Publications by authors named "Wei Deng"

986 Publications

The molecular characteristics of high-grade gastroenteropancreatic neuroendocrine neoplasms.

Endocr Relat Cancer 2021 Oct 1. Epub 2021 Oct 1.

S Knappskog, Department of Clinical Science, University of Bergen, Bergen, Norway.

High-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are rare but have a very poor prognosis and represent a severely understudied class of tumours. Molecular data for HG GEP-NEN are limited and treatment strategies for the carcinoma subgroup (HG GEP-NEC) are extrapolated from small-cell lung cancer (SCLC). After pathological re-evaluation, we analysed DNA from tumours and matched blood samples from 181 HG GEP-NEN patients; 152 neuroendocrine carcinomas (NEC) and 29 neuroendocrine tumours (NET G3). Based on sequencing of 360 cancer related genes, we assessed mutations and copy number alterations (CNA). For NEC, frequently mutated genes were TP53 (64%), APC (28%), KRAS (22%) and BRAF (20%). RB1 was only mutated in 14%, but CNAs affecting RB1 were seen in 34%. Other frequent copy number losses were ARID1A (35%), ESR1 (25%) and ATM (31%). Frequent amplifications/gains were found in MYC (51%) and KDM5A (45%). While these molecular features had limited similarities with SCLC, we found potentially targetable alterations in 66% of the NEC samples. Mutations and CNA varied according to primary tumour site with BRAF mutations mainly seen in colon (49%), and FBXW7 mutations mainly seen in rectal cancers (25%). 8/152 (5.3%) NEC were microsatellite instable (MSI). NET G3 had frequent mutations in MEN1 (21%), ATRX (17%), DAXX, SETD2 and TP53 (each 14%). We show molecular differences in HG GEP-NEN, related to morphological differentiation and site of origin. Limited similarities to SCLC and a high fraction of targetable alterations indicates a high potential for better personalized treatments.
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http://dx.doi.org/10.1530/ERC-21-0152DOI Listing
October 2021

Plasma Metabolomics Profiling of Metabolic Pathways Affected by Major Depressive Disorder.

Front Psychiatry 2021 27;12:644555. Epub 2021 Sep 27.

Psychiatric Laboratory and Mental Health Center, West China Hospital of Sichuan University, Chengdu, China.

Major depressive disorder (MDD) is a common disease which is complicated by metabolic disorder. Although MDD has been studied relatively intensively, its metabolism is yet to be elucidated. To profile the global pathophysiological processes of MDD patients, we used metabolomics to identify differential metabolites and applied a new database Metabolite set enrichment analysis (MSEA) to discover dysfunctions of metabolic pathways of this disease. Hydrophilic metabolomics were applied to identify metabolites by profiling the plasma from 55 MDD patients and 100 sex-, gender-, BMI-matched healthy controls. The metabolites were then analyzed in MSEA in an attempt to discover different metabolic pathways. To investigate dysregulated pathways, we further divided MDD patients into two cohorts: (1) MDD patients with anxiety symptoms and (2) MDD patients without anxiety symptoms. Metabolites which were hit in those pathways correlated with depressive and anxiety symptoms. Altogether, 17 metabolic pathways were enriched in MDD patients, and 23 metabolites were hit in those pathways. Three metabolic pathways were enriched in MDD patients without anxiety, including glycine and serine metabolism, arginine and proline metabolism, and phenylalanine and tyrosine metabolism. In addition, L-glutamic acid was positively correlated with the severity of depression and retardation if hit in MDD patients without anxiety symptoms. Different kinds of metabolic pathophysiological processes were found in MDD patients. Disorder of glycine and serine metabolism was observed in both MDD patients with anxiety and those without.
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http://dx.doi.org/10.3389/fpsyt.2021.644555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8502978PMC
September 2021

Molecular Characteristics of Repotrectinib That Enable Potent Inhibition of TRK Fusion Proteins and Resistant Mutations.

Mol Cancer Ther 2021 Oct 8. Epub 2021 Oct 8.

Department of Medicine, Memorial Sloan Kettering Cancer Center.

NTRK chromosomal rearrangements yield oncogenic TRK fusion proteins that are sensitive to TRK inhibitors (larotrectinib, entrectinib) but often mutate, limiting the durability of response for NTRK+ patients. Next-generation inhibitors with compact macrocyclic structures (repotrectinib, selitrectinib) were designed to avoid resistance mutations. Head-to-head potency comparisons of TRK inhibitors and molecular characterization of binding interactions are incomplete obscuring a detailed understanding of how molecular characteristics translate to potency. Larotrectinib, entrectinib, selitrectinib, and repotrectinib were characterized using cellular models of wild-type TRKA/B/C fusions and resistance mutant variants with a subset evaluated in xenograft tumor models. Crystal structures were determined for repotrectinib bound to TRKA (wild-type, solvent front mutant). TKI-naïve and pretreated case studies are presented. Repotrectinib was the most potent inhibitor of wild-type TRKA/B/C fusions and was more potent than selitrectinib against all tested resistance mutations, underscoring the importance of distinct features of the macrocycle structures. Co-crystal structures of repotrectinib with wild-type TRKA and the TRKAG595R SFM variant elucidated how differences in macrocyclic inhibitor structure, binding orientation, and conformational flexibility affect potency and mutant selectivity. The SFM crystal structure revealed an unexpected intramolecular arginine sidechain interaction. Repotrectinib caused tumor regression in LMNA-NTRK1 xenograft models harboring GKM, SFM, xDFG, and GKM+SFM compound mutations. Durable responses were observed in TKI-naïve and -pretreated patients with NTRK+ cancers treated with repotrectinib (NCT03093116). This comprehensive analysis of first- and second-generation TRK inhibitors informs the clinical utility, structural determinants of inhibitor potency, and design of new generations of macrocyclic inhibitors.
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http://dx.doi.org/10.1158/1535-7163.MCT-21-0632DOI Listing
October 2021

Impact of urban birth and upbringing on expression of psychosis in a Chinese undergraduate population.

