Arginine Citrullination at the C-Terminal Domain Controls RNA Polymerase II Transcription.

The post-translational modification of key residues at the C-terminal domain of RNA polymerase II (RNAP2-CTD) coordinates transcription, splicing, and RNA processing by modulating its capacity to act as a landing platform for a variety of protein complexes. Here, we identify a new modification at the CTD, the deimination of arginine and its conversion to citrulline by peptidyl arginine deiminase 2 (PADI2), an enzyme that has been associated with several diseases, including cancer. We show that, among PADI family members, only PADI2 citrullinates R1810 (Cit1810) at repeat 31 of the CTD. Depletion of PADI2 or loss of R1810 results in accumulation of RNAP2 at transcription start sites, reduced gene expression, and inhibition of cell proliferation. Cit1810 is needed for interaction with the P-TEFb (positive transcription elongation factor b) kinase complex and for its recruitment to chromatin. In this way, CTD-Cit1810 favors RNAP2 pause release and efficient transcription in breast cancer cells.

21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer.

BACKGROUND: The recurrence score based on the 21-gene breast-cancer assay has been clinically useful in predicting a chemotherapy benefit in hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, axillary lymph-node-negative breast cancer. In women with positive lymph-node disease, the role of the recurrence score with respect to predicting a benefit of adjuvant chemotherapy is unclear. METHODS: In a prospective trial, we randomly assigned women with hormone-receptor-positive, HER2-negative breast cancer, one to three positive axillary lymph nodes, and a recurrence score of 25 or lower (scores range from 0 to 100, with higher scores indicating a worse prognosis) to endocrine therapy only or to chemotherapy plus endocrine (chemoendocrine) therapy. The primary objective was to determine the effect of chemotherapy on invasive disease-free survival and whether the effect was influenced by the recurrence score. Secondary end points included distant relapse-free survival. RESULTS: A total of 5083 women (33.2% premenopausal and 66.8% postmenopausal) underwent randomization, and 5018 participated in the trial. At the prespecified third interim analysis, the chemotherapy benefit with respect to increasing invasive disease-free survival differed according to menopausal status (P = 0.008 for the comparison of chemotherapy benefit in premenopausal and postmenopausal participants), and separate prespecified analyses were conducted. Among postmenopausal women, invasive disease-free survival at 5 years was 91.9% in the endocrine-only group and 91.3% in the chemoendocrine group, with no chemotherapy benefit (hazard ratio for invasive disease recurrence, new primary cancer [breast cancer or another type], or death, 1.02; 95% confidence interval [CI], 0.82 to 1.26; P = 0.89). Among premenopausal women, invasive disease-free survival at 5 years was 89.0% with endocrine-only therapy and 93.9% with chemoendocrine therapy (hazard ratio, 0.60; 95% CI, 0.43 to 0.83; P = 0.002), with a similar increase in distant relapse-free survival (hazard ratio, 0.58; 95% CI, 0.39 to 0.87; P = 0.009). The relative chemotherapy benefit did not increase as the recurrence score increased. CONCLUSIONS: Among premenopausal women with one to three positive lymph nodes and a recurrence score of 25 or lower, those who received chemoendocrine therapy had longer invasive disease-free survival and distant relapse-free survival than those who received endocrine-only therapy, whereas postmenopausal women with similar characteristics did not benefit from adjuvant chemotherapy. (Funded by the National Cancer Institute and others; RxPONDER ClinicalTrials.gov number, NCT01272037.).

Rural-urban disparity in cancer burden and care: findings from an Indian cancer registry.

