Inducible gene expression of IκB-kinase ε is dependent on nuclear factor-κB in human pulmonary epithelial cells.

While IκB-kinase-ε (IKKε) induces immunomodulatory genes following viral stimuli, its up-regulation by inflammatory cytokines remains under-explored. Since airway epithelial cells respond to airborne insults and potentiate inflammation, IKKε expression was characterized in pulmonary epithelial cell lines (A549, BEAS-2B) and primary human bronchial epithelial cells grown as submersion or differentiated air-liquid interface cultures. IKKε expression was up-regulated by the pro-inflammatory cytokines, interleukin-1ß (IL-1ß) and tumour necrosis factor-α (TNFα). Thus, mechanistic interrogations in A549 cells were used to demonstrate the NF-κB dependence of cytokine-induced IKKε. Furthermore, chromatin immunoprecipitation in A549 and BEAS-2B cells revealed robust recruitment of the NF-κB subunit, p65, to one 5' and two intronic regions within the IKKε locus (IKBKE). In addition, IL-1ß and TNFα induced strong RNA polymerase 2 recruitment to the 5' region, the first intron, and the transcription start site. Stable transfection of the p65-binding regions into A549 cells revealed IL-1ß- and TNFα-inducible reporter activity that required NF-κB, but was not repressed by glucocorticoid. While critical NF-κB motifs were identified in the 5' and downstream intronic regions, the first intronic region did not contain functional NF-κB motifs. Thus, IL-1ß- and TNFα-induced IKKε expression involves three NF-κB-binding regions, containing multiple functional NF-κB motifs, and potentially other mechanisms of p65 binding through non-classical NF-κB binding motifs. By enhancing IKKε expression, IL-1ß may prime, or potentiate, responses to alternative stimuli, as modelled by IKKε phosphorylation induced by phorbol 12-myristate 13-acetate. However, since IKKε expression was only partially repressed by glucocorticoid, IKKε-dependent responses could contribute to glucocorticoid-resistant disease.

Synergy between Interleukin-1ß, Interferon-γ, and Glucocorticoids to Induce TLR2 Expression Involves NF-κB, STAT1, and the Glucocorticoid Receptor.

Glucocorticoids act via the glucocorticoid receptor (GR; NR3C1) to downregulate inflammatory gene expression and are effective treatments for mild to moderate asthma. However, in severe asthma and virus-induced exacerbations, glucocorticoid therapies are less efficacious, possibly due to reduced repressive ability and/or the increased expression of proinflammatory genes. In human A549 epithelial and primary human bronchial epithelial cells, toll-like receptor (TLR)-2 mRNA and protein were supra-additively induced by interleukin-1ß (IL-1ß) plus dexamethasone (IL-1ß+Dex), interferon-γ (IFN-γ) plus dexamethasone (IFN-γ+Dex), and IL-1ß plus IFN-γ plus dexamethasone (IL-1ß+IFN-γ+Dex). Indeed, ∼34- to 2100-fold increases were apparent at 24 hours for IL-1ß+IFN-γ+Dex, and this was greater than for any single or dual treatment. Using the A549 cell model, TLR2 induction by IL-1ß+IFN-γ+Dex was antagonized by Org34517, a competitive GR antagonist. Further, when combined with IL-1ß, IFN-γ, or IL-1ß+IFN-γ, the enhancements by dexamethasone on TLR2 expression required GR. Likewise, inhibitor of κB kinase 2 inhibitors reduced IL-1ß+IFN-γ+Dex-induced TLR2 expression, and TLR2 expression induced by IL-1ß+Dex, with or without IFN-γ, required the nuclear factor (NF)-κB subunit, p65. Similarly, signal transducer and activator of transcription (STAT)-1 phosphorylation and γ-interferon-activated sequence-dependent transcription were induced by IFN-γ These, along with IL-1ß+IFN-γ+Dex-induced TLR2 expression, were inhibited by Janus kinase (JAK) inhibitors. As IL-1ß+IFN-γ+Dex-induced TLR2 expression also required STAT1, this study reveals cooperation between JAK-STAT1, NF-κB, and GR to upregulate TLR2 expression. Since TLR2 agonism elicits inflammatory responses, we propose that synergies involving TLR2 may occur within the cytokine milieu present in the immunopathology of glucocorticoid-resistant disease, and this could promote glucocorticoid resistance. SIGNIFICANCE STATEMENT: This study highlights that in human pulmonary epithelial cells, glucocorticoids, when combined with the inflammatory cytokines interleukin-1ß (IL-1ß) and interferon-γ (IFN-γ), can synergistically induce the expression of inflammatory genes, such as TLR2. This effect involved positive combinatorial interactions between NF-κB/p65, glucocorticoid receptor, and JAK-STAT1 signaling to synergistically upregulate TLR2 expression. Thus, synergies involving glucocorticoid enhancement of TLR2 expression may occur in the immunopathology of glucocorticoid-resistant inflammatory diseases, including severe asthma.