BMC Psychiatry 2021 Oct 9;21(1):493. Epub 2021 Oct 9.

Mental Health Center and Psychiatric Laboratory, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, No. 28 Dianxin South street, Chengdu, 610041, Sichuan, China.

Background: Urban birth and upbringing show consistent associations with psychotic illness but the key urban exposures remain unknown. Associations with psychotic-like experiences (PEs) are inconsistent. These could be confounded by common mental disorders associated with PEs. Furthermore, associations between PEs and urban exposures may not extrapolate to psychotic disorders such as schizophrenia.

Methods: Annual cross-sectional surveys among first year Chinese undergraduates 2014-2019 (n = 47,004). Self-reported, hierarchical categorisation of psychosis: from psychoticism, paranoid ideation, schizotypal symptoms, nuclear syndrome using SCL-90-R, to clinical diagnosis of schizophrenia. Depressive symptoms using PHQ 9. Dissociative symptoms and posttraumatic stress disorder (PTSD) measured using PCL-C. Etiological factors of family history and childhood disadvantage. We studied effects of urban birth, urban living and critical times of exposure in childhood on psychosis phenotypes.

Results: Associations with urbanicity were found only after adjustments for depression. Urban birth was associated with paranoia (AOR 1.34, 1.18-1.53), schizotypal symptoms (AOR 1.59, 1.29-1.96), and schizophrenia (AOR 2.07, 1.10-3.87). The same phenotypes showed associations with urban residence > 10 years. Only schizophrenia showed an association with urban exposure birth-3 years (AOR 7.01, 1.90-25.86). Child maltreatment was associated with both psychosis and depression. Urbanicity measured across the total sample did not show any associations with demography, family history of psychosis, or child maltreatment. Sensitivity analysis additionally adjusting for dissociative symptoms and PTSD showed the same pattern of findings.

Conclusions: Urban birth and urban living showed a hierarchical pattern of increasing associations from paranoid ideation to schizotypal disorder to schizophrenia, confirming that associations for psychotic experiences could be extrapolated to schizophrenia, but only after adjusting for confounding from depression, dissociative symptoms and PTSD. Several etiological factors were the same for psychosis and depression. Future studies of PEs should adjust for confounding from common mental disorders and dissociative symptoms. Effects of urbanicity on psychosis were not explained by demography, family history of mental disorder, or child maltreatment.
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http://dx.doi.org/10.1186/s12888-021-03475-wDOI Listing
October 2021

Peak-fitting assisted SERS strategy for accurate discrimination of carboxylic acid enantiomers.

Chem Commun (Camb) 2021 Oct 5. Epub 2021 Oct 5.

School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, P. R. China.

A novel peak-fitting assisted SERS (PF-SERS) strategy was developed for the first time to discriminate carboxylic acid enantiomers. The PF-SERS method offered substantial improvement in accuracy, quantitative performance of enantioselective sensing and exceptionally strong enantiomeric recognition ability.
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http://dx.doi.org/10.1039/d1cc04506gDOI Listing
October 2021

Tissue dynamics of von Willebrand factor characterized by a novel fluorescent protein-von Willebrand factor chimera.

J Thromb Haemost 2021 Sep 30. Epub 2021 Sep 30.

Cyrus Tang Medical Institute and Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China.

Background: Tissue dynamics of von Willebrand factor (VWF) that are vital to its biological function have not been fully characterized.

Objective: To develop a new fluorescent protein--VWF chimera (FP-VWF) that has similar hematologic function to wild-type VWF and use it to monitor the tissue dynamics of VWF distribution.

Methods: Genotyping, platelet counting, tail bleeding time assay, agarose gels, western blot, platelet aggregation, proteolytic analysis, and ELISA were applied in characterizing the function of FP-VWF; fluorescence spectrometer and confocal fluorescence microscope were used to monitor the plasma and tissue distribution of FP-VWF.

Results: The transgenic mice that carry the FP-VWF retain hematologic activity of VWF with plasma levels of FP-VWF reduced by 50% and there are reduced high molecular weight FP-VWF multimers compared to the wild-type mice. The GPIb-binding and ADAMTS-13 (A Disintegrin and Metalloprotease with ThrombSpondin type 1 motif, member 13) proteolytic efficiency of FP-VWF are similar to wild-type VWF. The tissue distribution of FP-VWF was probed directly through its intrinsic fluorescence at normal or stimulated status, which indicated that the medicine-stimulated endogenous FP-VWF seems primarily released from the aorta and cleared in the spleen. Similar results were observed in non-fluorescent mice through a standard immunofluorescence approach. The fluorescence signals of FP-VWF were also similar to the standard dye-based approach in detecting the FeCl -induced blood clotting in vivo.

Conclusions: Together, these results suggest that this novel FP-VWF chimera is valuable in probing the tissue dynamics of VWF in quite a few biological and pharmaceutical applications.
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http://dx.doi.org/10.1111/jth.15542DOI Listing
September 2021

Structural Covariance of Depth-Dependent Intracortical Myelination in the Human Brain and Its Application to Drug-Naïve Schizophrenia: A T1w/T2w MRI Study.

