Induction of hepatitis by JNK-mediated expression of TNF-alpha.

The c-Jun NH(2)-terminal kinase (JNK) signaling pathway has been implicated in the development of tumor necrosis factor (TNF)-dependent hepatitis. JNK may play a critical role in hepatocytes during TNF-stimulated cell death in vivo. To test this hypothesis, we examined the phenotype of mice with compound disruption of the Jnk1 and Jnk2 genes. Mice with loss of JNK1/2 expression in hepatocytes exhibited no defects in the development of hepatitis compared with control mice, whereas mice with loss of JNK1/2 in the hematopoietic compartment exhibited a profound defect in hepatitis that was associated with markedly reduced expression of TNF-alpha. These data indicate that JNK is required for TNF-alpha expression but not for TNF-alpha-stimulated death of hepatocytes. Indeed, TNF-alpha induced similar hepatic damage in both mice with hepatocyte-specific JNK1/2 deficiency and control mice. These observations confirm a role for JNK in the development of hepatitis but identify hematopoietic cells as the site of the essential function of JNK.

Integrative Bioinformatics-Gene Network Approach Reveals Linkage between Estrogenic Endocrine Disruptors and Vascular Remodeling in Peripheral Arterial Disease.

Vascular diseases, including peripheral arterial disease (PAD), pulmonary arterial hypertension, and atherosclerosis, significantly impact global health due to their intricate relationship with vascular remodeling. This process, characterized by structural alterations in resistance vessels, is a hallmark of heightened vascular resistance seen in these disorders. The influence of environmental estrogenic endocrine disruptors (EEDs) on the vasculature suggests a potential exacerbation of these alterations. Our study employs an integrative approach, combining data mining with bioinformatics, to unravel the interactions between EEDs and vascular remodeling genes in the context of PAD. We explore the molecular dynamics by which EED exposure may alter vascular function in PAD patients. The investigation highlights the profound effect of EEDs on pivotal genes such as ID3, LY6E, FOS, PTP4A1, NAMPT, GADD45A, PDGF-BB, and NFKB, all of which play significant roles in PAD pathophysiology. The insights gained from our study enhance the understanding of genomic alterations induced by EEDs in vascular remodeling processes. Such knowledge is invaluable for developing strategies to prevent and manage vascular diseases, potentially mitigating the impact of harmful environmental pollutants like EEDs on conditions such as PAD.

Effectiveness of common macrophytes for phytoremediation of hexavalent Cr prevalent in chromite mining areas.

Hexavalent chromium Cr(VI) is carcinogenic. To reduce Cr(VI) toxicity, a study was undertaken to assess the effectiveness of common macrophytes in the range of Cr concentration prevalent in chromite mining areas at Sukinda, Odisha, India. The metal varied from 0.09 to 2.14 mg/L during 2016 - 2019 and indicated that ≅70% waterbodies are contaminated with Cr(VI). Phytoremediation experimentation using five common macrophytes resulted in Pistia stratiotes, Salvinia minima and Ipomoea aquatica as suitable species by remediating 57 to 100% Cr(VI) from 0.2 to 1.0 mg/L within 54 days. S. minima had then found to remove 1 to 1.8 and 1.6 to 2.8 times more Cr (total) than P. stratiotes and I. aquatica respectively from a level of 0.5 to 2.5 mg/L Cr(VI) within 49 days. Irrespective of plant-duration, P. stratiotes excelled over S. minima by 59 to 68% and I. aquatica by 55 to 89% in BCF value. S. minima thus proved best by removing maximum Cr per unit time while the combination of S. minima and P. stratiotes would have promise in respect of generating low volume of remediated biomass in phytoremediation of Cr(VI).Novelty statementMacrophytes differ in their response to remove metal, screening against a given metal concentration suggests the suitable species and testing signifies their effectiveness of remediating metal from contaminated sources.

New observations of the endangered giant freshwater whipray, Urogymnus polylepis, provide further evidence for its distribution and breeding in the north-east coast of India.

