Publications by authors named "Wen Xia"

172 Publications

METTL3 Is Suppressed by Circular RNA circMETTL3/miR-34c-3p Signaling and Limits the Tumor Growth and Metastasis in Triple Negative Breast Cancer.

Front Oncol 2021 22;11:778132. Epub 2021 Dec 22.

Department of Radiation Oncology, Jiangxi Cancer Hospital, Nanchang, China.

Despite N6-methyladenosine (mA) is functionally important in various biological processes, its role in the underlying regulatory mechanism in TNBC are lacking. In this study, we investigate the pathological role and the underlying mechanism of the mA methylated RNA level and its major methyltransferase METTL3 in the TNBC progression. We found that the mA methylated RNA was dramatically decreased in TNBC tissues and cell lines. Functionally, we demonstrated that METTL3 inhibits the proliferation, migration, and invasion ability of TNBC cells. Moreover, we found METTL3 is repressed by miR-34c-3p in TNBC cells. On the mechanism, we found that circMETTL3 could act as a sponge for miR-34c-3p and inhibits cell proliferation, invasion, tumor growth and metastasis by up-regulating the expression of miR-34c-3p target gene METTL3. In conclusion, our study demonstrates the functional importance and regulatory mechanism of METTL3 in suppressing the tumor growth of TNBC.
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http://dx.doi.org/10.3389/fonc.2021.778132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8727604PMC
December 2021

Aberrant Interhemispheric Functional Connectivity in Diabetic Retinopathy Patients.

Front Neurosci 2021 16;15:792264. Epub 2021 Dec 16.

Department of Ophthalmology, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, China.

Accumulating lines of evidence demonstrated that diabetic retinopathy (DR) patients trigger abnormalities in brain's functional connectivity (FC), whereas the alterations of interhemispheric coordination pattern occurring in DR are not well understood. Our study was to investigate alterations of interhemispheric coordination in DR patients. Thirty-four DR individuals (19 males and 15 females: mean age: 52.97 ± 8.35 years) and 37 healthy controls (HCs) (16 males and 21 females; mean age: 53.78 ± 7.24 years) were enrolled in the study. The voxel-mirrored homotopic connectivity (VMHC) method was conducted to investigate the different interhemispheric FC between two groups. Then, the seed-based FC method was applied to assess the different FCs with region of interest (ROI) in the brain regions of decreased VMHC between two groups. Compared with HC groups, DR groups showed decreased VMHC values in the bilateral middle temporal gyrus (MTG), lingual/calcarine/middle occipital gyrus (LING/CAL/MOG), superior temporal gyrus (STG), angular (ANG), postcentral gyrus (PosCG), inferior parietal lobule (IPL), and precentral gyrus (PreCG). Meanwhile, altered FC includes the regions of auditory network, visual network, default mode network, salience network, and sensorimotor network. Moreover, a significant positive correlation was observed between the visual acuity-oculus dexter (OD) and zVMHC values in the bilateral LING/CAL/MOG ( = 0.551, = 0.001), STG ( = 0.426, = 0.012), PosCG ( = 0.494, = 0.003), and IPL ( = 0.459, = 0.006) in DR patients. Our results highlighted that DR patients were associated with substantial impairment of interhemispheric coordination in auditory network, visual network, default mode network, and sensorimotor network. The VMHC might be a promising therapeutic target in the intervention of brain functional dysfunction in DR patients.
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http://dx.doi.org/10.3389/fnins.2021.792264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8716762PMC
December 2021

Unbiased immune profiling reveals a natural killer cell-peripheral nerve axis in fibromyalgia.

Pain 2021 Sep 24. Epub 2021 Sep 24.

Alan Edwards Centre for Research on Pain, McGill University, Montréal, QC, Canada Integrated Program in Neuroscience, Faculty of Medicine, McGill University, Montréal, QC, Canada Department of Neurology, Faculty of Medicine, Istanbul University, Istanbul, Turkey Department of Neurology, University Hospital of Würzburg, Würzburg, Germany Department of Microbiology and Immunology, Faculty of Medicine, McGill University, Montréal, QC, Canada Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montréal, QC, Canada Department of Physiology, Faculty of Medicine, McGill University, Montréal, QC, Canada McGill Research Centre on Complex Traits, McGill University, Montréal, QC, Canada Faculty of Dentistry, McGill University, Montréal, QC, Canada Department of Physiology and Pharmacology, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden Division of Clinical Neuroscience, Department of Research and Innovation, Oslo University Hospital, Oslo, Norway K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway Department of Neurology, Oslo University Hospital, Oslo, Norway Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, MI, United States Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway Department of Anesthesia, Faculty of Medicine, McGill University, Montréal, QC, Canada Division of Rheumatology, Faculty of Medicine, McGill University, Montréal, QC, Canada Division of Experimental Medicine, Faculty of Medicine, McGill University, Montréal, QC, Canada Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre, Montréal, QC, Canada.

Abstract: The pathophysiology of fibromyalgia syndrome (FMS) remains elusive, leading to a lack of objective diagnostic criteria and targeted treatment. We globally evaluated immune system changes in FMS by conducting multiparametric flow cytometry analyses of peripheral blood mononuclear cells and identified a natural killer (NK) cell decrease in patients with FMS. Circulating NK cells in FMS were exhausted yet activated, evidenced by lower surface expression of CD16, CD96, and CD226 and more CD107a and TIGIT. These NK cells were hyperresponsive, with increased CCL4 production and expression of CD107a when co-cultured with human leukocyte antigen null target cells. Genetic and transcriptomic pathway analyses identified significant enrichment of cell activation pathways in FMS driven by NK cells. Skin biopsies showed increased expression of NK activation ligand, unique long 16-binding protein, on subepidermal nerves of patients FMS and the presence of NK cells near peripheral nerves. Collectively, our results suggest that chronic activation and redistribution of circulating NK cells to the peripheral nerves contribute to the immunopathology associated with FMS.
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http://dx.doi.org/10.1097/j.pain.0000000000002498DOI Listing
September 2021

Establishment and Validation of Prognostic Nomograms Based on Serum Copper Level for Patients With Early-Stage Triple-Negative Breast Cancer.

Front Cell Dev Biol 2021 25;9:770115. Epub 2021 Nov 25.

Departments of Medical Oncology, The State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.

