Search

Background: Ocular surface squamous neoplasia (OSSN) encompasses a range of dysplastic changes from mild dysplasia to invasive carcinoma. This research aims to elucidate the cytomorphological spectrum of OSSN in the elderly age group and correlate these findings with clinical and pathological features. Methods: A retrospective analysis was conducted on elderly patients (>60 years) diagnosed with OSSN over a 5 year period. Cytological and histopathological findings were analyzed and correlated with clinical data. Results: The cytomorphological spectrum of OSSN in the elderly age group exhibited a broad range of cellular changes, from mild dysplasia to invasive squamous cell carcinoma. The predominant cytological features included increased nuclear–cytoplasmic ratio, pleomorphism, and abnormal mitotic figures. Clinically, OSSN presented most commonly as a unilateral conjunctival mass with a history of chronic irritation. Histopathologically, there was a significant correlation between the degree of dysplasia and the depth of invasion (P < 0.05). Conclusion: This research highlights the diverse cytomorphological spectrum of OSSN in the elderly age groups and emphasizes the importance of comprehensive clinicopathological correlation for accurate diagnosis and management. The predominant cytological features observed, including increased nuclear–cytoplasmic ratio, pleomorphism, and abnormal mitotic figures, reflect the underlying dysplastic alterations and provide valuable insights into the diagnosis and the classification of OSSN. Further studies are warranted to explore the potential role of impression cytology in the diagnosis and management of OSSN and to evaluate the efficacy of different treatment modalities in the elderly age group.

PURPOSEThis pilot study is aimed to analyze a novel strategy of cervical cancer screening by training of Accredited Social Health Activist (ASHA) workers via telemedicine to counsel women for human papillomavirus (HPV) self-sampling.MATERIALS AND METHODSThis is a pilot, community-based, prospective, single-arm study. Physicians trained the ASHA workers regarding self-sampled HPV testing via a mobile application and telephonically using videos and e-pamphlets, who in turn trained the clients in community. The HPV kits were transported via prepaid courier service.RESULTSFour hundred and sixty-five women of age group 30-65 years were tested by 47 teletrained ASHA workers. The mean age of ASHA worker and clients was 39.47 ± 6.45 and 37.26 ± 8.38 years, respectively. Of the ASHA workers, 91.7% were satisfied with the information provided during telecounseling, 95.7% could understand the contents of mobile app easily, and 93.6% could fill the data of clients in app easily. Of the clients, 99.6% were satisfied with counseling by ASHA workers and 98% found it easy to self-sample. The acceptability of this strategy among clients was 58.2%. The feasibility of this strategy (percentage of clients who find it easy/those who did self-sampling) was around 99%. Among those screened, 11.8% were high-risk HPV-positive and 85.5% had follow-up at the study center.CONCLUSIONThe current study highlights a novel strategy of cervical cancer screening by incorporating the role of telemedicine in training ASHA workers and their role in improving the screening by home-based delivery of HPV kits with promising results.

Reuse of wastewater is a promising response to water scarcity. For peri-urban areas served by decentralized wastewater treatment plants, the delivery of treated wastewater to the households may be a viable option to promote reuse on a larger scale. Based on a case study in Eastern India, this paper explores if households would accept recycled water for non-potable purposes and if they would pay for it. While the respondents to household surveys had very positive views about recycling, they were not willing to pay much, even if they were from a middle-income class and could afford more. A closer analysis of the attitudes towards recycling indicated knowledge gaps about the risks and advantages of using recycled water.

Autism Spectrum Disorders (ASDs) are neurodevelopmental disorders (NDDs) in which children display differences in social interaction/communication and repetitive stereotyped behaviors along with variable associated features. Cul3, a gene linked to ASD, encodes CUL3 (CULLIN-3), a protein that serves as a key component of a ubiquitin ligase complex with unclear function in neurons. Cul3 homozygous deletion in mice is embryonic lethal; thus, we examine the role of Cul3 deletion in early synapse development and neuronal morphology in hippocampal primary neuronal cultures. Homozygous deletion of Cul3 significantly decreased dendritic complexity and dendritic length, as well as axon formation. Synaptic spine density significantly increased, mainly in thin and stubby spines along with decreased average spine volume in Cul3 knockouts. Both heterozygous and homozygous knockout of Cul3 caused significant reductions in the density and colocalization of gephyrin/vGAT puncta, providing evidence of decreased inhibitory synapse number, while excitatory synaptic puncta vGulT1/PSD95 density remained unchanged. Based on previous studies implicating elevated caspase-3 after Cul3 deletion, we demonstrated increased caspase-3 in our neuronal cultures and decreased neuronal cell viability. We then examined the efficacy of the caspase-3 inhibitor Z-DEVD-FMK to rescue the decrease in neuronal cell viability, demonstrating reversal of the cell viability phenotype with caspase-3 inhibition. Studies have also implicated caspase-3 in neuronal morphological changes. We found that caspase-3 inhibition largely reversed the dendrite, axon, and spine morphological changes along with the inhibitory synaptic puncta changes. Overall, these data provide additional evidence that Cul3 regulates the formation or maintenance of cell morphology, GABAergic synaptic puncta, and neuronal viability in developing hippocampal neurons in culture.

Background Tumor budding (TB) has been identified in many solid cancers and thought to be involved in invasion and is the initial step in the metastatic process. Limited information is available documenting the role of tumor budding in breast carcinoma. With this aim, the present study evaluates the association of tumor budding, tumor microenvironment, and its correlation with clinicopathologic parameters. Materials and Methods A total of 102 cases were archived and evaluated for peripheral and intra tumoral budding along with tumor microenvironment on hematoxylin and eosin (H&E) slides. Statistical Analysis Correlation between tumor budding, tumor microenvironment, and other classical clinicopathological parameters was studied by Chi-square test. A p-value less than 0.05 was considered significant. Results Females constituted 99 cases out of 102 and 3 were males. We found 55.9% and 44.1% of patients in the age group less than or equal to 50 and greater than 50, respectively. Also, 65.6% of cases presented with small tumor size less than or equal to 5 cm, 80.39% with lymph node metastasis, and 76.4% with lympho-vascular emboli. High peripheral tumoral budding (PTB) was seen in 45.10%, low peripheral tumoral budding in 54.9%, high ITB in 53.9%, and low ITB in 46.1%. Necrosis was found only in 39.21%. Significant statistical association of PTB was found with lymph node metastasis, lymphovascular emboli, and tumor necrosis, whereas ITB with tumor grade, lymph node metastasis, lympho-vascular emboli, and necrosis. Both PTB and ITB showed no statistically significant correlation with age and size of the tumor. Conclusion Tumor budding is an independent adverse prognostic factor in invasive breast carcinoma. However, further work is needed to establish a standard method for the quantification of this parameter, which will help in effective stratification of patients in terms of disease-free survival and likely outcome.