Interplay between nuclear factor-κB, p38 MAPK, and glucocorticoid receptor signaling synergistically induces functional TLR2 in lung epithelial cells.

While glucocorticoids act via the glucocorticoid receptor (GR; NR3C1) to reduce the expression of many inflammatory genes, repression is not an invariable outcome. Here, we explore synergy occurring between synthetic glucocorticoids (dexamethasone and budesonide) and proinflammatory cytokines (IL1B and TNF) on the expression of the toll-like receptor 2 (TLR2). This effect is observed in epithelial cell lines and both undifferentiated and differentiated primary human bronchial epithelial cells (pHBECs). In A549 cells, IL1B-plus-glucocorticoid-induced TLR2 expression required nuclear factor (NF)-κB and GR. Likewise, in A549 cells, BEAS-2B cells, and pHBECs, chromatin immunoprecipitation identified GR- and NF-κB/p65-binding regions ∼32 kb (R1) and ∼7.3 kb (R2) upstream of the TLR2 gene. Treatment of BEAS-2B cells with TNF or/and dexamethasone followed by global run-on sequencing confirmed transcriptional activity at these regions. Furthermore, cloning R1 or R2 into luciferase reporters revealed transcriptional activation by budesonide or IL1B, respectively, while R1+R2 juxtaposition enabled synergistic activation by IL1B and budesonide. In addition, small-molecule inhibitors and siRNA knockdown showed p38α MAPK to negatively regulate both IL1B-induced TLR2 expression and R1+R2 reporter activity. Finally, agonism of IL1B-plus-dexamethasone-induced TLR2 in A549 cells and pHBECs stimulated NF-κB- and interferon regulatory factor-dependent reporter activity and chemokine release. We conclude that glucocorticoid-plus-cytokine-driven synergy at TLR2 involves GR and NF-κB acting via specific enhancer regions, which combined with the inhibition of p38α MAPK promotes TLR2 expression. Subsequent inflammatory effects that occur following TLR2 agonism may be pertinent in severe neutrophilic asthma or chronic obstructive pulmonary disease, where glucocorticoid-based therapies are less efficacious.

Genomic determinants implicated in the glucocorticoid-mediated induction of KLF9 in pulmonary epithelial cells.

Ligand-activated glucocorticoid receptor (GR) elicits variable glucocorticoid-modulated transcriptomes in different cell types. However, some genes, including Krüppel-like factor 9 (KLF9), a putative transcriptional repressor, demonstrate conserved responses. We show that glucocorticoids induce KLF9 expression in the human airways in vivo and in differentiated human bronchial epithelial (HBE) cells grown at air-liquid interface (ALI). In A549 and BEAS-2B pulmonary epithelial cells, glucocorticoids induce KLF9 expression with similar kinetics to primary HBE cells in submersion culture. A549 and BEAS-2B ChIP-seq data reveal four common glucocorticoid-induced GR binding sites (GBSs). Two GBSs mapped to the 5'-proximal region relative to KLF9 transcription start site (TSS) and two occurred at distal sites. These were all confirmed in primary HBE cells. Global run-on (GRO) sequencing indicated robust enhancer RNA (eRNA) production from three of these GBSs in BEAS-2B cells. This was confirmed in A549 cells, plus submersion, and ALI culture of HBE cells. Cloning each GBS into luciferase reporters revealed glucocorticoid-induced activity requiring a glucocorticoid response element (GRE) within each distal GBS. While the proximal GBSs drove modest reporter induction by glucocorticoids, this region exhibited basal eRNA production, RNA polymerase II enrichment, and looping to the TSS, plausibly underlying constitutive KLF9 expression. Post glucocorticoid treatment, interactions between distal and proximal GBSs and the TSS correlated with KLF9 induction. CBP/P300 silencing reduced proximal GBS activity, but negligibly affected KLF9 expression. Overall, a model for glucocorticoid-mediated regulation of KLF9 involving multiple GBSs is depicted. This work unequivocally demonstrates that mechanistic insights gained from cell lines can translate to physiologically relevant systems.

