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BackgroundVaccines for SARS-CoV-2 have been considerably effective in reducing rates of infection and severe COVID-19. However, many patients, especially those who are immunocompromised due to cancer or other factors, as well as individuals who are unable to receive vaccines or are in resource-poor countries, will continue to be at risk for COVID-19. We describe clinical, therapeutic, and immunologic correlatives in two patients with cancer and severe COVID-19 who were treated with leflunomide after failing to respond to standard-of-care comprising remdesivir and dexamethasone. Both patients had breast cancer and were on therapy for the malignancy.MethodsThe protocol is designed with the primary objective to assess the safety and tolerability of leflunomide in treating severe COVID-19 in patients with cancer. Leflunomide dosing consisted of a loading dose of 100 mg daily for the first three days, followed by daily dosing, at the assigned dose level (Dose Level 1: 40 mg, Dose Level -1, 20 mg; Dose Level 2, 60 mg), for an additional 11 days. At defined intervals, serial monitoring of blood samples for toxicity, pharmacokinetics, and immunologic correlative studies were performed, as well as nasopharyngeal swabs for PCR analysis of SARS-CoV-2.ResultsPreclinically, leflunomide impaired viral RNA replication, and clinically, it led to a rapid improvement in the two patients discussed herein. Both patients completely recovered, with minimal toxicities; all adverse events experienced were considered unrelated to leflunomide. Single-cell mass-cytometry analysis showed that leflunomide increased levels of CD8+ cytotoxic and terminal effector T cells and decreased naïve and memory B cells.ConclusionsWith ongoing COVID-19 transmission and occurrence of breakthrough infections in vaccinated individuals, including patients with cancer, therapeutic agents that target both the virus and host inflammatory response would be helpful despite the availability of currently approved anti-viral agents. Furthermore, from an access to care perspective, especially in resource-limited areas, an inexpensive, readily available, effective drug with existing safety data in humans is relevant in the real-world setting.

18F-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is one of the most widely used imaging techniques to detect multiple myeloma (MM). Intracellular FDG uptake depicts in vivo metabolic activity, which can be seen in both malignant and nonmalignant cells, resulting in limited sensitivity and specificity. Our group showed preclinically that tracing MM dissemination using a CD38-directed human antibody, daratumumab, that is radioconjugated with 64Cu via the chelator DOTA (64Cu-daratumumab), led to improved sensitivity and specificity over that of FDG. Here, we report the results of a phase 1 trial designed to (1) assess the safety and feasibility of 64Cu-daratumumab PET/CT and (2) preliminarily evaluate and characterize the ability of 64Cu-daratumumab to accurately detect or exclude MM lesions. A total of 12 daratumumab-naive patients were imaged. Prior to the injection of 15 mCi/5 mg of 64Cu-daratumumab, patients were treated with 0 (n = 3), 10 (n = 3), 45 (n = 3), or 95 mg (n = 3) of unlabeled daratumumab to assess its effect on image quality. No significant adverse events were observed from either unlabeled daratumumab or 64Cu-daratumumab. Of the dose levels tested, 45 mg unlabeled daratumumab was the most optimal in terms of removing background signal without saturating target sites. 64Cu-daratumumab PET/CT provided safe whole-body imaging of MM. A trial comparing the sensitivity and specificity of 64Cu-daratumumab PET/CT with that of FDG PET/CT is planned. This trial was registered at www.clinicaltrials.gov as #NCT03311828.

