Publications by authors named "Sheng Lin"

432 Publications

Clinical findings of Talaromyces marneffei infection among patients with anti-interferon-γ immunodeficiency: a prospective cohort study.

BMC Infect Dis 2021 Jun 19;21(1):587. Epub 2021 Jun 19.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, National Center for Respiratory Medicine, Guangzhou, 510120, China.

Background: Talaromyces marneffei (T. marneffei) infection has been associated with adult-onset immunodeficiency due to anti-IFN-γ autoantibodies. We aimed to investigate the clinical features of non-HIV-infected patients with T. marneffei infection in southern China.

Methods: Between January 2018 and September 2020, we enrolled patients with T. marneffei infection who were HIV-negative (group TM, n = 42), including anti-IFN-γ autoantibody-positive (group TMP, n = 22) and anti-IFN-γ autoantibody-negative (group TMN, n = 20) patients and healthy controls (group HC, n = 40). Anti-IFN-γ autoantibodies were detected by ELISA. Clinical characteristics and clinical laboratory parameters were recorded.

Results: Compared with anti-IFN-γ autoantibody-negative patients with T. marneffei infection, anti-IFN-γ autoantibody-positive patients did not have underlying respiratory disease; more frequently exhibited dissemination of systemic infections with severe pleural effusion; had higher WBC counts, C-reactive protein levels, erythrocyte sedimentation rates, and neutrophil and CD8 T cell counts; had lower hemoglobin levels; and were more likely to have other intracellular pathogen infections. Most of these patients had poor outcomes despite standardized antimicrobial therapy.

Conclusion: T. marneffei-infected patients with higher anti-IFN-γ autoantibody titers have more severe disease and complex clinical conditions.
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http://dx.doi.org/10.1186/s12879-021-06255-9DOI Listing
June 2021

Molecular Characterization of Glucose-6-Phosphate Dehydrogenase Deficiency in the Shenzhen Population.

Hum Hered 2021 Jun 16:1-7. Epub 2021 Jun 16.

Laboratory of Molecular Medicine, Shenzhen Health Development Research Center, Shenzhen, China.

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is caused by one or more mutations in the G6PD gene on chromosome X. This study aimed to characterize the G6PD gene variant distribution in Shenzhen of Guangdong province.

Methods: A total of 33,562 individuals were selected at the hospital for retrospective analysis, of which 1,213 cases with enzymatic activity-confirmed G6PD deficiency were screened for G6PD gene variants. Amplification refractory mutation system PCR was first used to screen the 6 dominant mutants in the Chinese population (c.1376G>T, c.1388G>A, c.95A>G, c.1024C>T, c.392G>T, and c.871G>A). If the 6 hotspot variants were not found, next-generation sequencing was then performed. Finally, Sanger sequencing was used to verify all the mutations.

Results: The incidence of G6PD deficiency in this study was 3.54%. A total of 26 kinds of mutants were found in the coding region, except for c.-8-624T>C, which was in the noncoding region. c.1376G>T and c.1388G>A, both located in exon 12, were the top 2 mutants, accounting for 68.43% of all individuals. The 6 hotspot mutations had a cumulative proportion of 94.02%.

Conclusions: This study provided detailed characteristics of G6PD gene variants in Shenzhen, and the results would be valuable to enrich the knowledge of G6PD deficiency.
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http://dx.doi.org/10.1159/000516808DOI Listing
June 2021

Predictive factors for survival following stereotactic body radiotherapy for hepatocellular carcinoma with portal vein tumour thrombosis and construction of a nomogram.

BMC Cancer 2021 Jun 15;21(1):701. Epub 2021 Jun 15.

Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China.

Background: We evaluated the treatment response and predictive factors for overall survival (OS) in patients with hepatocellular carcinoma (HCC) and portal vein tumour thrombosis (PVTT), who underwent stereotactic body radiotherapy (SBRT). Additionally, we developed and validated a personalised prediction model for patient survival.

Methods: Clinical information was retrospectively collected for 80 patients with HCC and PVTT, who were treated with SBRT at the Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital) between December 2015 and June 2019. A multivariate Cox proportional hazard regression model was used to identify the independent predictive factors for survival. Clinical factors were subsequently presented in a nomogram. The area under the receiver operating characteristic curve (AUC) and decision curve analysis (DCA) were used to evaluate the accuracy of the model and the net clinical benefit.

Results: All patients completed the planned radiotherapy treatment, and the median follow-up duration was 10 months (range, 1-35.3 months). The median survival duration was 11.5 months, with 3-, 6-, and 12-month survival rates of 92.5, 74.5, and 47.5%, respectively. The multivariable Cox regression model indicated that the following were significant independent predictors of OS: clinical T stage (p = 0.001, hazard ratio [HR] = 3.085, 95% confidence interval [CI]: 1.514-6.286), cirrhosis (p = 0.014, HR = 2.988, 95% CI: 1.246-7.168), age (p = 0.005, HR = 1.043, 95% CI: 1.013-1.075), alpha-fetoprotein level (p = 0.022, HR = 1.000, 95% CI: 1.000-1.000), and haemoglobin level (p = 0.008, HR = 0.979, 95% CI: 0.963-0.994). A nomogram based on five independent risk factors and DCA demonstrated a favourable predictive accuracy of patient survival (AUC = 0.74, 95% CI: 0.63-0.85) and the clinical usefulness of the model.