Vulval tumours are rare, representing merely 4% of all gynaecological neoplasms. 98% of vulvar lesions are benign, and only 2% are malignant. Of all vulvar malignancies, while squamous cell carcinoma is the most common malignancy, leiomyosarcomas of the vulva are extremely rare. Usually these tumours have nonspecific clinical manifestations, often leading to misdiagnoses of Bartholin cysts or abscesses. We describe a case of a 47-year-old woman who presented with a nonspecific painless swelling in the left vulva for 2 months which was diagnosed as leiomyosarcoma of the vulva on biopsy as well as resection.

Highlights: • Association Rule Mining tools predict the association of early-onset Myocardial Infarction with Hypertension and Diabetes Mellitus. • Association Rule Mining tools using clinical and biochemical attributes can predict the development of Hypertension and Diabetes Mellitus in Myocardial Infarction patients. Abstract: Cardiovascular diseases (CVDs) are a major cause of mortality in diabetic patients. Hypertensive patients are more likely to develop diabetes and hypertension contributes to the high prevalence of CVDs, in addition to dyslipidemia and smoking. This study was to find the different patterns and overall rules among CVD patients, including rules broken down by age, sex, cholesterol and triglyceride levels, smoking habits, myocardial infarction (MI) type on ECG, diabetes, and hypertension. The cross-sectional study was performed on 240 subjects (135 patients of ST-elevation MI below 45 years and 105 age matched controls). Association rule mining was used to detect new patterns for early-onset myocardial infarction. A hotspot algorithm was used to extract frequent patterns and various promising rules within real medical data. The experiment was carried out using "Weka'', a tool for extracting rules to find out the association between different stored real parameters. In this study, we found out various rules of hypertension like “Rule 6” says that if levels of BP Systolic > 131 mmHg, LpA2 > 43.2 ng/ml, hsCRP > 3.71 mg/L, initial creatinine > 0.5 mg/dl, and initial Hb ≤15 g/dl (antecedent), then the patient will have 88% chance of developing hypertension (consequent). Similarly for diabetes mellitus with finding their lift and confidence for different support like “Rule 6”, if MI type on ECG = ’Inferior Wall MI’ with STATIN=No, and levels of Triglycerides ≤325 (antecedent), then the patient had a 67% chance of developing diabetes mellitus. We concluded that early-onset myocardial infarction is significantly associated with hypertension and diabetes mellitus.Using association rule mining, we can predict the development of hypertension and diabetes mellitus in MI patients.

The dopamine transporter gene (DAT1), a recognized genetic risk factor for attention deficit hyperactivity disorder (ADHD) is principally responsible for the regulation of dopamine synaptic levels and serves as a key target in many psychostimulants drugs. DAT1 gene methylation has been considered an epigenetic marker in ADHD. The identification of G-rich sequence motifs potential to form G-quadruplexes is correlated with functionally important genomic regions. Herein, biophysical and biochemical techniques are employed to investigate the structural polymorphism along with the effect of cytosine methylation on a 26-nt G-rich sequence present in the promoter region of the DAT1 gene. The gel electrophoresis, circular dichroism spectroscopy, and UV-thermal melting data are well correlated and conclude the formation of a parallel (bimolecular), as well as antiparallel (tetramolecular) G-quadruplex in Na+ solution. Interestingly, the existence of uni-, bi-, tri-, and tetramolecular quadruplex structures in K+ solution exhibited only the parallel type G-quadruplex. The results demonstrate that in presence of either cation (Na+ or K+) the cytosine methylation reserved the structural topologies unaltered. However, methylation lowers the thermal stability of G-quadruplexes and the duplex structures, as well. These findings provide insights to understand the regulatory mechanisms underlying the formation of the G-quadruplex structure induced by DNA methylation.

Abstract Distillery industry is amidst the top source of surface water pollution owing to its very high content of recalcitrant organics, inorganics, and persistent turbidity contents. Melanoidins are the chief dark brown-colored complex contaminant existing in the distillery generated effluent with a very high organic load. The present investigation examined the melanoidin elimination from a model wastewater system utilizing Cu-impregnated activated carbon derived from waste leaves of Mangifera indica. With the initial surface characterization utilizing SEM equipped with EDX and FTIR, the Box-Behnken design of experiments was engaged for determining the influence of different factors for the melanoidin removal from the aqueous system. Adsorbent dose, initial melanoidin concentration, and contact time have imposed the maximum effect on to the melanoidin removal (73%) using the synthesized activated carbon, clearly showing its ability for the melanoidin removal from the aqueous contaminated system.

Three workshops with representatives of stakeholders from academia, business, civil society and government in India were organized in Chennai, Kolkata, and Mumbai with the aim to identify and elaborate on key barriers to resource recovery in wastewater treatment (WWT). A structured questionnaire was designed to capture the views of participating stakeholders. Using a new Mathematica function, namely, Around, the responses of the representatives of each stakeholder were aggregated to an approximate number representing that stakeholder’s view. Overall, the stakeholder consensus on WWT technologies was rather conservative, with a focus on the functioning of WWT. Concerning the drivers and barriers for resource recovery and policies to support the implementation of recycling technologies in WWT, stakeholders expected government action to drive recycling. A social network analysis identified potential conflicts between the stakeholder groups.

Autism Spectrum Disorder (ASD) is a developmental disorder in which children display repetitive behavior, restricted range of interests, and atypical social interaction and communication. CUL3, coding for a Cullin family scaffold protein mediating assembly of ubiquitin ligase complexes through BTB domain substrate-recruiting adaptors, has been identified as a high-risk gene for autism. Although complete knockout of Cul3 results in embryonic lethality, Cul3 heterozygous mice have reduced CUL3 protein, demonstrate comparable body weight, and display minimal behavioral differences including decreased spatial object recognition memory. In measures of reciprocal social interaction, Cul3 heterozygous mice behaved similarly to their wild-type littermates. In area CA1 of hippocampus, reduction of Cul3 significantly increased mEPSC frequency but not amplitude nor baseline evoked synaptic transmission or paired-pulse ratio. Sholl and spine analysis data suggest there is a small yet significant difference in CA1 pyramidal neuron dendritic branching and stubby spine density. Unbiased proteomic analysis of Cul3 heterozygous brain tissue revealed dysregulation of various cytoskeletal organization proteins, among others. Overall, our results suggest that Cul3 heterozygous deletion impairs spatial object recognition memory, alters cytoskeletal organization proteins, but does not cause major hippocampal neuronal morphology, functional, or behavioral abnormalities in adult global Cul3 heterozygous mice.