The present study reports observations of 13 giant freshwater whipray (Urogymnus polylepis) from commercial fish landings along the north-east coast of India and updates existing records based on field observations and local social media reports. The disc width of the landed specimens ranged from 120 to 223 cm and they weighed 95-300 kg. All 13 specimens observed were mature (nine females and four males) and three females were pregnant, with embryo numbers ranging between 4 and 15. Globally, U. polylepis is listed as 'Endangered', and greater protection measures are needed in India to assist in reversing current population declines.

Inclusion of multiple high-risk histopathological criteria improves the prediction of adjuvant chemotherapy efficacy in lung adenocarcinoma.

AIMS: The decision to consider adjuvant chemotherapy (AC) for non-small cell lung cancer is currently governed by clinical stage. This study aims to assess other routinely collected pathological variables related to metastasis and survival for their ability to predict the efficacy of AC in lung adenocarcinoma. METHODS AND RESULTS: A retrospective single-centre series of 620 resected lung non-mucinous adenocarcinoma cases from 2005 to 2015 was used. Digital images of all slides were subjected to central review, and data on tumour histopathology, AC treatment and patient survival were compiled. A statistical case matching approach was used to counter selection bias. Several high-risk pathological criteria predict both pathological nodal involvement and early death: positive vascular invasion status (VI+) (HR = 2.10, P < 0.001), positive visceral pleural invasion status (VPI+) (HR = 2.16, P < 0.001), and solid/micropapillary-predominant WHO tumour type (SPA/MPPA) (HR = 3.29, P < 0.001). Crucially, these criteria also identify patient groups benefiting from AC (VI + HR = 0.69, P = 0.167, VPI + HR = 0.44, P = 0.004, SPA/MPPA HR = 0.36, P = 0.006). Cases showing VI+/VPI+/SPA/MPPA histology in the absence of AC stage criteria were common (170 of 620 total), and 8 had actually received AC. This group showed much better outcomes than equivalent untreated cases in matched analysis (3-year OS 100.0% versus 31.3%). Inclusion of patients with VI+/VPI+/SPA/MPPA histology would increase AC-eligible patients from 51.0% to 84.0% of non-mucinous tumours in our cohort. CONCLUSIONS: Our data provide preliminary evidence that the consideration of AC in patients with additional high-risk pathological indicators may significantly improve outcomes in operable lung adenocarcinoma, and that AC may be currently underused.

Performance and efficiency services for the removal of hexavalent chromium from water by common macrophytes.

Water contamination by hexavalent chromium(Cr) is an emerging issue. The removal of Cr(VI) using phytoremediation via different macrophytes was investigated in this study. To reduce Cr(VI) to the permissible level in irrigation water, the ability of four common macrophytes, viz. Pistia stratiotes (PS), Salvinia minima (SM), Ipomoea aquatica (IA) and Eichhornia crassipes (EC), to remove from 0.5 to 2.0 mg Cr(VI)/L was analyzed. The overall growth of PS was enhanced by 11 to 24%, SM by 36 to 53%, EC by 65 to 101% and IA by 4 to 13% by reducing Cr from 48 to 87% within 29 days of the experiment. In successive experiments, chromium uptake by SM surpassed ∼11.86-, ∼17.17- and ∼94-fold that of PS, EC and IA, respectively, after 15 days of growth in 0.35 to 1.75 mg Cr(VI)/L. The bioconcentration factor of SM surpassed that of PS, IA and EC by 0.64 to 1.73, 1.09 to 4.07 and 0.71 to 1.85 times, while PS exceeded IA and EC by1.71 to 2.35 and 1.07 to 1.11 times, respectively. SM was thus shown to offer efficient removal of Cr(VI), from a level ≅2.0 mg/L, while a suitable combination of SM and PS was efficient at ≤1.0 mg/L. Novelty It unravels the appropriate macrophytes in terms of biomass production and Cr- uptake pattern under natural condition for phytoremediation of aqueous Cr(VI) and in turn offer services to clean the environment.

Tim-3 and its role in regulating anti-tumor immunity.