Conclusions: SBRT is an effective treatment for patients with HCC with PVTT. Notably, clinical T stage, presence of cirrhosis, age, alpha-fetoprotein levels, and haemoglobin levels are independent prognostic factors for survival. The presented nomogram can be used to predict the survival of patients with HCC and PVTT, who underwent SBRT.
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http://dx.doi.org/10.1186/s12885-021-08469-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204556PMC
June 2021

Novel association between a transient receptor potential cation channel subfamily M member 5 expression quantitative trait locus rs35197079 and decreased susceptibility of gestational diabetes mellitus in a Chinese population.

J Diabetes Investig 2021 May 12. Epub 2021 May 12.

Shenzhen Maternity and Child Healthcare Hospital, Shenzhen, China.

Aims/introduction: Emerging evidence suggests that expression quantitative trait loci (eQTLs) are more likely to associate with complex diseases. Transient receptor potential cation channel subfamily M member 5 (TRPM5) is a ubiquitously expressed voltage-gated cation channel that acts indispensably to trigger insulin secretion in pancreatic β-cells. The present study evaluated the association between TRPM5 eQTL single-nucleotide polymorphisms and the risk of gestational diabetes mellitus (GDM) in a Chinese population.

Materials And Methods: A total of 380 unrelated Chinese pregnant women including 241 GDM patients and 139 controls were included in this study. The eQTL single-nucleotide polymorphisms of TRPM5 were obtained from the GTEx eQTL Browser, and were subsequently genotyped using the Agena MassARRAY iPLEX platform.

Results: Logistic regression analysis and linear regression analysis showed that rs35197079 and rs74848824 were significantly associated with reduced GDM risk and lower fasting plasma glucose levels after adjusting confounder factors in dominant genetic models. Stratification analysis based on pre-pregnancy body mass index validated a strong association between rs35197079 and GDM susceptibility in underweight and normal weight individuals. Luciferase and electrophoretic mobility shift assays carried out in rat pancreatic β-cells showed that rs35197079 was functional.

Conclusions: The TRPM5 eQTL single-nucleotide polymorphism rs35197079 was associated with decreased GDM susceptibility in a Chinese population, especially in underweight and normal weight pregnant women, and it was functional in modulating gene transcription.
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http://dx.doi.org/10.1111/jdi.13572DOI Listing
May 2021

Nivolumab and Hypofractionated Radiotherapy in Patients With Advanced Lung Cancer: ABSCOPAL-1 Clinical Trial.

Front Oncol 2021 22;11:657024. Epub 2021 Apr 22.

Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.

Background: More clinical practice need to be performed to verify the toxicity of the hypofractionated radiotherapy (HFRT) combined with PD-1 blockade in lung cancer. This phase I study aimed to investigate the safety and efficacy of nivolumab combined with HFRT in patients with progressive advanced lung cancer following multiline treatment.

Methods: We enrolled 31 patients with advanced lung cancer pathologically confirmed to have progressive disease and treated with first-line or a higher therapy. Selected lesions were treated using HFRT, and nivolumab was administered within 7 days subsequently. Nivolumab was administered once a month following partial remission. Peripheral blood was collected before and after 1 month of treatment to evaluate relevant cytokines between nivolumab responders and non-responders.

Results: Overall, 23 patients who completed the treatment were evaluated. Of them, 9 and 14 patients underwent hypofractionated brachytherapy with 30 Gy in a single fraction percutaneous interstitial implantation of (192)Ir and 40-50 Gy in 5 fractions stereotactic body radiation therapy, respectively. The median follow-up period was 11 months. At the 1-year follow-up, no patient developed grade ≥ 3 pneumonitis. The overall objective response and complete remission rates were 39.13% and 13.04%, respectively. The 1-year overall survival and median progression-free survival were 60.9% and 6 months, respectively. The plasma levels of interleukin IL-6, IL-10, and IL-17A were significantly reduced after treatment in nivolumab responders.

Conclusions: HFRT could increase the responsivity to nivolumab and reduce its administration frequency. This combination treatment is well tolerated with acceptable toxicity and thus merits further trials to validate benefits.

Clinical Trial Registration: http://www.chictr.org.cn/index.aspx, identifier ChiCTR-1900027768.
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http://dx.doi.org/10.3389/fonc.2021.657024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100893PMC
April 2021

Crystal structure of SARS-CoV-2 nsp10 bound to nsp14-ExoN domain reveals an exoribonuclease with both structural and functional integrity.

Nucleic Acids Res 2021 05;49(9):5382-5392

West China Hospital Emergency Department (WCHED), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, China.

The emergence of SARS-CoV-2 infection has posed unprecedented threat to global public health. The virus-encoded non-structural protein 14 (nsp14) is a bi-functional enzyme consisting of an exoribonuclease (ExoN) domain and a methyltransferase (MTase) domain and plays a pivotal role in viral replication. Here, we report the structure of SARS-CoV-2 nsp14-ExoN domain bound to its co-factor nsp10 and show that, compared to the SARS-CoV nsp10/nsp14-full-length complex, SARS-CoV-2 nsp14-ExoN retains an integral exoribonuclease fold and preserves an active configuration in the catalytic center. Analysis of the nsp10/nsp14-ExoN interface reveals a footprint in nsp10 extensively overlapping with that observed in the nsp10/nsp16 structure. A marked difference in the co-factor when engaging nsp14 and nsp16 lies in helix-α1', which is further experimentally ascertained to be involved in nsp14-binding but not in nsp16-engagement. Finally, we also show that nsp10/nsp14-ExoN is enzymatically active despite the absence of nsp14-MTase domain. These data demonstrate that SARS-CoV-2 nsp10/nsp14-ExoN functions as an exoribonuclease with both structural and functional integrity.
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http://dx.doi.org/10.1093/nar/gkab320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136770PMC
May 2021

An induced pluripotent stem cell line (GZHMCi004-A) derived from a fetus with heterozygous G380R mutation in FGFR3 gene causing achondroplasia.