Altered copper levels have been observed in several cancers, but studies on the relationship between serum copper and early-stage triple-negative breast cancer (TNBC) remain scare. We sought to establish a predictive model incorporating serum copper levels for individualized survival predictions. We retrospectively analyzed clinicopathological information and baseline peripheric blood samples of patients diagnosed with early-stage TNBC between September 2005 and October 2016 at Sun Yat-sen University Cancer Center. The optimal cut-off point of serum copper level was determined using maximally selected log-rank statistics. Kaplan-Meier curves were used to estimate survival probabilities. Independent prognostic indicators associated with survival were identified using multivariate Cox regression analysis, and subsequently, prognostic nomograms were established to predict individualized disease-free survival (DFS) and overall survival (OS). The nomograms were validated in a separate cohort of 86 patients from the original randomized clinical trial SYSUCC-001 (SYSUCC-001 cohort). 350 patients were eligible in this study, including 264 in the training cohort and 86 in the SYSUCC-001 cohort. An optimal cut-off value of 21.3 μmol/L of serum copper was determined to maximally divide patients into low- and high-copper groups. After a median follow-up of 87.1 months, patients with high copper levels had significantly worse DFS ( = 0.002) and OS ( < 0.001) than those with low copper levels in the training cohort. Multivariate Cox regression analysis revealed that serum copper level was an independent factor for DFS and OS. Further, prognostic models based on serum copper were established for individualized predictions. These models showed excellent discrimination [C-index for DFS: 0.689, 95% confidence interval (CI): 0.621-0.757; C-index for OS: 0.728, 95% CI: 0.654-0.802] and predictive calibration, and were validated in the SYSUCC-001 cohort. Serum copper level is a potential predictive biomarker for patients with early-stage TNBC. Predictive nomograms based on serum copper might be served as a practical tool for individualized prognostication.
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http://dx.doi.org/10.3389/fcell.2021.770115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657150PMC
November 2021

Facile fabrication of Fe/FeC embedded in N-doped carbon nanofiber for efficient degradation of tetracycline via peroxymonosulfate activation: Role of superoxide radical and singlet oxygen.

J Colloid Interface Sci 2022 Mar 30;609:86-101. Epub 2021 Nov 30.

School of Materials and Energy, University of Electronic Science and Technology of China, Chengdu 611731, China; Research Branch of Advanced Functional Materials, School of Materials and Energy, University of Electronic Science and Technology of China, Chengdu 610054, China.

The toxic metal ions leaching and metal nanoparticles agglomeration were the critical issues for metal-based carbon materials during the peroxymonosulfate (PMS) activation processes. Herein, a facile strategy was first proposed that zero-dimensional Fe/FeC nanoparticles were embedded in one-dimensional N-doped carbon nanofiber (Fe/[email protected]) to solve the above challenges. The as-obtained Fe/[email protected] possessed a low E value (11.7 kJ/mol) and exhibited high activity for activating PMS to degrade tetracycline (TC) in a wide range of pH 3-11. As expected, the iron ions leaching concentration of Fe/[email protected] was very low (0.082 mg/L). Meanwhile, the Fe/[email protected] was easily recovered from the reaction solution due to its magnetic properties. Both superoxide radicals (O) and non-radical of singlet oxygen (O) were the primary reactive oxygen species (ROS) in the Fe/[email protected]/PMS system via quenching tests and electron spin resonance spectroscopy (ESR). The catalytic mechanism suggested that the Fe/FeC and graphitic N were the main active sites in the Fe/[email protected] for PMS activation. This work provided a facile method for the preparation of Fe-based carbon materials with high catalytic ability, low metal leaching and easy recycling, showing a broad prospect for environmental applications.
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http://dx.doi.org/10.1016/j.jcis.2021.11.178DOI Listing
March 2022

Distribution Characteristics and Prognostic Value of Immune Infiltration in Oligometastatic Breast Cancer.

Front Oncol 2021 11;11:747012. Epub 2021 Nov 11.

Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

Background: To assess the distribution characteristics and the prognostic value of immune infiltration in female oligometastatic breast cancer patients.

Methods: We retrospectively analyzed the clinicopathological data of oligometastatic breast cancer (OMBC) patients diagnosed between June 2000 and January 2020. Immune markers were quantified by immunohistochemistry on FFPE tissues in paired normal breast tissues, primary breast cancers and oligometastatic lesions. Survival analyses were performed using the Kaplan-Meier curves and Cox-proportional hazards model.

Results: A total of 95 female OMBC patients visited Sun Yat-sen University Cancer Center between June 2000 and January 2020, and 33 of them had matched normal breast tissues, primary cancers and oligometastatic lesions and were reviewed in immune infiltration analysis. CD8 of primary tumors had a higher expression than that in matched normal tissues. The expressions of CD8 and FOXP3 were higher in the primary sites than that in the oligometastatic lesions. CD3, CD4 and CD8 were significantly lower in the intratumoral regions than that in the peritumoral regions both in primary and oligometastatic lesions. Notably, the high percentage of CD3 in the intratumoral oligometastatic lesions predicted the longer PFS and OS, and higher CD4 in the same lesions also predicted a better OS. There was obviously positive correlation between CD4/CD3 and Ki-67 in primary cancers and negative correlation between CD4/CD3 and ER in oligometastatic sites.

Conclusion: We explored immune distribution and evolution in time and space in OMBC to provide new understandings for biological behaviors of this disease and further divided patients in different prognosis.
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http://dx.doi.org/10.3389/fonc.2021.747012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8632540PMC
November 2021

Trastuzumab Plus Endocrine Therapy or Chemotherapy as First-line Treatment for Patients with Hormone Receptor-Positive and HER2-Positive Metastatic Breast Cancer (SYSUCC-002).

Clin Cancer Res 2021 Nov 22. Epub 2021 Nov 22.

Department of Medical Oncology, the State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

Purpose: There is no research evidence demonstrate which is the better partner strategy, endocrine therapy or chemotherapy, to combine with anti-HER2 therapy as the first-line management of hormone receptor (HR)-positive (HR) and HER2-positive (HER2) metastatic breast cancer (MBC). We wished to ascertain if trastuzumab plus endocrine therapy is noninferior to trastuzumab plus chemotherapy.

Patients And Methods: We conducted an open-label, noninferiority, phase III, randomized, controlled trial (NCT01950182) at nine hospitals in China. Participants, stratified by previous adjuvant endocrine therapy and disease status (recurrent disease vs metastasis), were assigned randomly (1:1) to receive trastuzumab plus endocrine therapy (per investigator's choice of oestrogen-receptor modulators or aromatase inhibitor, with/without concurrent ovarian suppression) or chemotherapy (per investigator's choice of taxanes, capecitabine, or vinorelbine). The primary endpoint was progression-free survival (PFS) with a noninferiority upper margin of 1.35 for the HR. The intention-to-treat population was used in primary and safety analyses.

Results: A total of 392 patients were enrolled and assigned randomly to receive trastuzumab plus endocrine therapy (ET group, = 196) or trastuzumab plus chemotherapy (CT group, = 196). After a median follow-up of 30.2 months [interquartile range (IQR) 15.0-44.7], the median PFS was 19.2 months [95% confidence interval (CI), 16.7-21.7)] in the ET group and 14.8 months (12.8-16.8) in the CT group (hazard ratio, 0.88; 95% CI, 0.71-1.09; < 0.0001). A significantly higher prevalence of toxicity was observed in the CT group compared with the ET group.

Conclusions: Trastuzumab plus endocrine therapy was noninferior to trastuzumab plus chemotherapy in patients with HRHER2 MBC.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-3435DOI Listing
November 2021

A Novel Prognostic Model Based on the Serum Iron Level for Patients With Early-Stage Triple-Negative Breast Cancer.

Front Cell Dev Biol 2021 4;9:777215. Epub 2021 Nov 4.

Department of Medical Oncology, The State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.