Cereb Cortex 2021 Sep 28. Epub 2021 Sep 28.

Psychiatric Laboratory and Mental Health Center, The State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 610000, China.

Aberrations in intracortical myelination are increasingly being considered as a cardinal feature in the pathophysiology of schizophrenia. We investigated the network-level distribution of intracortical myelination across various cortex depths. We enrolled 126 healthy subjects and 106 first-episode drug-naïve schizophrenia patients. We used T1w/T2w ratio as a proxy of intracortical myelination, parcellated cortex into several equivolumetric surfaces based on cortical depths and mapped T1w/T2w ratios to each surface. Non-negative matrix factorization was used to generate depth-dependent structural covariance networks (dSCNs) of intracortical myelination from 2 healthy controls datasets-one from our study and another from 100-unrelated dataset of the Human Connectome Project. For patient versus control comparisons, partial least squares approach was used; we also related myelination to clinical features of schizophrenia. We found that dSCNs were highly reproducible in 2 independent samples. Network-level myelination was reduced in prefrontal and cingulate cortex and increased in perisylvian cortex in schizophrenia. The abnormal network-level myelination had a canonical correlation with symptom burden in schizophrenia. Moreover, myelination of prefrontal cortex correlated with duration of untreated psychosis. In conclusion, we offer a feasible and sensitive framework to study depth-dependent myelination and its relationship with clinical features.
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http://dx.doi.org/10.1093/cercor/bhab337DOI Listing
September 2021

Maternal fish and shellfish consumption and preterm birth: A retrospective study in urban China.

Br J Nutr 2021 Sep 24:1-31. Epub 2021 Sep 24.

Department of Pediatric Comprehensive Medicine,Gansu Provincial Maternity and Child Care Hospital, Lanzhou, 730050, China.

Preterm birth is the leading cause of perinatal mortality and morbidity. Some prospective cohort studies suggested that fish and shellfish consumption may affect the incidence of preterm birth. However, conflicting evidence exists on the relationship between fish and shellfish consumption and preterm birth. This retrospective study was conducted in Lanzhou, China, between 2010 and 2012. A total of 10,179 women were interviewed after delivery to collect information on their past intake of fish and shellfish using food frequency questionnaire. Clinical data including birth outcomes and maternal complications were extracted from medical records of the participants. Logistic regression models were used to estimate odds ratios and 95% confidence intervals to examine the association between fish and shellfish consumption and preterm birth and its clinical subtypes. Fish and shellfish consumption was associated with reduced risk of preterm birth (OR=0.65, 95%CI:0.56-0.77). Increasing frequency of fish and shellfish consumption, compared with no fish and shellfish consumption, were associated with decreasing odds of preterm birth: for ≤ 1 time/ week, OR = 0.74 (95% CI: 0.63-0.89); for ≥2 times a week, OR = 0.57 (95% CI:0.48-0.68). The P for trend was 0.023. Besides, increasing weekly total amount of fish and shellfish consumption, compared with no fish and shellfish consumption, were also associated with decreasing odds of preterm birth: for <350 g/week, OR = 0.67 (95% CI: 0.57-0.78); for ≥350 g/week, OR = 0.57 (95% CI:0.43-0.74). The P for trend was 0.011. Significant trend effect was also seen between fish and shellfish consumption and very preterm birth (P for trend =0.001) and spontaneous preterm birth (P for trend =0.003). Interaction was observed between total fish and shellfish consumption with maternal age (P for interaction=0.041) and pre-pregnancy BMI underweight (P for interaction=0.012). Maternal fish and shellfish consumption was associated with lower incidence of preterm birth. The findings support for the protective role of fish and shellfish consumption in preventing preterm birth and recommend for the national guideline of ≥350 g/week of fish and shellfish consumption among pregnant women.
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http://dx.doi.org/10.1017/S0007114521003858DOI Listing
September 2021

A Contour Stochastic Gradient Langevin Dynamics Algorithm for Simulations of Multi-modal Distributions.

Adv Neural Inf Process Syst 2020 Dec;34:15725-15736

Departments of Statistics, Purdue University, West Lafayette, IN, USA.

We propose an adaptively weighted stochastic gradient Langevin dynamics algorithm (SGLD), so-called contour stochastic gradient Langevin dynamics (CSGLD), for Bayesian learning in big data statistics. The proposed algorithm is essentially a , which automatically the target distribution such that the simulation for a multi-modal distribution can be greatly facilitated. Theoretically, we prove a stability condition and establish the asymptotic convergence of the self-adapting parameter to a , regardless of the non-convexity of the original energy function; we also present an error analysis for the weighted averaging estimators. Empirically, the CSGLD algorithm is tested on multiple benchmark datasets including CIFAR10 and CIFAR100. The numerical results indicate its superiority over the existing state-of-the-art algorithms in training deep neural networks.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457681PMC
December 2020

Engineering Leifsonia Alcohol Dehydrogenase for Thermostability and Catalytic Efficiency by Enhancing Subunit Interactions.

Chembiochem 2021 Sep 22. Epub 2021 Sep 22.

State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Rd., Shanghai, 200240, China.