Stem Cell Res 2021 May 5;53:102322. Epub 2021 Apr 5.

Department of Obstetrics and Gynecology, Department of Fetal Medicine and Prenatal Diagnosis, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. Electronic address:

Achondroplasia (ACH; MIM #100800) is an autosomal dominant genetic disease caused by gain-of-function mutations in FGFR3 gene and results in short-limb dwarfism. Here, we generated an induced pluripotent stem cell line GZHMCi004-A derived from umbilical cord blood mononuclear cells (UCBMCs) of a fetus with heterozygous G380R mutation in FGFR3 gene. This iPSC line is a valuable in vitro model to study the pathological mechanism and the treatment of ACH.
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http://dx.doi.org/10.1016/j.scr.2021.102322DOI Listing
May 2021

Antagonistic Activity of spp. Against in Rhizosphere of Triggers the Expression of Host Defense Genes and Improves Its Growth Under Long-Term Monoculture System.

Front Microbiol 2021 15;12:579920. Epub 2021 Mar 15.

College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, China.

Under consecutive monoculture, the abundance of pathogenic fungi, such as in the rhizosphere of , negatively affects the yield and quality of the plant. Therefore, it is pertinent to explore the role of antagonistic fungi for the management of fungal pathogens such as Our PCR-denatured gradient gel electrophoresis (DGGE) results revealed that the diversity of spp. was significantly declined due to extended monoculture. Similarly, quantitative PCR analysis showed a decline in spp., whereas a significant increase was observed in . Furthermore, seven isolates from the rhizosphere were identified and evaluated for their potentiality to antagonize . The highest and lowest percentage of inhibition (PI) observed among these isolates were 47.91 and 16.67%, respectively. In assays, the treated with four isolates, having PI > 30%, was used to evaluate the biocontrol efficiency against in which ZC51 enhanced the growth of the plant without displaying any disease symptoms. Furthermore, the expression of eight defense-related genes of in response to a combination of and ZC51 treatment was checked, and most of these defense genes were found to be upregulated. In conclusion, this study reveals that the extended monoculture of could alter the communities in the plant rhizosphere leading to relatively low level of antagonistic microorganisms. However, ZC51 could inhibit the pathogenic and induce the expression of defense genes. Hence, ZC51 improves the plant resistance and reduces the growth inhibitory effect of consecutive monoculture problem.
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http://dx.doi.org/10.3389/fmicb.2021.579920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005620PMC
March 2021

Proteolytic Shedding of Human Colony-Stimulating Factor 1 Receptor and its implication.

J Cell Mol Med 2021 May 30;25(9):4516-4521. Epub 2021 Mar 30.

Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, China.

Both Colony-stimulating factor 1 receptor (CSF1R) and triggering receptor expressed on myeloid cells-2 (TREM2) are trans-membrane receptors and are expressed in the brain primarily by microglia. Mutations in these two microglia-expressed genes associated with neurodegenerative disease have recently been grouped under the term "microgliopathy". Several literatures have indicated that CSF1R and TREM2 encounters a stepwise shedding and TREM2 variants impair or accelerate the processing. However, whether CSF1R variant affects the shedding of CSF1R remains elusive. Here, plasmids containing human CSF1R or TREM2 were transiently transfected into the human embryonic kidney (HEK) 293T cells. Using Western Blot and/or ELISA assay, we demonstrated that, similar to those of TREM2, an N-terminal fragment (NTF) shedding of CSF1R ectodomain and a subsequent C-terminal fragment (CTF) of CSF1R intra-membrane were generated by a disintegrin and metalloprotease (ADAM) family member and by γ-secretase, respectively. And the shedding was inhibited by treatment with Batimastat, an ADAM inhibitor, or DAPT or compound E, a γ-secretase inhibitor. Importantly, we show that the cleaved fragments, both extracellular domain and intracellular domain of a common disease associated I794T variant, were decreased significantly. Together, our studies demonstrate a stepwise approach of human CSF1R cleavage and contribute to understand the pathogenicity of CSF1R I794T variant in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). These studies also suggest that the cleaved ectodomain fragment released from CSF1R may be proposed as a diagnostic biomarker for ALSP.
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http://dx.doi.org/10.1111/jcmm.16474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093967PMC
May 2021

Intratumoral Injection of Anlotinib Hydrogel Combined With Radiotherapy Reduces Hypoxia in Lewis Lung Carcinoma Xenografts: Assessment by Micro Fluorine-18-fluoromisonidazole Positron Emission Tomography/Computed Tomography Hypoxia Imaging.

Front Oncol 2021 12;11:628895. Epub 2021 Mar 12.

Department of Oncology, Affiliated Hospital of Southwest Medical University, Luzhou, China.