The dysregulation of iron homeostasis has been explored in malignancies. However, studies focusing on the association between the serum iron level and prognosis of patients with early-stage triple-negative breast cancer (TNBC) are scarce. Accordingly, in current study, 272 patients with early-stage TNBC treated at Sun Yat-sen University Cancer Center (SYSUCC) between September 2005 and October 2016 were included as a training cohort, another 86 patients from a previous randomized trial, SYSUCC-001, were analyzed as a validation cohort (SYSUCC-001 cohort). We retrospectively collected their clinicopathological data and tested the serum iron level using blood samples at the diagnosis. In the training cohort, patients were divided into low-iron and high-iron groups according to the serum iron level cut-off of 17.84 μmol/L determined by maximally selected rank statistics. After a median follow-up of 87.10 months, patients with a low iron had a significantly longer median disease-free survival (DFS) of 89.13 [interquartile range (IQR): 66.88-117.38] months and median overall survival (OS) of 92.85 (IQR: 68.83-117.38) months than those in the high-iron group (median DFS: 75.25, IQR: 39.76-105.70 months, = 0.015; median OS: 77.17, IQR: 59.38-110.28 months, = 0.015). Univariate and multivariate Cox analysis demonstrated the serum iron level to be an independent predictor for DFS and OS. Then, a prognostic nomogram incorporating the serum iron level, T stage and N stage was developed for individualized prognosis predictions. It had good discriminative ability with a C-index of DFS (0.729; 95% CI 0.666-0.792) and OS (0.739; 95% CI 0.666-0.812), respectively. Furtherly, we validated the predictive model in the SYSUCC-001 cohort, which also showed excellent predictive performance with a C-index of DFS (0.735; 95% CI 0.614-0.855) and OS (0.722; 95% CI 0.577-0.867), respectively. All these suggested that the serum iron level might be a potential prognostic biomarker for patients with early-stage TNBC, the predictive model based on it might be served as a practical tool for individualized survival predictions.
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http://dx.doi.org/10.3389/fcell.2021.777215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8599954PMC
November 2021

Glyoxalase 1 Confers Susceptibility to Schizophrenia: From Genetic Variants to Phenotypes of Neural Function.

Front Mol Neurosci 2021 1;14:739526. Epub 2021 Nov 1.

Maternal and Children's Health Research Institute, Shunde Maternal and Children's Hospital, Guangdong Medical University, Foshan, China.

This research aimed to investigate the role of glyoxalase 1 (Glo-1) polymorphisms in the susceptibility of schizophrenia. Using the real-time polymerase chain reaction (PCR) and spectrophotometric assays technology, significant differences in Glo-1 messenger ribonucleic acid (mRNA) expression ( = 3.98 × 10) and enzymatic activity ( = 1.40 × 10) were found in peripheral blood of first-onset antipsychotic-naïve patients with schizophrenia and controls. The following receiver operating characteristic (ROC) curves analysis showed that Glo-1 could predict the schizophrenia risk ( = 4.75 × 10 in mRNA, = 1.43 × 10 in enzymatic activity, respectively). To identify the genetic source of Glo-1 risk in schizophrenia, Glo-1 polymorphisms (rs1781735, rs1130534, rs4746, and rs9470916) were genotyped with SNaPshot technology in 1,069 patients with schizophrenia and 1,023 healthy individuals. Then, the impact of risk polymorphism on the promoter activity, mRNA expression, and enzymatic activity was analyzed. The results revealed significant differences in the distributions of genotype ( = 0.020, false discovery rate (FDR) correction) and allele ( = 0.020, FDR correction) in rs1781735, in which G > T mutation significantly showed reduction in the promoter activity ( = 0.016), mRNA expression, and enzymatic activity = 0.001 and = 0.015, respectively, GG vs. TT, in peripheral blood of patients with schizophrenia) of Glo-1. The expression quantitative trait locus (eQTL) findings were followed up with the resting-state functional magnetic resonance imaging (fMRI) analysis. The TT genotype of rs1781735, associated with lower RNA expression in the brain ( < 0.05), showed decreased neuronal activation in the left middle frontal gyrus in schizophrenia ( < 0.001). In aggregate, this study for the first time demonstrates how the genetic and biochemical basis of Glo-1 polymorphism culminates in the brain function changes associated with increased schizophrenia risk. Thus, establishing a combination of multiple levels of changes ranging from genetic variants, transcription, protein function, and brain function changes is a better predictor of schizophrenia risk.
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http://dx.doi.org/10.3389/fnmol.2021.739526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8592033PMC
November 2021

An Aging-Related Gene Signature-Based Model for Risk Stratification and Prognosis Prediction in Breast Cancer.

Int J Womens Health 2021 3;13:1053-1064. Epub 2021 Nov 3.

Departments of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China.

Background: Aging, an inevitable process characterized by functional decline over time, is a significant risk factor for various tumors. However, little is known about aging-related genes (ARGs) in breast cancer (BC). We aimed to explore the potential prognostic role of ARGs and to develop an ARG-based prognosis signature for BC.

Methods: RNA-sequencing expression profiles and corresponding clinicopathological data of female patients with BC were obtained from public databases in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). An ARG-based risk signature was constructed in the TCGA cohort based on results of least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis, and its prognostic value was further validated in the GSE20685 cohort.

Results: A six ARG-based signature, including and , was developed in the TCGA cohort and significantly stratified patients into low- and high-risk groups. Patients in the former group showed significantly better prognosis than those in the latter. Multivariate Cox regression analysis demonstrated that the ARG risk score was an independent prognostic factor for BC. A predictive nomogram integrating the ARG risk score and three identified factors (age, N- and M-classification) was established in the TCGA cohort and validated in the GSE20685 cohort. Calibration plots showed good consistency between predicted survival probabilities and actual observations.

Conclusion: A novel ARG-based risk signature was developed for patients with BC, which can be used for individual prognosis prediction and promoting personalized treatment.
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http://dx.doi.org/10.2147/IJWH.S334756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8578840PMC
November 2021

The recurrence of prolactinoma after withdrawal of dopamine agonist: a systematic review and meta-analysis.

BMC Endocr Disord 2021 Nov 13;21(1):225. Epub 2021 Nov 13.

Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.

Background: Prolactinoma is the major cause of hyperprolactinemia, and dopamine agonists (DAs) are generally the first-line treatment for them. Several studies have reviewed the recurrent rate of hyperprolactinemia after DAs withdrawal. However, few of them have concerned the recurrence risk of prolactinoma following the withdrawal of DAs.

Methods: Three medical databases, PubMed, EMBASE and Cochrane library, were retrieved up to February, 14, 2021 to identify studies related to recurrence of prolactinoma and withdrawal of DAs. Statistical analyses including meta-analysis, sensitivity analysis, meta-regression, funnel plot and Egger test were performed through software R.

Results: A total of 3225 studies were retrieved from the three data bases, and 13 studies consisted of 616 patients and 19 arms were finally included in this systematic analysis. There was no significant heterogeneity among the included studies, and fixed effect model was thus used. The pooled recurrence proportion of prolactinoma after withdrawal of DA was 2% with a 95% confidence interval (CI) of 1-3%.

Conclusion: Our study showed a very low recurrent rate of prolactinomas after DAs withdrawal. Much more prospective studies with larger cases and longer follow-up period are encouraged to confirm our finding.

Trial Registration: Registration number CRD42021245888 (PROSPERO).
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http://dx.doi.org/10.1186/s12902-021-00889-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8590353PMC
November 2021

Metagenomic analysis of microbial communities and antibiotic resistance genes in spoiled household chemicals.

Chemosphere 2021 Nov 2:132766. Epub 2021 Nov 2.

Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, Guangdong, 510070, People's Republic of China. Electronic address:

Numerous attempts have been utilized to unveil the occurrences of antibiotic resistance genes (ARGs) in human-associated and non-human-associated samples. However, spoiled household chemicals, which are usually neglected by the public, may be also a reservoir of ARGs because of the excessive and inappropriate uses of industrial drugs. Based upon the Comprehensive Antibiotic Research Database, a metagenomic sequencing method was utilized to detect and quantify Antibiotic Resistance Ontology (AROs) in six spoiled household chemicals, including hair conditioner, dishwashing detergent, bath shampoo, hand sanitizer, and laundry detergent. Proteobacteria was found to be the dominant phylum in all the samples. Functional annotation of the unigenes obtained against the KEGG pathway, eggNOG and CAZy databases demonstrated a diversity of their functions. Moreover, 186 types of AROs that were members of 72 drug classes were identified. Multidrug resistance genes were the most dominant types, and there were 17 AROs whose resistance mechanisms were categorized into the resistance-nodulation-cell division antibiotic efflux pump among the top 20 AROs. Moreover, Proteobacteria was the dominant carrier of AROs with the primary resistance mechanism of antibiotic efflux. The maximum temperature of the months of collection significantly affected the distributions of AROs. Additionally, the isolated individual bacterium from spoiled household chemicals and artificial mixed communities of isolated bacteria demonstrated diverse resistant abilities to different biocides. This study demonstrated that there are abundant microorganisms and a broad spectrum profile of AROs in spoiled household chemicals that might induce a severe threat to public healthy securities and merit particular attention.
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http://dx.doi.org/10.1016/j.chemosphere.2021.132766DOI Listing
November 2021

Pathogen change of avian influenza virus in the live poultry market before and after vaccination of poultry in southern China.

Virol J 2021 Oct 29;18(1):213. Epub 2021 Oct 29.

The Collaboration Unit for Field Epidemiology of State Key Laboratory of Infectious Disease Prevention and Control, Jiangxi Provincial Key Laboratory of Animal-Origin and Vector-Borne Diseases, Nanchang Center for Disease Control and Prevention, Nanchang, 330038, People's Republic of China.

Background: The fifth wave of H7N9 avian influenza virus caused a large number of human infections and a large number of poultry deaths in China. Since September 2017, mainland China has begun to vaccinate poultry with H5 + H7 avian influenza vaccine. We investigated the avian influenza virus infections in different types of live poultry markets and samples before and after genotype H5 + H7 vaccination in Nanchang, and analyzed the changes of the HA subtypes of AIVs.

Methods: From 2016 to 2019, we monitored different live poultry markets and collected specimens, using real-time reverse transcription polymerase chain reaction (RT-PCR) technology to detect the nucleic acid of type A avian influenza virus in the samples. The H5, H7 and H9 subtypes of influenza viruses were further classified for the positive results. The χ test was used to compare the differences in the separation rates of different avian influenza subtypes.

Results: We analyzed 5,196 samples collected before and after vaccination and found that the infection rate of AIV in wholesale market (21.73%) was lower than that in retail market (24.74%) (P < 0.05). Among all the samples, the positive rate of sewage samples (33.90%) was the highest (P < 0.001). After vaccination, the positive rate of H5 and H7 subtypes decreased, and the positive rate of H9 subtype and untypable HA type increased significantly (P < 0.001). The positive rates of H9 subtype in different types of LPMs and different types of samples increased significantly (P < 0.01), and the positive rates of untypable HA type increased significantly in all environmental samples (P < 0.05).

Conclusions: Since vaccination, the positive rates of H5 and H7 subtypes have decreased, but the positive rates of H9 subtypes have increased to varying degrees in different testing locations and all samples. This results show that the government should establish more complete measures to achieve long-term control of the avian influenza virus.
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http://dx.doi.org/10.1186/s12985-021-01683-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8554751PMC
October 2021

The Impact of the Closure of the Live Poultry Market due to COVID-19 on the Avian Influenza Virus in Nanchang, Jiangxi Province, China.

Am J Trop Med Hyg 2021 10 29;106(1):127-131. Epub 2021 Oct 29.

The Collaboration Unit for Field Epidemiology of State Key Laboratory of Infectious Disease Prevention and Control, Jiangxi Provincial Key Laboratory of Animal-origin and Vector-borne Diseases, Nanchang Center for Disease Control and Prevention, Nanchang 330038, PR China.

This article aims to understand the changes in the detection rates of H5, H7, and H9 subtypes of avian influenza viruses (AIVs) in the live poultry markets (LPMs) in Nanchang City, Jiangxi Province, before and after the outbreak of the COVID-19. From 2019 to 2020, we monitored the LPM and collected specimens, using real-time reverse transcription polymerase chain reaction technology to detect the nucleic acid of type A AIV in the samples. The H5, H7, and H9 subtypes of influenza viruses were further classified for positive results. We analyzed 1,959 samples before and after the outbreak and found that the positive rates of avian influenza A virus (39.69%) and H9 subtype (30.66%) after the outbreak were significantly higher than before the outbreak (26.84% and 20.90%, respectively; P < 0.001). In various LPMs, the positive rate of H9 subtypes has increased significantly (P ≤ 0.001). Positive rates of the H9 subtype in duck, fecal, daub, and sewage samples, but not chicken samples, have increased to varying degrees. This study shows that additional measures are needed to strengthen the control of AIVs now that LPMs have reopened after the relaxing of COVID-19-related restrictions.
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http://dx.doi.org/10.4269/ajtmh.21-0732DOI Listing
October 2021

Comparison of phytochemical profiles, antioxidant and antiproliferative activities in Chinese bayberry (Myrica rubra Sieb. et Zucc.) fruits.

J Food Sci 2021 Oct 21;86(10):4691-4703. Epub 2021 Sep 21.

Department of Food Science, Cornell University, Ithaca, New York, USA.

Here, we examined the phytochemical profiles, antioxidant activity (AA), and antiproliferative activity (APA) of four Chinese bayberry (Myrica rubra Sieb. et Zucc.) pulp extracts. They were found to be rich in total phenolics content (TPC; 186.45 ± 5.42 to 498.94 ± 8.25 mg of gallic acid equiv./100 g FW) and total flavonoids content (TFC; 126.28 ± 4.18 to 194.35 ± 12.03 mg of catechin equiv./100 g FW). For all varieties, the free flavonoid/phenolic/anthocyanin contents were higher than that the bound fractions. Wild pink bayberry (WPB) displayed the highest values of TPC and TFC, and also showed the highest total antioxidant activity (TAA) as revealed by peroxyl radical scavenging capacity (PSC) (451.47 ± 8.01 µmol Vit. C equiv./100 g FW), and free cellular antioxidant activity (CAA) (184.99 ± 6.11 µmol quercetin equiv./100 g FW, no PBS wash; 117.78 ± 2.34 µmol quercetin equiv./100 g FW, PBS wash) assays. Bayberry extracts had a marked reduction in the APA of HepG2 cells, and WPB exhibited the lowest EC (8.50 ± 0.83 mg/ml) value, which was probably associated with cell cycle arrest and apoptosis induction. PRACTICAL APPLICATION: Chinese bayberry (Myrica rubra Sieb. et Zucc.) fruit is rich in natural phenolic compounds, which might be a functional ingredient in food and nutraceutical products. Our findings would provide a logical strategy to promote the comprehensive utilization of phenolics in bayberry fruit with both health and economy benefits.
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http://dx.doi.org/10.1111/1750-3841.15899DOI Listing
October 2021

A novel compound heterozygous mutation of the MTO1 gene associated with complex oxidative phosphorylation deficiency type 10.

