👤 Simmi Saini

Innate lymphoid cells (ILCs) are rare, tissue-resident innate lymphocytes that functionally mirror CD4+ T helper cell lineages but lack antigen receptors. Type 3 ILCs (ILC3s) are enriched in the gut, airways, and mucosal lymphoid tissues, where they regulate inflammation and promote barrier integrity. To define the regulatory architecture of primary human ILC3s, we map promoter-anchored chromosomal contacts using high-resolution, low-input Promoter Capture Hi-C (PCHi-C) in these cells alongside CD4+ T cells. By combining statistical detection with a PCHi-C-adapted Activity-by-Contact approach, we link promoters to distal regulatory elements, identifying hundreds of ILC3-specific contacts. We use these maps to connect genome-wide association study (GWAS) risk variants for Crohn's disease to target genes using multiCOGS, a Bayesian framework that integrates PCHi-C with summary-statistic imputation and multivariate fine-mapping. This analysis highlights both known and unanticipated candidates, including Show less

Tuberculous pyomyositis is a rare and often under-recognized extrapulmonary manifestation of tuberculosis, presenting with non-specific symptoms such as fever and abscess, that may delay diagnosis. We report a unique case of disseminated tuberculous pyomyositis in a 56-year-old male with underlying chronic inflammatory arthritis. The diagnosis was confirmed using CBNAAT, line probe assay (LPA), and histopathology. Currently MRI is the standard imaging modality in use for imaging pyomyositis. Show less

Circulating tumor cells (CTCs) drive metastasis, the leading cause of death in individuals with breast cancer. Due to their low abundance in the circulation, robust CTC expansion protocols are urgently needed to effectively study disease progression and therapy responses. Here we present the establishment of long-term CTC-derived organoids from female individuals with metastatic breast cancer. Multiomics analysis of CTC-derived organoids along with preclinical modeling with xenografts identified neuregulin 1 (NRG1)-ERBB2 receptor tyrosine kinase 3 (ERBB3/HER3) signaling as a key pathway required for CTC survival, growth and dissemination. Genome-wide CRISPR activation screens revealed that fibroblast growth factor receptor 1 (FGFR1) signaling serves a compensatory function to the NRG1-HER3 axis and rescues NRG1 deficiency in CTCs. Conversely, NRG1-HER3 activation induced resistance to FGFR1 inhibition, whereas combinatorial blockade impaired CTC growth. The dynamic interplay between NRG1-HER3 and FGFR1 signaling reveals the molecular basis of cancer cell plasticity and clinically relevant strategies to target it. Our CTC organoid platform enables the identification and validation of patient-specific vulnerabilities and represents an innovative tool for precision medicine. Show less

Recent data have suggested that germline genetic aberrations can affect outcomes in patients with large B-cell lymphoma (LBCL) treated with chimeric antigen receptor T-cell therapy (CART). However, a comprehensive analysis of germline determinants of response and toxicity after CART has not yet been described. Genome-wide genotyping was performed in 170 patients with LBCL treated with standard of care axicabtagene ciloleucel. Polygenic risk score instruments for blood cell traits and inflammatory markers were obtained from the PGS Catalog and analyzed using PRSice-2. Exploratory gene-based and genome-wide association study analyses were performed. Genetic ancestry of the patients with LBCL was estimated using ADMIXTURE. Analysis was conducted to identify genetic risk of toxicity and efficacy endpoints. Increasing PRS for monocyte count was associated with increased risk of cytokine release syndrome of any grade (OR 2.49, 95% CI 1.18 to 5.25, p=0.016). Similarly, genetically predicted interleukin (IL)-1Rα and (IL)-27 levels were decreased (p=0.002) and increased (p=0.012) in patients with G3-4 day 30 cytopenia, respectively. The latter was also associated with variation in the hemophagocytic lymphohistiocytosis-related gene Germline genetic aberrations relevant to myeloid cell biology can predict toxicity and efficacy of CART in patients with LBCL. Elucidating such intrinsic determinants may help improve patient selection and develop strategies to enhance the therapeutic index of CART. Show less