Leifsonia alcohol dehydrogenase (LnADH) is a promising biocatalyst for the synthesis of chiral alcohols. However, limitations of wild-type LnADH observed for practical application include low activity and poor stability. In this work, protein engineering was employed to improve its thermostability and catalytic efficiency by altering the subunit interfaces. Residues T100 and S148 were identified to be significant for thermostability and activity, and the melting temperature (ΔT ) and catalytic efficiency of the mutant T100R/S148I toward ketone substrates was improved by 18.7 °C and 1.8-5.5-fold. Solving the crystal structures of the wild-type enzyme and T100R/S148L revealed beneficial effects of mutations on stability and catalytic activity. The most robust mutant T100R/S148I is promising for industrial applications and can produce 200 g liter  day chiral alcohols at 50 °C by only a 1 : 500 ratio of enzyme to substrate.
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http://dx.doi.org/10.1002/cbic.202100431DOI Listing
September 2021

Visible-light-promoted direct C3-trifluoromethylation and perfluoroalkylation of imidazopyridines.

Org Biomol Chem 2021 Oct 6;19(38):8301-8306. Epub 2021 Oct 6.

State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China.

An efficient method for direct trifluoromethylation and perfluoroalkylation at C3 of imidazopyridines through visible light-promoted C-H bond functionalization was developed. Under the irradiation of a blue LED, a series of C3-perfluoroalkyl-substituted imidazopyridines were synthesized from the corresponding imidazopyridines and perfluoroalkyl iodides in moderate to good yields at room temperature. It should be mentioned that this reaction proceeded in the absence of any transition-metal catalyst, oxidant and photocatalyst.
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http://dx.doi.org/10.1039/d1ob01417jDOI Listing
October 2021

SARS-CoV-2 crosses the blood-brain barrier accompanied with basement membrane disruption without tight junctions alteration.

Signal Transduct Target Ther 2021 09 6;6(1):337. Epub 2021 Sep 6.

NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.

SARS-CoV-2 has been reported to show a capacity for invading the brains of humans and model animals. However, it remains unclear whether and how SARS-CoV-2 crosses the blood-brain barrier (BBB). Herein, SARS-CoV-2 RNA was occasionally detected in the vascular wall and perivascular space, as well as in brain microvascular endothelial cells (BMECs) in the infected K18-hACE2 transgenic mice. Moreover, the permeability of the infected vessel was increased. Furthermore, disintegrity of BBB was discovered in the infected hamsters by administration of Evans blue. Interestingly, the expression of claudin5, ZO-1, occludin and the ultrastructure of tight junctions (TJs) showed unchanged, whereas, the basement membrane was disrupted in the infected animals. Using an in vitro BBB model that comprises primary BMECs with astrocytes, SARS-CoV-2 was found to infect and cross through the BMECs. Consistent with in vivo experiments, the expression of MMP9 was increased and collagen IV was decreased while the markers for TJs were not altered in the SARS-CoV-2-infected BMECs. Besides, inflammatory responses including vasculitis, glial activation, and upregulated inflammatory factors occurred after SARS-CoV-2 infection. Overall, our results provide evidence supporting that SARS-CoV-2 can cross the BBB in a transcellular pathway accompanied with basement membrane disrupted without obvious alteration of TJs.
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http://dx.doi.org/10.1038/s41392-021-00719-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419672PMC
September 2021

SARS-CoV-2 leads to myocardial injury in rhesus macaque.

Signal Transduct Target Ther 2021 09 6;6(1):338. Epub 2021 Sep 6.

Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.

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http://dx.doi.org/10.1038/s41392-021-00747-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419658PMC
September 2021

Auditory event-related potentials, neurocognition, and global functioning in drug naïve first-episode schizophrenia and bipolar disorder.

Psychol Med 2021 Sep 3:1-10. Epub 2021 Sep 3.

Mental Health Center and Psychiatric Laboratory, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China.

Background: Deficits in event-related potential (ERP) including duration mismatch negativity (MMN) and P3a have been demonstrated widely in chronic schizophrenia (SZ) but inconsistent findings were reported in first-episode patients. Psychotropic medications and diagnosis might contribute to different findings on MMN/P3a ERP in first-episode patients. The present study examined MMN and P3a in first episode drug naïve SZ and bipolar disorder (BPD) patients and explored the relationships among ERPs, neurocognition and global functioning.

Methods: Twenty SZ, 24 BPD and 49 age and sex-matched healthy controls were enrolled in this study. Data of clinical symptoms [Positive and Negative Symptoms Scale (PANSS), Young Manic Rating Scale (YMRS), Hamilton Depression Rating Scale (HAMD)], neurocognition [Wechsler Adult Intelligence Scale (WAIS), Cattell's Culture Fair Intelligence Test (CCFT), Delay Matching to Sample (DMS), Rapid Visual Information Processing (RVP)], and functioning [Functioning Assessment Short Test (FAST)] were collected. P3a and MMN were elicited using a passive auditory oddball paradigm.

Results: Significant MMN and P3a deficits and impaired neurocognition were found in both SZ and BPD patients. In SZ, MMN was significantly correlated with FAST (r = 0.48) and CCFT (r = -0.31). In BPD, MMN was significantly correlated with DMS (r = -0.54). For P3a, RVP and FAST scores were significant predictors in SZ, whereas RVP, WAIS and FAST were significant predictors in BPD.

Conclusions: The present study found deficits in MMN, P3a, neurocognition in drug naïve SZ and BPD patients. These deficits appeared to link with levels of higher-order cognition and functioning.
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http://dx.doi.org/10.1017/S0033291721002130DOI Listing
September 2021

C-terminal-truncated hepatitis B virus X protein promotes hepatocarcinogenesis by activating the MAPK pathway.

Microb Pathog 2021 Oct 12;159:105136. Epub 2021 Aug 12.

Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, China. Electronic address:

Purpose: C-terminally truncated hepatitis B virus X (ctHBx) is frequently detected in hepatocellular carcinoma (HCC) patients with hepatitis B virus (HBV) integrated into their genomes, but the molecular mechanisms of ctHBx-related oncogenic signaling remain unclear. In this study, the effects of ctHBx on HepG2 cells were investigated by measuring ctHBx-induced changes in the cell cycle-related target proteins cell division cycle 25C (cdc25C) and p53 downstream of the mitogen-activated protein kinase (MAPK) pathway.

Materials And Methods: ctHBx lentiviruses were constructed and transfected into HepG2 cells. Then, we investigated HepG2 cell line function by conducting the Cell Counting Kit-8 (CCK8) assay, clone formation assay, scratch wound testing, Transwell assays and flow cytometry to examine cell cycle and apoptosis. Western blotting (WB) was performed to detect proteins related to and downstream of the extracellular signal-regulated kinase(ERK)/c-Jun N-terminal kinase(JNK)/p38 MAPK pathway, including cdc25C and p53.

Results: ctHBx significantly enhanced the proliferation, migration, invasion and colony-forming capability of HepG2 cells. In addition, ctHBx activated the ERK/JNK/p38 MAPK signaling pathway to regulate cell viability by affecting the expression of cyclin-related proteins, including cdc25C and p53.

Conclusion: The present study demonstrates that ctHBx promote the formation and development of HCC via regulating MAPK/cdc25C and p53 axis. ctHBx should be the driving factor of HBV-induced hepatocarcinogenesis.
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http://dx.doi.org/10.1016/j.micpath.2021.105136DOI Listing
October 2021

Patient-reported outcomes in Chinese rheumatoid arthritis patients: a systematic review and meta-analysis.

Chin Med J (Engl) 2021 Aug 4. Epub 2021 Aug 4.

Division of Rheumatology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China Lilly Suzhou Pharmaceutical Co., Ltd Shanghai Branch, Shanghai 200041, China Medieco Group Co., Ltd (Beijing), Beijing 100000, China.

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http://dx.doi.org/10.1097/CM9.0000000000001582DOI Listing
August 2021

The Gender-Sensitive Social Risk Factors for Internet Addiction in College Undergraduate Students.

Psychiatry Investig 2021 Jul 22;18(7):636-644. Epub 2021 Jul 22.

Mental Health Center and Psychiatric Laboratory, Huaxi Brain Research Center, West China Hospital of Sichuan University, Chengdu, China.

Objective: The current study aims to explore precipitating and social risk factors for internet addiction (IA) in university undergraduate students, and to provide evidence for interventions and the early prevention of IA in different genders.

Methods: Four thousand eight hundred and fifty-eight college sophomores completed an online survey on their internet use-related behaviours and social risk factors.

Results: We found that more male (8.3%) than female students (5.4%) had moderate and severe IA. The main online activity in the moderate and severe IA groups was online gaming in males and online streaming in females. Roommates engaging in similar internetbased entertainment was a risk factor of IA only for males, while not being in a romantic relationship was a risk factor of IA for females only. Infatuation with the internet before college and adjustment problems for college life were shared risk factors for both genders in the mild and moderate IA groups.

Conclusion: IA was a common phenomenon in college students with shared and unique precipitating and social risk factors in males and females. The gender-sensitive risk factors for IA warranted earlier and individualized intervention and prevention strategies for IA in this population.
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http://dx.doi.org/10.30773/pi.2020.0277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328835PMC
July 2021

Continuous rhomboid intercostal nerve block for thoracoscopic postoperative analgesia.

Ann Thorac Surg 2021 Jul 30. Epub 2021 Jul 30.

Department of Anesthesiology and Pain medicine, the Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang Province, China. Electronic address:

Background: Rhomboid intercostal block is a new type of plane block used for postoperative analgesia after video-assisted thoracoscopic surgery. We performed a prospective randomized controlled trial to investigate the effects of ultrasound-guided continuous rhomboid intercostal nerve block (CRIB) on the global quality of recovery scores (QoR-40) and postoperative analgesia after video-assisted thoracoscopic surgery.

Methods: Sixty-six adult patients scheduled for elective unilateral video-assisted thoracoscopic surgery were randomly allocated to group C and group CRIB. In group C, patients were administered patient-controlled intravenous analgesia with sufentanil after operation. Patients in group CRIB received patient-controlled analgesia with ropivacaine CRIB. All patients completed the QoR-40 test during the preoperative evaluation and again 24 h after the operation. Information regarding the 48-h postoperative pain and adverse events were recorded.

Results: The QoR-40 scores of group C were significantly lower than that of group CRIB (155.4±6.1 vs.172.6±6.3, p<0.001), with a mean difference of -17.2 (95% confidence interval -20.4--13.9) 24 h after operation. The postoperative numerical rating scale scores in group CRIB at 6, 12, 18, and 24 h after the surgery, when patients were at rest, were significantly lower than those in group C (all p< 0.05). The postoperative numerical rating scale scores in group CRIB at 1, 3, 6, 12, 18, 24, and 36 h after surgery, when patients were moving, were significantly lower than that in group C (all p< 0.05).

Conclusions: In patients who underwent video-assisted thoracoscopic surgery, continuous rhomboid intercostal nerve block led to improved quality of recovery and postoperative analgesia.
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http://dx.doi.org/10.1016/j.athoracsur.2021.06.068DOI Listing
July 2021

Genetic evidence for the causal association between programmed death-ligand 1 and lung cancer.

J Cancer Res Clin Oncol 2021 Nov 29;147(11):3279-3288. Epub 2021 Jul 29.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiation Oncology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, People's Republic of China.

