Publications by authors named "Hua Liang"

337 Publications

A novel model-checking approach for dose-response relationships.

Stat Methods Med Res 2021 Jul 28:9622802211032695. Epub 2021 Jul 28.

Department of Statistics, George Washington University, Washington, DC, USA.

We propose a test for assessing nonlinear dose-response models based on a Crámer-von Mises statistic. We establish the asymptotic distribution of the test and demonstrate that the test can detect the local alternative converging to the null at the parametric rate . We provide a bootstrap resampling technique to calculate the critical values. It is observed that the test has good power performance in small sample sizes. We apply the proposed method to analyze 250 datasets from a pharmacologic study and conduct two small simulation experiments to explore the numerical performance of the proposed test and compare one commonly used test in practice.
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http://dx.doi.org/10.1177/09622802211032695DOI Listing
July 2021

Convolutional Rebalancing Network for the Classification of Large Imbalanced Rice Pest and Disease Datasets in the Field.

Front Plant Sci 2021 5;12:671134. Epub 2021 Jul 5.

Institute of Agricultural Economics and Information, Jiangxi Academy of Agricultural Sciences, Nanchang, China.

The accurate classification of crop pests and diseases is essential for their prevention and control. However, datasets of pest and disease images collected in the field usually exhibit long-tailed distributions with heavy category imbalance, posing great challenges for a deep recognition and classification model. This paper proposes a novel convolutional rebalancing network to classify rice pests and diseases from image datasets collected in the field. To improve the classification performance, the proposed network includes a convolutional rebalancing module, an image augmentation module, and a feature fusion module. In the convolutional rebalancing module, instance-balanced sampling is used to extract features of the images in the rice pest and disease dataset, while reversed sampling is used to improve feature extraction of the categories with fewer images in the dataset. Building on the convolutional rebalancing module, we design an image augmentation module to augment the training data effectively. To further enhance the classification performance, a feature fusion module fuses the image features learned by the convolutional rebalancing module and ensures that the feature extraction of the imbalanced dataset is more comprehensive. Extensive experiments in the large-scale imbalanced dataset of rice pests and diseases (18,391 images), publicly available plant image datasets (Flavia, Swedish Leaf, and UCI Leaf) and pest image datasets (SMALL and IP102) verify the robustness of the proposed network, and the results demonstrate its superior performance over state-of-the-art methods, with an accuracy of 97.58% on rice pest and disease image dataset. We conclude that the proposed network can provide an important tool for the intelligent control of rice pests and diseases in the field.
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http://dx.doi.org/10.3389/fpls.2021.671134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287420PMC
July 2021

Updated Evidence of the Association Between Elevated Serum Uric Acid Level and Psoriasis.

Front Med (Lausanne) 2021 29;8:645550. Epub 2021 Jun 29.

Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

Our earlier meta-analysis showed that the correlation between psoriasis and hyperuricemia might be region-dependent and that hyperuricemia was more common in patients with psoriasis in Western Europe. However, no further analysis could be conducted owing to the scarcity of data. Our study aimed to further explore the association between psoriasis and hyperuricemia. Six databases (PubMed, Embase, the Cochrane Central Register of Controlled Trials, the China National Knowledge Infrastructure database, the Chinese Scientific Journals Full Text Database, and the Wanfang Data Knowledge Service Platform) were searched for studies published between January 1980 and February 2021. The search strategy yielded 291 relevant studies, of which 27 observational studies were included in this analysis. Serum uric acid (SUA) levels (mean difference [MD] 0.99, 95% confidence interval [CI] 0.48-1.49, = 0.0001) and hyperuricemia frequency (odds ratio [OR] 5.39, 95% CI 1.88-15.40, = 0.002) were higher in the psoriasis group than in the control group, and the subgroup differences were significant. In addition, SUA levels were significantly higher in patients with moderate to severe psoriasis from European and American countries (MD 0.89, 95% CI 0.18-1.60, = 0.01) and Southeast Asia (MD 1.79, 95% CI 0.55-3.02, = 0.004), while no significant differences were found between the Middle East subgroup (MD 0.63, 95% CI -0.33 to 1.59, = 0.20). Similar results were obtained from the meta-analysis of SUA levels in patients with metabolic syndrome, obesity, or a special type of psoriasis (such as arthritic or erythrodermic psoriasis). Our meta-analysis study provides extended data regarding the correlation between psoriasis and hyperuricemia and the differences in SUA levels between psoriasis patients and controls in Southeast Asia, the Middle East, and European and American countries. Patients with moderate to severe psoriasis in European and American countries and Southeast Asia or those with metabolic syndrome and obesity were more likely to have higher uric acid levels. PROSPERO, identifier: CRD42014015091.
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http://dx.doi.org/10.3389/fmed.2021.645550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275838PMC
June 2021

Natural killer T cell/IL-4 signaling promotes bone marrow-derived fibroblast activation and M2 macrophage-to-myofibroblast transition in renal fibrosis.