Clin Chim Acta 2021 Dec 20;523:172-177. Epub 2021 Sep 20.

Department of Laboratory Medicine, Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Luzhou, Sichuan 646000, China. Electronic address:

Background: The mitochondrial tRNA translation optimization 1 (MTO1) gene, which is closely related to defective mitochondrial oxidative phosphorylation, is an evolutionarily conserved protein expressed in high energy-demanding tissues and is associated with complex oxidative phosphorylation deficiency type 10 (COXPD10) in humans. Related cases and studies are still scarce and have not been reported in the Chinese region.

Materials And Methods: Detailed clinical assessment was applied to the patient. Based on next-generation sequencing technology, we performed whole-exome sequencing of the patient and the parents. Sanger sequencing was used for validation. Bioinformatics software and protein simulations were used to predict the pathogenicity of the variants.

Results: The patient was diagnosed with a possible association with mitochondrial disease according to the clinical manifestations and physical examination. A novel frameshift mutation c.344delA (p. Asn115Thrfs*11) and a novel point mutation c.1055C > T (p. Thr352Met) in the MTO1 gene were identified. They were found to cause abnormal changes in amino acids and the protein by biochemical tools, indicating it may be pathogenic.

Conclusion: We present two novel and possibly pathogenic variants in the MTO1 gene in a Chinese Han family.
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http://dx.doi.org/10.1016/j.cca.2021.09.014DOI Listing
December 2021

Establishment of Prognostic Nomograms for Predicting the Survival of HR-Positive, HER2-Negative Metastatic Breast Cancer Patients Treated with Everolimus.

Drug Des Devel Ther 2021 10;15:3463-3473. Epub 2021 Aug 10.

Departments of Medical Oncology, Sun Yat-sen University Cancer Center, The State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People's Republic of China.

Background: There are no clinically available prognostic models for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer treated with everolimus. We aimed to develop a tool to predict the progression-free survival (PFS) and overall survival (OS) of these patients and to identify optimal candidates who would benefit from everolimus-based treatment in this heterogeneous patient population.

Methods: The clinical data of patients with HR+, HER2- metastatic breast cancer receiving everolimus between May 2012 and January 2018 at Sun Yat-sen University Cancer Center were retrospectively retrieved. Based on potential prognostic factors derived from multivariate Cox analysis, we established predictive nomogram models for PFS and OS and evaluated their predictive values by means of the concordance index (C-index). Calibration curves were used to estimate the consistency between the actual observations and the nomogram-predicted probabilities.

Results: A total of 116 patients with HR+, HER2- metastatic breast cancer were enrolled in this study. Three independent prognostic factors, including the line of everolimus in the metastatic setting, everolimus clinical benefit rate and number of liver metastatic lesions, were identified from the multivariate Cox analysis. Prognostic models for individual survival prediction were established and graphically presented as nomograms. The C-index was 0.738 (95% confidence interval [CI]: 0.710-0.767) for the PFS nomogram and 0.752 (95% CI: 0.717-0.788) for the OS nomogram, which showed favourable discrimination. The calibration curves for the probabilities of 6-, 9-, and 12-month PFS and 1-, 2-, and 3-year OS suggested satisfactory consistency between the actual observations and the predicted probabilities.

Conclusion: We constructed convenient nomogram models for patients with HR+, HER2- metastatic breast cancer to individually predict their potential benefits from everolimus in the metastatic setting. The models showed good performance in terms of accuracy, discrimination capacity and clinical application value.
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http://dx.doi.org/10.2147/DDDT.S314723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364432PMC
January 2022

Systematic review and meta-analysis of clinical efficacy of drug therapy for acute myelogenous leukemia.

Ann Palliat Med 2021 Jul;10(7):7884-7893

Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China; Digestive Endoscopy Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.

Background: A meta-analysis was performed to examine the clinical efficacy of drugs in the treatment of acute myelogenous leukemia (AML).

Methods: combinations of terms of "acute myeloid leukemia", "fludara", "cytarabine", "cladribine", "aclacinomycin", "granulocyte colony-stimulating factor (G-CSF)", and "hyaluronic acid" were searched in Chinese databases. "acute myelogenous leukemia", "fludara", "cytarabine", "cladribine", "aclacinomycin", "granulocyte colony-stimulating factor", and "hyaluronic acid" were searched in English databases. Review Manager 5.3 was employed for the meta-analysis.

Results: Ultimately, 12 articles were included. Most of the articles had a low-risk bias, and were of medium or high quality. The complete remission rates were tested for heterogeneity [chi-square test (Chi2) =4.10, degrees of freedom (df)=10, I2=0%; P=0.94]. The fixed effect model analysis showed that the difference between experimental participants and controls was considerable [Z=13.15, odds ratio (OR) =12.82, 95% confidence interval (CI): (8.77, 18.76); P<0.01]. The overall effective rates were tested for heterogeneity (Chi2=1.58, df=7, I2=0%; P=0.98), and difference between experimental participants and controls was considerable [Z=10.70, OR =1.32, 95% CI: (7.32,17.89); P<0.01]. The overall adverse reaction rates were tested for heterogeneity (Chi2=0.42, df=5, I2=0%; P=0.99), and the difference between experimental participants and controls was considerable [Z=5.00, OR =0.38, 95% CI: (0.26, 0.55); P<0.01]. The circles of some studies in the funnel diagrams were symmetrical with the midline, the accuracy of included trials was high, the publications were not biased, and the final conclusions were reliable.

Conclusions: This meta-analysis showed that drug treatments of AML can improve complete remission and total effective rates and reduce adverse reaction rates, and thus are worthy of clinical promotion.
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http://dx.doi.org/10.21037/apm-21-1390DOI Listing
July 2021

Genetic Contribution of Synapse-Associated Protein 97 to Orbitofrontal-Striatal-Thalamic Circuitry Connectivity Changes in First-Episode Schizophrenia.

Front Psychiatry 2021 19;12:691007. Epub 2021 Jul 19.

Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.

Functional and structural disturbances in the orbitofrontal-striatal-thalamic circuitry are thought to be associated with mental symptoms and neurocognitive impairments in schizophrenia. This study tested whether synapse-associated protein 97 (SAP97), a reasonable candidate gene for schizophrenia, is related to orbitofrontal-striatal-thalamic connection changes in first-episode schizophrenia (FES) patients and the clinical performance of schizophrenic patients by affecting this integrity. Fifty-two FES patients and 52 matched healthy controls were recruited. All subjects underwent genotyping via the improved multiplex ligation detection reaction technique and scanning with magnetic resonance imaging (MRI) to provide orbitofrontal-striatal-thalamic functional and structural imaging data. A two-way analysis of covariance model was employed to examine abnormal brain connectivities, and Spearman correlations were applied to estimate the relationships between brain connectivity and clinical manifestations. In the FES group, those with the SAP97 rs3915512 TT genotype showed lower structural and functional connectivity than A allele carriers between the orbitofrontal gyrus and striatum/thalamus. In the FES group, negative correlations were found between resting-state functional connectivity (RSFC) in the orbitofrontal gyrus and thalamus, and positive symptoms between structural connections in the orbitofrontal gyrus and striatum and cognitive functions, and positive correlations were suggested between RSFC in the orbitofrontal gyrus and thalamus and negative symptoms. Our findings suggested that the SAP97 rs3915512 polymorphism may be involved in mental symptoms and cognitive dysfunction in FES patients by influencing structural and functional connectivity of the orbitofrontal-striatal and orbitofrontal-thalamic regions.
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http://dx.doi.org/10.3389/fpsyt.2021.691007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326367PMC
July 2021

Establishment and Validation of Nomogram Based on Combination of Pretreatment C-Reactive Protein/Albumin Ratio-EBV DNA Grade in Nasopharyngeal Carcinoma Patients Who Received Concurrent Chemoradiotherapy.