Immunotherapy is being increasingly recognized as a key therapeutic modality to treat cancer and represents one of the most exciting treatments for the disease. Fighting cancer with immunotherapy has revolutionized treatment for some patients and therapies targeting the immune checkpoint molecules such as CTLA-4 and PD-1 have achieved durable responses in melanoma, renal cancer, Hodgkin's diseases and lung cancer. However, the success rate of these treatments has been low and a large number of cancers, including colorectal cancer remain largely refractory to CTLA-4 and PD-1 blockade. This has provided impetus to identify other co-inhibitory receptors that could be exploited to enhance response rates of current immunotherapeutic agents and achieve responses to the cancers that are refectory to immunotherapy. Tim-3 is a co-inhibitory receptor that is expressed on IFN-g-producing T cells, FoxP3+ Treg cells and innate immune cells (macrophages and dendritic cells) where it has been shown to suppress their responses upon interaction with their ligand(s). Tim-3 has gained prominence as a potential candidate for cancer immunotherapy, where it has been shown that in vivo blockade of Tim-3 with other check-point inhibitors enhances anti-tumor immunity and suppresses tumor growth in several preclinical tumor models. This review discusses the recent findings on Tim-3, the role it plays in regulating immune responses in different cell types and the rationale for targeting Tim-3 for effective cancer immunotherapy.

In situ growth in early lung adenocarcinoma may represent precursor growth or invasive clone outgrowth-a clinically relevant distinction.

The switch from in situ to invasive tumor growth represents a crucial stage in the evolution of lung adenocarcinoma. However, the biological understanding of this shift is limited, and 'Noguchi Type C' tumors, being early lung adenocarcinomas with mixed in situ and invasive growth, represent those that are highly valuable in advancing our understanding of this process. All Noguchi Type C adenocarcinomas (n = 110) from the LATTICE-A cohort were reviewed and two patterns of in situ tumor growth were identified: those deemed likely to represent a true shift from precursor in situ to invasive disease ('Noguchi C1') and those in which the lepidic component appeared to represent outgrowth of the invasive tumor along existing airspaces ('Noguchi C2'). Overall Ki67 fraction was greater in C2 tumors and only C1 tumors showed significant increasing Ki67 from in situ to invasive disease. P53 positivity was acquired from in situ to invasive disease in C1 tumors but both components were positive in C2 tumors. Likewise, vimentin expression was increased from in situ to invasive tumor in C1 tumors only. Targeted next generation sequencing of 18 C1 tumors identified four mutations private to the invasive regions, including two in TP53, while 6 C2 tumors showed no private mutations. In the full LATTICe-A cohort, Ki67 fraction classified as either less than or greater than 10% within the in situ component of lung adenocarcinoma was identified as a strong predictor of patient outcome. This supports the proposition that tumors of all stages that have 'high grade' in situ components represent those with aggressive lepidic growth of the invasive clone. Overall these data support that the combined growth of Noguchi C tumors can represent two differing biological states and that 'Noguchi C1' tumors represent the genuine biological shift from in situ to invasive disease.

JNK regulates FoxO-dependent autophagy in neurons.

The cJun N-terminal kinase (JNK) signal transduction pathway is implicated in the regulation of neuronal function. JNK is encoded by three genes that play partially redundant roles. Here we report the creation of mice with targeted ablation of all three Jnk genes in neurons. Compound JNK-deficient neurons are dependent on autophagy for survival. This autophagic response is caused by FoxO-induced expression of Bnip3 that displaces the autophagic effector Beclin-1 from inactive Bcl-XL complexes. These data identify JNK as a potent negative regulator of FoxO-dependent autophagy in neurons.

The role of JNK in the development of hepatocellular carcinoma.

The cJun NH(2)-terminal kinase (JNK) signal transduction pathway has been implicated in the growth of carcinogen-induced hepatocellular carcinoma. However, the mechanism that accounts for JNK-regulated tumor growth is unclear. Here we demonstrate that compound deficiency of the two ubiquitously expressed JNK isoforms (JNK1 and JNK2) in hepatocytes does not prevent hepatocellular carcinoma development. Indeed, JNK deficiency in hepatocytes increased the tumor burden. In contrast, compound JNK deficiency in hepatocytes and nonparenchymal cells reduced both hepatic inflammation and tumorigenesis. These data indicate that JNK plays a dual role in the development of hepatocellular carcinoma. JNK promotes an inflammatory hepatic environment that supports tumor development, but also functions in hepatocytes to reduce tumor development.

Contesting restrictive mobility norms among female mentors implementing a sport based programme for young girls in a Mumbai slum.