Hypoxia is a common feature of solid tumors that increases tumor invasiveness and resistance to radiotherapy (RT) and chemotherapy. Local application of anlotinib (AL) might increase the regulation of new blood vessel growth and improve tumor hypoxia in RT. Therefore, it is essential to fully understand the drug delivery system of AL. Herein, we applied hypoxia imaging using micro fluorine-18-fluoromisonidazole positron emission tomography/computed tomography (micro 18F-FMISO PET/CT) to assess responses to intratumoral injections of an AL hydrogel (AL-HA-Tyr) combined with RT in mice bearing Lewis lung carcinoma (LLC). We formed AL-HA-Tyr by encapsulating AL with hyaluronic acid-tyramine (HA-Tyr) conjugates the oxidative coupling of tyramine moieties catalyzed by HO and horseradish peroxidase. AL-HA-Tyr restrained the proliferation of human umbilical endothelial cells (HUVECs) in colony formation assays (p < 0.001). We established a subcutaneous LLC xenograft model using C57BL/6J mice that were randomly assigned to six groups that were treated with AL, HA-Tyr, AL-HA-Tyr, RT, and RT+AL-HA-Tyr, or untreated (controls). Tumor volume and weight were dynamically measured. Post treatment changes in hypoxia were assessed in some mice using micro 18F-FMISO PET/CT, and survival was assessed in others. We histopathologically examined toxicity in visceral tissues and Ki-67, VEGF-A, -H2AX, and HIF-1 expression using immunohistochemistry. Direct intratumoral injections of AL-HA-Tyr exerted anti-tumor effects and improved hypoxia like orally administered AL (p > 0.05), but reduced visceral toxicity and prolonged survival. The uptake of 18F-FMISO did not significantly differ among the AL, AL-HA-Tyr, and RT+AL-HA-Tyr treated groups. Compared with the other agents, RT+AL-HA-Tyr decreased HIF-1, Ki67, and VEGF-A expression, and increased -H2AX levels in tumor cells. Overall, compared with AL and AL-HA-Tyr, RT+AL-HA-Tyr improved tumor hypoxia, enhanced anti-tumor effects, and prolonged the survival of mice bearing LLC.
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http://dx.doi.org/10.3389/fonc.2021.628895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994889PMC
March 2021

Non-Structured DNN Weight Pruning--Is It Beneficial in Any Platform?

IEEE Trans Neural Netw Learn Syst 2021 Mar 18;PP. Epub 2021 Mar 18.

Large deep neural network (DNN) models pose the key challenge to energy efficiency due to the significantly higher energy consumption of off-chip DRAM accesses than arithmetic or SRAM operations. It motivates the intensive research on model compression with two main approaches. Weight pruning leverages the redundancy in the number of weights and can be performed in a non-structured, which has higher flexibility and pruning rate but incurs index accesses due to irregular weights, or structured manner, which preserves the full matrix structure with a lower pruning rate. Weight quantization leverages the redundancy in the number of bits in weights. Compared to pruning, quantization is much more hardware-friendly and has become a ``must-do'' step for FPGA and ASIC implementations. Thus, any evaluation of the effectiveness of pruning should be on top of quantization. The key open question is, with quantization, what kind of pruning (non-structured versus structured) is most beneficial? This question is fundamental because the answer will determine the design aspects that we should really focus on to avoid the diminishing return of certain optimizations. This article provides a definitive answer to the question for the first time. First, we build ADMM-NN-S by extending and enhancing ADMM-NN, a recently proposed joint weight pruning and quantization framework, with the algorithmic supports for structured pruning, dynamic ADMM regulation, and masked mapping and retraining. Second, we develop a methodology for fair and fundamental comparison of non-structured and structured pruning in terms of both storage and computation efficiency. Our results show that ADMM-NN-S consistently outperforms the prior art: 1) it achieves 348x, 36x, and 8x overall weight pruning on LeNet-5, AlexNet, and ResNet-50, respectively, with (almost) zero accuracy loss and 2) we demonstrate the first fully binarized (for all layers) DNNs can be lossless in accuracy in many cases. These results provide a strong baseline and credibility of our study. Based on the proposed comparison framework, with the same accuracy and quantization, the results show that non-structured pruning is not competitive in terms of both storage and computation efficiency. Thus, we conclude that structured pruning has a greater potential compared to non-structured pruning. We encourage the community to focus on studying the DNN inference acceleration with structured sparsity.
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http://dx.doi.org/10.1109/TNNLS.2021.3063265DOI Listing
March 2021

Positron Emission Tomography-Based Short-Term Efficacy Evaluation and Prediction in Patients With Non-Small Cell Lung Cancer Treated With Hypo-Fractionated Radiotherapy.

Front Oncol 2021 25;11:590836. Epub 2021 Feb 25.

Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.

Background: Positron emission tomography is known to provide more accurate estimates than computed tomography when staging non-small cell lung cancer. The aims of this prospective study were to contrast the short-term efficacy of the two imaging methods while evaluating the effects of hypo-fractionated radiotherapy in non-small cell lung cancer, and to establish a short-term efficacy prediction model based on the radiomics features of positron emission tomography.

Methods: This nonrandomized-controlled trial was conducted from March 2015 to June 2019. Thirty-one lesions of 30 patients underwent the delineation of the regions of interest on positron emission tomography and computed tomography 1 month before, and 3 months after hypo-fractionated radiotherapy. Each patient was evaluated for the differences in local objective response rate between the two images. The Kaplan Meier method was used to analyze the local objective response and subsequent survival duration of the two imaging methods. The 3D Slicer was used to extract the radiomics features based on positron emission tomography. Least absolute shrinkage and selection operator regression was used to eliminate redundant features, and logistic regression analysis was used to develop the curative-effect-predicting model, which was displayed through a radiomics nomogram. Receiver operating characteristic curve and decision curve were used to evaluate the accuracy and clinical usefulness of the prediction model.