Summary: Biologically active small molecules can impart modulatory effects, in some cases providing extended long-term memory. In a screen of biologically active small molecules for regulators of tumor necrosis factor (TNF) induction, we identify several compounds with the ability to induce training effects on human macrophages. Rutaecarpine shows acute and long-term modulation, enhancing lipopolysaccharide (LPS)-induced pro-inflammatory cytokine secretion and relieving LPS tolerance in human macrophages. Rutaecarpine inhibits β-glucan-induced H3K4Me3 marks at the promoters of several pro-inflammatory cytokines, highlighting the potential of this molecule to modulate chromosomal topology. Syk kinase inhibitor (SYKi IV), another screen hit, promotes an enhanced response to LPS similar to that previously reported for β-glucan-induced training. Macrophages trained with SYKi IV show a high degree of resistance to influenza A, multiple variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and OC43 coronavirus infection, highlighting a potential application of this molecule and other SYKis as prophylactic treatments for viral susceptibility.

Abstract MicroRNA miR-155 is an important regulatory molecule in the immune system and is highly expressed and functional in Th17 cells, a subset of CD4+ T helper cells which are key players in autoimmune diseases. Small molecules that can modulate miR-155 may potentially provide new therapeutic avenues to inhibit Th17 cell-mediated autoimmune diseases. Here, we present a novel high-throughput screening assay using primary T cells from genetically engineered Mir155 reporter mice, and its use to screen libraries of small molecules to identify novel modulators of Th17 cell function. We have discovered a chemical series of (E)-1-(phenylsulfonyl)-2-styryl-1H-benzo[d] imidazoles as novel down-regulators of Mir155 reporter and cytokine expression in Th17 cells. In addition, we found that FDA approved antiparasitic agents belonging to the ‘azole’ family also down-regulate Mir155 reporter and cytokine expression in Th17 cells, and thus could potentially be repurposed to treat Th17-driven immunopathologies.

In the need of more facilities and comfort, people are compelled to migrate from rural areas to developed cities. The growing population in urban areas, demand dense and facilitated building structure along with peripheral infrastructure. The current study uses OpenFOAM to analyse the impact of infrastructure development on wind profile and temperature of the surrounding area along with the cooling effect of vegetation cover. Air temperature and wind velocity are calculated at different points in the study region and are compared for various scenarios. The maximum change in the air temperature and wind velocity is found as 0.7 K and 0.4 m/s respectively due to an increase in building temperature during the day, while the minimum change is about 0.05 K and 0.1 m/s in densely vegetated areas. An assumption also has been taken to predict the vegetation cooling effects in surrounding buildings and is analysed with the temperature difference of 0.1 K to 0.5 K. The integrated analysis of wind and temperature around the infrastructure shows the magnitude of the impact constructed sites generates on urban microclimate and the results can be used for designing of a regulated area in terms of microclimate.

Background: Prevention of the debris from extruding to the periapical region is an important aspect to be taken care of as its extrusion can result in pain, periapical inflammation, and delayed healing owing to the presence of highly infective components in the debris. Aim: The present trial was aimed to compare and assess the amount of debris extruded apically using the single-file reciprocating system - WaveOne GOLD and single file rotary system - OneShape in root canal preparations in vitro. Materials and Methods: Thirty mandibular premolars were divided into two groups (15 samples each) prepared with a single-file reciprocating system - WaveOne GOLD and single-file rotary system - OneShape. Debris extruded was collected and then stored in an incubator. The final weight was calculated after obtaining the mean of three consecutive weights obtained for each tooth. The data were compared using the ANOVA and Turkey's post hoc analysis. Results: Debris extrusions were recorded in both groups and analysis revealed statistical differences in weight before and after the instrumentation procedures in both groups. When compared, reciprocating single file – WaveOne GOLD extruded more debris than rotary single file system – OneShape with a P < 0.001. Conclusions: The rotary instrumentation systems extrude lesser debris apically than the reciprocating instrumentation system. The difference found was statistically significant.

Abstract Background JIA studies demonstrate that there is a “window of opportunity” early in the disease course during which appropriate management improves outcomes. No data is available regarding patients’ pathway, before first pediatric rheumatology (PR) evaluation in India, a country where health-care costs are self- paid by patients and where a significant shortage of pediatric rheumatologists (PRsts) is known. This study aimed to describe time from onset of symptoms to first PR visit of JIA patients to a tertiary center in India and factors that impact this. Methods This retrospective study is from data collected at the PR center, Sir Ganga Ram Hospital (SGRH) in New Delhi. JIA patients fulfilling ILAR 2004 criteria and seen at least twice from 1st October 2013 to 30th September 2018 were included. Data collected were: demographic details, history of disease, referral practitioner, clinical and laboratory features, treatments. Mann-Whitney U-test, Chi square and logistic regression were used as appropriate to study factors that determined time to first PR visit. Results Five hundred and twenty patients were included: 396 were diagnosed at this PR center (group A), 124 were previously diagnosed as JIA and managed by non PRsts before first PR visit (group B). Median time from symptom onset to first PR visit was 4.1 months and median distance travelled 119.5 km. Despite ongoing treatment, group B patients had more aggressive disease and resided further away as compared to Group A patients. On univariate analysis, factors that predicted PR visit within 3 months were private patients, short distance to travel, family history of inflammatory disease, history of fever, history of acute uveitis or high ESR. On multivariate analysis all these factors were significant except high ESR and acute uveitis. Conclusion Time to first PR assessment at this center was comparable to that seen in western countries. Cost of care and long distance to the center delayed consultation; acuity of complaints and family history of rheumatologic condition hastened referral. Possible solutions to improve referral to PR centers would be to increase the number of PRsts and to improve medical insurance coverage.