BACKGROUND: Harmful gender norms are known structural barriers to many public health and development interventions involving adolescent girls. In India, restrictions on girls' liberty to move freely in public spaces contribute to school dropout and early marriage, and negatively affect girls' health and wellbeing, from adolescence into adulthood. We report on mechanisms of change among female mentors 18 to 24 years old who contested discriminatory norms while implementing a sports-based programme for adolescent girls in a Mumbai slum. METHODS: We adopted a prospective qualitative research design. Our analysis is based on case studies derived from two rounds of face to face, in -depth interviews with 10 young women recruited to serve as mentors for the project's young female athletes. We combined both thematic and narrative analysis. RESULTS: The programme created opportunities for collective action, increasing mentors' ability to think and relate in a collectivized manner, and challenged the traditional female identity constructed for young women, which centres on domestic duties. The mentors themselves negotiated freedoms both in and outside their homes, which required careful and strategic bargaining. They changed the nature of key day-to-day social interactions with parents and brothers, as well as with neighbours, parents of their groups of athletes and men on the streets. They formed a new reference group for each other in terms of what was possible and acceptable. Demonstrating greater negotiation skills within the family helped win parents' trust in the mentor's ability to be safe in public spaces. Parents became active supporters by not giving into social sanctions of neighbours and relatives thus co-producing a new identity for their daughters as respectable young women doing 'good work'. They effectively side stepped reputational risk with their presence in public spaces becoming de-sexualised. CONCLUSIONS: Mentors contested mobility restrictions by taking risks as a group first, with collective agency an important step towards greater individual agency. This research provides important insights into addressing embedded social norms that perpetuate gender discriminatory practices and the social patterning of health inequalities.

Small Vessel Vasculitis, an Uncommon Presentation of Systemic Lupus Erythematosus.

We report a nineteen year old female with gangrene of toes as the only clinical feature of systemic lupus erythematosus. She was treated successfully with pulse cyclophosphamide and steroid.

Stromal genes discriminate preinvasive from invasive disease, predict outcome, and highlight inflammatory pathways in digestive cancers.

The stromal compartment is increasingly recognized to play a role in cancer. However, its role in the transition from preinvasive to invasive disease is unknown. Most gastrointestinal tumors have clearly defined premalignant stages, and Barrett's esophagus (BE) is an ideal research model. Supervised clustering of gene expression profiles from microdissected stroma identified a gene signature that could distinguish between BE metaplasia, dysplasia, and esophageal adenocarcinoma (EAC). EAC patients overexpressing any of the five genes (TMEPAI, JMY, TSP1, FAPalpha, and BCL6) identified from this stromal signature had a significantly poorer outcome. Gene ontology analysis identified a strong inflammatory component in BE disease progression, and key pathways included cytokine-cytokine receptor interactions and TGF-beta. Increased protein levels of inflammatory-related genes significantly up-regulated in EAC compared with preinvasive stages were confirmed in the stroma of independent samples, and in vitro assays confirmed functional relevance of these genes. Gene set enrichment analysis of external datasets demonstrated that the stromal signature was also relevant in the preinvasive to invasive transition of the stomach, colon, and pancreas. These data implicate inflammatory pathways in the genesis of gastrointestinal tract cancers, which can affect prognosis.

HIV testing among pregnant wives of migrant men in a rural district of India: urgent call for scale up.

In India, despite the fact that more pregnant women are being tested for HIV under the purview of the Prevention of Parent-to-Child HIV Transmission program, official figures indicate low rates of HIV testing, evidencing missed opportunities for HIV prevention. The present study examined the prevalence of HIV testing and the barriers to testing among pregnant women, whose vulnerability to HIV is enhanced by their spouses' risky behaviors. A cross-sectional study was conducted from November 2010 to January 2011 among 357 women who had given birth in the last two years in a district in Orissa. Only one-third of women had been tested for HIV during pregnancy. Women with more than six years of education (OR: 2.39, 95% CI: 1.06-5.39), having knowledge of sexually transmitted infections (OR: 12.37, 95% CI: 5.55-27.58), having discussions with spouses about HIV (OR: 3.56, 95% CI: 1.61-7.86), and seeking antenatal care in government district hospitals and private clinics as opposed to peripheral community health centers, were more likely to receive HIV testing during pregnancy. The findings point to the need to widen HIV testing to community-based services, increase coverage of HIV/sexually transmitted infection awareness and prevention programs, and encourage spousal communication through quality counseling.