Int Immunopharmacol 2021 Jul 6;98:107907. Epub 2021 Jul 6.

Department of Anesthesiology, The First Affiliated Hospital of SUN YAT-SEN University, Guangzhou 510080, China.

Renal fibrosis is a histological manifestation of chronic kidney disease. Natural killer T (NKT) cells have a critical role in the pathogenesis of fibrotic disorder. However, the role of NKT cells in regulating kidney fibrosis remains largely unknown. In the current study, we showed that the percentages of NKT cells and NKT-IL-4 cells were notably increased in folic acid (FA) and obstructive nephropathy. CD1d deficiency protected mice from renal fibrosis induced by FA and obstructive injury. Specifically, Loss of CD1d reduced bone marrow-derived myofibroblasts and CD206/α-smooth muscle actin cells in the kidneys of injured mice. But mice treated with α-galactosylceramide (α-GC, a specific activator of NKT cells) developed more severe fibrosis, accumulated more myeloid myofibroblasts and M2 macrophages-myofibroblasts transition (M2MMT) cells in FA injured kidneys. Furthermore, IL-4 expression was markedly reduced in CD1d deficiency mice but increased in α-GC-treated mice. Administration of IL-4 abrogates the inhibiting effect of CD1d deficiency on renal fibrosis, bone marrow-derived fibroblasts activation, and M2MMT in FA injured kidneys. Conversely, pharmacological inhibition of IL-4 attenuated the development of renal fibrosis, decreased bone marrow-derived myofibroblasts, and suppressed M2MMT. Thus, this study revealed a novel role of NKT cells in the bone marrow-derived fibroblasts activation and M2MMT during renal fibrosis. Targeting NKT cell/IL-4 signaling may be an effective treatment for renal fibrosis.
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http://dx.doi.org/10.1016/j.intimp.2021.107907DOI Listing
July 2021

The relationship between expression of PD-L1 and HIF-1α in glioma cells under hypoxia.

J Hematol Oncol 2021 Jun 12;14(1):92. Epub 2021 Jun 12.

Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, No. 440 Ji Yan Road, Jinan, Shandong, China.

Hypoxia inducible factor-1α (HIF-1α) up-regulates the expression of programmed death ligand-1 (PD-L1) in some extracranial malignancies. However, whether it could increase PD-L1 expression in intracranial tumor is still unknown. Here, we explored the relationship between HIF-1α and PD-L1 expression in glioma, and investigated their clinical significance. In glioma patients, HIF-1α and PD-L1 were overexpressed in high grade glioma tissues and were significantly associated with poor survival. In glioma cells, PD-L1 expression was induced under hypoxia condition, and the enhanced PD-L1 expression was abrogated by either HIF-1α knock-down or HIF-1α inhibitor treatment. Furthermore, ChIP-qPCR analysis showed the direct binding of HIF-1α to PD-L1 proximal promoter region, providing evidence that HIF-1α up-regulates PD-L1 in glioma. In glioma murine model, the combination treatment with HIF-1α inhibitor and anti-PD-L1 antibody caused a more pronounced suppressive effect on tumor growth compared to either monotherapy. Immunologically, the combination treatment improved both dendritic cell (DC) and CD8 T cell activation. Overall, our results demonstrated that positive correlation between PD-L1 and HIF-1α in glioma, and provide an alternative strategy, inhibiting HIF-1α, as combination therapies with immunotherapies to advance glioma treatment.
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http://dx.doi.org/10.1186/s13045-021-01102-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199387PMC
June 2021

A familial case of basophilic stippling cells in lead poisoning.

Int J Lab Hematol 2021 Jun 1. Epub 2021 Jun 1.

Department of Laboratory Medicine, Sichuan Provincial Maternity and Child Health Care Hospital, and Women's and Children's Hospital, Chengdu Medical College, Chengdu, China.