BACKGROUND: Cancer incidence and mortality vary across the globe, with nearly two-thirds of cancer-related deaths occurring in low- and middle-income countries. The rural-urban disparity in socio-demographic, behavioural, and lifestyle-related factors, as well as in access to cancer care, is one of the contributing factors. Population-based cancer registries serve as a measure for understanding the burden of cancer. We aimed to evaluate the rural-urban disparity in cancer burden and care of patients registered by an Indian population-based cancer registry. METHODS: This study collected data from Varanasi, Uttar Pradesh, India, between 2017 and 2019. Sex and site-specific age-standardised rates for incidence and mortality per 100,000 population were calculated. Rural-urban disparities in cancer incidence and mortality were estimated through rate differences and standardised rate ratios (with 95% confidence intervals). Univariable and multivariable regressions were applied to determine any significant differences in socio-demographic and cancer-related variables according to place of residence (rural/urban). Crude and adjusted odds ratios with 95% confidence intervals were calculated. RESULTS: 6721 cancer patients were registered during the study duration. Urban patients were older and had better literacy and socioeconomic levels, while rural patients had higher odds of having unskilled or semi-skilled professions. Diagnostic and clinical confirmation for cancer was significantly higher in urban patients, while verbal autopsy-based confirmation was higher in rural patients. Rural patients were more likely to receive palliative or alternative systems of medicine, and urban patients had higher chances of treatment completion. Significantly higher incidence and mortality were observed for oral cancer among urban men and for cervical cancer among rural women. Despite the higher incidence of breast cancer in urban women, significantly higher mortality was observed in rural women. CONCLUSIONS: Low- and middle-income countries are facing dual challenges for cancer control and prevention. Their urban populations experience unhealthy lifestyles, while their rural populations lack healthcare accessibility. The distinctness in cancer burden and pattern calls for a re-evaluation of cancer control strategies that are tailor-made with an understanding of urban-rural disparities. Context-specific interventional programmes targeting risk-factor modifications, cancer awareness, early detection, and accessibility to diagnosis and care are essential.

Sustainable and Eco-Friendly DLC Fabrication for Replacing Chrome on a Gravure Cylinder Surface.

This paper evaluates the potential of diamond-like carbon (DLC) as a durable surface protection to replace the chromium (Cr) layer, which is traditionally applied to gravure print cylinders and other components through a galvanic electroplating process. The fabrication of DLC is more eco-friendly and could reduce the environmental hazard posed by hexavalent chromium in liquid form that is used in Cr application and better adhere to environmental regulations. This could encourage businesses to bring the DLC fabrication process in-house, sharing resources such as materials, labor, and equipment, to help reduce costs. Four DLC variants (standard DLC, A-DLC, S-DLC, and organic silica) and chrome were analyzed and tested for their surface properties and durability. Data suggest that both standard DLC and S-DLC had higher surface free energy, allowing for good ink wetting on the surface when compared to chrome. In addition, the standard DLC and S-DLC surfaces are generally smoother than the chrome, resulting in lower relative hydrophilicity and allowing for easier removal of ink in the nonimage regions with the doctor blade. The elcometer adhesion test demonstrated that the bond strength of the DLC variants to their base layer was comparable to the bond strength of chrome, indicating that the adhesion strength of the two materials was similar. Furthermore, in the abrasion test, the wear on the standard DLC surface and the corresponding wear on the lamella tip of the metal doctor blades were notably lower than that observed on chrome. This distinction is particularly evident in each of the test trials, specifically run 1, which involved 2,000,000 wiping actions of a metal doctor blade in the presence of abrasive TiO2 ink pigments. Statistical analysis on standard DLC versus chrome suggests that DLC fabrication is effective and durable on plain and patterned surfaces. Therefore, from a sustainable and eco-friendly perspective, standard DLC and S-DLC would be good alternative durable surfaces for print cylinders and other components used in various industries due to superior wear resistance properties.

Rothia in Nonsmall Cell Lung Cancer is Associated With Worse Survival.

INTRODUCTION: The microbiome is known to play a significant role in cancer biology; however, few studies have elucidated its relationship with Nonsmall Cell Lung Cancer (NSCLC) patient outcomes. We hypothesized that there are specific microorganisms that are closely related with NSCLC patient survival. METHODS: Total of 647 NSCLC (Adenocarcinoma and Squamous Cell Carcinoma combined) patients in The Cancer Genome Atlas (TCGA) were analyzed using the R software. RESULTS: A Volcano Plot was analyzed with the patients divided into Short and Long Survivors by overall survival of 0.9 years, and we found that a bacterium Rothia was significantly abundant in Short Survivors, and Blastococcus, Leptospira, and Haematobacter in Long Survivors, but presence of Rothia alone was associated with overall survival. The age, race, subtype, and sex were not significantly different by the presence of Rothia in NSCLC. Unexpectedly, Rothia-positive NSCLC was associated with less cell proliferation by gene set enrichment analysis, Mki67 expression, proliferation score, with less fraction altered and homologous recombination deficiency, and with high infiltration of stromal cells, indicating favorable oncological characteristics. Further, Rothia-positive tumors were associated with significantly higher infiltration of CD8 T cells, CD4 T cells, Monocytes, and NK cells, and high interferon-gamma response, T-cell receptor richness, cytolytic activity, indicating favorable tumor immune microenvironment. CONCLUSIONS: NSCLC with Rothia was associated with worse survival but also with favorable oncological characteristics such as less cell proliferation and favorable tumor immune microenvironment. We cannot help but speculate that Rothia in NSCLC is associated with mortality unrelated to oncological characteristics.