Malignant gliomas (MGs) are the most common primary brain malignancies and are considered universally fatal. Oncolytic herpes simplex viruses (oHSVs) are promising immunotherapeutics capable of selectively lysing cancer cells, eliciting antitumor immunity, and providing local delivery of immune-activating transgenes. Interleukin 27 (IL-27) is a pleiotropic cytokine capable of enhancing tumor-reactive cytotoxic T lymphocyte (CTL) function while also possessing neuroprotective properties. We hypothesized that IL-27 expression by oHSV would enhance CTL function and improve antiglioma therapeutic activity. We developed an oHSV that expresses IL-27 (C027). The antiglioma efficacy of C027 was tested in three syngeneic orthotopic glioma models derived from both chemical (CT-2A) and genetic (SB28, KR158) glioma lines. Spectral flow cytometry was used to assess immunophenotypic and functional changes in the tumor infiltrates and systemically. To further investigate the C027-related CTL activity, we employed in vivo cell-specific depletion and IL-27 blockade alongside in vitro T cell stimulation assays. Local and systemic antitumor memory was evaluated by both orthotopic and flank tumor rechallenge of C027-treated long-term survivors. C027 significantly prolonged survival in syngeneic orthotopic glioma models derived from both chemical (CT-2A) and genetic (KR158, SB28) glioma lines. In the CT-2A model, IL-27-expressing oHSV treatment was associated with increased intratumoral multifunctional effector CTLs and functional T cell populations systemically. Mechanistically, both CD8 T cells and IL-27 were required for the C027 survival benefit in vivo and IL-27 enhanced CTL function in vitro. C027-treated mice that survived their initial tumors had local and systemic antiglioma memory rejecting tumors on rechallenge. Our findings demonstrate that IL-27 expression by oHSV significantly improves antiglioma therapeutic efficacy, enhances CTL effector function, and induces durable immune memory. Thus, IL-27-oHSV may provide a promising therapeutic approach for MGs. Show less

Malignant gliomas (MG) are the most common primary brain malignancies and are considered universally fatal. Oncolytic HSVs (oHSV) are promising immunotherapeutics capable of selectively lysing cancer cells, eliciting anti-tumor immunity, and providing local delivery of immune-activating transgenes. IL-27 is a pleiotropic cytokine capable of enhancing tumor-reactive cytotoxic T cell (CTL) function while also possessing neuroprotective properties. We hypothesized that IL-27 expression by oHSV would enhance CTL function and improve anti-glioma therapeutic activity. We developed an oncolytic herpes simplex virus (oHSV) that expresses IL-27 (C027). The anti-glioma efficacy of C027 was tested in three syngeneic orthotopic glioma models derived from both chemical (CT-2A) and genetic (SB28, KR158) glioma lines. Spectral flow cytometry was used to assess immunophenotypic and functional changes in the tumor infiltrates and systemically. To further investigate the C027-related CTL activity, we employed C027 significantly prolonged survival in syngeneic orthotopic glioma models derived from both chemical (CT-2A) and genetic (KR158, SB28) glioma lines. In the CT-2A model, IL-27-expressing oHSV treatment was associated with increased intratumoral multifunctional effector cytotoxic T lymphocytes (CTL) and functional T cell populations systemically. Mechanistically, both CD8 T cells and IL-27 were required for the C027 survival benefit Our findings demonstrate that IL-27 expression by oHSV significantly improves anti-glioma therapeutic efficacy, enhances CTL effector function, and induces durable immune memory. Thus, IL-27-oHSV may provide a promising therapeutic approach for malignant gliomas. Show less

Many traditional treatments include honey owing to its magnificent health beneficiary effects. Recent studies have demonstrated the potent anti-diabetic activity of honey. However, its actual mechanism of action remains elusive. Moreover, being rich in sugar (75%-80%), its role in maintaining glucose homeostasis remains questionable. Although the polyphenol content of honey aids its hypoglycaemic activity, the small quantity of bioactive compounds in honey (0.5%-1.0%) may not be solely responsible for this. In the current study, an attempt was made to understand the role of Indian lychee honey (LyH) in regulating blood glucose levels under diabetic conditions. This study investigated whether LyH, although rich in sugars, can be used as an alternative to regulate glucose and lipid homeostasis under insulin-resistant conditions by regulating the ChREBP/Glut4 signalling pathway. This study was first performed Show less