Introduction: Mandibular angle fracture is common in road traffic accidents. This study was conducted to compare 3D miniplate system with 2D plates for treatment of mandibular angle fractures. Materials and Methods: The study was conducted on 120 patients with mandibular angle fracture of both genders. After selecting patients, patients were divided into 2 groups of 60 each. In group I, patients were treated with 3D, 2.0-mm titanium plates, and in group II, patients were treated with 2D, 2.0-mm titanium miniplate in mandibular angle fracture. Patients were evaluated regularly after 1, 3, and 6 months for outcome of treatment. Results: In group I, males were 22 and females were 38. In group II, males were 40 and females were 20. Right angle fracture was seen in 32 patients in group I and 26 in group II. Left angle fracture was seen in 24 in group I and 28 in group II. Right angle and left parasymphysis fracture was seen in 3 in group I and 4 in group II. Left angle and right parasymphysis fracture was seen in 1 in group I and 2 in group II. [Table 3], [Graph 1] shows that in group I, after 1 month sensory deficit was present in 5 patients and in group II in 12 patients. After 3 months, there were no patients with sensory deficit in group I and 2 in group II. Preoperatively in group I, mouth opening was 24 mm and in group II patients was 25.80 mm, which increased to 31.20 mm in group I and 28.20 mm in group II at 1 month, 32 mm in group I and 30 mm in group II at 3 months, and 37.20 and 32.12 mm in groups I and II, respectively, at 6 months. The difference was significant (P < 0.05). Conclusion: 3D miniplate system is reliable and effective treatment modality for mandibular angle fractures as compared with traditional 2D miniplates.[INLINE:1]

Aim: Single- and multiple-visit root canal treatment has been the subject of long-standing debate in the endodontic community, so the purpose of this study was to determine the incidence of postoperative flare-up after single- and multiple-visit endodontic therapy in permanent teeth. Materials and Methods: A total of 65 children aged >10 years who underwent root canal treatment were randomly categorized equally into two treatment groups: the first group underwent single-visit treatment, and the other group underwent multiple-visit therapy. The visual analog scale was employed to evaluate pain preoperatively and postoperatively after obturation. Recall visits were carried out after 1 week, 1 and 3, 6 and 9 months. The Statistical Package for the Social Sciences version 15.0 was employed for statistical analysis. Results: Except at the baseline, at all the other time intervals, the mean pain score in the multiple-visit group was higher as compared to that of the single-visit group; statistically no significant difference was found. Conclusion: The mean pain score in the single-visit group was lower as compared to that of the multiple-visit group; however, the difference between the two groups was statistically significant (P > 0.05).

Background: Pits and Fissures are recognized as being highly susceptible to caries. Pit and fissure sealants are one of the best methods of preventing caries as it occludes the fissures and pits from the accumulation of plaque and cariogenic microflora. There are different methods of cleaning and preparing occlusal pits and fissures for preventing caries which helps in alleviating oral health status of paediatric population. Aim: The aim of the present study was to evaluate and compare the microleakage of pit and fissure sealants after using five different preparation techniques, namely: A) Conventional technique using pumice prophylaxis, B) enameloplasty with round carbide bur, C) enameloplasty with fissurotomy bur, D) air polisher, and E) air abrasion. Materials and Methods: The study was conducted on 50 caries-free premolars extracted for orthodontic purpose. These teeth were randomly assigned to five groups, 10 teeth in each for receiving fissure sealant after different surface preparation; thermocycling and sectioning of samples were performed and microleakage was assessed under a stereomicroscope after methylene blue dye immersion. Results: The results of air abrasion groups were significantly superior with “0” microleakage when compared to all other groups followed by round bur, fissurotomy bur, air polisher and pumice prophylaxis. Conclusion: To improve the marginal adaptation of the sealants, minimally invasive methods are the most favoured methods of occlusal preparation. This study promises to show positive results for fissure sealants which are likely to play an important role in caries prevention and techniques that are intended to protect caries susceptible surfaces.

Background: Kids and teenagers are more prone to oral diseases. Poor oral health has a significant impact on oral well-being–associated quality of life. Thus, we performed an investigation to examine the outcome of oral health status on the quality of life of children and adolescents in Indian population, by using the Oral Health Impact Profile-14 (OHIP-14). Materials and Methods: A total of 100 children, ranging between 1 and 19 years of age who attended Indian hospitals from November 2016 to October 2019, were included in the study. The DMFT Index (Decayed, Missing, and Filled Teeth) and OHIP-14 were used as data collection tools. Association of the total OHIP-14 score and seven subscales associated with it was evaluated using Spearman’s correlations. Results: The results showed statistically noteworthy association between the toothbrushing regularity, number of dental appointments, history of oral trauma, smoking, and subdomains of OHIP-14 (P < 0.05)Conclusion: Dental and oral health of an individual has a great impact on their quality of life.

Chorioangioma is the most common benign non trophoblastic tumor of the placenta. It is a rare presentation with incidence of 0.6-1% of all pregnancies. It is associated with feto maternal complications like polyhydramnios, cervical incompetence, preterm labor, increased rate of cesarean delivery, abruptio placentae, malpresentation, postpartum hemorrhage, fetal growth restriction, fetal anemia, fetal thrombocytopenia, non immune hydrops, fetal cardiac failure, cerebral embolism, cerebral infarction, intrauterine fetal and neonatal death. Ultrasound is the gold standard for diagnosis . Here we present a case of giant chorioangioma of 6 * 5 cm with complication of polyhydramnios, preterm labor, abruptio placenta and placenta previa successfully managed with good maternal and fetal outcome.

Cell-based immunotherapies have had remarkable success in the clinic, specifically in the treatment of hematologic malignancies. However, these strategies have had limited efficacy in patients with solid tumors. To better understand the challenges involved, the National Cancer Institute (NCI) convened an initial workshop with immuno-oncology thought leaders in December 2018 and a follow-up workshop in December 2020. The goals of the NCI workshops on cell-based immunotherapy for solid tumors were to discuss the current state of the field of cell-based immunotherapy, obtain insights into critical knowledge gaps, and identify ways in which NCI could facilitate progress. At both meetings, subjects emphasized four main types of challenges in further developing cell-based immunotherapy for patients with solid tumors: scientific, technical, clinical, and regulatory. The scientific barriers include selecting appropriate targets, ensuring adequate trafficking of cell therapy products to tumor sites, overcoming the immunosuppressive tumor microenvironment, and identifying appropriate models for these investigations. While mouse models may provide some useful data, the majority of those that are commonly used are immunodeficient and unable to fully recapitulate the immune response in patients. There is therefore a need for enhanced support of small early-phase human clinical studies, preferably with adaptive trial designs, to provide proof of concept for novel cell therapy approaches. Furthermore, the requirements for manufacturing, shipping, and distributing cell-based therapies present technical challenges and regulatory questions, which many research institutions are not equipped to address. Overall, workshop subjects identified key areas where NCI support might help the research community in driving forward innovation and clinical utility: 1) provide focused research support on topics such as tumor target selection, immune cell fitness and persistence, cell trafficking, and the immunosuppressive tumor microenvironment; 2) support the rapid translation of preclinical findings into proof of concept clinical testing, harmonize clinical trial regimens, and facilitate early trial data sharing (including negative results); 3) expand manufacturing support for cell therapies, including vectors and reagents, and provide training programs for technical staff; and 4) develop and share standard operating procedures for cell handling and analytical assays, and work with the Food and Drug Administration to harmonize product characterization specifications.

