During a 28-year field survey in India (1988–2016), groundwater arsenic contamination and its health effects were registered in the states of West Bengal, Jharkhand, Bihar and Uttar Pradesh in the ...Ganga River flood plain, and the states of Assam and Manipur in the flood plain of Brahamaputra and Imphal rivers. Groundwater of Rajnandgaon village in Chhattisgarh state, which is not in a flood plain, is also arsenic contaminated. More than 170,000 tubewell water samples from the affected states were analyzed and half of the samples had arsenic >10 μg/L (maximum concentration 3,700 μg/L). Chronic exposure to arsenic through drinking water causes various health problems, like dermal, neurological, reproductive and pregnancy effects, cardiovascular effects, diabetes mellitus, diseases of the respiratory and gastrointestinal systems, and cancers, typically involving the skin, lungs, liver, bladder, etc. About 4.5% of the 8,000 children from arsenic-affected villages of affected states were registered with mild to moderate arsenical skin lesions. In the preliminary survey, more than 10,000 patients were registered with different types of arsenic-related signs and symptoms, out of more than 100,000 people screened from affected states. Elevated levels of arsenic were also found in biological samples (urine, hair, nails) of the people living in affected states. The study reveals that the population who had severe arsenical skin lesions may suffer from multiple Bowens/cancers in the long term. Some unusual symptoms, such as burning sensation, skin itching and watering of eyes in the presence of sun light, were also noticed in arsenicosis patients.
Chronic activation of B-cell receptor (BCR) signaling via Bruton tyrosine kinase (BTK) is largely considered to be one of the primary mechanisms driving disease progression in B-Cell lymphomas. ...Although the BTK-targeting agent ibrutinib has shown promising clinical responses, the presence of primary or acquired resistance is common and often leads to dismal clinical outcomes. Resistance to ibrutinib therapy can be mediated through genetic mutations, up-regulation of alternative survival pathways, or other unknown factors that are not targeted by ibrutinib therapy. Understanding the key determinants, including tumor heterogeneity and rewiring of the molecular networks during disease progression and therapy, will assist exploration of alternative therapeutic strategies. Towards the goal of overcoming ibrutinib resistance, multiple alternative therapeutic agents, including second- and third-generation BTK inhibitors and immunomodulatory drugs, have been discovered and tested in both pre-clinical and clinical settings. Although these agents have shown high response rates alone or in combination with ibrutinib in ibrutinib-treated relapsed/refractory(R/R) lymphoma patients, overall clinical outcomes have not been satisfactory due to drug-associated toxicities and incomplete remission. In this review, we discuss the mechanisms of ibrutinib resistance development in B-cell lymphoma including complexities associated with genomic alterations, non-genetic acquired resistance, cancer stem cells, and the tumor microenvironment. Furthermore, we focus our discussion on more comprehensive views of recent developments in therapeutic strategies to overcome ibrutinib resistance, including novel BTK inhibitors, clinical therapeutic agents, proteolysis-targeting chimeras and immunotherapy regimens.
The proteasome subunit β5 (PSMβ5) is a chief target of proteasome inhibitors (PIs) for treatment of multiple myeloma (MM). The relevance of PSMβ5 mutations and their functional impact on the ...development of resistance to PIs have been demonstrated recently. Therefore, this present study deals with an in-depth E-pharmacophore based screening and repurposing of FDA-approved drugs that could target PSMβ5 for MM. Our molecular docking-based investigation revealed risedronate and zoledronate as potential alternative therapeutic molecules for targeting the PSMβ5 gene. Risedronate and zoledronate displayed high binding affinity (−9.51 and −8.56 kcal/mol respectively) to PSMβ5. Moreover, 100 ns molecular dynamics simulation analysis of docking complexes revealed risedronate and zoledronate with a superior binding free energies and stable interactions with PSMβ5. The RMSD plot shows that the risedronate-PSMβ5 (mean: 0.24 nm) and zoledronate-PSMβ5 (mean: 0.25 nm) complexes are identical and stays stable until 100 ns. We further validated the activity of zoledronate in MM cell lines RPMI8226 and U266 where zoledronate showed significant anti-proliferative and apoptotic activity. Importantly, zoledronate showed an enhanced anti-proliferative activity when combined with bortezomib in MM cell lines. Thus, this study demonstrates that combining bortezomib with zoledronate could have a significant impact on reducing MM cell growth and can be an alternative strategy for treating MM.