Nanocellulose for Sustainable Water Purification.

Nanocelluloses (NC) are nature-based sustainable biomaterials, which not only possess cellulosic properties but also have the important hallmarks of nanomaterials, such as large surface area, versatile reactive sites or functionalities, and scaffolding stability to host inorganic nanoparticles. This class of nanomaterials offers new opportunities for a broad spectrum of applications for clean water production that were once thought impractical. This Review covers substantial discussions based on evaluative judgments of the recent literature and technical advancements in the fields of coagulation/flocculation, adsorption, photocatalysis, and membrane filtration for water decontamination through proper understanding of fundamental knowledge of NC, such as purity, crystallinity, surface chemistry and charge, suspension rheology, morphology, mechanical properties, and film stability. To supplement these, discussions on low-cost and scalable NC extraction, new characterizations including solution small-angle X-ray scattering evaluation, and structure-property relationships of NC are also reviewed. Identifying knowledge gaps and drawing perspectives could generate guidance to overcome uncertainties associated with the adaptation of NC-enabled water purification technologies. Furthermore, the topics of simultaneous removal of multipollutants disposal and proper handling of post/spent NC are discussed. We believe NC-enabled remediation nanomaterials can be integrated into a broad range of water treatments, greatly improving the cost-effectiveness and sustainability of water purification.

Syntheses and characterization of novel antimony (III) and bismuth (III) derivatives containing ß-enamino ester along with antimicrobial evaluation, DFT calculation, and cytotoxic study.

Four novel antimony (III) and bismuth(III) complexes of the kind Cl-Sb-O-C(OR)-CH(CH3 )C-NH-(CH2 )2 -NH-C(CH3 )CH:C(OR)-O [where R = -CH3 , M = Sb (1a); R = -C2 H5 , M = Sb (1b); R = -CH3, M = Bi (1c); R = -C2 H5 , M = Bi (1d)] were successfully prepared by reacting antimony(III)chloride and bismuth(III)chloride with sodium salt of ß-enamino esters in 1:1 stoichiometry, which were further structurally characterized by physicochemical and IR, 1 H, 13 C NMR spectral and mass spectrometry. Structural analysis revealed that all four derivatives of both antimony and bismuth display octahedarl geometry which has been optimized through computational studies. These derivatives along with their parent ligands were subsequently assayed in vitro for antibacterial (Bacillus subtilis, Pseudomonas aeruginosa) and antifungal (Aspergillus niger and Candida albicans) activities. Synthesized complexes were more efficacious in terms of biological activities as compared to parent ligands Further synthesized compounds were evaluated for their in vitro cytotoxic activity against lung cancer cell line A549 using MTT method. IC50 value for all four complexes was determined and all of them are found active. Computational studies of the representative complexes have been done using B3LYP/631-G* basis sets to provide optimized geometry.

Drought stress in Lens culinaris: effects, tolerance mechanism, and its smart reprogramming by using modern biotechnological approaches.

Among legumes, lentil serves as an imperative source of dietary proteins and are considered an important pillar of global food and nutritional security. The crop is majorly cultivated in arid and semi-arid regions and exposed to different abiotic stresses. Drought stress is a polygenic stress that poses a major threat to the crop productivity of lentils. It negatively influenced the seed emergence, water relations traits, photosynthetic machinery, metabolites, seed development, quality, and yield in lentil. Plants develop several complex physiological and molecular protective mechanisms for tolerance against drought stress. These complicated networks are enabled to enhance the cellular potential to survive under extreme water-scarce conditions. As a result, proper drought stress-mitigating novel and modern approaches are required to improve lentil productivity. The currently existing biotechnological techniques such as transcriptomics, genomics, proteomics, metabolomics, CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/cas9), and detection of QTLs (quantitative trait loci), proteins, and genes responsible for drought tolerance have gained appreciation among plant breeders for developing climate-resilient lentil varieties. In this review, we critically elaborate the impact of drought on lentil, mechanisms employed by plants to tolerate drought, and the contribution of omics approaches in lentils for dealing with drought, providing deep insights to enhance lentil productivity and improve resistance against abiotic stresses. We hope this updated review will directly help the lentil breeders to develop resistance against drought stress.