PD-1/PD-L1 might have a causal role in operating lung cancer risk. However, such an association has not been investigated in the general population. We assessed whether PD-L1 has an independent effect on lung cancer risk using two-sample Mendelian randomization (MR) based on a proteomic genome-wide association study (3301 health participants) of European ancestry and the International Lung cancer Consortium (11,348 cases and 15,861 controls). Negative control analyses using chronic obstructive pulmonary disease (COPD)/asthma/interstitial lung disease (ILD)-related infection (~ 22,730 cases and ~ 112,908 controls) were also conducted to enhance the credibility of the selected instruments and MR-based estimates. This study found that genetically predicted PD-1/PD-L1 were not significantly associated with lung cancer after adjustment for multiplicity. However, suggestive evidence was observed for the total effect of higher PD-1 with decreased lung cancer risk and the direct effect (i.e., not mediated by PD-1 and smoking) of lower PD-L1 with decreased lung cancer risk. No association between genetically predicted PD-L1 and COPD/asthma/ILD related infection was noted. Taken together, our findings suggest that interventions decreasing PD-L1 might have a role in lowering lung cancer risk.
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http://dx.doi.org/10.1007/s00432-021-03740-1DOI Listing
November 2021

[Animal Experimental Study of the Role of Menthol and Cineole, Two Tobacco Additives, on Nicotine Dependence].

Sichuan Da Xue Xue Bao Yi Xue Ban 2021 Jul;52(4):649-654

Mental Health Center, West China Hospital, Sichuan University, Chengdu 610041, China.

Objective: To establish a nicotine intravenous self-administration rat model, and to examine, with this model, the effects of two flavoring additives, menthol and cineole, on nicotine dependence.

Methods: Thirty male Sprague-Dawley (SD) rats were included in the study. After jugular venous catheterization was performed, fixed concentration of nicotine was administered in order to train the rats and establish the rat model of intravenous self-administration groups, receiving intraperitoneal injection of menthol, cineole, and dimethyl sulfoxide (DMSO), the vehicle that was used for the control group. The rats were tested with different fixed-ratio (FR) schedules, including FR1 schedule, in which the rat received one nicotine infusion for every active nose poke, FR2 schedule, in which the rat received one nicotine infusion for every two active nose pokes, and FR5 schedule, in which the rat received one nicotine infusion for every five active nose pokes. The number of active and inactive poke responses and the number of nicotine infusion were documented accordingly.

Results: After 10 days of training in nicotine self-administration, the 30 rats demonstrated significant increase in the number of active poke responses and the number of nicotine infusion, which were maintained at a stable and relatively high level. The number of active poke responses was significantly higher that of inactive poke responses ( < 0.001). The rat model of intravenous nicotine self-administration was successfully established. In the testing phase, under the FR2 schedule, the menthol group showed a reduced number of active poke responses ( =0.020). Under the FR5 schedule, the groups showed obvious interaction between time and the number of active poke responses ( <0.011), with the menthol group showing reduced number of active poke responses on day three ( =0.011) and the cineole group showing rising number of active poke responses on day three ( =0.003). The DMSO control group did not show any significant change.

Conclusions: Menthol and cineole are shown to have an effect on nicotine dependence. When there is relative difficulty involved in obtaining nicotine, menthol suppresses nicotine dependence, whereas cineole enhances nicotine dependence.
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http://dx.doi.org/10.12182/20210760202DOI Listing
July 2021

The interactions between childhood adversities and recent stress were associated with early-adulthood depression among Chinese undergraduate students.

Depress Anxiety 2021 09 22;38(9):961-971. Epub 2021 Jul 22.

Mental Health Center and Psychiatric Laboratory, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China.

Background: It is widely acknowledged that childhood adversities (CAs) and recent stress are potential risk factors for adult depression. However, the mechanism(s) by which interactions of CAs with recent stress affect adult depression remain unclear.

Aims: To investigate the predictive association of the interaction among CAs and recent stress with early-adult depression.

Method: We conducted an annual survey of all freshmen for the period of 2016-2018 in a Chinese comprehensive university, with a sample size of 23,206. An online questionnaire including standardized self-report instruments was used to assess sociodemographic factors, childhood experiences of left-behind (CELB), and maltreatments (CEMTs) including beating (CEB), neglect (CEN), sexual abuse (CESA), recent stress, and current depression (measured by the 9-item Patient Health Questionnaire).

Results: The correlation of Individual CAs and recent stress was significant. In addition to their significant independent/direct incremental effects, all surveyed CAs were associated with increased severity of early-adult depression, and increased frequency of clinically significant depression (CSD), through significant associations with recent stress (mediation effect). History of CEMTs including CEB, CEN, and CESA significantly increased the effects of recent stress on depression (moderation effect).

Conclusions: Chinese undergraduate students reported frequent history of exposure to CAs, which increased the likelihood of depression in early adulthood, not only directly but also through the increasing the likelihood (mediation effect) and impact (moderation effect) of recent stress on depression. These novel findings may help to extend our understanding of environmental determinants of depression, and to guide further research, clinical practice, and policy in this context.
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http://dx.doi.org/10.1002/da.23201DOI Listing
September 2021

A Critical Review of LET-Based Intensity-Modulated Proton Therapy Plan Evaluation and Optimization for Head and Neck Cancer Management.

Int J Part Ther 2021 25;8(1):36-49. Epub 2021 Jun 25.

Department of Radiation Oncology, Mayo Clinic, Phoenix, AZ, USA.