Background: Reovirus (RV) is an oncolytic virus with natural tropism for cancer cells. We previously showed that RV administration in multiple myeloma (MM) patients was safe, but disease control associated with viral replication in the cancer cells was not observed. The combination with proteasome inhibitors (PIs) has shown to enhance RV therapeutic activity, but the mechanisms of action have not been fully elucidated. Methods: Electron microscopy, q-RT-PCR, single-cell mass cytometry (CyTOF), flow cytometry, plaque assays, immunohistochemistry, and Western blot analysis were used to assess RV infection of both myeloma and immune cells. Immune fluorescence, flow cytometry, and luciferase reporter assays were used to assess NF-κB pathway activation upon RV treatments. Immune profiling changes, both ex vivo and in MM patients, were analyzed by flow cytometry and CyTOF analysis. T-cell receptor (TCR) sequencing was also conducted both in immune competent MM mice and in patients enrolled in a phase 1b trial per a standard 3 + 3 dose escalation schedule. Results: Here we show ex vivo and in vivo that proteasome inhibitors (PIs) potentiate reovirus replication in circulating classical monocytes, increasing viral delivery to myeloma cells. We found that the anti-viral signals in monocytes primarily rely on NF-κB activation and that this effect is impaired by the addition of PIs. Conversely, the addition of PIs to RV therapy supports immune activation and killing of MM, independently of direct PI sensitivity. To validate the importance of PIs in enhancing oncolytic viral therapy independently of their killing activity on cancer cells, we then conducted a phase 1b trial of the reovirus Pelareorep together with the PI carfilzomib in 13 heavily pretreated PI-resistant MM patients. Objective responses, which were associated with active reovirus replication in MM cells, T cell activation, and monocytic expansion, were noted in 70% of patients. Conclusions: Although characterized as immunosuppressive drugs, PIs improved RV delivery to MM cells but also enhanced anti-MM efficacy through immune-mediated killing of myeloma cells, independently of their PI sensitivity. These results highlight a more generalizable use of PIs as therapeutic companions to support oncolytic-based therapies in cancers. Trial registration: clinicaltrials.gov, NCT 02101944. [ABSTRACT FROM AUTHOR]

Linseed is an oldest oilseed crops having multiplicity of uses, grown for yielding oil as well as fibre. Among the various biotic factors affecting linseed productivity, weeds are regarded as most disdain to crop production, because of the initial slow growth and relatively lower canopy spread, resulting in non-realization of desired level of productivity of the crop. Weed dynamics in linseed depends on agroclimatic situation, soil characteristics, cropping pattern, crop management practices and availability of soil moisture in the field. Manual weeding is labour intensive and is comparatively more time consuming, which necessitates a cost-effective chemical weed management practice for controlling weeds. Combination of pre-emergence herbicides followed by post-emergence herbicides provides an effective weed management since the pre-emergence herbicides does not allow the emergence of most of weeds through their action in inhibiting root and shoot growth, whereas, post-emergence application controls effectively the weed flush which germinates after getting the first irrigation. This article critically reviews the crop-weed competition, weed dynamics and their impact on linseed yield, including various research efforts taken by researchers in controlling the weeds. As very less research work is being conducted in India by various Agricultural Universities on weed management aspects of linseed, the future challenge should focus research on major areas of weed ecology, assessment of on-farm losses caused by weeds, bio-efficacy of post-emergence herbicides and on-farm assessment of available integrated weed management options in linseed for sustainable linseed production. [ABSTRACT FROM AUTHOR]

Aim: Rutin is a flavonoid glycoside obtained from the plant Ruta graveolens. It was known to have immunosuppressant activities. This study was focused on effect of rutin against immunoglobulin A (IgA) nephropathy. Methods: IgA nephropathy was induced in Sprague–Dawley rats with various inducing agents described in text. During the later part of the induction phase, rutin was administered. Control group rats did not receive any treatment or inducing agent, induced group rats received only the inducing agents, whereas treatment group received the inducing agents as well as rutin. Results: During the study, various biochemical parameters pertaining to kidney function were evaluated and also, the expression of proteins and cytokines responsible for inflammation and fibrosis were assessed. The effect of rutin in IgA nephropathy was promising as treatment with rutin reduced the deposition of IgA in the glomeruli of rats. Along with this we also tried to establish the probable mechanism of action of rutin and based on the summary of the results it was concluded that rutin reduced the inflammation and fibrosis related to IgA nephropathy by inhibiting the TGF‐β/SMAD pathways and ultimately reducing the expression of α‐smooth muscle actin (α‐SMA). Conclusion: Comprehending all the above consideration, it may be safely said that that rutin alleviated inflammation and also fibrosis mediated by IgA, by suppressing the transforming growth factor‐β (TGF‐β) activities through suppressor of mothers against decapentaplegic pathways and reduced the epithelial‐to‐mesenchymal transition by downregulating the α‐SMA which is a marker for fibrosis. [ABSTRACT FROM AUTHOR]