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http://dx.doi.org/10.1111/ijlh.13614DOI Listing
June 2021

Case Report: F-PSMA PET/CT May Improve the Clinical Management of Penile Metastases From Prostate Cancer.

Front Oncol 2021 13;11:683343. Epub 2021 May 13.

Department of Urology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Metastases from prostate cancer (PCa) to the penis are extremely rare, and few case reports exist in the literature. Because most patients usually present with multiple distant metastases at diagnosis, the prognosis is very poor. With the wide application of prostate-specific membrane antigen (PSMA) PET/CT, penile metastases may be detected at an early stage. Thus, questions regarding whether early diagnosis and precise treatment will equate to a survival advantage have recently been raised. In the present study, we reported 3 cases of penile metastasis from castration-resistant PCa. Moreover, a patient with asymptomatic penile metastases was diagnosed by F-PSMA PET/CT followed by lesion biopsy, and the prognosis was very well, despite with an aggressive pathological feature and low treatment intensity. In addition, we performed a literature review and found 62.5% of asymptomatic penile metastases were diagnosed by PSMA PET/CT in past seven years. Thus, we believe that PSMA PET/CT may detect more asymptomatic penile metastases in future, which led to early diagnosis, treatment and survival advantage.
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http://dx.doi.org/10.3389/fonc.2021.683343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155605PMC
May 2021

HLA class I genes modulate disease risk and age at onset together with DR-DQ in Chinese patients with insulin-requiring type 1 diabetes.

Diabetologia 2021 May 22. Epub 2021 May 22.

Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Aims/hypothesis: The study aimed to investigate the effects of HLA class I genes on susceptibility to type 1 diabetes with different onset ages, in addition to the well-established effects of HLA class II genes.

Methods: A total of 361 patients with type 1 diabetes (192 patients with onset <18 years and 169 patients with onset ≥18 years) and 500 healthy control participants from China were enrolled and genotyped for the HLA-A, -B, -C, -DQA1, -DQB1 and -DRB1 genes using next-generation sequencing.

Results: The susceptible DR3 (β = -0.09, p = 0.0009) and DR4-DQ8 (β = -0.13, p = 0.0059) haplotypes were negatively associated with onset age, while the protective DR11 (β = 0.21, p = 0.0314) and DR12 (β = 0.27, p < 0.0001) haplotypes were positively associated with onset age. After adjustment for linkage disequilibrium with DR-DQ haplotypes, A*11:01:01 was positively associated with onset age (β = 0.06, p = 0.0370), while the susceptible C*15:02:01 was negatively associated with onset age (β = -0.21, p = 0.0050). The unit for β was double square-root (fourth root) transformed years of change in onset age associated with per copy of the HLA haplotype/allele. In addition, B*46:01:01 was protective (OR 0.41, 0.46; pc [corrected for multiple comparisons] = 0.0044, 0.0040), whereas A*24:02:01 (OR 2.71, 2.25; pc = 0.0003, 0.0002) and B*54:01:01 (OR 3.96, 3.79; pc = 0.0018, 0.0004) were predisposing in both the <18 group and the ≥18 group compared with healthy control participants. In the context of DR4-DQ4, A*11:01:01 (61.29% vs 28.26%, pc = 0.0144) was increased while the predisposing A*24:02:01 (19.35% vs 47.83%, pc = 0.0403) was decreased in patients with onset ≥18 years when compared with patients with onset <18 years.

Conclusions/interpretation: In addition to DR-DQ haplotypes, novel HLA class I alleles were detected to play a role in susceptibility to type 1 diabetes with different onset ages, which could improve the understanding of disease heterogeneity and has implications for the design of future studies.
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http://dx.doi.org/10.1007/s00125-021-05476-6DOI Listing
May 2021

Osthole improves pulmonary artery hypertension by inducing apoptosis in pulmonary artery smooth muscle cells.

J Pharm Pharmacol 2021 Jul;73(8):1109-1117

Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Key Laboratory of Basic Pharmacology of Guizhou Province, Department of Pharmacology, School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou, China.

Objectives: The objectives of this study were to explore the effect of Osthole (Ost) on apoptosis in pulmonary artery smooth muscle cells (PASMCs) and investigate the potential mechanism of this effect.