In this review article, we review the 3 important aspects of linear-energy-transfer (LET) in intensity-modulated proton therapy (IMPT) for head and neck (H&N) cancer management. Accurate LET calculation methods are essential for LET-guided plan evaluation and optimization, which can be calculated either by analytical methods or by Monte Carlo (MC) simulations. Recently, some new 3D analytical approaches to calculate LET accurately and efficiently have been proposed. On the other hand, several fast MC codes have also been developed to speed up the MC simulation by simplifying nonessential physics models and/or using the graphics processor unit (GPU)-acceleration approach. Some concepts related to LET are also briefly summarized including (1) dose-weighted versus fluence-weighted LET; (2) restricted versus unrestricted LET; and (3) microdosimetry versus macrodosimetry. LET-guided plan evaluation has been clinically done in some proton centers. Recently, more and more studies using patient outcomes as the biological endpoint have shown a positive correlation between high LET and adverse events sites, indicating the importance of LET-guided plan evaluation in proton clinics. Various LET-guided plan optimization methods have been proposed to generate proton plans to achieve biologically optimized IMPT plans. Different optimization frameworks were used, including 2-step optimization, 1-step optimization, and worst-case robust optimization. They either indirectly or directly optimize the LET distribution in patients while trying to maintain the same dose distribution and plan robustness. It is important to consider the impact of uncertainties in LET-guided optimization (ie, LET-guided robust optimization) in IMPT, since IMPT is sensitive to uncertainties including both the dose and LET distributions. We believe that the advancement of the LET-guided plan evaluation and optimization will help us exploit the unique biological characteristics of proton beams to improve the therapeutic ratio of IMPT to treat H&N and other cancers.
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http://dx.doi.org/10.14338/IJPT-20-00049.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270082PMC
June 2021

Epigenetic Regulation of Hepatic Stellate Cell Activation and Macrophage in Chronic Liver Inflammation.

Front Physiol 2021 1;12:683526. Epub 2021 Jul 1.

Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China.

Chronic liver inflammation is a complex pathological process under different stress conditions, and the roles of stellate cells and macrophages in chronic liver inflammation have been widely reported. Moderate liver inflammation can protect the liver from damage and facilitate the recovery of liver injury. However, an inflammatory response that is too intense can result in massive death of hepatocytes, which leads to irreversible damage to the liver parenchyma. Epigenetic regulation plays a key part in liver inflammation. This study reviews the regulation of epigenetics on stellate cells and macrophages to explore the new mechanisms of epigenetics on liver inflammation and provide new ideas for the treatment of liver disease.
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http://dx.doi.org/10.3389/fphys.2021.683526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281248PMC
July 2021

Correction to: Transmission of H7N9 influenza virus in mice by different infective routes.

Virol J 2021 Jul 6;18(1):140. Epub 2021 Jul 6.

Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Center, Peking Union Medical Collage (PUMC); Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, No. 5 Pan Jia Yuan Nan Li, Chaoyang District, Beijing, 100021, China.

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http://dx.doi.org/10.1186/s12985-021-01603-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261966PMC
July 2021

Risk factors for venous thromboembolism in patients with diabetes undergoing joint arthroplasty.

BMC Musculoskelet Disord 2021 Jul 6;22(1):608. Epub 2021 Jul 6.

Department of Spine Surgery, Beijing Jishuitan Hospital, No. 31, Xinjiekou East Street, Xicheng District, 100035, Beijing, People's Republic of China.

Background: Venous thromboembolism (VTE) is a significant complication after joint arthroplasty. Diabetes is related to a few changes in coagulation and fibrinolysis that may lead to thrombophilia. We aimed to investigate the incidence of postoperative VTE and associated risk factors among patients with diabetes undergoing total hip (THA) or total knee anthroplasty (TKA) in a single centre in China.

Methods: Patients with diabetes who underwent THA or TKA from January 2016 to December 2018 (n = 400) at Beijing Jishuitan Hospital were recruited in this study. Lower limb venous Doppler ultrasound was performed before and after surgery to confirm deep venous thrombosis (DVT). Computer tomography pulmonary angiography was done to confirm pulmonary embolism (PE) for those with new postoperative DVT and typical symptoms of PE. A multivariate logistic regression model was conducted to examine factors associated with the development of postoperative VTE.

Results: The overall incidence of postoperative VTE in patients with diabetes after THA or TKA was 46.8 % (187 out of 400). Among the 187 VTE patients, 7.5 % (14 out of 187) had proximal vein thrombosis and 92.5 % (173 out of 187) had distal vein thrombosis. No PE occurred. Female patients and patients undergoing TKA had higher incidence of postoperative VTE. Patients who developed postoperative VTE were older, and had higher levels of preoperative D-Dimer and Caprini score. A high level of preoperative D-dimer (OR = 2.11, 95 %CI = 1.35-3.30) and the surgery of TKA (OR = 2.29, 95 %CI = 1.29-4.01) significantly increased the risk of developing postoperative VTE. Postoperative initiation of concomitant mechanical prophylaxis and low molecular weight heparin (LMWH) was protective for postoperative VTE (OR = 0.56, 95 %CI = 0.37-0.86).

Conclusions: VTE is common in patients with diabetes undergoing joint arthroplasty. Patients undergoing TKA or with a high level of preoperative D-dimer are at a considerable risk of developing postoperative VTE. There may be a protective role of postoperative initiation of concomitant mechanical prophylaxis and LMWH for VTE.
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http://dx.doi.org/10.1186/s12891-021-04453-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261962PMC
July 2021

Sitagliptin on carotid intima-media thickness in type 2 diabetes and hyperuricemia patients: a subgroup analysis of the PROLOGUE study.

Ther Adv Chronic Dis 2021 22;12:20406223211026993. Epub 2021 Jun 22.