The British enacted the Criminal Tribes Act in 1871 to control Indian society after the rebellion against colonial rule in 1857. By means of the Act, the British depicted entire communities and groups as hereditary criminals – without any substantive legal or incriminating evidence – using the concept of race, used in anthropology and anthropometry, and of caste. They termed the groups 'tribes' instead of 'castes' to evoke qualities of wildness and savagery in a way that the term 'caste' could not. The British also used the Act to term the tribes 'criminal'. In ascribing criminality, they misinterpreted texts, folklore and proverbs, and they relied on the biased advice of upper caste elite native informants. This systematic sociopolitical and legal subjugation stigmatized, ostracized and impoverished many so-called lower-caste and tribal communities. Even 75 years after Independence and denotification of the 'criminal' status, these communities remain outcastes. This paper traces the making of the category of 'criminal tribe' in colonial times – by charting the discourses, practices, processes and legal landmarks that led to the enactment, subsequent amendments and, finally, repeal of the Criminal Tribes Act, 1871 – and its afterlife in postcolonial India. The paper argues that although the category of 'criminal caste' did exist before colonial times, the British colonialists applied the category of 'tribe' to the criminal castes for rhetorical and administrative purposes, and that the socio-legal construction of criminal tribes happened through a concatenation of contradictory notions that made the label of 'criminal tribe' a patchwork of mutually untenable discourses. [ABSTRACT FROM AUTHOR]

Background: Thyroid hormones play a crucial role in major metabolic pathways in the body and dyslipidemia is a major metabolic abnormality seen in thyroid disorders. Cardiovascular diseases (CVDs) are now emerging as the leading cause of morbidity and mortality worldwide and the most important risk factor for CVDs is dyslipidemia. The lipid ratios that have a positive association with CVD risk are atherogenic index of plasma (AIP), Castelli’s risk index (CRI)-I and II, and atherogenic coefficient (AC). Clinically, both an excess and deficiency of thyroid hormones can exacerbate or induce CVDs and lipid ratio can be used as an inexpensive marker for predicting CVD risk. Aims and Objectives: This study aims to evaluate the lipid ratios (AIP, CRI-I, CRI-II, AC) in patients with thyroid dysfunction and compare the results with lipid ratios in euthyroid individuals. This study also aims to find any correlation, if exists, between lipid ratios and serum thyroid-stimulating hormone (TSH) levels in thyroid dysfunction. Materials and Methods: The serum TSH and lipid profile were evaluated in fifty euthyroid, fifty hypothyroid, fifty subclinical hypothyroid, and fifty hyperthyroid patients. The lipid ratios (AIP, CRI-I, CRI-II, AC) were calculated from the lipid profile. Results: The mean lipid ratios were higher in hypothyroid, followed by subclinical hypothyroid cases when compared to euthyroid controls and hyperthyroid patients. A positive correlation was observed between the TSH and lipid ratios in euthyroid, hypothyroid, and subclinical hypothyroid subjects. There was no significant correlation between TSH and lipid ratios in hyperthyroid patients. Conclusion: This study demonstrates that the evaluation of lipid ratios along with TSH can provide an effective screening tool to assess the cardiovascular risk in patients with subclinical and overt hypothyroidism, especially in the absence of imaging techniques in resource-limited centers. [ABSTRACT FROM AUTHOR]