Crystallographic Structures of IlvN·Val/Ile Complexes: Conformational Selectivity for Feedback Inhibition of Aceto Hydroxy Acid Synthases.

Conformational factors that predicate selectivity for valine or isoleucine binding to IlvN leading to the regulation of aceto hydroxy acid synthase I (AHAS I) of Escherichia coli have been determined for the first time from high-resolution (1.9-2.43 Å) crystal structures of IlvN·Val and IlvN·Ile complexes. The valine and isoleucine ligand binding pockets are located at the dimer interface. In the IlvN·Ile complex, among residues in the binding pocket, the side chain of Cys43 is 2-fold disordered (χ1 angles of gauche- and trans). Only one conformation can be observed for the identical residue in the IlvN·Val complexes. In a reversal, the side chain of His53, located at the surface of the protein, exhibits two conformations in the IlvN·Val complex. The concerted conformational switch in the side chains of Cys43 and His53 may play an important role in the regulation of the AHAS I holoenzyme activity. A significant result is the establishment of the subunit composition in the AHAS I holoenzyme by analytical ultracentrifugation. Solution nuclear magnetic resonance and analytical ultracentrifugation experiments have also provided important insights into the hydrodynamic properties of IlvN in the ligand-free and -bound states. The structural and biophysical data unequivocally establish the molecular basis for differential binding of the ligands to IlvN and a rationale for the resistance of IlvM to feedback inhibition by the branched-chain amino acids.

Effect of p53 codon 72 polymorphism on the survival outcome in advanced stage cervical cancer patients in India.

BACKGROUND & OBJECTIVES: The Arg>Pro polymorphism in codon 72 of p53 gene is known to affect the susceptibility of cervical cancer differently in different population worldwide although information regarding its role in determining survival status and disease outcome in patients is lacking. The present study was conducted to determine the genotype frequency and prognostic role of p53 codon 72 Arg>Pro polymorphism in patients with advanced stage cervical cancer in India. METHODS: The p53 codon 72 polymorphism was determined in tumour biopsies (n = 107) and matched blood samples (n = 19) in cervical cancer patients using polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP). Effect of p53 genotype on the overall survival (OS) and recurrence-free survival (RFS) was analyzed. Individual Arg or Pro alleles were studied for their significance on survival as Pro carriers (Pro/Pro + Arg/Pro) versus Arg/Arg individuals or Arg carriers (Arg/Arg + Arg/Pro) versus Pro/Pro individuals. RESULTS: The frequencies for Arg/Arg, Arg/Pro and Pro/Pro genotypes were 27.2, 49.5 and 23.3 per cent, respectively. There was no significant difference in the genotypes with respect to patients' OS or RFS. INTERPRETATION & CONCLUSIONS: The findings of our study indicated that p53 codon 72 polymorphism might not be an independent marker in predicting clinical outcome in advanced stage cervical cancer patients. Further studies need to be done in larger samples to confirm these findings.

Cryo-EM structure of a catalytic amyloid fibril.

Catalytic amyloid fibrils are novel types of bioinspired, functional materials that combine the chemical and mechanical robustness of amyloids with the ability to catalyze a certain chemical reaction. In this study we used cryo-electron microcopy to analyze the amyloid fibril structure and the catalytic center of amyloid fibrils that hydrolyze ester bonds. Our findings show that catalytic amyloid fibrils are polymorphic and consist of similarly structured, zipper-like building blocks that consist of mated cross-ß sheets. These building blocks define the fibril core, which is decorated by a peripheral leaflet of peptide molecules. The observed structural arrangement differs from previously described catalytic amyloid fibrils and yielded a new model of the catalytic center.

Quality improvement initiative for a sustained increase in human milk donation during the hospital stay.