Methods: Rats were injected subcutaneously with monocrotaline (MCT) to establish a PAH model, and Ost were intragastrically administrated from day 1 to day 35. After 35 days administration, the mean pulmonary artery pressure and lung weight index were measured. HE and TUNEL staining were used to observe the morphology of pulmonary artery and the apoptosis of PASMCs. In addition, the apoptosis of PASMCs were detected by flow cytometry in cultured PASMCs. The proteins of Bax and Bcl-2, and the levels of p-ASK1 and cleaved caspase 3 were measured by Western blot.

Key Findings: Ost decreased the mean pulmonary artery pressure and lung weight index in MCT-induced rats, and promoted apoptosis in PASMCs in MCT-induced rats and PDGF-BB stimulated PASMCs. Ost increased the ratio of Bax/Bcl-2 and the levels of p-ASK1, cleaved caspase 3 in MCT-induced rats and PDGF-BB stimulated PASMCs.

Conclusion: Ost promoted apoptosis in PASMCs in vivo and in vitro, and the mechanism may be associated with upregulation of ASK1 and the Bax/Bcl-2-caspase 3 signalling pathway.
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http://dx.doi.org/10.1093/jpp/rgab068DOI Listing
July 2021

Pharmacological inhibition of SETD7 by PFI-2 attenuates renal fibrosis following folic acid and obstruction injury.

Eur J Pharmacol 2021 Jun 19;901:174097. Epub 2021 Apr 19.

Department of Anesthesiology, The First Affiliated Hospital of SUN YAT-SEN University, Guangzhou, 510080, China.

Renal fibrosis is the common pathological hallmark of chronic kidney disease, and SET domain containing lysine methyltransferase 7 (SETD7) promote considerably renal fibrosis. However, the signaling mechanisms underlying SETD7 driving renal fibrosis are not fully understood. Here, we investigated the role of SETD7 in M2 macrophages-myofibroblasts transition and the myeloid fibroblasts activation in folic acid and obstruction-induced renal fibrosis. Mice treated with PFI-2, an inhibitor of SETD7, presented less bone marrow-derived myofibroblasts, fewer CD206+/α-smooth muscle actin + cells and developed less renal fibrosis (P<0.01). Furthermore, SETD7 inhibition reduced the infiltration of inflammatory cells and decreased the production of pro-inflammatory cytokines and chemokines in the kidneys after folic acid treatment (P<0.01). Finally, SETD7 inhibition suppressed the accumulation of NF-κB p65+ cells in folic acid nephropathy (P<0.01). Taken together, SETD7 mediates M2 macrophages-myofibroblasts transition, bone marrow-derived myofibroblasts activation, and inflammation response in the development of renal fibrosis.
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http://dx.doi.org/10.1016/j.ejphar.2021.174097DOI Listing
June 2021

A simple yet powerful test for assessing goodness-of-fit of high-dimensional linear models.

Stat Med 2021 06 31;40(13):3153-3166. Epub 2021 Mar 31.

Department of Statistics, George Washington University, Washington, District of Columbia, USA.

We evaluate the validity of a projection-based test checking linear models when the number of covariates tends to infinity, and analyze two gene expression datasets. We show that the test is still consistent and derive the asymptotic distributions under the null and alternative hypotheses. The asymptotic properties are almost the same as those when the number of covariates is fixed as long as p/n → 0 with additional mild assumptions. The test dramatically gains dimension reduction, and its numerical performance is remarkable.
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http://dx.doi.org/10.1002/sim.8968DOI Listing
June 2021

Comment on "COVID-19 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children and adolescents: a systematic review of critically unwell children and the association with underlying comorbidities".

Eur J Pediatr 2021 Mar 25. Epub 2021 Mar 25.

Department of Pharmacy, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, No.1314 Riyue Avenue, Qingyang District, Chengdu City, 610041, China.

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http://dx.doi.org/10.1007/s00431-021-04036-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990616PMC
March 2021

Characterization of antibody-dependent cellular cytotoxicity induced by the plasma from persons living with HIV-1 based on target cells with or without CD4 molecules.

Microbes Infect 2021 May-Jun;23(4-5):104805. Epub 2021 Mar 9.