Results: Positron emission tomography-based local objective response rate was significantly higher than that based on computed tomography [70.97% (22/31) and 12.90% (4/31), respectively (p<0.001)]. The mean survival time of responders and non-responders assessed by positron emission tomography was 28.6 months vs. 11.4 months (p=0.29), whereas that assessed by computed tomography was 24.5 months vs. 26 months (p=0.66), respectively. Three radiomics features were screened to establish a personalized prediction nomogram with high area under curve (0.94, 95% CI 0.85-0.99, p<0.001). The decision curve showed a high clinical value of the radiomics nomogram.

Conclusions: We recommend positron emission tomography for evaluating the short-term efficacy of hypo-fractionated radiotherapy in non-small cell lung cancer, and that the radiomics nomogram could be an important technique for the prediction of short-term efficacy, which might enable an improved and precise treatment.

Registration Number/url: ChiCTR1900027768/http://www.chictr.org.cn/showprojen.aspx?proj=46057.
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http://dx.doi.org/10.3389/fonc.2021.590836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947869PMC
February 2021

Paeonone A, a novel nonanortriterpenoid from the roots of Paeonia lactiflora.

Bioorg Chem 2021 May 2;110:104783. Epub 2021 Mar 2.

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China. Electronic address:

Paeonone A (1), a unique nonanortriterpenoid, and a new octanortriterpenoid, paeonone B (2), were isolated from the roots of Paeonia lactiflora, together with a known analogue, palbinone (3). Paeonone A (1) is the first example of naturally occurring nonanortriterpenoid with a diketo acid group. Extensive NMR and HRESIMS experiments were applied to identify the structures of 1 and 2, and their absolute configurations were solved by single-crystal X-ray diffraction and ECD data. Biological properties of 1-3 were explored against pancreatic lipase and cancer cell lines.
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http://dx.doi.org/10.1016/j.bioorg.2021.104783DOI Listing
May 2021

The spectrum of FVIII gene variants detected by next generation sequencing in 236 Chinese non-inversion hemophilia A pedigrees.

Thromb Res 2021 06 3;202:8-13. Epub 2021 Mar 3.

Institute of Antibody Engineering, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China. Electronic address:

Introduction: The reported variants of hemophilia A are mainly from European subjects and American subjects of European descent, and limited data are available from more diverse ethnic backgrounds. This study was performed to identify the causative variants in a large HA cohort from Chinese population.

Materials And Methods: A total of 236 HA pedigrees were included. Molecular analysis of F8 gene was performed using next-generation sequencing (NGS) and then validated by Sanger sequencing and multiplex ligation probe amplification (MLPA) results. Variants were classified as pathogenic, likely pathogenic, variant of unknown significance, likely benign, and benign according to the American College of Medical Genetics and Genomics guidelines.

Results: A total of 186 F8 variants were identified, with 139 (139/186, 74.73%) point mutations, 44 (44/186, 23.66%) small insertions/deletions (InDels), and 3 (3/186, 1.61%) large deletions, they included 80 pathogenic and 84 likely pathogenic variants. Of these variants, 119 had been reported previously, and 67 were novel. No potentially causative mutations were found in the targeted F8 region in seventeen HA pedigrees.

Conclusions: The spectrum of F8 variants identified in this study provides additional information about HA and enriches our knowledge of the variant spectrum in a wider range of ethnic backgrounds.
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http://dx.doi.org/10.1016/j.thromres.2021.02.027DOI Listing
June 2021

Low-Coverage Sequencing of Urine Sediment DNA for Detection of Copy Number Aberrations in Bladder Cancer.

Cancer Manag Res 2021 26;13:1943-1953. Epub 2021 Feb 26.

Shenzhen Key Laboratory of Viral Oncology, The Clinical Innovation & Research Center (CIRC), Shenzhen Hospital, Southern Medical University, Shenzhen, 518110, People's Republic of China.

Purpose: Chromosomal copy number aberrations (CNAs) are a hallmark of bladder cancer and a useful target for diagnostic explorations. Here we constructed a low-coverage whole-genome sequencing method for the detection of CNAs in urine sediment DNA from patients with bladder cancer.

Patients And Methods: We conducted a prospective study using urine sediment samples from 65 patients with bladder tumors, including 54 patients with bladder cancer and 11 patients with benign bladder tumors. Forty-three healthy individuals were included as normal controls. DNA was extracted from urine sediments and analyzed by low-coverage whole-genome sequencing to compare differences in CNAs among these three groups. CNAs are defined by arbitrary R values (normal range ± 2). When these values exceed ± 0.2 of normal range, gain/duplication or loss/deletion are suspected.

Results: With this method, CNAs were detected in 39 of 51 patients with bladder cancer, 2 of 10 patients with benign bladder tumors, and 8 of 39 normal controls. The lengths of DNA deletion and duplication were significantly larger in patients with bladder cancer than in patients with benign tumors or normal controls (P < 0.05). Bladder cancer duplicate CNAs mainly occurred on chromosomes 1q, 5p, 6p, 7p, 8q, and 13q, while deletions mainly occurred on 2q, 8p, 9q, 9p, and 11p. Those regions contained bladder cancer tumor-related genes, such as STK3, COX6C, SPAG1, CDKAL1, C9orf53, CDKN2A, CDKN2B, MIR31, and IFNA1. The number of CNAs detected in urine sediment DNA during the follow-up period was significantly reduced.