Cisplatin with veliparib or placebo in metastatic triple-negative breast cancer and BRCA mutation-associated breast cancer (S1416): a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitors are effective in germline BRCA1 or BRCA2 (BRCA1/2) mutation-associated metastatic breast cancer. However, studies evaluating PARP inhibitors plus platinum-based chemotherapy in germline BRCA1/2-wildtype triple-negative breast cancer are scarce. A large proportion of germline BRCA1/2-wildtype triple-negative breast cancer shows homologous recombination deficiency (HRD), resulting in a BRCA-like phenotype that might render sensitivity to PARP inhibitors. The S1416 trial assessed the efficacy of cisplatin combined with the PARP inhibitor veliparib in three predefined groups of metastatic breast cancer: germline BRCA1/2-mutated, BRCA-like, and non-BRCA-like. METHODS: S1416 was a randomised, double-blind, placebo-controlled, phase 2 trial conducted at 154 community and academic clinical sites across the USA. Eligible patients aged 18 years or older had metastatic or recurrent triple-negative breast cancer or germline BRCA1/2-associated metastatic or recurrent breast cancer, an Eastern Cooperative Oncology Group performance status of 0-2, and had received up to one line of chemotherapy for metastatic disease. Patients were randomly assigned (1:1) via the National Clinical Trials Network open interactive system with dynamic balancing on number of previous cytotoxic regimens for metastatic disease to receive intravenous cisplatin (75 mg/m2, day 1) combined with either veliparib or matching placebo (300 mg orally twice a day, days 1-14) on a 21-day cycle. Investigators, patients, and the sponsors were masked to treatment assignment; the study statisticians were unmasked. Central testing after ran domisation classified patients as having mutated or wildtype germline BRCA1/2. A biomarker panel established a priori was used to classify patients with wildtype germline BRCA1/2 into BRCA-like and non-BRCA-like phenotype groups, with BRCA-like status based on at least one of the biomarkers: genomic instability score (≥42), somatic BRCA1/2 mutations, BRCA1 promoter methylation, or non-BRCA1/2 homologous recombination repair germline mutations. The primary endpoint was investigator-assessed progression-free survival, analysed separately for the three predefined biomarker groups with a prespecified α value for each analysis. Efficacy analyses were done by intention to treat and included all eligible patients. Safety analyses of toxicities attributed to treatment included all patients who received at least one dose of veliparib or placebo. The study is ongoing and registered with ClinicalTrials.gov, NCT02595905. FINDINGS: Between July 7, 2016, and June 15, 2019, 335 patients were enrolled and randomly assigned. 320 patients (n=162 to cisplatin plus veliparib, all women; and n=158 to cisplatin plus placebo, 157 women and one man) were eligible for efficacy evaluation. 247 patients were classified into the three biomarker groups: germline BRCA1/2-mutated (n=37), BRCA-like (n=101), and non-BRCA-like (n=109). 73 patients could not be classified due to missing biomarker information. Median follow-up was 11·1 months (IQR 5·6-20·8). In the germline BRCA1/2-mutated group, median progression-free survival was 6·2 months (95% CI 2·3-9·2) in the cisplatin plus veliparib group and 6·4 months (4·3-8·2) in the cisplatin plus placebo group (HR 0·79 [95% CI 0·38-1·67]; log-rank p=0·54). In the BRCA-like group, median progression-free survival was 5·9 months (95% CI 4·3-7·8) in the cisplatin plus veliparib group versus 4·2 months (2·3-5·0) in the cisplatin plus placebo group (HR 0·57 [95% CI 0·37-0·88]; p=0·010). In the non-BRCA-like group, median progression-free survival was 4·0 months (95% CI 2·5-4·7) in the cisplatin plus veliparib group versus 3·0 months (2·2-4·4) in the cisplatin plus placebo group (HR 0·89 [95% CI 0·60-1·33]; p=0·57). The most common grade 3 or worse adverse events attributed to treatment were neutropenia (71 [46%] of 155 patients in the cisplatin plus veliparib group vs 29 [20%] of 147 in the cisplatin plus placebo group), leukopenia (42 [27%] vs 11 [7%]), anaemia (35 [23%] vs 12 [8%]), and thrombocytopenia (29 [19%] vs four [3%]). Serious adverse events attributed to treatment occurred in 48 (31%) patients in the cisplatin plus veliparib group and 53 (36%) patients in the cisplatin plus placebo group. Treatment-related adverse events led to death in one patient in the cisplatin plus veliparib group (sepsis) and one patient in the cisplatin plus placebo group (acute kidney injury due to cisplatin plus heart failure from previous doxorubicin exposure). INTERPRETATION: The addition of veliparib to cisplatin significantly improved progression-free survival in patients with BRCA-like metastatic triple-negative breast cancer, but not in patients with non-BRCA-like metastatic breast cancer. PARP inhibitors combined with platinum-based chemotherapy should be explored further in BRCA-like triple-negative breast cancer. FUNDING: National Cancer Institute and National Institute of General Medical Sciences (US National Institutes of Health); AbbVie; Myriad Genetics; the Biomarker, Imaging, and Quality of Life Studies Funding Program (awarded by the National Cancer Institute); and The University of Kansas Cancer Center.