BACKGROUND: The demand for donors' human milk is much more than the availability of the same due to the myriad challenges faced during the collection process. METHODS: Baseline milk volume donation done in a human milk bank facility located in tertiary care government institute in a low-middle income country was assessed. It was initially aimed to increase the absolute quantity of milk volume donation by 30% over a period of 6 months, which was subsequently continued following COVID-19 emergence (over another 12 months) along with a particular emphasis on the sustenance of milk donation activities. INTERVENTIONS: Counselling of both the healthcare workers and stakeholders, standardising the timing of milk donation and other policies, equipment in proportion to demand and supply and addition of human resource were done as a multiprong approach to have sustained increase in human milk donation. RESULTS: The median control line (MCL) showed a shift of 27.8%; from a baseline of 5032 mL to 6971 mL during intervention phase I comprising of five plan do study act cycles spread over a period of 6 months. During the sustenance phase I even though the monthly collection was non-uniform, there was a further 16% upward shift in MCL to 8122 mL. During the second intervention phase, each component of the Ishikawa diagram was worked on (people, policy, place, procedure) resulting in a more than 100% increase from sustenance phase I taking the MCL to 17 181 mL with an overall increase of 3.41 times from the baseline. CONCLUSION: Dedicated counselling and constant motivation have been conventionally considered as the utmost measure to increase milk volume donation in milk bank. Our study highlights the need to introduce scheduled timings along with sufficient equipment and manpower to overcome the shortage of milk donation in human milk bank facilities.

A national level survey on knowledge, attitude and practices among Indian nurses on viral hepatitis.

BACKGROUND: Despite being preventable and treatable, viral hepatitis remains a major public health problem in India. In the line of their duties, nursing professionals are constantly at risk of infection. To combat viral hepatitis, it is essential to ascertain the level of knowledge, attitude, and practices among nursing professionals. MATERIALS AND METHODS: A descriptive cross-section study was conducted at a tertiary public hospital, as a nation-wide online survey after ethical clearance and participants' consent. A convenience sampling, from November 2021 to September 2022, yielded a total of 4532 nurses, nursing students and educators. A self-administered 62-item questionnaire on viral hepatitis with four sections: demographic details, knowledge (33-items), attitude (5-items), and practice (24-itmes) was prepared by expert panel and had a content validity and reliability >0.8. The scale was compiled onto the SurveyMonkey app, field tested before administration and widely circulated on email. RESULT: The response rate of the survey was 77%. Frequency, percentage, and the odds ratio (at 95% confidence interval) were analyzed on SPSS v22.0. Majority were females (87.1%) aged <30 years (60%) with <5 years' experience (57.8%). Almost equal number worked in public or private sector and was holders of diploma (44.5%) or degree (43.8%). Overall poor knowledge (85.3%), unfavorable attitude (86.2%), and unsafe practices (55.6%) were exhibited by nurses; 42.2% encountered needle stick injury last year and 49.8% had never checked Anti-HBs titer. In the event of needle stick injury, 74.78% cleansed with soap and water; used antiseptics or washes (33.5%), placed finger in mouth (5.10%), forced wound bleed (17.3%), scrub wound (17.54%), or apply bandage (12.58%). Multivariate analysis of factors influencing knowledge of viral hepatitis was educational qualification, designation, and type of health facility. CONCLUSION: As nursing professionals are constantly at risk, there is an urgent need to raise awareness about hepatitis, the post-exposure prophylaxis and vaccination status. Every healthcare facility should include training and capacity building for nurses about risk, prevention, transmission, and management of viral hepatitis, as an integral part of orientation and continuing education on-the-job; follow stringent policies; and set-up mechanisms for monitoring and follow up. Further, policymakers and statutory bodies need to ensure the standards of nursing practice and improve the health of nurses and their patients.

Differential regulation of BIRC2 and BIRC3 expression by inflammatory cytokines and glucocorticoids in pulmonary epithelial cells.

Roles for the baculoviral inhibitor of apoptosis repeat-containing (BIRC) genes, BIRC2 and BIRC3, may include signaling to the inflammatory transcription factor, nuclear factor-κB (NF-κB) and protection from cell death. However, distinct functions for each BIRC are not well-delineated. Given roles for the epithelium in barrier function and host defence, BIRC2 and BIRC3 expression was characterized in pulmonary epithelial cell lines and primary human bronchial epithelial cells (pHBECs) grown as undifferentiated cells in submersion culture (SC) or as highly differentiated cells at air-liquid interface (ALI). In A549 cells, interleukin-1ß (IL1B) and tumor necrosis factor α (TNF) induced BIRC3 mRNA (~20-50-fold), with maximal protein expression from 6-24 h. Similar effects occurred in BEAS-2B and Calu-3 cells, as well as SC and ALI pHBECs. BIRC2 protein was readily detected in unstimulated cells, but was not markedly modulated by IL1B or TNF. Glucocorticoids (dexamethasone, budesonide) modestly increased BIRC3 mRNA and protein, but showed little effect on BIRC2 expression. In A549 cells, BIRC3 mRNA induced by IL1B was unchanged by glucocorticoids and showed supra-additivity with TNF-plus-glucocorticoid. Supra-additivity was also evident for IL1B-plus-budesonide induced-BIRC3 in SC and ALI pHBECs. Using A549 cells, IL1B- and TNF-induced BIRC3 expression, and to a lesser extent, BIRC2, was prevented by NF-κB inhibition. Glucocorticoid-induced BIRC3 expression was prevented by silencing and antagonism of the glucocorticoid receptor. Whereas TNF, but not IL1B, induced degradation of basal BIRC2 and BIRC3 protein, IL1B- and TNF-induced BIRC3 protein remained stable. Differential regulation by cytokines and glucocorticoids shows BIRC2 protein expression to be consistent with roles in rapid signaling events, whereas cytokine-induced BIRC3 may be more important in later effects. While TNF-induced degradation of both BIRCs may restrict their activity, cytokine-enhanced BIRC3 expression could prime for its function. Finally, shielding from glucocorticoid repression, or further enhancement by glucocorticoid, may indicate a key protective role for BIRC3.