Pool vs single sample determination of serum prolactin to explore venipuncture associated stress induced variation.

Stress is identified as a cause of transient hyperprolactinemia, whereas venipuncture is considered a source of stress for patient. The aim of this study was to investigate the association of venipuncture-induced stress with elevation of serum prolactin. This was a cross-sectional observational study conducted on a group of 150 outdoor patients visiting a tertiary care hospital. Serial sampling was performed by drawing venous blood at different time intervals (0, 30 and 60 min) by single venipuncture to measure serum prolactin to diagnose stress-induced hyperprolactinemia. The study was conducted in two phases, namely, Phase 1 and Phase 2, at different times. The Phase 1 results were divided into two groups: Group 1 (0 min) and Group 5 (pool prepared from samples collected at 0 + 30 + 60 min). Likewise, the results of Phase 2 were segregated into five groups; Group 1 (0 min), Group 2 (30 min), Group 3 (60 min), Group 4 (average of three groups), and Group 5 (pool from samples collected at 0 + 30 + 60 min). In both Phase 1 and Phase 2 of the study, there was a statistically significant (p = 0.0003 in Phase 1 and p = 0.02 in Phase 2) decrease in the mean prolactin (17.99 ± 24.76 ng/mL in Phase 1 and 19.61 ± 23.42 ng/mL in Phase 2) in the pooled samples (Group 5) in comparison to the mean prolactin (19.67 ± 27.69 ng/mL in Phase 1 and 21.06 ± 25.06 ng/mL in Phase 2) of the serum collected at 0 h (Group 1). There was no significant difference in the mean prolactin measured from the pooled samples and average prolactin calculated after individual testing from each sample collected at 0 h, 30 min and 60 min. Venipuncture-triggered fear and apprehension may result in transient hyperprolactinemia. In comparison to performing multiple testing on the samples collected at different time intervals and determining the mean, measurement of the analyte from the pooled serum is the better alternative as it can conserve both time and resources.

Homocysteine, Vitamins B6, B12, and Folate and the Risk of Ischemic and Hemorrhagic Stroke: A Case-control Study from Northeast India.

Background: Stroke is a major leading global health complication. Identification and management of risk factors associated with stroke can help in prior detection, prevention, and improvement in patient care. Purpose: To investigate the prevalence of hyperhomocysteinemia (HHcy) and Vitamins B6, B12, and folate deficiency in stroke patients and also to assess other risk factors associated with ischemic and hemorrhagic stroke. Methods: Detail history of all the subjects in the study including history of hypertension, anemia, fasting glucose, carotid artery thickness, smoking, alcohol, and dietary intake was recorded. Standard assays for homocysteine (Hcy), Vitamins B6, B12, and folate estimation were done. Lipid and renal profile tests were also performed. The prevalence and odds of having HHcy, Vitamins B6, B12, and folate deficiency, and other risk factors in ischemic and hemorrhagic stroke patients were evaluated. Student's t-tests and chi-square tests were done for statistical validation of the data. Results: Prevalence of HHcy and Vitamins B6, B12, and folate deficiency was not observed in ischemic cases. HHcy and folate deficiency was found to be prevalent in hemorrhagic stroke patients. The odds that a person with HHcy and folate deficiency has hemorrhagic stroke was found to be significantly high. Conclusion: In our study, high Hcy and low folate levels emerged as risk factors for hemorrhagic stroke.

Inside-Out of Complement in Cancer.

The role of complement in cancer has received increasing attention over the last decade. Recent studies provide compelling evidence that complement accelerates cancer progression. Despite the pivotal role of complement in fighting microbes, complement seems to suppress antitumor immunity via regulation of host cell in the tumor microenvironment. Although most studies link complement in cancer to complement activation in the extracellular space, the discovery of intracellular activation of complement, raises the question: what is the relevance of this process for malignancy? Intracellular activation is pivotal for the survival of immune cells. Therefore, complement can be important for tumor cell survival and growth regardless of the role in immunosuppression. On the other hand, because intracellular complement (the complosome) is indispensable for activation of T cells, these functions will be essential for priming antitumor T cell responses. Here, we review functions of complement in cancer with the consideration of extra and intracellular pathways of complement activation and spatial distribution of complement proteins in tumors and periphery and provide our take on potential significance of complement as biomarker and target for cancer therapy.