De novo chromosome level assembly of a plant genome from long read sequence data.

Recent advances in the sequencing and assembly of plant genomes have allowed the generation of genomes with increasing contiguity and sequence accuracy. Chromosome level genome assemblies using sequence contigs generated from long read sequencing have involved the use of proximity analysis (Hi-C) or traditional genetic maps to guide the placement of sequence contigs within chromosomes. The development of highly accurate long reads by repeated sequencing of circularized DNA (HiFi; PacBio) has greatly increased the size of contigs. We now report the use of HiFiasm to assemble the genome of Macadamia jansenii, a genome that has been used as a model to test sequencing and assembly. This achieved almost complete chromosome level assembly from the sequence data alone without the need for higher level chromosome map information. Eight of the 14 chromosomes were represented by a single large contig (six with telomere repeats at both ends) and the other six assembled from two to four main contigs. The small number of chromosome breaks appears to be the result of highly repetitive regions including ribosomal genes that cannot be assembled by these approaches. De novo assembly of near complete chromosome level plant genomes now appears possible using these sequencing and assembly tools. Further targeted strategies might allow these remaining gaps to be closed.

Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2.

BACKGROUND: The distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system. METHODS: Data for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies. Likelihood ratios (LR) were calculated for the association of ovarian cancer histology and other characteristics, with BRCA1 and BRCA2 variant pathogenicity. Estimates were aligned to ACMG/AMP code strengths (supporting, moderate, strong). RESULTS: No histological subtype provided informative ACMG/AMP evidence in favour of BRCA1 and BRCA2 variant pathogenicity. Evidence against variant pathogenicity was estimated for the mucinous and clear cell histologies (supporting) and borderline cases (moderate). Refined associations are provided according to tumour grade, invasion and age at diagnosis. CONCLUSIONS: We provide detailed estimates for predicting BRCA1 and BRCA2 variant pathogenicity based on ovarian tumour characteristics. This evidence can be combined with other variant information under the ACMG/AMP classification system, to improve classification and carrier clinical management.

Morphological, phytochemical, and transcriptome analyses provide insights into the biosynthesis of monoterpenes in Monarda citriodora.

MAIN CONCLUSION: Morphological, phytochemical, and transcriptome analyses revealed candidate genes involved in the biosynthesis of volatile monoterpenes and development of glandular trichomes in Monarda citriodora. Monarda citriodora Cerv. ex Lag. is a valuable aromatic plant due to the presence of monoterpenes as major constituents in its essential oil (EO). Thus, it is of sheer importance to gain knowledge about the site of the biosynthesis of these terpenoid compounds in M. citriodora, as well as the genes involved in their biosynthesis. In this study, we studied different types of trichomes and their relative densities in three different developmental stages of leaves, early stage of leaf development (L1), mid-stage of leaf development (L2), and later stage of leaf development (L3) and the histochemistry of trichomes for the presence of lipid and terpenoid compounds. Further, the phytochemical analysis of this plant through GC-MS indicated a higher content of monoterpenes (thymol, thymoquinone, γ-terpinene, p-cymene, and carvacrol) in the L1 stage with a substantial decrease in the L3 stage of leaf development. This considerable decrease in the content of monoterpenes was attributed to the decrease in the trichome density from L1 to L3. Further, we developed a de novo transcriptome assembly by carrying out RNA sequencing of different plant parts of M. citriodora. The transcriptome data revealed several putative unigenes involved in the biosynthesis of specialized terpenoid compounds, as well as regulatory genes involved in glandular trichome development. The data generated in the present study build a strong foundation for further improvement of M. citriodora, in terms of quantity and quality of its essential oil, through genetic engineering.