Display omitted
•Risedronate and zoledronate displayed high binding affinity to PSMβ5.•Risedronate and zoledronate-PSMβ5 complex are stable until 100 ns simulation.•Zoledronate showed anti-proliferative activity in multiple myeloma cells.•Zoledronate showed synergist activity with bortezomib in multiple myeloma cells.
Lesion mimic (Lm) mutants display hypersensitive responses (HR) without any pathogen attack; their symptoms are similar to those produced by a pathogen and result in cell death. In wheat, such ...mutants have been reported to be resistant against leaf rust due to their biotrophic nature. However, Lm mutants tend to encourage spot blotch (SB) disease caused by Bipolarissorokiniana since dead cells facilitate pathogen multiplication. In this study, 289 diverse wheat germplasm lines were phenotyped in three consecutive growing seasons (2012-2015). Genotype data was generated using the Illumina iSelect beadchip assay platform for wheat germplasm lines. A total of 13,589 single-nucleotide polymorphisms (SNPs) were selected andused for further association mapping. Lm was positively associated with Area Under Disease Progress Curve (AUDPC) for SB but negatively with glaucous index (GI), leaf tip necrosis (Ltn) and latent period (LP). Ltn had a negative association with AUDPC and Lm but a positive one with LP. In a genome-wide association study (GWAS), 29 markers were significantly associated with these traits and 27 were an notated. Seven SNP markers associated with Lm were on chromosome 6A; another on 1B was found to be linked with Ltn. Like wise, seven SNP markers were associated with GI; one on chromosome 6A with the others on 6B. Five SNP markers on chromosomes 3B and 3Dwere significantly correlated with LP, while nine SNP markers on chromosomes 5A and 5B were significantly associated with AUDPC for SB. This study is the first to explore the interaction in wheat between Lm mutants and the hemibiotrophic SB pathogen B.sorokiniana.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: Cutaneous manifestations of hematological neoplasms can be divided into three broad categories - direct infiltration, paraneoplastic conditions, and those due to the treatment of ...hematological cancers. Objectives: To study the frequency and patterns of mucocutaneous manifestations in patients with hematolymphoid neoplasms and those due to chemotherapy. Materials and Methods: This was an observational study done with 172 patients. Categorization of mucocutaneous manifestations was done into malignancy-associated and chemotherapeutic drugs-associated and data was analyzed. Results: Out of a total of 172 patients, 15.6% (27/172) had malignancy-related mucocutaneous manifestations. Among these, 4.6% (8/172) had direct infiltration of malignant cells into the skin and 11% (19/172) had paraneoplastic manifestations. The most common chemotherapy-related mucocutaneous manifestations were nail changes - 47.1% (81/172), of which transverse melanonychia was the most common (20.9%). About 44.2% (76/172) had a cutaneous infection, the commonest of which was a fungal infection (15.1%). Chemotherapy-induced alopecia was noted in 46.5% (80/172) and found to be significantly associated with cytarabine, daunorubicin, doxorubicin, methotrexate, and vincristine. Cutaneous hyperpigmentation was found to be significantly associated with cytarabine, doxorubicin, and vincristine. Conclusion: Mucocutaneous manifestations cause additional discomfort to a patient undergoing chemotherapy. Early recognition and timely and appropriate management facilitate symptom control and prevent treatment-related morbidity. A multidisciplinary approach involving hemato-oncologists and dermatologists can help achieve this target.
