu and Kashmir.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the most common lung cancer, accounting for 80-85% of all lung cancer cases. Various genetic studies have associated REV3L (Protein reversion less 3-like) gene mutations, which encodes the catalytic subunit of error prone translesion synthesis polymerase zeta with cancer, including lung cancer; however, no such data is available from any North Indian population. In this study we attempted to screen the North Indian population of Jammu and Kashmir (J&K) for the potential role of REV3L gene polymorphisms in NSCLC. METHODS: A total of four REV3L single nucleotide variants were selected for genotyping based on the available literature. The genotyping was carried out by using the TaqMan allele discrimination assay in 500 subjects (200 NSCLC patients and 300 age and sex matched healthy controls). The association of variants with NSCLC was evaluated by logistic regression. RESULTS: Out of the four REV3L variants genotyped; rs1002481, rs462779, and rs465646 were found significantly associated with NSCLC risk under the recessive model, with an Odds Ratio (OR) of 3.52(2.14-5.8 at 95% CI, p-value = 0.00000062), 3.7 (1.8-7.6 at 95% CI, p-value = 0.00031), and 2.2 (1.47-3.37 at 95% CI, p-value = 0.0003), respectively. DISCUSSION: Our data supports a strong association between variants rs1002481, rs462779, rs465646 and NSCLC, indicating a potential role of these REV3L variants in increasing the risk for the development of NSCLC in the studied population. Although a first report from any Indian population, these variants have been previously reported to be associated with lung and colorectal cancers in different world populations. Our data along with the existing data supports the notation that these variants can be used as potential genetic predisposition markers. AVAILABILITY OF DATA AND MATERIALS: Data generated and analysed during study is not available publicly but can be made available from the corresponding author upon reasonable request.

Polymorphism in the TP63 gene imparts a potential risk for leukemia in the North Indian population.

BACKGROUND: The role of single nucleotide polymorphism rs10937405 (C>T) of the TP63 gene in cancer including leukemia has previously been studied in different world populations; however, the role of this variant in leukemia in the North Indian population of Jammu and Kashmir is still unknown. OBJECTIVES: In the present study, we investigated the association of genetic variant rs10937405 with leukemic in the Jammu and Kashmir population. METHODS: A total of 588 subjects, (188 cases and 400 controls) were recruited for the study. The rs10937405 variant was genotyped by using the real-time based TaqMan assay. RESULTS: A statistically significant association was observed between the rs10937405 and leukemia [OR of 1.94 (95% CI 1.51-2.48), p=1.2x10-6]. CONCLUSION: The current study concludes that the rs10937405 variant is a risk factor for the development of leukemia in the population of Jammu and Kashmir, North India. However, it would be interesting to explore the contribution of this variant in other cancers as well. Our findings will help in the development of diagnostic markers for leukemia in the studied population and potentially for other North Indian populations.

Genetic evaluation of the variants using MassARRAY in non-small cell lung cancer among North Indians.

Lung cancer is genetically diverse and a major health burden. Non-small cell lung cancer (NSCLC) accounts for 80% of total lung cancer cases and 20% cases are Small cell lung cancer (SCLC). The present case-control association study focused on the cost effective high throughput genotyping using Agena MassARRAY matrix-assisted laser desorption/ionization-time of flight, mass spectrometry (MALDI-TOF) platform to analyze the genetic association of candidate genetic variants. We performed multiplex PCR and genotyped twelve single nucleotide polymorphisms (SNPs) in 723 samples (162 NSCLC cases and 592 healthy controls). These genetic variants were selected from literature for their association with various cancers worldwide and this is the first study from the region to examine these critically important genetic variants. With prospective case-control association study design, twelve variants from ten genes were evaluated. Amongst these six variants, TCF21 (rs12190287), ERCC1 (rs2298881, 11615), ERCC5 (rs751402), ARNTL (rs4757151), BRIP1 (rs4986764) showed significant association with NSCLC risk (p ≤ 0.003) in Jammu and Kashmir population. In-silico findings of these genetic variants showed remarkable functional roles that needs in-vitro validations. It is further anticipated that such case control studies will help us in understanding the missing heritability of non-small cell lung cancer.