Acute metabolic alterations in the hippocampus are associated with decreased acetylation after blast induced TBI.

INTRODUCTION: Blast induced Traumatic brain injury (BI-TBI) is common among military personnels as well as war affected civilians. In the war zone, people can also encounter repeated exposure of blast wave, which may affect their cognition and metabolic alterations. OBJECTIVE: In this study we assess the metabolic and histological changes in the hippocampus of rats at 24 h post injury. METHOD: Rats were divided into four groups: (i) Sham; (ii) Mild TBI (mi); (iii) Moderate TBI (mo); and (iv) Repetitive mild TBI (rm TBI) and then subjected to different intensities of blast exposure. Hippocampal tissues were collected after 24 h of injury for proton nuclear magnetic resonance spectroscopy (1H NMR spectroscopy) and immunohistochemical (IHC) analysis. RESULTS: The metabolic alterations were found in the hippocampal tissue samples and these alterations showed significant change in glutamate, N-Acetylaspartic acid (NAA), acetate, creatine, phosphoethanolamine (PE), ethanolamine and PC/choline concentrations in rmTBI rats only. IHC studies revealed that AH3 (Acetyl histone) positive cells were decreased in rm TBI tissue samples in comparison to other TBI groups and sham rats. This might reflect an epigenetic alteration due to repeated blast exposure at 24 h post injury. Additionally, astrogliosis was observed in miTBI and moTBI hippocampal tissue while no change was observed in rmTBI tissues. CONCLUSION: The present study reports altered acetylation in the presence of altered metabolism in hippocampal tissue of blast induced rmTBI at 24 h post injury. Mechanistic understanding of these intertwined processes may help in the development of better therapeutic pathways and agents for blast induced TBI in near future.

Role of verbal autopsy in cancer registration: A mixed-methods study from the population-based cancer registry of Northern India.

OBJECTIVES: To describe utilisation of verbal autopsy as one of the data collection approaches in cancer registration in an Indian setting. We aimed to estimate the proportion and epidemiological characteristics of malignancies identified by the Varanasi population-based cancer registry (PBCR) using verbal autopsy between 2017 and 2019 and to develop a thematic network for implementing verbal autopsy. METHODS: This was a cross-sectional mixed-methods study. Quantitative methods were applied to analyse information from PBCR proforma of the verbal autopsy-confirmed cancers; qualitative methods were applied to evaluate verbal autopsy conducted by field staff from key informants. In-depth interviews of field staff for the challenges and potential solutions during verbal autopsy were assessed. RESULTS: Of 6466 registered cancers, 1103 (17.1%) were verbal autopsy-confirmed cancers, which had no other source of information. The majority of verbal autopsy cases were from vulnerable populations who were aged >50 years (721, 65.4%), female (607, 55.1%), from rural backgrounds (853, 77.3%), illiterate or just able to read and write (636, 57.7%), and from lower and middle-income groups (823, 74.6%). Verbal autopsy helped provide information about symptoms and site of disease, diagnostic and treatment details, and disease status. Major challenges during verbal autopsy described by field staff were incomplete cancer treatment, destruction of medical records and non-cooperation by the community and lack of support from the local workforce as cancer is not notifiable. CONCLUSION: Verbal autopsy helped identify cancers that would have been missed during active case finding from available resources. The majority of verbal autopsy-confirmed patients belonged to vulnerable populations. Non-cooperation from community and local health systems was major challenge during verbal autopsy. Developing robust cancer awareness, patient navigation, and social support programmes will strengthen verbal autopsy. Integration of standardised and reproducible methods of verbal autopsy in cancer registry and digitalization of health information, especially in limited-resource settings with weak vital registration, will facilitate completeness in cancer registration.

Nitric oxide: An emerging warrior of plant physiology under abiotic stress.