Conclusion: Our sequencing method is highly sensitive and can detect a minimal chromosome repeat/microdeletion change of 0.15 Mb. The use of 0.1~0.3× low-coverage whole-genome sequencing can be used to detect bladder cancer CNAs in urine sediment DNA. This method provides a promising method for noninvasive diagnosis of bladder cancer, but still needs further verification in a larger sample size.
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http://dx.doi.org/10.2147/CMAR.S295675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924115PMC
February 2021

[Construction and application of pharmacophore model of human carboxylesterase 2 inhibitors].

Zhongguo Zhong Yao Za Zhi 2021 Feb;46(3):638-644

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050, China.

According to human carboxylesterase 2(hCE2) inhibitors reported in the literature, the pharmacophore model of hCE2 inhibitors was developed using HipHop module in Discovery Studio 2016. The optimized pharmacophore model, which was validated by test set, contained two hydrophobic, one hydrogen bond acceptor, and one aromatic ring features. Using the pharmacophore model established, 5 potential hCE2 inhibitors(CS-1,CS-2,CS-3,CS-6 and CS-8) were screened from 20 compounds isolated from the roots of Paeonia lactiflora, which were further confirmed in vitro, with the IC_(50) values of 5.04, 5.21, 5.95, 6.64 and 7.94 μmol·L~(-1), respectively. The results demonstrated that the pharmacophore model exerted excellent forecasting ability with high precision, which could be applied to screen novel hCE2 inhibitors from Chinese medicinal materials.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20190603.203DOI Listing
February 2021

Meta-analysis of P53 expression and sensitivity to platinum-based chemotherapy in patients with non-small cell lung cancer.

Medicine (Baltimore) 2021 Feb;100(5):e24194

Department of Respiratory and Critical Care Medicine, Fujian Provincial Hospital,Shengli Clinical Medical College of Fujian Medical University, Dongjie,Road No 134, Fuzhou, Fujian, China.

Background: The relationship between p53 expression and chemosensitivity of non-small cell lung cancer (NSCLC) is unclear. This study aims to explore the correlation between p53 expression and sensitivity to platinum-based chemotherapy in patients with NSCLC.

Methods: Pubmed, Web of Science, EMBASE, CNKI, China Wanfang databases were searched for studies on the relationship between the p53 expression and the chemosensitivity to platinum drugs in patients with NSCLC. The last search time was May 2020. Stata 15.0 software was used for statistical analysis.

Results: A total of 21 studies were included, covering 1387 patients in total. The results showed that the pooled OR = 1.55 (95%CI: 1.05∼2.29, P < .05), for Asian population, the pooled OR = 1.67 (95%CI: 0.95∼3.09, P > .05), for Caucasian population, the pooled OR = 1.34 (95%CI: 0.74∼2.43), there was no significant difference between Asian and Caucasian. The results of subgroup analysis of publication year showed that, the pooled OR = 2.07 (95%CI: 1.39∼3.07, P < .01), the heterogeneity among the studies decreased remarkably after 2005. The subgroup analysis of advanced patients showed that the pooled OR = 1.93 (95%CI: 1.27∼2.93), the difference was statistically significant.

Conclusion: Patients with p53 negative expression is more sensitive to platinum-based chemotherapy than those with p53 positive expression in NSCLC, especially in advanced NSCLC.
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http://dx.doi.org/10.1097/MD.0000000000024194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870161PMC
February 2021

Bioinformatics Analysis of Key micro-RNAs and mRNAs under the Hand, Foot, and Mouth Disease Virus Infection.

Pol J Microbiol 2020 Dec 27;69(4):479-490. Epub 2020 Dec 27.

Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, China.

To clarify crucial key micro-RNAs and mRNAs associated with hand, foot, and mouth disease (HFMD) virus infection, we conducted this bioinformatics analysis from four GEO datasets. The following datasets were used for the analysis: GSE85829, GSE94551, GSE52780, and GSE45589. Differentially expressed genes (DEGs) were acquired, and the analysis of functional and pathway enrichment and the relative regulatory network were conducted. After screening common differentially expressed miRNAs (DE-miRNAs), five key miRNAs were acquired: miR-100-3p, miR-125a-3p, miR-1273g-3p, miR-5585-3p, and miR-671-5p. There were three common enriched GO terms between miRNA-derived prediction and mRNA-derived analysis: biosynthetic process, cytosol, and nucleoplasm. There was one common KEGG pathway, i.e., cell cycle shared between miRNA-based and mRNA-based enrichment. Using TarBase V8 in DIANA tools, we acquired 1,520 potential targets (mRNA) from the five key DE-miRNAs, among which the159 DE-mRNAs also included 11 DEGs. These common DEGs showed a PPI network mainly connected by SMC1A, SMARCC1, SF3B3, LIG1, and BRMS1L. Together, changes in five key miRNAs and 11 key mRNAs may play crucial roles in HFMD progression. A combination of these roles may benefit the early diagnosis and treatment of HFMD.
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http://dx.doi.org/10.33073/pjm-2020-052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812361PMC
December 2020

[Chemical constituents from ethyl acetate soluble extraction of Litsea cubeba].

Zhongguo Zhong Yao Za Zhi 2020 Dec;45(24):5877-5883

Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine Beijing 100700, China State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050, China.

Chemical investigation on the constituents of the ethyl acetate soluble extraction of Litsea cubeba has resulted in the isolation and structure elucidation of thirty compounds, including one sesquiterpene(1), four monoterpenes(2-5), two γ-butyrolactone derivatives(6 and 7), seven tyramine derivatives(8-14), fifteen aromatic compounds(15-29), and one pyrone derivative(30) via various chromatographic techniques and spectroscopic data analysis(MS, IR, 1 D and 2 D NMR). Compounds 1-7, 13 and 14 were obtained from the genus Litsea for the first time.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20200820.202DOI Listing
December 2020

[Research progress on animal models of chronic pain and its application in traditional Chinese medicine research].