State Key Laboratory of Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Chinese Center for Disease Control and Prevention, Beijing 102206, China. Electronic address:

Antibody-dependent cellular cytotoxicity (ADCC) is essential for reducing the reservoir of latent virus in persons living with HIV-1 (PLWH). This study evaluated the plasma's ADCC activity from treatment-naïve PLWH based on target cells with or without CD4 molecules. We found that the distribution of plasma activities to mediate ADCC is different between 8E5 cells (CD4-) and NL4-3-infected CEM.NKR.CCR5 cells (CD4+). There was no correlation between the IgG-binding ability and ADCC activity. The binding ability of the 8E5 cells (2.2%) to A32 antibody was significantly lower than that of CEM.NKR.CCR5 cells (69.3%). After incubating the 8E5 cells with CD4-mimetic compound, it did not increase the binding ability with the A32 antibody. After incubation with CD4+ T cells, the binding ability of the 8E5 cells for the A32 antibody increased significantly, which implies that the conformation of the Env protein open and expose the CD4-induced epitopes. The effect of the ADCC in plasma directly applied to 8E5 cells was positively correlated with that of the NL4-3-infected CEM.NKR.CCR5 cells. In conclusion, ADCC induction in plasma was general in the treatment-naïve PLWH. The ADCC activity levels differed when target cells with or without CD4 molecules were evaluated; When designing experiments on ADCC, full consideration should be given to this immune phenomenon.
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http://dx.doi.org/10.1016/j.micinf.2021.104805DOI Listing
March 2021

GG induces cGAS/STING- dependent type I interferon and improves response to immune checkpoint blockade.

Gut 2021 Mar 8. Epub 2021 Mar 8.

Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois, USA

Objective: Our goals were to evaluate the antitumour efficacy of GG (LGG) in combination with immune checkpoint blockade (ICB) immunotherapies on tumour growth and to investigate the underlying mechanisms.

Design: We used murine models of colorectal cancer and melanoma to evaluate whether oral administration of LGG improves the efficacy of ICB therapies. We performed the whole genome shotgun metagenome sequencing of intestinal contents and RNA sequencing of dendritic cells (DCs). In a series of in vitro and in vivo experiments, we further defined the immunological and molecular mechanisms of LGG-mediated antitumour immunity.

Results: We demonstrate that oral administration of live LGG augmented the antitumour activity of anti-programmed cell death 1 (PD-1) immunotherapy by increasing tumour-infiltrating DCs and T cells. Moreover, the combination treatment shifted the gut microbial community towards enrichment in and , that are known to increase DC activation and CD8tumour recruitment. Mechanistically, treatment with live LGG alone or in combination with anti-PD-1 antibody triggered type I interferon (IFN) production in DCs, enhancing the cross-priming of antitumour CD8 T cells. In DCs, cyclic GMP-AMP synthase (cGAS)/stimulator of IFN genes (STING) was required for IFN-β induction in response to LGG, as evidenced by the significant decrease in IFN-β levels in cGAS or STING-deficient DCs. LGG induces IFN-β production via the cGAS/STING/TANK binding kinase 1/interferon regulatory factor 7 axis in DCs.

Conclusion: Our findings have offered valuable insight into the molecular mechanisms of live LGG-mediated antitumour immunity and establish an empirical basis for developing oral administration of live LGG as a combination agent with ICB for cancer therapies.
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http://dx.doi.org/10.1136/gutjnl-2020-323426DOI Listing
March 2021

Cesarean Section or Vaginal Delivery to Prevent Possible Vertical Transmission From a Pregnant Mother Confirmed With COVID-19 to a Neonate: A Systematic Review.

Front Med (Lausanne) 2021 17;8:634949. Epub 2021 Feb 17.

Department of Pharmacy, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.