Medical education in post-pandemic times: Online or offline mode of learning?

Background and Objective: With the advent of the COVID-19 pandemic, face-to-face training was suspended considering social-distancing norms. The training needs of the healthcare workers (HCWs) were being met by the online mode. Initially, the use of the online mode was limited but was eventually popularized with increased use. This would have led to a change in the perception toward the online mode. However, the use of online learning has financial and temporal obstacles. With this objective, a study was conducted among the HCWs to assess the perception, satisfaction, and preference associated with the modes of learning. Methods: A cross-sectional study was conducted from February to April 2021 among the HCWs. An online link to the survey was circulated among the HCWs who attended online or/and offline training. The questionnaire had 38 questions assessing the sociodemographic details, perception, satisfaction level, and preferences of the participants. Univariable and multivariate logistic regression were performed using SPSS v-22. Results: A total of 1,113 responses were received with the mean age of 33.17 ± 8.13 years and approximately 63% of the participants were females. Approximately 54% perceived the online mode of learning as a better mode of learning. Also, 67% preferred and 80.5% recommended the online mode whereas mean satisfaction was found to be more for the offline mode as compared to the online mode. Interpretation and Conclusions: The study concludes that the online mode of learning is the most preferred and recommended mode among the HCWs, whereas there is more dissatisfaction with respect to the online mode. The study also emphasizes that the instructors need to improve the practical knowledge of the learners by integrating technical modalities.

Capacity building of healthcare workers: Key step towards elimination of viral hepatitis in developing countries.

BACKGROUND: Lack of awareness about viral hepatitis (VH) potentially predisposes the healthcare workers (HCWs) to a higher risk of infection and may in turn increase the risk of transmission of the infection to their families and in the community. Thus, combating VH, requires adequate and updated training to the HCWs. With this objective, Project PRAKASH designed a meticulously planned training program, aimed to assess the effect of a one-day training on VH among in-service nurses. METHODS AND MATERIAL: The content and schedule of scientific sessions of the training program were decided by subject experts to improve knowledge, attitude and practice(KAP) related to VH among in-service nurses. A 54-item questionnaire divided into four domains: Transmission and Risk Factors; Prevention; Treatment; Pathophysiology and Disease Progression were used to assess the KAP related to VH. The questionnaire consisted of four sections: demographic details, knowledge(30-items), attitude(12-items) and practice(12-itmes) with a total score of 30, 60 and 24 respectively in each section. The pre-post knowledge assessment was done and impact assessment survey was undertaken among the participants who completed six months post-training period. Paired-t-test was used to assess the effect of training on knowledge using SPSSv-22. RESULTS: A total of 5253 HCWs were trained through 32 one-day trainings, however data for 4474 HCWs was included in final pre-post knowledge analysis after removing the missing/incomplete data. Mean age of participants was 33.7±8.4 with median experience of 8(IQR: 3-13). Mean improvement in knowledge score was found to be significant (p<0.001) with mean knowledge score of 19.3±4.4 in pre-test and 25.7±3.9 in the post-test out of 30. Impact assessment survey suggested change in attitude and practice of HCWs. CONCLUSION: The one-day training programs helped the in-service nurses to enhance their knowledge related to viral hepatitis. The study provided a roadmap to combating viral hepatitis through health education among HCWs about viral hepatitis.