Patients with nonfunctioning adenomas (NFAs), adenomas with mild autonomous cortisol secretion (MACS) and Cushing syndrome (CS) demonstrate an increased cardiovascular risk. This work aimed to determine the extent of lipoprotein abnormalities in NFA, MACS, and CS. We conducted a single-center, cross-sectional study of patients with NFA (n = 167), MACS (n = 213), CS (n = 142), and referent individuals (n = 202) between January 2015 and July 2022. Triglyceride-rich lipoprotein particles (TRLP), low-density lipoprotein particles (LDLP), high-density lipoprotein particles (HDLP), their subclasses and sizes were measured using nuclear magnetic resonance spectroscopy. Multivariable logistic analyses were adjusted for age, sex, body mass index, smoking, hypertension, diabetes and lipid-lowering drug therapy. In age- and sex-adjusted analysis, all patients categories demonstrated increased very large TRLP, large TRLP, and greater TRLP size (odds ratio [OR], 1.22-2.08) and total LDLP (OR, 1.22-1.75) and decreased LDL and HDL size compared to referent individuals. In fully adjusted analysis, LDLP concentrations remained elevated in all patient categories (OR, 1.31-1.84). Total cholesterol, LDL cholesterol, triglycerides, and apolipoprotein B (ApoB) were also higher in all patient categories in age- and sex-adjusted analysis, with ApoB remaining elevated in all patient categories in fully adjusted analysis. Similar LDLP and ApoB elevations were observed in all patient categories after excluding individuals on lipid-lowering therapy. Patients with overt, mild, and even absent cortisol excess demonstrate lipoprotein profile abnormalities, in particular, high LDLP and ApoB concentrations, which conceivably contribute to high cardiometabolic risk. Show less

Alzheimer's disease (AD) is the leading cause of dementia worldwide with therapeutic lacunae till date. The beta-amyloid (Aβ) accumulation triggers AD pathogenesis, though clinical trials lowering Aβ have not altered disease outcomes suggesting other interacting factors to be identified for drug design of AD. Therefore, it is of interest to identify potential hub proteins interlinked with disease-driving pathways using a network-based approach for AD therapeutic designing. Literature mining was done to identify proteins implicated in AD etiology. Protein-protein interactions (PPIs) were retrieved from the STRING database and merged into a single network using Cytoscape 3.10.1. The hub proteins involved in AD etiology were predicted based on the topological algorithms of CytoHubba. Six major proteins, with STRING database identifiers - APP, BACE1, PSEN1, MAPT, APOE4 and TREM2, were identified to be involved in AD pathogenesis. The merged network of PPIs of these proteins contained 51 nodes and 211 edges, as predicted by Analyzer module of Cytoscape. The Amyloid precursor protein (APP) emerged as the highest-scoring hub protein across multiple centrality measures and topological algorithms. Thus, current data provides evidence to support the ongoing investigation of APP's multifaceted functions and therapeutic potential for AD. Show less

Alzheimer's disease (AD), a debilitating neurodegenerative condition, is characterized by progressive cognitive decline brought about by the deposition of amyloid beta (Aβ) plaques in the brain initiates downstream neuronal dysfunction and death in AD pathogenesis. The β-secretase (BACE-1) enzyme plays a crucial role in generating Aβ from amyloid precursor protein (APP). Hence, we report the virtual screening of marine phytochemicals as BACE-1 inhibitors. 2583 compounds, retrieved from Comprehensive Marine Natural Product Database (CMNPD), were primarily screened for drug-likeliness and blood-brain barrier permeability using admetSAR 2.0 and Show less