The natural environment of plants comprises a complex set of various abiotic stresses and their capability to react and survive under this anticipated changing climate is highly flexible and involves a series of balanced interactions between signaling molecules where nitric oxide becomes a crucial component. In this article, we focussed on the role of nitric oxide (NO) in various signal transduction pathways of plants and its positive impact on maintaining cellular homeostasis under various abiotic stresses. Besides this, the recent data on interactions of NO with various phytohormones to control physiological and biochemical processes to attain abiotic stress tolerance have also been considered. These crosstalks modulate the plant's defense mechanism and help in alleviating the negative impact of stress. While focusing on the diverse functions of NO, an effort has been made to explore the functions of NO-mediated post-translational modifications, such as the N-end rule pathway, tyrosine nitration, and S-nitrosylation which revealed the exact mechanism and characterization of proteins that modify various metabolic processes in stressed conditions. Considering all of these factors, the present review emphasizes the role of NO and its interlinking with various phytohormones in maintaining developmental processes in plants, specifically under unfavorable environments.

Thymidine kinase activity levels in serum can identify HR+ metastatic breast cancer patients with a low risk of early progression (SWOG S0226).

BACKGROUND: Some patients with metastatic breast cancer (MBC) stay on endocrine therapy (ET) for years and others progress quickly. Serum thymidine kinase activity (TKa), an indicator of cell-proliferation, is a potential biomarker for monitoring ET and predicting MBC outcome. We have previously reported TKa as being prognostic in MBC in SWOG S0226. Here, new data on progression within 30/60 days post sampling, with a new, FDA approved version of DiviTum®TKa highlighting differences vs. a Research Use Only version is reported. METHODS: 1,546 serum samples from 454 patients were assessed, collected at baseline and at 4 subsequent timepoints during treatment. A new predefined cut-off tested the ability to predict disease progression. A new measuring unit, DuA (DiviTum® unit of Activity) is adopted. RESULTS: A DiviTum®TKa score <250 DuA provides a much lower risk of progression within 30/60 days after blood draw, the negative predictive value (NPV) was 96.7% and 93.5%, respectively. Patients <250 DuA experienced significantly longer progression-free survival and overall survival, demonstrated at baseline and for all time intervals. CONCLUSIONS: DiviTum®TKa provides clinically meaningful information for patients with HR+ MBC. Low TKa levels provide such a high NPV for rapid progression that such patients might forego additional therapy added to single agent ET.Trial registration: NCT00075764.

Design, synthesis and antidiabetic study of triazole clubbed indole derivatives as α-glucosidase inhibitors.

α -Glucosidase is an enzyme present near the brush boundary of the small intestine that is essential in the hydrolysis of carbohydrates to glucose. Because inhibiting this enzyme slows the release of glucose, α-Glucosidase inhibitors are appealing medications for treating diabetes as a carbohydrate-related illness. The present study includes the design, synthesis and antidiabetic potential of novel triazole based indole derivatives as α-glucosidase inhibitor. Among them, the compound R1 was found to be most potent with promising candidate with IC50 value of 10.1 µM and R2 and R3 showed the good inhibitory potency with IC50 values 12.95 µM, 11.35 µM, respectively when compared to the standard drug acarbose having IC50 value of 13.5 µM. In in vivo studies, body weight of the mice was increased when compared to standard drug acarbose, the blood glucose level of the mice was decreased, same as the total cholesterol level, LDL, and triglycerides level decreased in comparison to standard drug. The level HDL was increased as it is a good cholesterol in comparison to standard drug acarbose. Furthermore, these synthesized compounds were docked with α-glucosidase using PDB ID:3WY1 which showed that compound R1 having good docking score -6.734 kcal/mol and compound R2, R3 showed docking score -6.14, -6.10 kcal/mol, respectively when compared with standard acarbose having docking score -4.55 kcal/mol. R1 showed the similar interaction with amino acid PHE166, GLU271, comparison with standard drug Acarbose. The synthesized compounds have been confirmed for antidiabetic activity and may be used for further development of potent compounds.

Trends in carbapenem resistance in Pre-COVID and COVID times in a tertiary care hospital in North India.