Zhongguo Zhong Yao Za Zhi 2020 Dec;45(24):5866-5876

Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital,Beijing University of Chinese Medicine Beijing 100700, China.

The classification of chronic pain is complex and its pathogenesis is not clear, which led to the limited progress of treatment measures.Traditional Chinese medicine(TCM) has certain advantages in the treatment of chronic pain, and its mechanism needs further exploration. The ideal animal model is helpful to elucidate the key mechanism of the occurrence and development of chronic pain and play an important role in the discovery of new drug targets, the development of new therapies and the research on the analgesic mechanism of TCM.In recent years, many scholars at home and abroad have done a lot of research to explore the pathogenesis of chronic pain and the mechanism of TCM, which have achieved some results. On this basis, this study summarizes the selection of experimental animals for chronic pain and the commonly evaluation methods of animal models. According to the latest international classification of diseases, this review organizes the induced methods, evaluation indicators, advantages and disadvantages of seven kinds of chronic pain animal models, such as chronic primary pain, chronic cancer-related pain and so on. Next, this review introduces the chronic pain animal models commonly used in TCM research, in order to provide guidance for the targeted selection of animal models when carrying out relevant experiments in the future.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20200924.201DOI Listing
December 2020

[Research progress of natural non-alkaloids with analgesic activity].

Zhongguo Zhong Yao Za Zhi 2020 Dec;45(24):5840-5865

Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing,Dongzhimen Hospital,Beijing University of Chinese Medicine Beijing 100700,China State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050,China.

Pain is a complex, unpleasant feeling and emotional experience associated with actual or potential tissue damage, and manifests itself in certain autonomous psychological and behavioral responses. The commonly used opioid and non-steroidal anti-inflammatory analgesics(NSAIDs) may cause adverse reactions to the kidney, liver, cardiovascular or gastrointestinal system and cause problems of drug abuse. Therefore, it is necessary to study new analgesic drugs with less side effects and significant analgesic effects. A variety of natural products derived from terrestrial plants, microorganisms, marine organisms and fungi have been an important source of clinical medicines and provide an inexhaustible resource for the development and innovation of modern medicines. Therefore, this paper mainly reviews the natural non-alkaloids with analgesic activity in order to provide reference for the research and development of analgesic drugs derived from natural products.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20201104.201DOI Listing
December 2020

[Research progress of natural alkaloids with analgesic activity].

Zhongguo Zhong Yao Za Zhi 2020 Dec;45(24):5829-5839

Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing,Dongzhimen Hospital,Beijing University of Chinese Medicine Beijing 100700,China State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050,China.

Pain is a protective defense response of the body to harmful stimuli. Long-term pain not only seriously affects the body of the patient and brings great pain to the patient, but also brings huge economic burden to the patient's family and society. It has become one of the most serious problems affecting human health. At present, opioids and non-steroidal anti-inflammatory drugs(NSAIDs) are commonly used as painkillers, but they tend to cause a variety of adverse reactions or risk of addiction. To find and develop new analgesic drugs, which are safer and more effective, has become the hot spot and difficulty in medical research. A variety of alkaloids derived from terrestrial plants, microorganisms, marine organisms and fungi have been an important source of clinical analgesic medicines. Various alkaloids have been proved to have good analgesic effects, such as morphine and the related to opioids, the main analgesic active components from Corydalis Rhizoma and Aconiti Lateralis Radix Praeparata. Here we summarized the research progress of natural alkaloids with analgesic activity, in order to provide reference for the research and development of analgesic drugs based on natural products.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20200909.201DOI Listing
December 2020

An induced pluripotent stem cell line (GZHMCi003-A) derived from a fetus with exon 3 heterozygous deletion in RUNX2 gene causing cleidocranial dysplasia.

Stem Cell Res 2021 03 9;51:102166. Epub 2021 Jan 9.

Department of Obstetrics and Gynecology, Department of Fetal Medicine and Prenatal Diagnosis, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China.

Cleidocranial dysplasia (CCD; MIM #119600) is an autosomal dominant genetic disorder caused by heterozygous loss-of-function mutation of the RUNX2 gene, which is important in the differentiation of osteoblasts and maturation of chondrocytes. In this study, we generated an induced pluripotent stem cell line GZHMCi003-A derived from umbilical cord blood mononuclear cells (UCBMCs) of a fetus with heterozygous deletion of the exon 3 in RUNX2 gene. This iPSC line is an ideal in vitro model to study the pathological mechanism and the treatment of CCD.
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http://dx.doi.org/10.1016/j.scr.2021.102166DOI Listing
March 2021

Next-generation sequencing and RT-PCR to identify a 32-day SARS-CoV-2 carrier.

Clin Chem Lab Med 2021 05 19;59(6):e251-e254. Epub 2021 Jan 19.

Non-coding RNA and Drug Discovery Key Laboratory of Sichuan Province, Chengdu Medical College, Chengdu, Sichuan, P.R. China.

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http://dx.doi.org/10.1515/cclm-2020-1629DOI Listing
May 2021

Publisher Correction: A vaccine targeting the RBD of the S protein of SARS-CoV-2 induces protective immunity.

Nature 2021 Feb;590(7844):E23

Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, 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.