Mycobacterium tuberculosis (MTB) is the causative organism of tuberculosis. Cholesterol is a crucial carbon source required for the survival of MTB in host cells. Transcription factor NR1H3 along with its important target genes ABCA1 and ApoE play important role in removal of extra cholesterol from cells. Changes in the gene expression of NR1H3, ABCA1 and ApoE can affect cholesterol homeostasis and thus the survival of MTB in host cells.Therefore, the present study was designed to analyze the mRNA expression of NR1H3, ABCA1 and ApoE in pulmonary TB (PTB) patients from the population of Punjab, India. In this study, mRNA expression of the transcription factor NR1H3 and its target genes ABCA1 and ApoE was analyzed in 89 subjects, including 41 PTB patients and 48 healthy controls (HCs) by real-time quantitative PCR. It was found that the mRNA expression of both NR1H3 and ABCA1 genes was significantly lower in TB patients than in HCs (p < 0.001). Even after sex-wise stratification of the subjects, mRNA expression of NR1H3 and ABCA1 was found to be down-regulated in both male and female TB patients. No significant difference was observed in expression of ApoE (p = 0.98). The present study found that the mRNA expression of NR1H3 and ABCA1 is down-regulated in TB patients from Punjab state of India. Show less

To study rare ocular findings in a rare case of hereditary multiple exostoses (HME) and to study HME in one family. HME is an autosomal dominant genetic disease characterized by the presence of multiple exostoses (osteochondromas). It is caused by mutations in two genes: exostosin-1 (EXT1) and exostosin-2 (EXT2). We report HME in a family over three generations. The index case was a 14-year-old female who presented with an ocular mass and multiple hard nodules in the upper and lower limbs. Family history revealed similar multiple nodules in the younger brother, father, and grandfather. Hence, the paternal family history for HME is positive. All the family members were examined. Family members who were diagnosed with HME had a series of radiology tests completed. Furthermore, the family members with HME were also seen by an orthopedic surgeon. Family history and physical examination revealed multiple exostoses in the younger brother, father, and grandfather. They were all diagnosed with HME. The index case also had an ocular surface mass with scleral ectasia in the right eye. HME is a rare, genetic disorder. Cases of HME with ocular findings are rare. This patient has a paternal family history of HME and presents with an ocular surface mass. Show less

The association of melanocortin receptor 4 (MC4R) gene with adiposity measures is widely studied in European populations. Only six studies have investigated the role of MC4R gene with adiposity measures among Indian populations. We have evaluated the role of MC4R (rs17782313) gene polymorphism in influencing adiposity measures in India among children and adults. The present population based cross sectional study was conducted among 303 individuals (208 children and 95 adults) of age group 10-30 years, belonging to Rajasthan. Somatometric measurements (standing height, weight, and waist and hip girths) and blood samples were taken after obtaining written informed consent. Genotyping of MC4R rs17782313 single nucleotide polymorphism was done using restriction fragment length polymorphism method for polymerase chain reaction amplified fragments. We examined association between rs17782313 and different adiposity measures (height, weight, BMI, WHR, and waist and hip girths) using linear regression models. The MC4R variant (rs17782313) predicted increased body weight (0.15 kg, S.E ± 0.076, P = 0.043) among children. In combined population, the rs17782313 variant was moderately associated with body weight (0.13 kg, S.E ± 0.070, P = 0.057). This variant was not found to be associated with any other adiposity measure. Further studies are needed to evaluate the association of MC4R variants through sequencing and functional genomics with different adiposity measures in Indian populations for understanding the genetic underpinnings of adiposity in India. Show less

