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The novel Bruton's tyrosine kinase inhibitor ibrutinib has demonstrated high response rates in B-cell lymphomas; however, a growing number of ibrutinib-treated patients relapse with resistance and fulminant progression. Using chemical proteomics and an organotypic cell-based drug screening assay, we determine the functional role of the tumour microenvironment (TME) in ibrutinib activity and acquired ibrutinib resistance. We demonstrate that MCL cells develop ibrutinib resistance through evolutionary processes driven by dynamic feedback between MCL cells and TME, leading to kinome adaptive reprogramming, bypassing the effect of ibrutinib and reciprocal activation of PI3K-AKT-mTOR and integrin-β1 signalling. Combinatorial disruption of B-cell receptor signalling and PI3K-AKT-mTOR axis leads to release of MCL cells from TME, reversal of drug resistance and enhanced anti-MCL activity in MCL patient samples and patient-derived xenograft models. This study unifies TME-mediated de novo and acquired drug resistance mechanisms and provides a novel combination therapeutic strategy against MCL and other B-cell malignancies.

We recently reported that a conditioned stimulus (CS) memory retrieval-extinction procedure decreases reinstatement of cocaine and heroin seeking in rats and heroin craving in humans. Here we show that non-contingent cocaine or methylphenidate injections (UCS retrieval) 1 h before the extinction sessions decreases cocaine-priming-induced reinstatement, spontaneous recovery, and renewal of cocaine seeking in rats. Unlike the CS-based memory retrieval-extinction procedure, the UCS memory retrieval manipulation decreases renewal and reinstatement of cocaine seeking in the presence of cocaine cues that were not present during extinction training and also decreases cocaine seeking when the procedure commences after 28 days of abstinence. The inhibitory effect of the UCS retrieval manipulation on cocaine-priming-induced reinstatement is mediated by regulation of AMPA-receptor endocytosis in the basolateral amygdala. The UCS memory retrieval-extinction procedure has superior relapse prevention characteristics than the CS memory retrieval-extinction procedure and could be a promising method for decreasing relapse in human addicts.

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To improve the quality control of drugs, we predicted the absorption, distribution, metabolism, excretion, and toxicity (ADMET) of ceftazidime (CAZ) and its impurities via in silico methods. We used three types of quantitative structure-activity relationship and docking software for precise prediction: Discovery Studio 4.0, OECD QSAR Toolbox 4.1, Toxtree, and the pkCSM approach. The pharmacokinetics and toxicity of ceftazidime and impurity A (Δ-2-CAZ) are similar. The biological properties of impurity B (CAZ E -isomer) are different from CAZ. Therefore, we focused on drug stability to analyze impurity B. Impurities D and I have strong lipophilicity, good intestinal absorption, and poor excretion in the body. Impurity D is particularly neurotoxic and genotoxic. It is important to control the content of impurity D. The toxicity of impurity F is low, but the toxicity is enhanced when it becomes the C-3 side chain of CAZ and forms a quaternary amine group. We conclude that the beta-lactam ring of nucleus, the quaternary amine group at the C-3 side chain, and the acetates at the C-7 side chain of CAZ are the main toxic functional groups. Impurities B and D may be the genetic impurity in CAZ and may also have neurotoxicity. This in silico approach can predict the toxicity of other cephalosporins and impurities.

The present study suggests that highly aggressive PTMCs may arise in a subset of patients with BRAF(V600E) mutation and tumors greater than 5 mm. Extrathyroidal invasion, lymph node metastases, and the type of surgical procedures were significantly associated with tumor recurrence. Although multivariate analysis showed that tumor recurrence was not associated with BRAF(V600E) mutation, it has not been shown that treating these patients more aggressively changes outcomes.

Background Coronavirus disease 2019 (COVID-19) has evolved into a worldwide pandemic, and has been found to be closely associated with mental and neurological disorders. We aimed to comprehensively quantify the association between mental and neurological disorders, both pre-existing and subsequent, and the risk of susceptibility, severity and mortality of COVID-19. Methods In this systematic review and meta-analysis, we searched PubMed, Web of Science, Embase, PsycINFO, and Cochrane library databases for studies published from the inception up to January 16, 2021 and updated at July 7, 2021. Observational studies including cohort and case-control, cross-sectional studies and case series that reported risk estimates of the association between mental or neurological disorders and COVID-19 susceptibility, illness severity and mortality were included. Two researchers independently extracted data and conducted the quality assessment. Based on I 2 heterogeneity, we used a random effects model to calculate pooled odds ratios (OR) and 95% confidence intervals (95% CI). Subgroup analyses and meta-regression analysis were also performed. This study was registered on PROSPERO (registration number: CRD 42021230832). Finding A total of 149 studies (227,351,954 participants, 89,235,737 COVID-19 patients) were included in this analysis, in which 27 reported morbidity (132,727,798), 56 reported illness severity (83,097,968) and 115 reported mortality (88,878,662). Overall, mental and neurological disorders were associated with a significant high risk of infection (pre-existing mental: OR 1·67, 95% CI 1·12-2·49; and pre-existing neurological: 2·05, 1·58-2·67), illness severity (mental: pre-existing, 1·40, 1·25-1·57; sequelae, 4·85, 2·53-9·32; neurological: pre-existing, 1·43, 1·09-1·88; sequelae, 2·17, 1·45-3·24), and mortality (mental: pre-existing, 1·47, 1·26-1·72; neurological: pre-existing, 2·08, 1·61-2·69; sequelae, 2·03, 1·66-2·49) from COVID-19. Subgroup analysis revealed that association with illness severity was stronger among younger COVID-19 patients, and those with subsequent mental disorders, living in low- and middle-income regions. Younger patients with mental and neurological disorders were associated with higher mortality than elders. For type-specific mental disorders, susceptibility to contracting COVID-19 was associated with pre-existing mood disorders, anxiety, and attention-deficit hyperactivity disorder (ADHD); illness severity was associated with both pre-existing and subsequent mood disorders as well as sleep disturbance; and mortality was associated with pre-existing schizophrenia. For neurological disorders, susceptibility was associated with pre-existing dementia; both severity and mortality were associated with subsequent delirium and altered mental status; besides, mortality was associated with pre-existing and subsequent dementia and multiple specific neurological diseases. Heterogeneities were su...

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