During our last 27 years of field survey in India, we have studied the magnitude of groundwater arsenic and fluoride contamination and its resulting health effects from numerous states. India is the ...worst groundwater fluoride and arsenic affected country in the world. Fluoride results the most prevalent groundwater related diseases in India. Out of a total 29 states in India, groundwater of 20 states is fluoride affected. Total population of fluoride endemic 201 districts of India is 411 million (40% of Indian population) and more than 66 million people are estimated to be suffering from fluorosis including 6 million children below 14 years of age. Fluoride may cause a crippling disease. In 6 states of the Ganga-Brahmaputra Plain (GB-Plain), 70.4 million people are potentially at risk from groundwater arsenic toxicity. Three additional states in the non GB-Plain are mildly arsenic affected. For arsenic with substantial cumulative exposure can aggravate the risk of cancers along with various other diseases. Clinical effects of fluoride includes abnormal tooth enamel in children; adults had joint pain and deformity of the limbs, spine etc. The affected population chronically exposed to arsenic and fluoride from groundwater is in danger and there is no available medicine for those suffering from the toxicity. Arsenic and fluoride safe water and nutritious food are suggested to prevent further aggravation of toxicity. The World Health Organization (WHO) points out that social problems arising from arsenic and fluoride toxicity eventually create pressure on the economy of the affected areas. In arsenic and fluoride affected areas in India, crisis is not always having too little safe water to satisfy our need, it is the crisis of managing the water.
In tropical and sub-tropical regions, biomass carbon (C) losses through forest degradation are recognized as central to global terrestrial carbon cycles. Accurate estimation of forest biomass C is ...needed to provide information on C fluxes and balances in such systems. The objective of this study was to develop generalized biomass models using harvest data covering tropical semi-evergreen, tropical wet evergreen, sub-tropical broad leaved, and sub-tropical pine forest in North East India (NEI). Among the four biomass estimation models (BEMs) tested AGBest = 0.32(D2Hδ)0.75 × 1.34 and AGBest = 0.18D2.16 × 1.32 were found to be the first and second best models for the different forest types in NEI. The study also revealed that four commonly used generic models developed by Chambers (2001), Brown (1989), Chave (2005) and Chave (2014) overestimated biomass stocks by 300–591 kg tree−1, while our highest rated model overestimated biomass by 197 kg tree−1. We believe the BEMs we developed will be useful for practitioners involved in remote sensing, biomass estimation and in projects on climate change mitigation, and payment for ecosystem services. We recommend future studies to address country scale estimation of forest biomass covering different forest types.
Introduction: Kawasaki Disease (KD) is an acute self-limiting systemic vasculitis involving medium and small-sized arteries. It may soon replace rheumatic fever to become the most common cause of ...acquired heart disease in Indian children. Coronary Artery Aneurysm (CAA) which can develop in 15-25% of untreated children remains the most dreaded complication of KD. Predicting the risk of CAA and taking timely measures can help in reducing the fatality of the condition. Aim: To study the spectrum of cardiovascular complications in patients with KD and also to assess associated risk factors for developing CAA in the patients under study. Materials and Methods: This prospective clinical study was carried out in the Paediatric Medicine Ward, Burdwan Medical College and Hospital, West Bengal, Eastern India, from 1st January, 2020 to 31st May, 2021. Total 52 children diagnosed with KD, aged between one month to 12 years, were included and followed-up for six months. Data regarding demographic variables, duration of fever, Intravenous Immunoglobulin (IVIG) resistance, hepatomegaly, neutrophilia, thrombocytopenia, haematocrit, Erythrocyte Sedimentation Rate (ESR), C-Reactive Protein (CRP), hepatic transaminases (alanine transaminase, aspartate amino-transferase), hyponatremia, hypoalbuminemia, and N-terminal-brain natriuretic peptide (NT-proBNP) were collected. Univariate and multivariate regression analyses were done using these variables for assessment of risk factors. Results: In the present study, out of 52 children, 28 (53.85%) were males and 24 (46.15%) were females with mean age of 3.74±2.55 years. Cardiovascular complications were observed in 27 (51.92%) patients, of whom 19 (35.54%) had CAA. Duration of fever ≥10 days, IVIG resistance, thrombocytopenia, low hematocrit, Alanine Transaminase (ALT) ≥100 U/L, hypoalbuminemia, and raised NT-proBNP were proven to be significant risk factors for development of CAA on univariate analysis. Thrombocytopenia and raised NT-proBNP came across as significant on binary logistic regression analysis. Conclusion: In this study, one or more types of cardiovascular abnormalities were present in 51.92% cases. Seven risk factors were identified to be significant in development of CAA on univariate analysis and among them two were proven significant in binary logistic regression.