Introduction Cut throat injuries are well recognized in homicide but less recognized in suicides. The incidence of suicide is increasing worldwide owing to the more stressful strenuous lifestyle and other risk factors like substance abuse. Suicide by incising one’s own throat is associated with hesitation marks whereas homicidal wounds are not. Case Report We present an interesting case of a suicidal cut throat of the victim being a butcher who was on alcohol abstinence since 3 days with severe injuries of supraglottic larynx and cricopharynx, surprisingly without any evidence of hesitation marks. He underwent immediate neck exploration and suturing of the injured structures without the need of a tracheostomy. Discussion A multidisciplinary approach by Otolaryngologists, Psychiatrists, Intensivists, and Anaesthetists is required in the effective management of these victims. A thorough proper early assessment can totally avoid the need of tracheostomy which is recommended in practice, hence preventing complications arising out of this unnecessary but advocated procedure.

Urban open and green spaces provide various ecosystem services such as aesthetics, biodiversity, recreation and most importantly health. These spaces, especially in an urban area, are beneficial for the physical and mental health of people. These services become more important at the time of social and health crisis such as COVID-19. Access to urban open and green space with suitable precautionary measures such as social distancing and personal hygiene would have improved individuals resilience during the pandemic. Due to the COVID-19 imposed lockdown, people were forced to isolate with no access to any of the recreational spaces to combat the global challenge. Once the lockdown was eased in India, the public focus shifted towards the need for urban green and open spaces along with hygiene. The present study examined the change in need, usage patterns, hygiene and infrastructure facilities for such urban green and open spaces in cities. Multi-parameter analysis was conducted for the data collected from 27 cities, especially with respect to age and behavioral patterns. 170 valid responses for the designed survey were received from 27 Indian cities and towns. The results indicated that these areas were important for a wide range of activities, such as walking and jogging, relaxation, health, and yoga, meeting with friends, etc. The study results show that 62.35% of people feel that urban open and green spaces should be increased while 31.18% of people feel that more facilities should increase in current open and green spaces. 85% of people feel that yoga activities have increased in urban open and green spaces during post COVID-19 imposed lockdown compared to pre COVID-19 era. 99% of individuals agree that to make their immune system healthy and to mentally and physically prepare for such pandemic, they need to more often use green spaces for yoga and other health-related activities. Whereas, 90% of visitors admitted that urban green and open spaces help them cope with their physical and mental health concerns. People started using green and open spaces for productive purposes and avoided social gatherings as far as possible in such areas. The results were validated with statistical analysis using ANOVA in MINITAB14. The statistical analysis indicates a clear effect of age group and lockdowns on the people's activities, specially for Health and Yoga with p

Port site metastasis is a rare complication and carcinosarcoma is itself a rare malignant tumour of the ovary. Hereby, Authors report a case of an ovarian carcinosarcoma which was retrospectively diagnosed from the metastasis which developed at the specimen retrieval port site of primary laparoscopic surgery. A 48-year-old nulliparous lady underwent laparoscopic cystectomy previously for endometrioma. Six months postlaparoscopy, she developed pain and palpable mass at the trochar site. Fine Needle Aspiration Cytology (FNAC) showed metastatic adenocarcinoma of ovarian origin confirmed by immunohistochemistry. Six cycles of chemotherapy followed by total hysterectomy, resection of the mass and attached tubal segment, opposite salpingo-oophorectomy and omentectomy was done. Post-surgery, patient was followed-up with three chemotherapy sessions. Final histopathological report showed carcinosarcoma of ovary at port site with omental deposit.

Introduction Cut throat injuries are well recognized in homicide but less recognized in suicides. The incidence of suicide is increasing worldwide owing to the more stressful strenuous lifestyle and other risk factors like substance abuse. Suicide by incising one’s own throat is associated with hesitation marks whereas homicidal wounds are not. Case Report We present an interesting case of a suicidal cut throat of the victim being a butcher who was on alcohol abstinence since 3 days with severe injuries of supraglottic larynx and cricopharynx, surprisingly without any evidence of hesitation marks. He underwent immediate neck exploration and suturing of the injured structures without the need of a tracheostomy. Discussion A multidisciplinary approach by Otolaryngologists, Psychiatrists, Intensivists, and Anaesthetists is required in the effective management of these victims. A thorough proper early assessment can totally avoid the need of tracheostomy which is recommended in practice, hence preventing complications arising out of this unnecessary but advocated procedure.

As the assessment of the economic, environmental, institutional, and social sustainability of wastewater treatment systems may have several conceivable goals and intended recipients, there are numerous different approaches. This paper surveys certain aspects of sustainability assessment that may be of interest to the planners of wastewater treatment systems. Here, the key criteria assess the system’s costs and financing, including its affordability for the users, the environmental impact, the benefits for health and hygiene, the cultural acceptance of the system and its recycled products, the technical functioning, and the administrative, political, and legal framework for its construction and operation. A multi-criteria approach may then be used to analyze possible trade-offs and identify the most suitable system for a certain location.

Oxidative stress (OS) is a metabolic dysfunction mediated by the imbalance between the biochemical processes leading to elevated production of reactive oxygen species (ROS) and the antioxidant defense system of the body. It has a ubiquitous role in the development of numerous noncommunicable maladies including cardiovascular diseases, cancers, neurodegenerative diseases, aging and respiratory diseases. Diseases associated with metabolic dysfunction may be influenced by changes in the redox balance. Lately, there has been increasing awareness and evidence that diabetes mellitus (DM), particularly type 2 diabetes, is significantly modulated by oxidative stress. DM is a state of impaired metabolism characterized by hyperglycemia, resulting from defects in insulin secretion or action, or both. ROS such as hydrogen peroxide and the superoxide anion introduce chemical changes virtually in all cellular components, causing deleterious effects on the islets of β-cells, in turn affecting insulin production. Under hyperglycemic conditions, various signaling pathways such as nuclear factor-κβ (NF-κβ) and protein kinase C (PKC) are also activated by ROS. All of these can be linked to a hindrance in insulin signaling pathways, leading to insulin resistance. Hyperglycemia-induced oxidative stress plays a substantial role in complications including diabetic nephropathy. DM patients are more prone to microvascular as well as atherosclerotic macrovascular diseases. This systemic disease affects most countries around the world, owing to population explosion, aging, urbanization, obesity, lifestyle, etc. However, some modulators, with their free radical scavenging properties, can play a prospective role in overcoming the debilitating effects of OS. This review is a modest approach to summarizing the basics and interlinkages of oxidative stress, its modulators and diabetes mellitus. It may add to the understanding of and insight into the pathophysiology of diabetes and the crucial role of antioxidants to weaken the complications and morbidity resulting from this chronic disease.