BACKGROUND: Carbapenem resistance is endemic in the Indian sub-continent. In this study, carbapenem resistance rates and the prevalence of different carbapenemases were determined in Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa during two periods; Pre-COVID (August to October 2019) and COVID (January to February 2021) in a north-Indian tertiary care hospital. METHODS: Details of patient demographics and clinical condition was collated from the Hospital Information System and detection of carbapenemases NDM, OXA-48, VIM, IMP and KPC was done by Polymerase chain reaction (PCR) in 152 and 138 non-consecutive carbapenem resistant isolates during the two study periods respectively. Conjugation assay and sequencing of NDM and OXA-48 gene was done on a few selected isolates. RESULTS: As compared to Pre-COVID period, co-morbidities and the mortality rates were higher in patients harbouring carbapenem resistant organisms during the COVID period. The overall carbapenem resistance rate for all the four organisms increased from 23 to 41% between the two periods of study; with Pseudomonas aeruginosa and Klebsiella pneumoniae showing significant increase (p < 0.05). OXA-48, NDM and co-expression of NDM and OXA-48 were the most common genotypes detected. NDM-5 and OXA-232 were most common variants of NDM and OXA-48 family respectively during both the study periods. CONCLUSION: Higher rate of carbapenem resistance in COVID times could be attributed to increase in number of patients with co-morbidities. However, genetic elements of carbapenem resistance largely remained the same in the two time periods.

A sustainable approach to the degradation of dyes by fungal species isolated from industrial wastewaters: Performance, parametric optimization, kinetics and degradation mechanism.

Fungal abetted processes are among the finest approaches for the transformation or degradation and decolorization of dyes in effluents. In this piece of research; biodegradation and metabolic pathways of two toxic dyes Congo Red (CR) and Reactive black 5 (RB5) by two strains of Aspergillus sp. fungus in batch experiments has been investigated. Morphological characteristics of the isolates were observed with both light and electron microscopies. Based on molecular characterization the isolates were identified as Aspergillus flavus and Aspergillus niger. The degradation was also optimized via. operational parameters such as pH, temperature, incubation time, inoculums size, dye concentration, carbon sources and nitrogen sources. Degradation measurements revealed that the isolates effectively degraded 90% and 96% of CR and RB5 respectively. Metabolites were identified with Liquid chromatography-mass spectrometry (LCMS) and degradation pathways of the dyes were proposed. Toxicity assay Phaseolus mungo seeds showed that pure CR and RB5 dyes exhibits significant toxicity whereas fungal treated dye solution resulted in an abatement of the toxicity and cell viability was increased. The results stipulated in this article clearly showed the effectiveness of the isolates on detoxification of CR and RB5 dyes.

Pyrus pashia fruit extract and its major phytometabolite chrysin prevent hippocampal apoptosis and memory impairment in PTZ-kindled mice.

OBJECTIVES: Epilepsy is a chronic neurological condition with recurrent seizures. One-third of epilepsy patients experience unacceptable side effects from antiepileptic drugs. Pyrus pashia is a deciduous tree from southern Asia. Ethnomedicinally, Malakand tribes use its fruits for epilepsy treatment. Our prior research demonstrated the anticonvulsive properties of ethanolic extract of Pyrus pashia (EPP) and its bioactive compound chrysin in acute seizure tests. This study aims to investigate the impact of EPP and chrysin on cognitive impairment in a PTZ-induced kindling mice model of epilepsy. METHODS: Swiss albino male mice were equally divided into four groups. The first group received 0.5% carboxy methyl cellulose dissolved in normal saline while the other three groups were pre-treated with Diazepam (DZP) (1 mg/kg, i.p.), EPP (200 mg/kg, p.o.) and chrysin (5 mg/kg, p.o.). After 30 min, all groups were administered PTZ (35 mg/kg, i.p.) and evaluated for seizure severity, cognitive function, and neuronal apoptosis. Western blot analysis was conducted to analyze the expressions of apoptosis biomarkers and memory-related genes, including cAMP response element-binding protein (CREB) and Brain Derived Neurotrophic Factor (BDNF). RESULTS: The therapeutic effects of EPP and Chrysin were comparable to DZP in terms of reducing seizure severity, but unlike DZP, they prevented PTZ-induced memory impairment in experimental animals. Additionally, they increased the levels of BDNF and CREB while reducing apoptotic biomarkers in the hippocampus of experimental animals. CONCLUSIONS: Based on the leads offered by this study EPP and its major bioactive constituent, could be developed as the treatment option for epilepsy.