ObjectivesThe study aimed to compare early molecular response (EMR) rates at 3 months of imatinib therapy with and without vitamin D3 supplementation in patients newly diagnosed with chronic-phase ...chronic myeloid leukaemia (CML-CP). The secondary objective was to assess the effects of vitamin D3 on complete haematological response (CHR) and its safety.DesignDouble-blind, placebo-controlled, exploratory randomised trial.SettingTertiary care hospital in northern India.ParticipantsTreatment-naive patients with chronic phase chronic myeloid leukaemia (n=62) aged >12 years were recruited from January 2020 to January 2021. Patients with progressive disease, pregnancy and hypercalcaemia were excluded.InterventionOral vitamin D3 supplementation (60 000 IU) or matched placebo was given once weekly for an initial 8 weeks along with imatinib after randomisation with 1:1 allocation ratio.Primary and secondary outcome measuresThe primary outcome was to compare EMR (defined as BCR-ABL1 transcript level ≤10%, international scale) at 3 months. The secondary outcomes were to compare effect of the intervention on CHR, correlation of 25(OH)2D3 levels with treatment response and safety according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.ResultsAt baseline, 14.5% of the patients had normal vitamin D3 levels. EMR at 3 months was attained in 24 patients (82.7%) of the vitamin D3 group and 21 (75%) of the placebo group (OR 1.6, 95% CI 0.37 to 7.37, p=0.4). A significant difference in vitamin D3 levels from baseline to the end of study was observed. Patients with vitamin D3 supplementation did not achieve higher CHR in comparison with placebo (OR 1.3, 95% CI 0.25 to 7.23, p=1.0). Vitamin D3 levels were not significantly correlated with BCR-ABL1 levels. No dose-limiting toxicities were observed.ConclusionVitamin D3 levels were low among patients with CML-CP in this study. Vitamin D3 supplementation with imatinib therapy did not have significant effect on EMR or CHR. Further clinical trials could be undertaken to assess the effective dosage and duration of vitamin D3 supplementation in these patients.Trial registration numberCTRI/2019/09/021164.
Abstract The objective of the investigation was to explore the abundance, composition, and diversity patterns of the fish fauna along the temporal and spatial scale and study the influence of ...environmental parameters on the fish assemblage in the Rihand reservoir, a large sub-tropical Indian reservoir in India. On the temporal scale, the highest abundance was recorded in the summer season and the lowest in the monsoon season, while on the spatial scale, the highest abundance was recorded from the riverine and the minimum from the lacustrine zone. The highest species richness and diversity were recorded from the riverine zone followed by the transitional and lacustrine zones, respectively. The analysis of the variance of fish abundance revealed insignificant differences between the riverine and the transitional zones. The trophic guild analysis indicated the dominance of carnivores. The output of canonical correspondence analysis depicted the significant influence of the physico-chemical traits on the abundance of fish species. The transparency and specific conductivity were found to be the most critical factors affecting fish assemblages in the Rihand reservoir. This study generated important baseline ecological information that would be useful for the monitoring, conservation, and management of the reservoir ecosystem.
PDF