A 65-year-old multiparous female was evaluated for postmenopausal bleeding. Imaging was strongly suggestive of malignancy. However, hysteroscopic-guided endometrial biopsy revealed tuberculous endometritis. The patient responded to antitubercular therapy and recovered completely. Genital tuberculosis is typically considered a disease of young women presenting with infertility. However, tuberculous endometritis should be considered in a patient of postmenopausal bleeding, particularly in developing countries. It is a rare, but curable cause of postmenopausal bleeding.

Valproic acid (VPA) is a well-established anticonvulsant drug discovered serendipitously and marketed for the treatment of epilepsy, migraine, bipolar disorder and neuropathic pain. Apart from this, VPA has potential therapeutic applications in other central nervous system (CNS) disorders and in various cancer types. Since the discovery of its anticonvulsant activity, substantial efforts have been made to develop structural analogues and derivatives in an attempt to increase potency and decrease adverse side effects, the most significant being teratogenicity and hepatotoxicity. Most of these compounds have shown reduced toxicity with improved potency. The simple structure of VPA offers a great advantage to its modification. This review briefly discusses the pharmacology and molecular targets of VPA. The article then elaborates on the structural modifications in VPA including amide-derivatives, acid and cyclic analogues, urea derivatives and pro-drugs, and compares their pharmacological profile with that of the parent molecule. The current challenges for the clinical use of these derivatives are also discussed. The review is expected to provide necessary knowledgebase for the further development of VPA-derived compounds.

Introduction: There is a great need for identifying fearful children, who often present problems in patient management, thus affecting the quality of dental care rendered to them. This study is unique in the way that dental fear was assessed through three fear scales as research has suggested the use of more than one scale because each scale has its own restrictions and is open to criticism. Aim: The aim of this study was to evaluate dental fear and anxiety (DFA) among children aged 3–14 years using three fear measurement scales. Methods: The study was conducted on children (3–14 years) who visited the Department of Pedodontics and Preventive Dentistry at Maulana Azad Institute of Dental Sciences, New Delhi. The DFA levels were measured using three fear measurement scales, i.e., facial image scale (FIS), dental fear scale (DFS), and children's fear survey schedule-dental subscale (CFSS-DS). The dental behavior was estimated using the Frankl's behavior rating scale (FBRS). Results: The prevalence of dental fear according to FIS was 14.3%, according to DFS was 22.6%, and according to CFSS-DS was 7.4%. In assessment of the behavior of children in the clinics through FBRS, it was observed that he maximum number of respondents (69.8%) showed Frankl's Rating 3 i.e. positive. In the DFS and CFSS-DS, the factor which caused most fear was “feeling the needle injected” and “injections,” respectively. Conclusion: Assessment of dental fear is an extremely useful tool for the dental practitioner, who can use it to customize the behavioral treatment and management for child patients.

ObjectivesThe objectives of the study were to assess the knowledge and skills of medical interns and nurses regarding family planning (FP) services, and document the prevailing FP practices in the teaching hospitals in India.Study designA cross-sectional study was conducted in three states (Delhi, Rajasthan, and Maharashtra) of India, among randomly selected 163 participants, including medical interns (n = 81) and in-service nurses (n = 82), during 2017. The semi-structured, pre-tested interview schedule, was used to assess the knowledge and status of training received; and objective structured clinical examination (OSCE) based checklist was used to evaluate the skills.ResultsAbout 60% of the interns and 48% of the nurses knew more than five contraceptives that could be offered to the clients. About 22% (11.1% interns and 33.3% nurses) respondents believed that contraceptives should not be given to a married woman coming alone, and 31.9% (17.3% interns and 46.3% nurses) respondents reported that it was illegal to provide contraceptives to unmarried people. Nearly 43.3% interns and 69.5% nurses refused to demonstrate intrauterine contraceptive device (IUCD) insertion in the dummy uterus as per OSCE, and among those who did, 12.3% interns and 18.3% nurses had failed. About 63% interns and 63.4% of nurses had observed IUCD insertion, and 12.3% interns and 17.1% had performed IUCD insertion, during their training.ConclusionsKnowledge and skills of interns and nurses regarding FP services were inadequate. The medical training during graduation or internship, and during the job, was found to be inadequate to provide quality FP services as per guidelines of nursing/medical council of India and Government of India on FP.

Structural polymorphism of DNA has constantly been evolving from the time of illustration of the double helical model of DNA by Watson and Crick. A variety of non-canonical DNA structures have constantly been documented across the globe. DNA attracted worldwide attention as a carrier of genetic information. In addition to the classical Watson–Crick duplex, DNA can actually adopt diverse structures during its active participation in cellular processes like replication, transcription, recombination and repair. Structures like hairpin, cruciform, triplex, G-triplex, quadruplex, i-motif and other alternative non-canonical DNA structures have been studied at length and have also shown their in vivo occurrence. This review mainly focuses on non-canonical structures adopted by DNA oligonucleotides which have certain prerequisites for their formation in terms of sequence, its length, number and orientation of strands along with varied solution conditions. This conformational polymorphism of DNA might be the basis of different functional properties of a specific set of DNA sequences, further giving some insights for various extremely complicated biological phenomena. Many of these structures have already shown their linkages with diseases like cancer and genetic disorders, hence making them an extremely striking target for structure-specific drug designing and therapeutic applications.

The targeting of immunogens/vaccines to specific immune cells is a promising approach for amplifying immune responses in the absence of exogenous adjuvants. However, the targeting approaches reported thus far require novel, labor-intensive reagents for each vaccine and have primarily been shown as proof-of-concept with isolated proteins and/or inactivated bacteria. We have engineered a plasmid-based, complement receptor-targeting platform that is readily applicable to live forms of multiple gram-negative bacteria, including, but not limited to, Escherichia coli, Klebsiella pneumoniae, and Francisella tularensis. Using F. tularensis as a model, we find that targeted bacteria show increased binding and uptake by macrophages, which coincides with increased p38 and p65 phosphorylation. Mice vaccinated with targeted bacteria produce higher titers of specific antibody that recognizes a greater diversity of bacterial antigens. Following challenge with homologous or heterologous isolates, these mice exhibited less weight loss and/or accelerated weight recovery as compared to counterparts vaccinated with non-targeted immunogens. Collectively, these findings provide proof-of-concept for plasmid-based, complement receptor-targeting of live gram-negative bacteria.