Empowering in-service nurses in management of viral hepatitis through Programmed Approach to Knowledge and Sensitization on Hepatitis (PRAKASH): An experience from a capacity building initiative.

BACKGROUND: Nursing fraternity are at an increased risk of acquiring hepatitis B and hepatitis C infections mainly attributable to occupational risk and close contact with the patients while treatment. However, unawareness and negligence about the severity, mode of transmission and preventive measures about the disease can further predispose the nursing fraternity to a higher risk of infection. To overcome these lacunae in knowledge, a training program named Project PRAKASH was initiated for in-service nurses across the country. The objective of the program was to impart up-to-date knowledge to the nursing professionals in the management of viral hepatitis and to assess the effectiveness of the training program through pre-post-knowledge assessment survey. METHODOLOGY: One-day training program titled 'Hepatitis Induction Program' was conducted for a period of 2 years (2018-2020) among nursing professionals. It was accompanied by administration of 54-item knowledge, attitude and practice (KAP) questionnaire with four sections: demographic details, knowledge (30 items), attitude (11 items) and practice (13 items), followed by post-knowledge assessment. An Impact Assessment Survey (IAS) was also administered to assess the change in attitude and practice among 10% of the attendees, at least 6 months post training. RESULT: A total of 32 one-day training programmes were organised which witnessed the training of 5,253 nursing professionals from 292 institutions across 12 states. A data of 4,474 participants were included in the final analysis: improvement in the knowledge score was significant (P-value < 0.001) with mean knowledge score of 19.3 ± 4.4 in pre-test and 25.7 ± 3.9 in the post-test. CONCLUSION: The one-day training resulted in improvement of knowledge and significant changes in the attitude and practices of the nursing professionals.

AA amyloid fibrils from diseased tissue are structurally different from in vitro formed SAA fibrils.

Systemic AA amyloidosis is a world-wide occurring protein misfolding disease of humans and animals. It arises from the formation of amyloid fibrils from serum amyloid A (SAA) protein. Using cryo electron microscopy we here show that amyloid fibrils which were purified from AA amyloidotic mice are structurally different from fibrils formed from recombinant SAA protein in vitro. Ex vivo amyloid fibrils consist of fibril proteins that contain more residues within their ordered parts and possess a higher ß-sheet content than in vitro fibril proteins. They are also more resistant to proteolysis than their in vitro formed counterparts. These data suggest that pathogenic amyloid fibrils may originate from proteolytic selection, allowing specific fibril morphologies to proliferate and to cause damage to the surrounding tissue.

Cryo-EM reveals structural breaks in a patient-derived amyloid fibril from systemic AL amyloidosis.

Systemic AL amyloidosis is a debilitating and potentially fatal disease that arises from the misfolding and fibrillation of immunoglobulin light chains (LCs). The disease is patient-specific with essentially each patient possessing a unique LC sequence. In this study, we present two ex vivo fibril structures of a λ3 LC. The fibrils were extracted from the explanted heart of a patient (FOR005) and consist of 115-residue fibril proteins, mainly from the LC variable domain. The fibril structures imply that a 180° rotation around the disulfide bond and a major unfolding step are necessary for fibrils to form. The two fibril structures show highly similar fibril protein folds, differing in only a 12-residue segment. Remarkably, the two structures do not represent separate fibril morphologies, as they can co-exist at different z-axial positions within the same fibril. Our data imply the presence of structural breaks at the interface of the two structural forms.

Somatic Variations in Cervical Cancers in Indian Patients.

There are very few reports that describe the mutational landscape of cervical cancer, one of the leading cancers in Indian women. The aim of the present study was to investigate the somatic mutations that occur in cervical cancer. Whole exome sequencing of 10 treatment naïve tumour biopsies with matched blood samples, from a cohort of Indian patients with locally advanced disease, was performed. The data revealed missense mutations across 1282 genes, out of 1831 genes harbouring somatic mutations. These missense mutations (nonsynonymous + stop-gained) when compared with pre-existing mutations in the COSMIC database showed that 272 mutations in 250 genes were already reported although from cancers other than cervical cancer. More than 1000 novel somatic variations were obtained in matched tumour samples. Pathways / genes that are frequently mutated in various other cancers were found to be mutated in cervical cancers. A significant enrichment of somatic mutations in the MAPK pathway was observed, some of which could be potentially targetable. This is the first report of whole exome sequencing of well annotated cervical cancer samples from Indian women and helps identify trends in mutation profiles that are found in an Indian cohort of cervical cancer.