Restless legs syndrome (RLS) is a neurological disorder with a strong genetic susceptibility. A painful RLS sub-phenotype has been described previously but the neurobiological basis for this phenotypic variant remains unknown. This study investigated whether any of the six initially discovered genomic loci associating with RLS (BTBD9, MEIS1, PTPRD, MAP2K5/SKOR1, TOX3, and an intergenic region on chromosome 2), were more strongly associated with complaints of painful versus non-painful RLS. RLS patients (N = 199; Age = 53.1 ± 16.8; 100% Caucasians; 57% women) diagnosed clinically were genotyped for known variants associating with RLS. Definition of painful RLS required that subjects selected "painful" from a list of 14 adjectives to describe their RLS sensory experience and answered positively to a separate question that queried specifically as to whether they perceived their RLS sensations as painful. Genotype association tests employed logistic regression analyses with assumption of an additive genetic model. Analyses were performed using PLINK software v1.07. We identified two RLS patient subgroups: a painful (n = 41) and non-painful (n = 158). Among 10 tested SNPs, only rs3104767 (related to the TOX3 gene locus) was more associated with painful RLS. The minor allele T of SNP rs3104767 was associated with an increased risk of RLS being perceived as painful with an OR of 1.67 [CI = (1.01-2.74); p = 0.049]. Notably, this minor T allele associated with pain sensation in RLS patients in this study was the non-risk allele for RLS in the original RLS genome wide association study, but a similar trend was observed in a recent Parkinson disease sample study. This study might suggest the TOX3 gene variant as a potential genetic substrate for the painful RLS sub-phenotype. This was an exploratory small study and correction for multiple comparisons would have rendered the results not significant. Therefore, the above findings require replication in larger clinical as well as population-based samples of RLS subjects. Show less

This investigation was undertaken to assess the population of indigenous (Bareilly local) pigs for meat quality genes (RYR1, PRKAG3, HFABP, MYF-5, and MC4R). The results showed that indigenous pigs were monomorphic at RYR1locus (100% NN genotype), HFABP locus (100% HH genotype), and MYF-5 locus (100% DD genotype). Homozygote RR and heterozygote QR genotypes were observed at PRKAG3 (c.599 G>A) SNP locus with 89 and 11% frequency. The frequency of wild (R) and mutant (Q) allele at the said locus was 95 and 5%. The MC4R SNP had three genotypes; homozygote AA with 5% frequency, heterozygote AG with 53% frequency, and homozygote GG with 42% frequency. Corresponding frequency of A and G allele was 32 and 68%, respectively. Monomorphic status at RYR1locus for NN genotype, HFABP locus for HH genotype, and MYF-5 locus for DD genotype indicated that favorable genes for quality pork production have been fixed in the population. The higher frequency of RR genotype (89%) at PRKAG3 and GG genotype (42%) at MC4R locus further explained the existence of favorable genotypes in indigenous pigs. Show less

This study was designed to screen the crossbred pigs for SNPs in five candidate genes, associated with pork quality traits and to differentiate their genotypes by PCR-RFLP. The results indicated that genotypes of crossbred pigs were NN (90%) and Nn (10%) for RYR1; RR (83%) and QR (17%) for PRKAG3; HH (98%), Hh (1%) and hh (1%) for HFABP; DD (99%) and CD (1%) for MYF-5; and AG (57%), GG (26%) and AA (17%) for MC4R SNPs, respectively. Allelic frequencies for five SNPs {RYR1 (1843C>T), PRKAG3 (c.599G>A), HFABP (c.1322C>T), MYF-5 (c.1205A>C) and MC4R (c.1426A>G)} were 0.95 and 0.05 (N/n), 0.08 and 0.92 (Q/R), 0.99 and 0.01 (H/h), 0.00 and 1.00 (C/D) and 0.45 and 0.55 (A/G), respectively. The effect of RYR1 (1843C>T) SNP was significant on pH Show less

Obesity is one of the largest global health problems associated with increased morbidity and mortality mediated by its association with several other metabolic disorders. The interaction between the genes and environment plays an important role in the manifestation of obesity. Despite a high heritability (40-70%) of obesity, the search for genetic variants associated with obesity susceptibility has been a challenging task. To date, limited studies have been conducted in India, restricted to the validation of few genetic variants identified by genomewide association studies. In this critical review, we sought to examine the current knowledge of genetic basis of obesity and its measures in the Indian population. A comprehensive literature search was performed using 'PubMed', 'Medline' and 'IndMed' databases to search for citations published until 31st May 2017, using the key terms as 'Genetics' AND 'obesity' AND 'India'. We identified 48 potential studies which fulfilled the eligibility criteria. The findings indicated that Show less