Background: Small and medium enterprises (SMEs) are often the main pillar of an economy. Minor accidents, ergonomics problems, old and outdated machinery, and lack of awareness have created a need for implementation of safety practices in SMEs. Implementation of healthy working conditions creates positive impacts on economic and social development. Methods: In this study, a questionnaire was developed and administered to 30 randomly chosen SMEs in and around Mumbai, Maharashtra, and other states in India to evaluate safety practices implemented in their facilities. The study also looked into the barriers and drivers for technology innovation and suggestions were also received from the respondent SMEs for best practices on safety issues. Results: In some SMEs, risks associated with safety issues were increased whereas risks were decreased in others. Safety management practices are inadequate in most SMEs. Market competitiveness, better efficiency, less risk, and stringent laws were found to be most significant drivers; and financial constraints, lack of awareness, resistance to change, and lack of training for employees were found to be main barriers. Conclusion: Competition between SMEs was found to be major reason for implementation of safety practices in the SMEs. The major contribution of the study has been awareness building on safety issues in the SMEs that participated in the project.

Aim: This study was aimed to compare the diagnostic outcome of the WHO criteria, ICDAS-II criteria and laser fluorescence measurements in measuring the caries ratings of children. Settings and Design: Cross-sectional study. Materials and Methods: The study involved 31 children between 3 and 14 years of age, attending the Department of Pedodontics at Maulana Azad College of Dental Sciences, New Delhi. The surface-related caries status was registered according to the WHO basic method criteria (1997). Additionally, the ICDAS-II visual criteria and the DIAGNOdent readings were documented. Statistical analysis used: The data were analysed with ezANOVA and Excel 2000 (Microsoft Corporation, Redmond, WA, USA). Results: The mean ICDAS-II values amounted to 8.76 ± 0.72. The mean values for DMFS/def were 7.67 ± 0.91, whereas for DIAGNOdent it amounted to 4.00 ± 0.62. Conclusions: In conclusion, this study showed the diagnostic potential of the ICDAS-II criteria in comparison to the traditional WHO criteria by means of the non-cavitated caries lesions additionally detected. The DIAGNOdent use in field studies that already apply detailed visual criteria seems to bring limited additional information.

The gram-negative bacterium Francisella tularensis (Ft) is both a potential biological weapon and a naturally occurring microbe that survives in arthropods, fresh water amoeba, and mammals with distinct phenotypes in various environments. Previously, we used a number of measurements to characterize Ft grown in Brain-Heart Infusion (BHI) broth as (1) more similar to infection-derived bacteria, and (2) slightly more virulent in naïve animals, compared to Ft grown in Mueller Hinton Broth (MHB). In these studies we observed that the free amino acids in MHB repress expression of select Ft virulence factors by an unknown mechanism. Here, we tested the hypotheses that Ft grown in BHI (BHI-Ft) accurately displays a full protein composition more similar to that reported for infection-derived Ft and that this similarity would make BHI-Ft more susceptible to pre-existing, vaccine-induced immunity than MHB-Ft. We performed comprehensive proteomic analysis of Ft grown in MHB, BHI, and BHI supplemented with casamino acids (BCA) and compared our findings to published “omics” data derived from Ft grown in vivo. Based on the abundance of ~1,000 proteins, the fingerprint of BHI-Ft is one of nutrient-deprived bacteria that—through induction of a stringent-starvation-like response—have induced the FevR regulon for expression of the bacterium's virulence factors, immuno-dominant antigens, and surface-carbohydrate synthases. To test the notion that increased abundance of dominant antigens expressed by BHI-Ft would render these bacteria more susceptible to pre-existing, vaccine-induced immunity, we employed a battery of LVS-vaccination and S4-challenge protocols using MHB- and BHI-grown Ft S4. Contrary to our hypothesis, these experiments reveal that LVS-immunization provides a barrier to infection that is significantly more effective against an MHB-S4 challenge than a BHI-S4 challenge. The differences in apparent virulence to immunized mice are profoundly greater than those observed with primary infection of naïve mice. Our findings suggest that tularemia vaccination studies should be critically evaluated in regard to the growth conditions of the challenge agent.

[This corrects the article DOI: 10.1371/journal.pone.0163716.].

Oxidative stress is proposed as a regulatory element in ageing and various neurological disorders. The excess of oxidants causes a reduction of antioxidants, which in turn produce an oxidation–reduction imbalance in organisms. Paucity of the antioxidant system generates oxidative-stress, characterized by elevated levels of reactive species (oxygen, hydroxyl free radical, and so on). Mitochondria play a key role in ATP supply to cells via oxidative phosphorylation, as well as synthesis of essential biological molecules. Various redox reactions catalyzed by enzymes take place in the oxidative phosphorylation process. An inefficient oxidative phosphorylation may generate reactive oxygen species (ROS), leading to mitochondrial dysfunction. Mitochondrial redox metabolism, phospholipid metabolism, and proteolytic pathways are found to be the major and potential source of free radicals. A lower concentration of ROS is essential for normal cellular signaling, whereas the higher concentration and long-time exposure of ROS cause damage to cellular macromolecules such as DNA, lipids and proteins, ultimately resulting in necrosis and apoptotic cell death. Normal and proper functioning of the central nervous system (CNS) is entirely dependent on the chemical integrity of brain. It is well established that the brain consumes a large amount of oxygen and is highly rich in lipid content, becoming prone to oxidative stress. A high consumption of oxygen leads to excessive production of ROS. Apart from this, the neuronal membranes are found to be rich in polyunsaturated fatty acids, which are highly susceptible to ROS. Various neurodegenerative diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), among others, can be the result of biochemical alteration (due to oxidative stress) in bimolecular components. There is a need to understand the processes and role of oxidative stress in neurodegenerative diseases. This review is an effort towards improving our understanding of the pivotal role played by OS in neurodegenerative disorders.

COPD patients have high pulmonary and systemic oxidative stress that correlates with severity of disease. Sulforaphane has been shown to induce expression of antioxidant genes via activation of a transcription factor, nuclear factor erythroid-2 related factor 2 (Nrf2).This parallel, placebo-controlled, phase 2, randomized trial was conducted at three US academic medical centers. Patients who met GOLD criteria for COPD and were able to tolerate bronchoscopies were randomly assigned (1:1:1) to receive placebo, 25 μmoles, or 150 μmoles sulforaphane daily by mouth for four weeks. The primary outcomes were changes in Nrf2 target gene expression (NQ01, HO1, AKR1C1 and AKR1C3) in alveolar macrophages and bronchial epithelial cells. Secondary outcomes included measures of oxidative stress and airway inflammation, and pulmonary function tests.Between July 2011 and May 2013, 89 patients were enrolled and randomized. Sulforaphane was absorbed in the patients as evident from their plasma metabolite levels. Changes in Nrf2 target gene expression relative to baseline ranged from 0.79 to 1.45 and there was no consistent pattern among the three groups; the changes were not statistically significantly different from baseline. Changes in measures of inflammation and pulmonary function tests were not different among the groups. Sulforaphane was well tolerated at both dose levels.Sulforaphane administered for four weeks at doses of 25 μmoles and 150 μmoles to patients with COPD did not stimulate the expression of Nrf2 target genes or have an effect on levels of other anti-oxidants or markers of inflammation.Clinicaltrials.gov: NCT01335971.