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http://dx.doi.org/10.1038/s41586-020-03108-4DOI Listing
February 2021

A Fluidic Isolation-Assisted Homogeneous-Flow-Pressure Chip-Solid Phase Extraction-Mass Spectrometry System for Online Dynamic Monitoring of 25-Hydroxyvitamin D Biotransformation in Cells.

Anal Chem 2021 02 14;93(4):2273-2280. Epub 2021 Jan 14.

Department of Chemistry, Beijing Key Laboratory of Microanalytical Methods and Instrumentation, MOE Key Laboratory of Bioorganic Phosphorus Chemistry &Chemical Biology, Tsinghua University, Beijing 100084, China.

It is well known that cell can response to various chemical and mechanical stimuli. Therefore, flow pressure variation induced by sample loading and elution should be small enough to ignore the physical impact on cells when we use a Chip-SPE-MS system for cells. However, most existent Chip-SPE-MS systems ignored the pressure alternation because it is extremely difficult to develop a homogeneous-flow-pressure hyphenated module. Herein, we developed an interesting fluidic isolation-assisted homogeneous-flow-pressure Chip-SPE-MS system and demonstrated that it is adequate for online high-throughput determination and quantification of the 25-hydroxyvitamin D (25(OH)D) biotransformation in different cells. Briefly, the homogeneous ambient flow pressure is achieved by fluidic isolation between the cell culture channel and the SPE column, and an automatic sampling probe could accomplish the sample loading and dispensing to fulfill online pretreatment of the sample. Through this new system, the expression levels of 24,25-dihydroxyvitamin D (24,25(OH)D) can be determined in real time with a detection limit of 2.54 nM. In addition, the results revealed that 25(OH)D metabolic activity differed significantly between normal L-02 cells and cancerous HepG2 cells. Treatment of L-02 cells with a high dose of 25(OH)D was found to increase significant formation of 24,25(OH)D, but this change was not apparent in HepG2 cells. The presented system promises to be a versatile tool for online accurate molecule biotransformation investigation and drug screening processes.
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http://dx.doi.org/10.1021/acs.analchem.0c04147DOI Listing
February 2021

Anti-tumor effect of local injectable hydrogel-loaded endostatin alone and in combination with radiotherapy for lung cancer.

Drug Deliv 2021 Dec;28(1):183-194

Department of Oncology, Affiliated Hospital of Southwest Medical University, Luzhou, China.

Endostatin (ES) can effectively inhibit neovascularization in most solid tumors and has the potential to make oxygen delivery more efficient and increase the efficacy of radiotherapy (RT). With a short half-life, ES is mainly administered systemically, which leads to low intake in tumor tissue and often toxic systemic side effects. In this study, we used hyaluronic acid-tyramine as a carrier to synthesize an ES-loaded hydrogel drug (ES/HA-Tyr) that can be injected locally. ES/HA-Tyr has a longer half-life and fewer systemic toxic side effects, and it exerts a better anti-angiogenic effect and anti-tumor effect with RT. , ES/HA-Tyr showed sustained release in the release assay and a stronger ability to inhibit the proliferation of human umbilical vascular endothelial cells (HUVECs) in the MTT assay; it exhibited a more potent effect against HUVEC invasion and a stronger anti-angiogenic effect on HUVECs in tube formation. , ES/HA-Tyr increased local drug concentration, decreased blood drug concentration, and caused less systemic toxicity. Further, ES/HA-Tyr effectively reduced tumor microvessel density, increased tumor pericyte coverage, decreased tumor hypoxia, and increased RT response. ES/HA-Tyr + RT also had increased anti-tumor and anti-angiogenic effects in Lewis lung cancer (LLC) xenograft models. In conclusion, ES/HA-Tyr showed sustained release, lower systemic toxicity, and better anti-tumor effects than ES. In addition, ES/HA-Tyr + RT enhanced anti-angiogenic effects, reduced tumor hypoxia, and increased the efficacy of RT in LLC-bearing mice.
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http://dx.doi.org/10.1080/10717544.2020.1869864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808389PMC
December 2021

Assessment of the association between the polymorphism rs1256031 of the estrogen receptor β gene and GDM susceptibility.

Nagoya J Med Sci 2020 Nov;82(4):703-709

Laboratory of Medical Genetics, Shenzhen Health Development Research Center, Shenzhen, China.

Estrogen has an important role in regulating glucose homeostasis, and existing evidence indicates that it might be involved in the development of hyperglycemia in pregnancy. It mediates its effect through estrogen receptors including the nuclear receptor ERβ encoded by . The association between the polymorphism rs1256031 and GDM susceptibility has not been investigated yet. This study aimed to evaluate the relationship between rs1256031 and GDM risk in Chinese population. A total of 241 GDM patients and 139 healthy pregnant women were recruited for this study. The rs1256031 genotype was examined by time-of-flight mass spectrometry and the association between rs1256031 and GDM susceptibility was assessed by binary logistic regression in three different genetic models. The polymorphism rs1256031 was not associated with GDM susceptibility in additive [OR (95% CI) = 0.871 (0.453,1.675); = 0.680], dominant [OR (95% CI) = 0.908 (0.495,1.665); = 0.755] or recessive [OR (95% CI) = 0.912 (0.591,1.408); = 0.677] models after adjusting for confounding factors. We observed no association between the polymorphism rs1256031 in the ESR2 gene and GDM susceptibility in Chinese pregnant women.
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http://dx.doi.org/10.18999/nagjms.82.4.703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719448PMC
November 2020