Front Oncol 2021 15;11:583283. Epub 2021 Jul 15.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.

Background: A higher ratio of pretreatment C-reactive protein/albumin ratio (CAR) is associated with poor prognosis in nasopharyngeal carcinoma (NPC), and Epstein-Barr virus (EBV) DNA level is known to not only participate in the occurrence of nasopharyngeal carcinoma but also affect the development and prognosis of the disease. Herein, we proposed that a combination of both these markers could improve the predictive prognostic ability.

Methods: In all, 842 NPC patients who received concurrent chemoradiotherapy (CCRT) were entered in this study. We collected all patients' blood samples and EBV DNA copy numbers within one week before any treatment. Receiver operating characteristic (ROC) curve was used to determine the optimal cut-off. We employed the Kaplan-Meier method for survival analyses and the univariate and multivariate analyses (Cox proportional hazards regression model) for statistical analysis. A nomogram was constructed based on multivariate analyses results of the validation set. The model was internally validated using 1000 bootstrap samples to avoid overfitting. Another validation of 10-fold cross-validation was also applied. Calibration curves and concordance index (C-index) were calculated to determine predictive and discriminatory capacity.

Results: In the whole cohort, we observed that higher CAR, EBV DNA level, and CAR-EBV DNA (C-E) grade were associated with shorter overall survival (OS) and distant metastasis-free survival (DMFS) (all P<0.05). In univariate and multivariate analyses, C-E grade was an independent prognostic factor (all P<0.05). In the training set, we gained the similar results with the whole set. According to multivariate analyses of the training set, we constructed a nomogram. The results of bootstrap samples and 10-fold cross-validation showed favorable predictive efficacy. And calibration curves of the model provided credibility to its predictive capability.

Conclusion: C-E grade was confirmed as an independent prognostic predictor in patients with NPC who received CCRT. Higher level of pretreatment C-E grade could signify a higher risk of metastasis and shorter OS. The prognostic nomogram based on C-E grade was dependable in nasopharyngeal carcinoma patients.
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http://dx.doi.org/10.3389/fonc.2021.583283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320887PMC
July 2021

Optimization of 1,4-bis(arylsulfonamido)naphthalene-N,N'-diacetic acids as inhibitors of Keap1-Nrf2 protein-protein interaction to suppress neuroinflammation.

Bioorg Med Chem 2021 08 1;44:116300. Epub 2021 Jul 1.

Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA. Electronic address:

The protein-protein interaction (PPI) between kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2) is recognized as a promising target for the prevention and treatment of oxidative stress-related inflammatory diseases. Herein, a series of novel 1,4-bis(arylsulfonamido)naphthalene-N,N'-diacetic acid analogs (7p-t and 8c) were designed to further explore the structure-activity relationships of the series. Their activities were measured first with a fluorescence polarization (FP) assay and more potent compounds were further evaluated using a more sensitive time-resolved fluorescence energy transfer (TR-FRET) assay, demonstrating IC values between 7.2 and 31.3 nM. In cytotoxicity studies, the naphthalene derivatives did not show noticeable toxicity to human HepG2-C8 and mouse brain BV-2 microglia cells. Among them, compound 7q bearing oxygen-containing fused rings was shown to significantly stimulate the cellular Nrf2 signaling pathway, including activation of antioxidant response element (ARE)-controlled expression of Nrf2 target genes and proteins. More importantly, 7q suppressed up-regulation of several pro-inflammatory cytokines in lipopolysaccharide (LPS)-challenged BV-2 microglial cells, representing a potential therapeutic application for controlling neuroinflammatory disorders.
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http://dx.doi.org/10.1016/j.bmc.2021.116300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349900PMC
August 2021

In Vitro Inhibition of Renal OCT2 and MATE1 Secretion by Antiemetic Drugs.

Int J Mol Sci 2021 Jun 16;22(12). Epub 2021 Jun 16.

Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, 170 Frelinghuysen Road, Piscataway, NJ 08854, USA.

The organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) mediate the renal secretion of drugs. Recent studies suggest that ondansetron, a 5-HT antagonist drug used to prevent nausea and vomiting, can inhibit OCT2- and MATE1-mediated transport. The purpose of this study was to test the ability of five 5-HT antagonist drugs to inhibit the OCT2 and MATE1 transporters. The transport of the OCT2/MATE1 probe substrate ASP was assessed using two models: (1) HEK293 kidney cells overexpressing human OCT2 or MATE1, and (2) MDCK cells transfected with human OCT2 and MATE1. In HEK293 cells, the inhibition of ASP uptake by OCT2 listed in order of potency was palonosetron (IC: 2.6 μM) > ondansetron > granisetron > tropisetron > dolasetron (IC: 85.4 μM) and the inhibition of ASP uptake by MATE1 in order of potency was ondansetron (IC: 0.1 μM) > palonosetron = tropisetron > granisetron > dolasetron (IC: 27.4 μM). Ondansetron (0.5-20 μM) inhibited the basolateral-to-apical transcellular transport of ASP up to 64%. Higher concentrations (10 and 20 μM) of palonosetron, tropisetron, and dolasetron similarly reduced the transcellular transport of ASP. In double-transfected OCT2-MATE1 MDCK cells, ondansetron at concentrations of 0.5 and 2.5 μM caused significant intracellular accumulation of ASP. Taken together, these data suggest that 5-HT antagonist drugs may inhibit the renal secretion of cationic drugs by interfering with OCT2 and/or MATE1 function.
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http://dx.doi.org/10.3390/ijms22126439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234231PMC
June 2021

Changes of avian influenza virus subtypes before and after vaccination in live poultry in Nanchang, China from 2016 to 2019.

Microbes Infect 2021 Nov-Dec;23(9-10):104848. Epub 2021 Jun 8.