Francisella tularensis (Ft) is a highly infectious intracellular pathogen and the causative agent of tularemia. Because Ft can be dispersed via small droplet-aerosols and has a very low infectious dose it is characterized as a category A Select Agent of biological warfare. Respiratory infection with the attenuated Live Vaccine Strain (LVS) and the highly virulent SchuS4 strain of Ft engenders intense peribronchiolar and perivascular inflammation, but fails to elicit select pro-inflammatory mediators (e.g., TNF, IL-1β, IL-6, IL-12, and IFN-γ) within the first ~72 h. This in vivo finding is discordant with the principally TH1-oriented response to Ft frequently observed in cell-based studies wherein the aforementioned cytokines are produced. An often overlooked confounding factor in the interpretation of experimental results is the influence of environmental cues on the bacterium's capacity to elicit certain host responses. Herein, we reveal that adaptation of Ft to its mammalian host imparts an inability to elicit select pro-inflammatory mediators throughout the course of infection. Furthermore, in vitro findings that non-host adapted Ft elicits such a response from host cells reflect aberrant recognition of the DNA of structurally-compromised bacteria by AIM2-dependent and -independent host cell cytosolic DNA sensors. Growth of Ft in Muller-Hinton Broth or on Muller-Hinton-based chocolate agar plates or genetic mutation of Ft was found to compromise the structural integrity of the bacterium thus rendering it capable of aberrantly eliciting pro-inflammatory mediators (e.g., TNF, IL-1β, IL-6, IL-12, and IFN-γ). Our studies highlight the profound impact of different growth conditions on host cell response to infection and demonstrate that not all in vitro-derived findings may be relevant to tularemia pathogenesis in the mammalian host. Rational development of a vaccine and immunotherapeutics can only proceed from a foundation of knowledge based upon in vitro findings that recapitulate those observed during natural infection.

Pseudohypoparathyroidism is rare during pregnancy and poses multiple challenges related to its diagnosis and management during pregnancy. We hereby report a case of a young woman who was diagnosed to have type 1a pseudohypoparathyroidism. She was managed by multidisciplinary team and had good maternal and perinatal outcome. Management-related issues are discussed here in detail.

The gram-negative bacterium Francisella tularensis survives in arthropods, fresh water amoeba, and mammals with both intracellular and extracellular phases and could reasonably be expected to express distinct phenotypes in these environments. The presence of a capsule on this bacterium has been controversial with some groups finding such a structure while other groups report that no capsule could be identified. Previously we reported in vitro culture conditions for this bacterium which, in contrast to typical methods, yielded a bacterial phenotype that mimics that of the bacterium's mammalian, extracellular phase.SDS-PAGE and carbohydrate analysis of differentially-cultivated F. tularensis LVS revealed that bacteria displaying the host-adapted phenotype produce both longer polymers of LPS O-antigen (OAg) and additional HMW carbohydrates/glycoproteins that are reduced/absent in non-host-adapted bacteria. Analysis of wildtype and OAg-mutant bacteria indicated that the induced changes in surface carbohydrates involved both OAg and non-OAg species. To assess the impact of these HMW carbohydrates on the access of outer membrane constituents to antibody we used differentially-cultivated bacteria in vitro to immunoprecipitate antibodies directed against outer membrane moieties. We observed that the surface-carbohydrates induced during host-adaptation shield many outer membrane antigens from binding by antibody. Similar assays with normal mouse serum indicate that the induced HMW carbohydrates also impede complement deposition. Using an in vitro macrophage infection assay, we find that the bacterial HMW carbohydrate impedes TLR2-dependent, pro-inflammatory cytokine production by macrophages. Lastly we show that upon host-adaptation, the human-virulent strain, F. tularensis SchuS4 also induces capsule production with the effect of reducing macrophage-activation and accelerating tularemia pathogenesis in mice.F. tularensis undergoes host-adaptation which includes production of multiple capsular materials. These capsules impede recognition of bacterial outer membrane constituents by antibody, complement, and Toll-Like Receptor 2. These changes in the host-pathogen interface have profound implications for pathogenesis and vaccine development.

Nuclear factor erythroid-2 related factor 2 (NRF2) is a redox-sensitive transcription factor that positively regulates the expression of genes encoding antioxidants, xenobiotic detoxification enzymes, and drug efflux pumps, and confers cytoprotection against oxidative stress and xenobiotics in normal cells. Kelch-like ECH-associated protein 1 (KEAP1) negatively regulates NRF2 activity by targeting it to proteasomal degradation. Increased expression of cellular antioxidants and xenobiotic detoxification enzymes has been implicated in resistance of tumor cells against chemotherapeutic drugs.Here we report a systematic analysis of the KEAP1 genomic locus in lung cancer patients and cell lines that revealed deletion, insertion, and missense mutations in functionally important domains of KEAP1 and a very high percentage of loss of heterozygosity at 19p13.2, suggesting that biallelic inactivation of KEAP1 in lung cancer is a common event. Sequencing of KEAP1 in 12 cell lines and 54 non-small-cell lung cancer (NSCLC) samples revealed somatic mutations in KEAP1 in a total of six cell lines and ten tumors at a frequency of 50% and 19%, respectively. All the mutations were within highly conserved amino acid residues located in the Kelch or intervening region domain of the KEAP1 protein, suggesting that these mutations would likely abolish KEAP1 repressor activity. Evaluation of loss of heterozygosity at 19p13.2 revealed allelic losses in 61% of the NSCLC cell lines and 41% of the tumor samples. Decreased KEAP1 activity in cancer cells induced greater nuclear accumulation of NRF2, causing enhanced transcriptional induction of antioxidants, xenobiotic metabolism enzymes, and drug efflux pumps.This is the first study to our knowledge to demonstrate that biallelic inactivation of KEAP1 is a frequent genetic alteration in NSCLC. Loss of KEAP1 function leading to constitutive activation of NRF2-mediated gene expression in cancer suggests that tumor cells manipulate the NRF2 pathway for their survival against chemotherapeutic agents.