The pathogenesis of mesothelioma is driven by a dysregulated translatome.

Malignant mesothelioma (MpM) is an aggressive, invariably fatal tumour that is causally linked with asbestos exposure. The disease primarily results from loss of tumour suppressor gene function and there are no 'druggable' driver oncogenes associated with MpM. To identify opportunities for management of this disease we have carried out polysome profiling to define the MpM translatome. We show that in MpM there is a selective increase in the translation of mRNAs encoding proteins required for ribosome assembly and mitochondrial biogenesis. This results in an enhanced rate of mRNA translation, abnormal mitochondrial morphology and oxygen consumption, and a reprogramming of metabolic outputs. These alterations delimit the cellular capacity for protein biosynthesis, accelerate growth and drive disease progression. Importantly, we show that inhibition of mRNA translation, particularly through combined pharmacological targeting of mTORC1 and 2, reverses these changes and inhibits malignant cell growth in vitro and in ex-vivo tumour tissue from patients with end-stage disease. Critically, we show that these pharmacological interventions prolong survival in animal models of asbestos-induced mesothelioma, providing the basis for a targeted, viable therapeutic option for patients with this incurable disease.

Evaluation of drinking quality of groundwater through multivariate techniques in urban area.

Groundwater is a major source of drinking water in urban areas. Because of the growing threat of debasing water quality due to urbanization and development, monitoring water quality is a prerequisite to ensure its suitability for use in drinking. But analysis of a large number of properties and parameter to parameter basis evaluation of water quality is not feasible in a regular interval. Multivariate techniques could streamline the data without much loss of information to a reasonably manageable data set. In this study, using principal component analysis, 11 relevant properties of 58 water samples were grouped into three statistical factors. Discriminant analysis identified "pH influence" as the most distinguished factor and pH, Fe, and NO3⁻ as the most discriminating variables and could be treated as water quality indicators. These were utilized to classify the sampling sites into homogeneous clusters that reflect location-wise importance of specific indicator/s for use to monitor drinking water quality in the whole study area.

A cross-sectional study of association of serostatus and extra-articular manifestations in patients with rheumatoid arthritis in a teaching hospital.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease, which mistakenly attacks the joints and induces the inflammatory changes that thicken the joints (the synovium) resulting in swelling and pain in and around the joints. It causes pain, joint deformity, and also affects the quality of life. The joint is affected symmetrically. It also can affect body systems, such as the cardiovascular, respiratory systems, or other systems, which manifest as extra-articular manifestations. Extra-articular manifestations of RA are documented less in India hence this study was undertaken to correlate RA with extra-articular manifestations as well as its relationship with serostatus in patients with extra-articular manifestations. MATERIALS AND METHODS: Sixty patients (age between 18-60 years) attending Medicine/Rheumatology outpatient department were included in the study (12 months) who fulfilled the 2010 RA classification criteria laid down by American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) for RA. All the subjects underwent a thorough history, clinical examination, and laboratory investigations. The relevant data were analyzed with appropriate statistical methods after 12 months' duration. RESULTS: Nearly 68.33% of the subjects were found to have extra-articular manifestations mostly in the age group of 31-40 years with prevalence higher in the female. In the seropositive patients, early morning stiffness (EMS) constitutes 63.82% of the total extra-articular manifestations in the patients followed by anemia (38.29%) and peripheral neuropathy (34.04%). On the other hand, in the seronegative cases, EMS (61.53%) followed by anemia (23.07), peripheral neuropathy (15.38%), and keratoconjunctivitis sicca (15.38%). Extra-articular manifestations in seropositive patients have a statistically significant relationship with the increase in the duration of the disease. CONCLUSION: Extra-articular manifestations need to be looked carefully as it is associated with more severe disease. Seropositivity and extra-articular manifestations both usually indicate that the RA is more severe and may affect the quality of life.