The Collaboration Unit for Field Epidemiology of State Key Laboratory of Infectious Disease Prevention and Control, Jiangxi Provincial Key Laboratory of Animal-origin and Vector-borne Diseases, Nanchang Center for Disease Control and Prevention, Nanchang, 330038, PR China. Electronic address:

We investigated fluctuations in the detection rates of avian influenza virus (AIV) subtypes H5, H7, and H9 in live poultry in Nanchang city, Chinese province Jiangxi, before and after the Chinese nationwide AIV vaccination campaign against highly pathogenic (HP) AIV subtype H5 and H7. Samples were tested for nucleic acid of type A avian influenza virus by real-time reverse transcription polymerase chain reaction technology. The H5, H7 and H9 subtypes of influenza viruses were further classified for the positive results. Based on the analysis of 2119 samples collected from February 2016 to December 2019, we found that AIV subtypes H5, H7, H9 showed a seasonal pattern, and the positive rate of avian influenza tended to reach its peak in the colder season. The detection rate of AIV subtypes H5, H7, H9 of chickens (39.26%) was significantly higher than that of ducks (5.78%) and pigeons (4.31%). After vaccination, the positive rates of the H5 subtype (0.27%) and the H7 subtype (0.00%) decreased significantly, while the positive rate of the H9 subtype (29.95%) increased significantly. The H9 subtype has become the dominant subtype detected in live poultry and occupies a dominant position in the live bird market. This study showed that the government of China should establish measures for the long-term control of avian influenza.
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http://dx.doi.org/10.1016/j.micinf.2021.104848DOI Listing
June 2021

BCRP/ Transporter Regulates Accumulation of Cadmium in Kidney Cells: Role of the Q141K Variant in Modulating Nephrotoxicity.

Drug Metab Dispos 2021 08 1;49(8):629-637. Epub 2021 Jun 1.

Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, New Jersey (X.W., D.K., L.M.A.); Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey (X.W., R.Z., C.D., B.B., E.B., L.M.A.); and Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, New Jersey (R.Z., E.B.)

Exposure to the environmental pollutant cadmium is ubiquitous, as it is present in cigarette smoke and the food supply. Over time, cadmium enters and accumulates in the kidneys, where it causes tubular injury. The breast cancer resistance protein (BCRP, ATP-Binding Cassette G2 ) is an efflux transporter that mediates the urinary secretion of pharmaceuticals and toxins. The genetic variant Q141K exhibits altered membrane trafficking that results in reduced efflux of BCRP substrates. Here, we sought to 1) evaluate the in vitro and in vivo ability of BCRP to transport cadmium and protect kidney cells from toxicity and 2) determine whether this protection is impaired by the Q141K variant. Cadmium concentrations, cellular stress, and toxicity were quantified in human embryonic kidney 293 cells expressing an empty vector (EV), BCRP wild-type (WT), or variant (Q141K) gene. Treatment with CdCl resulted in greater accumulation of cadmium and apoptosis in EV cells relative to WT cells. Exposure to CdCl induced expression of stress-related genes and proteins including MT-1A/MT-2A, NAD(P)H quinone dehydrogenase 1, and heme oxygenase-1 to a higher extent in EV cells compared with WT cells. Notably, the Q141K variant protected against CdCl-induced activation of stress genes and cytotoxicity, but this protection was to a lesser magnitude than observed with WT BCRP. Lastly, concentrations of cadmium in the kidneys of Bcrp knockout mice were 40% higher than in WT mice, confirming that cadmium is an in vivo substrate of BCRP. In conclusion, BCRP prevents the accumulation of cadmium and protects against toxicity, a response that is impaired by the Q141K variant. SIGNIFICANCE STATEMENT: The breast cancer resistance protein transporter lowers cellular accumulation of the toxic heavy metal cadmium. This protective function is partially attenuated by the Q141K genetic variant in the gene.
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http://dx.doi.org/10.1124/dmd.121.000446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382159PMC
August 2021

Nucks1 gene polymorphism rs823114 is associated with the positive symptoms and neurocognitive function of patients with schizophrenia in parts of southern China.

Psychiatr Genet 2021 08;31(4):119-125

Medical Genetics Laboratory, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, China.

Nuclear casein kinase and cyclin-dependent kinase substrate 1 (nucks1) are considered a potential susceptibility gene for certain neurological diseases, such as Parkinson's disease (PD). In our study, we genotyped three single nucleotide polymorphisms (SNPs) (rs4951261, rs823114 and rs951366) of the nucks1 gene in 774 schizophrenic patients and 819 healthy controls using the improved multiplex ligation detection reaction (imLDR) technique. Furthermore, we also studied the relationship between the above SNPs and the clinical psychiatric symptoms and neurocognitive function of the patients. Genotype distributions and allele frequencies of these SNPs showed no significant differences and were found between patients and healthy controls. However, in an analysis of the positive symptom score of rs823114 among male patients, we found that the score of the A/A genotype was lower than that of the G/A+G/G genotypes (P = 0.001, P(corr) = 0.003]. Additionally, we also found that among the female patients, G allele carriers with rs823114 had lower semantic fluency scores than subjects with the A/A genotype (P = 0.010, P(corr) = 0.030]. Our data show for the first time that rs823114 polymorphism of nucks1 may affect positive symptoms and neurocognitive function in patients with schizophrenia in parts of southern China.
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http://dx.doi.org/10.1097/YPG.0000000000000285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265546PMC
August 2021

In vitro and in vivo study on the osseointegration of magnesium and strontium ion with two different proportions of mineralized collagen and its mechanism.

J Biomater Appl 2021 09 18;36(3):528-540. Epub 2021 May 18.

School of Stomatology, Wannan Medical College, WuHu, Anhui, PR China.

To explore the optimal combination of Mg, Sr and mineralized collagen (nHAC) with two different proportions of hydroxyapatite (HA) and collagen (COL) on differentiation of MC3T3-E1 and the underlying mechanism, as well as achieve bone osseointegration. MC3T3-E1 cells were cultured in a complete medium with Mg at the concentration of 0, 4, 8, 12, 16, 20 mmol/L, Sr at the concentration of 0, 3, 6, 12 mmol/L, and the impregnation solution of 3:7 and 5:5nHAC. The differentiation of MC3T3-E1 was measured by expression of osteogenic genes and proteins including Runx-2, BMP-2 and OCN and determined the activation of PI3K/AKT/GSK3β/β-catenin signaling pathway in 12 mmol/LMg+3 mmol/LSr+3:7nHAC group. Osteoporosis was induced in 18 female rats by means of ovariectomy, the implants were immersed in 60 mmol/LMg+15 mmol/LSr+3:7nHAC impregnation solution and implanted into the mesial alveolar fossa for immediate implantation. The osseointegration of the implants was observed by Confocal laser scanning microscopy (CLSM) and histology at 4 and 8 weeks. The groups cultured with 12 mmol/LMg, 3 mmol/LSr and 3:7nHAC impregnation solution showed the osteogenic genes and proteins were significantly higher respectively (P < 0.05), as well as p-Akt, p-GSK3β and β-catenin proteins (P < 0.05). CLSM and histology showed that the implant surface was surrounded by thick lamellar bone plate, and the trabecular bone were dense and continuous in the impregnation solution. These results found that magnesium and strontium ion-loaded mineralized collagen play an critical role in up-regulating the cells activity through PI3K/AKT/GSK3β/β-catenin signaling pathway and could be promote the formation of osseointegration.
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http://dx.doi.org/10.1177/08853282211016934DOI Listing
September 2021

An update on genetic basis of generalized pustular psoriasis (Review).

Int J Mol Med 2021 Jun 6;47(6). Epub 2021 May 6.

Department of Laboratory Medicine, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China.