Department of General practice, The Second Affiliated Hospital of Chongqing Medical University, No 76 Linjiang Road, Chongqing, 400010, China.

Background And Aims: Studies have shown that dipeptidyl peptidase-4 (DDP-4) inhibitors have anti-atherosclerotic effects. However, in the PROLOGUE study, sitagliptin failed to slow the progression of carotid intima-media thickness (CIMT) relative to conventional therapy. We conducted a analysis of the PROLOGUE study and compared the effects of sitagliptin and conventional therapy on changes in CIMT in subgroups with or without hyperuricemia.

Methods: The PROLOGUE study was a randomized controlled trial of 442 patients with type 2 diabetes mellitus (T2DM). Patients were randomized to receive sitagliptin added therapy or conventional therapy. Based on the serum uric acid levels of all study populations in the PROLOGUE study, we divided them into hyperuricemia subgroup ( = 104) and non-hyperuricemia subgroup ( = 331). The primary outcome was changed in carotid intima-media thickness (CIMT) parameters compared with baseline during the 24 months treatment period.

Results: In the hyperuricemia subgroup, compared with the conventional therapy group, the changes in the mean internal carotid artery (ICA)-IMT and max ICA-IMT at 24 months were significantly lower in the sitagliptin group [-0.233 mm, 95% confidence interval (CI) (-0.419 to 0.046),  = 0.015 and -0.325 mm, 95% CI (-0.583 to -0.068),  = 0.014], although there was no significant difference in the common carotid artery CIMT.

Conclusion: The results of our analysis indicated that sitagliptin attenuated the progression of CIMT than conventional therapy in T2DM and hyperuricemia patients.
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http://dx.doi.org/10.1177/20406223211026993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221703PMC
June 2021

TPX-0131, a Potent CNS-penetrant, Next-generation Inhibitor of Wild-type ALK and ALK-resistant Mutations.

Mol Cancer Ther 2021 Sep 22;20(9):1499-1507. Epub 2021 Jun 22.

Turning Point Therapeutics, San Diego, California.

Since 2011, with the approval of crizotinib and subsequent approval of four additional targeted therapies, anaplastic lymphoma kinase (ALK) inhibitors have become important treatments for a subset of patients with lung cancer. Each generation of ALK inhibitor showed improvements in terms of central nervous system (CNS) penetration and potency against wild-type (WT) ALK, yet a key continued limitation is their susceptibility to resistance from ALK active-site mutations. The solvent front mutation (G1202R) and gatekeeper mutation (L1196M) are major resistance mechanisms to the first two generations of inhibitors while patients treated with the third-generation ALK inhibitor lorlatinib often experience progressive disease with multiple mutations on the same allele (mutations , compound mutations). TPX-0131 is a compact macrocyclic molecule designed to fit within the ATP-binding boundary to inhibit ALK fusion proteins. In cellular assays, TPX-0131 was more potent than all five approved ALK inhibitors against WT ALK and many types of resistance mutations, e.g., G1202R, L1196M, and compound mutations. In biochemical assays, TPX-0131 potently inhibited (IC <10 nmol/L) WT ALK and 26 ALK mutants (single and compound mutations). TPX-0131, but not lorlatinib, caused complete tumor regression in ALK (G1202R) and ALK compound mutation-dependent xenograft models. Following repeat oral administration of TPX-0131 to rats, brain levels of TPX-0131 were approximately 66% of those observed in plasma. Taken together, preclinical studies show that TPX-0131 is a CNS-penetrant, next-generation ALK inhibitor that has potency against WT ALK and a spectrum of acquired resistance mutations, especially the G1202R solvent front mutation and compound mutations, for which there are currently no effective therapies.
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http://dx.doi.org/10.1158/1535-7163.MCT-21-0221DOI Listing
September 2021

High Li-Ion Conductivity Artificial Interface Enabled by Li-Grafted Graphene Oxide for Stable Li Metal Pouch Cell.

ACS Appl Mater Interfaces 2021 Jun 22;13(25):29500-29510. Epub 2021 Jun 22.

Advanced Li-ion Battery Engineering Laboratory of Zhejiang Province, Key Laboratory of Graphene Technologies and Applications of Zhejiang Province, and CAS Engineering Laboratory for Graphene, Ningbo Institute of Materials Technology & Engineering, Chinese Academy of Sciences, Zhejiang 315201, P. R. China.

The fragile electrolyte/Li interface is responsible for the long-lasting consumption of Li resources and fast failure of Li metal batteries. The polymer artificial interface with high mechanical flexibility is a promising candidate to maintain the stability of the electrolyte/Li interface; however, sluggish Li-ion transportation of the conventional polymer interface hinders the application. In this work, Li-functionalized graphene oxide (GO-ADP-Li), which is synthesized by covalent grafting of adenosine 5'-diphosphate lithium on GO nanosheets, is used as a functional additive to improve the Li-ion conductivity of the polymer artificial interface based on PVDF-HFP/LiTFSI. The enhanced Li-ion conductivity is contributed by accelerated Li-ion hopping at the surface between polymer chains and functionalized GO as well as the reduced crystallization degree of PVDF-HFP by this novel additive. The use of this modified polymer as an artificial interface on Li foil enables highly reversible Li stripping/plating and a high capacity retention of 78.4% after 150 cycles for a 0.2 A h Li metal pouch cell (Li/NCM811, strictly following practical conditions). This Li-grafted strategy on GO sheets provides an alternative for designing a compatible electrolyte/Li interface for practical Li metal batteries.
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http://dx.doi.org/10.1021/acsami.1c04135DOI Listing
June 2021
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