Generalized pustular psoriasis (GPP) is a rare and severe auto‑inflammatory skin disease that is characterized by recurrent, acute onset, and generalized pustular eruptions on erythematous, inflamed skin. GPP is traditionally classified as a variant of psoriasis vulgaris, even though recent clinical, histological and genetic evidence suggests that it is a heterogeneous disease and requires a separate diagnosis. In recent years, variants of , , and genes have been identified as causative or contributing to genetic defects in a proportion of patients affected by GPP. These disease‑related genes are involved in common inflammatory pathways, in particular in the IL‑1/IL‑36‑chemokines‑neutrophil pathogenic axis. At present, no standard therapeutic guidelines have been established for GPP management, and there is a profound need for novel efficacious treatments of GPP. Among them, biological agents antagonizing the IL‑36 pathway are promising therapeutics. The aim of the present review is to provide the most recent updates on the genetics, genotype‑phenotype correlation and pathological basis of GPP, as well as on biologic treatments available for GPP and relative clinical courses.
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http://dx.doi.org/10.3892/ijmm.2021.4951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083806PMC
June 2021

CARD-Associated Risk Score Features the Immune Landscape and Predicts the Responsiveness to Anti-PD-1 Therapy in IDH Wild-Type Gliomas.

Front Cell Dev Biol 2021 19;9:653240. Epub 2021 Mar 19.

Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.

Background: Proteins containing the caspase recruitment domain (CARD) play critical roles in cell apoptosis and immunity. However, the impact of CARD genes in tumor immune cell infiltration, responsiveness to checkpoint immunotherapy, and clinical outcomes of gliomas remains unclear. Here, we explore using CARD genes to depict the immune microenvironment and predict the responsiveness of gliomas to anti-PD-1 therapy.

Methods: The genome and transcriptome data of 231 patients with isocitrate dehydrogenase wild-type (IDH-wt) gliomas were retrieved from The Cancer Genome Atlas (TCGA) database to screen CARD genes associated with T lymphocyte infiltration in gliomas. Weighted co-expression network and LASSO penalized regression were employed to generate a CARD-associated risk score (CARS). Two independent and publicly available datasets were used to validate the effectiveness of CARS.

Results: The CARS divided the 231 glioma patients into high- and low-risk subgroups with distinct immune microenvironment and molecular features. The high-risk group had high CARS and was characterized by enrichment of dysfunctional T lymphocytes in a profound immunosuppressive microenvironment, whereas the low-risk group had low CARS and exhibited an immune exclusion genotype. Moreover, signaling aberrations including upregulation of PI3K/Akt/mTOR, NF-κB, and TGF-β were found in the high-risk group. In contrast, the activated WNT pathway was more evident in the low-risk group. Furthermore, we found that an elevated CARS indicated a decreased overall survival for IDH-wt gliomas under standard care but a clinical benefit from checkpoint immunotherapy.

Conclusion: This study developed an immune- and prognosis-relevant risk score, which could be used to enhance our understanding of the heterogeneity of immune microenvironment of gliomas and facilitate to identify patients who will benefit from checkpoint immunotherapy.
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http://dx.doi.org/10.3389/fcell.2021.653240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009185PMC
March 2021

High-dose tamoxifen in high-hormone-receptor-expressing advanced breast cancer patients: a phase II pilot study.

Ther Adv Med Oncol 2021 26;13:1758835921993436. Epub 2021 Feb 26.

Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng East Road, Guangzhou 510000, China.

Background: Tumor progression following endocrine therapy is considered to indicate resistance to endocrine drugs due to a variety of mechanisms. An insufficient dose of endocrine drugs is one of the causes for treatment failure in some patients with high hormone-receptor (HR)-expressing advanced breast cancer. This study aimed to explore the efficacy of high-dose tamoxifen (TAM) treatment in patients with advanced breast cancer with highly expressed HR.

Materials & Methods: This was a single-arm, phase II pilot study that enrolled patients with advanced breast cancer with high HR expression (estrogen receptor ⩾60% and/or progesterone receptor ⩾60%) following routine endocrine therapy. All enrolled patients received a high-dose of TAM (100 mg/day) until disease progression. The primary endpoint was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS), and safety. Exploratory endpoints included the predictive value of α-F-β-fluoroestradiol quantitative positron emission tomography/computed tomography (F-FES PET/CT) for treatment efficacy.

Results: A total of 30 patients were enrolled between September 2017 and February 2019. The median PFS was 6 months [95% confidence interval (CI) 4.9-7.1] and the median OS was 15.6 months (95% CI 8.3-22.9). Five patients experienced a partial response (PR) and none experienced a complete response (CR), with an ORR of 16.7% and CBR of 33.3%. No severe adverse events were observed. Lesions with F-FES maximum standardized uptake value (SUVmax) ⩾4 had a significantly longer PFS [median 9.2 months, (95% CI 6.9-11.6)] compared with lesions with a F-FES SUVmax <4 [median 4.8 months, (95% CI 3.9-5.6);  = 0.022].

Conclusion: A high-dose of TAM is effective and safe for patients with advanced breast cancer with high HR expression. F-FES SUVmax values may predict the local clinical benefits of high-dose TAM .

Trial Registration: [ClinicalTrials.gov identifier: NCT0304565].
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http://dx.doi.org/10.1177/1758835921993436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934038PMC
February 2021

Sex-Specific Associations of Polymorphisms With Schizophrenia in a Han Chinese Cohort.

Front Genet 2021 23;12:627874. Epub 2021 Feb 23.

Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.

: To investigate the effects of microRNA-137 () polymorphisms (rs1198588 and rs2660304) on the risk of schizophrenia in a Han Chinese population. : Schizophrenia was diagnosed according to the DSM-5. Clinical symptoms and cognitive functions were assessed with the Positive and Negative Symptom Scale (PANSS) and Brief Assessment of Cognition in Schizophrenia (BACS), respectively. The polymorphisms were genotyped by improved multiplex ligation detection reaction (iMLDR) technology in 1,116 patients with schizophrenia and 1,039 healthy controls. : Significant associations were found between schizophrenia and in the distributions of genotypes ( = 0.037 for rs1198588; = 0.037 for rs2660304, FDR corrected) and alleles ( = 0.043 for rs1198588; = 0.043 for rs2660304, FDR corrected) of two SNPs. When the population was stratified by sex, we found female-specific associations between and schizophrenia in terms of genotype and allele distributions of rs1198588 ( = 4.41, = 0.036 and = 4.86, = 0.029, respectively, FDR corrected) and rs2660304 ( = 4.74, =0.036 and = 4.80, = 0.029, respectively, FDR corrected). Analysis of the haplotype rs1198588-rs2660304 showed a significant association with schizophrenia in haplotype T-T [ = 4.60, = 0.032, OR = 1.32, 95% CI (1.02-1.70)]. Then, significant female-specific associations were found with the haplotypes T-T and G-A [ = 4.92, = 0.027, OR = 1.62, 95% CI (1.05-2.50); = 4.42, = 0.035, OR = 0.62, 95% CI (0.39-0.97), respectively]. When the TT genotype of rs1198588 was compared to the GT+GG genotype, a clinical characteristics analysis also showed a female-specific association in category instances ( = 2.76, = 0.042, FDR corrected). : The polymorphisms within the gene are associated with susceptibility to schizophrenia, and a female-specific association of with schizophrenia was reported in a Han Chinese population.
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http://dx.doi.org/10.3389/fgene.2021.627874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942225PMC
February 2021
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