The impact of delivery mode on the infection rates of Coronavirus disease 2019 (COVID-19) in the newborn remains unknown. We aimed to summarize the existing literature on COVID-19 infection during pregnancy to evaluate which mode of delivery is better for preventing possible vertical transmission from a pregnant mother confirmed with COVID-19 to a neonate. We performed a comprehensive literature search of PubMed, Embase, Cochrane Library, Web of Science, Google Scholar, and the Chinese Biomedical Literature database (CBM) from 31 December 2019 to 18 June 2020. We applied no language restrictions. We screened abstracts for relevance, extracted data, and assessed the risk of bias in duplicate. We rated the certainty of evidence using the GRADE approach. The primary outcome was severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test positivity in neonates born to mothers with confirmed COVID-19 following different delivery modes. Secondary outcomes were neonatal deaths and maternal deaths. This study is registered with PROSPERO, CRD42020194049. Sixty-eight observational studies meeting inclusion criteria were included in the current study, with no randomized controlled trials. In total, information on the mode of delivery, detailed neonatal outcomes, and SARS-CoV-2 status were available for 1,019 pregnant women and 1,035 neonates. Six hundred and eighteen (59.71%) neonates were born through cesarean section and 417(40.29%) through vaginal delivery. Probable congenital SARS-CoV-2 infections were reported in 34/1,035 (3.29%) neonates. Of babies born vaginally, 9/417 (2.16%) were tested positive compared with 25/618 (4.05%) born by cesarean. Of babies born vaginally, 0/417 (0.00%) neonatal deaths were reported compared with 6/618 (0.97%) born by cesarean. Of women who delivered vaginally, 1/416 (0.24%) maternal deaths were reported compared with 11/603 (1.82%) delivered by cesarean. Two women died before delivery. Sensitivity analyses and subgroup analyses showed similar findings. The rate of neonatal COVID-19 infection, neonatal deaths, and maternal deaths are no greater when the mother gave birth through vaginal delivery. Based on the evidence available, there is no sufficient evidence supporting that the cesarean section is better than vaginal delivery in preventing possible vertical transmission from a pregnant mother confirmed with COVID-19 to a neonate. The mode of birth should be individualized and based on disease severity and obstetric indications. Additional good-quality studies with comprehensive serial tests from multiple specimens are urgently needed. : PROSPERO CRD42020194049.
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http://dx.doi.org/10.3389/fmed.2021.634949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926203PMC
February 2021

Radiotherapy and immunotherapy converge on elimination of tumor-promoting erythroid progenitor cells through adaptive immunity.

Sci Transl Med 2021 02;13(582)

Ludwig Center for Metastasis Research, Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637 USA.

Tumor-induced CD45Ter119CD71 erythroid progenitor cells, termed "Ter cells," promote tumor progression by secreting artemin (ARTN), a neurotrophic peptide that activates REarranged during Transfection (RET) signaling. We demonstrate that both local tumor ionizing radiation (IR) and anti-programmed death ligand 1 (PD-L1) treatment decreased tumor-induced Ter cell abundance in the mouse spleen and ARTN secretion outside the irradiation field in an interferon- and CD8 T cell-dependent manner. Recombinant erythropoietin promoted resistance to radiotherapy or anti-PD-L1 therapies by restoring Ter cell numbers and serum ARTN concentration. Blockade of ARTN or potential ARTN signaling partners, or depletion of Ter cells augmented the antitumor effects of both IR and anti-PD-L1 therapies in mice. Analysis of samples from patients who received radioimmunotherapy demonstrated that IR-mediated reduction of Ter cells, ARTN, and GFRα3, an ARTN signaling partner, were each associated with tumor regression. Patients with melanoma who received immunotherapy exhibited favorable outcomes associated with decreased expression of GFRα3. These findings demonstrate an out-of-field, or "abscopal," effect mediated by adaptive immunity, which is induced during local tumor irradiation. This effect, in turn, governs the therapeutic effects of radiation and immunotherapy. Therefore, our results identify multiple targets to potentially improve outcomes after radiotherapy and immunotherapy.
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http://dx.doi.org/10.1126/scitranslmed.abb0130DOI Listing
February 2021

Suppression of local type I interferon by gut microbiota-derived butyrate impairs antitumor effects of ionizing radiation.

J Exp Med 2021 Mar;218(3)

Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL.

The antitumor effects of ionizing radiation (IR) are mediated in part through activation of innate and adaptive immunity. Here we report that gut microbiota influences tumor control following IR. Vancomycin decreased the abundance of butyrate-producing gut bacteria and enhanced antitumor responses to IR. Oral administration of Lachnospiraceae, a family of vancomycin-sensitive bacteria, was associated with increased systemic and intratumoral butyric acid levels and impaired the efficacy of IR in germ-free (GF) mice. Local butyrate inhibited STING-activated type I IFN expression in dendritic cells (DCs) through blockade of TBK1 and IRF3 phosphorylation, which abrogated IR-induced tumor-specific cytotoxic T cell immune responses without directly protecting tumor cells from radiation. Our findings demonstrate that the selective targeting of butyrate-producing microbiota may provide a novel therapeutic option to enhance tumor radiation sensitivity.
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http://dx.doi.org/10.1084/jem.20201915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844434PMC
March 2021

Intravenous versus Volatile Anesthetic Effects on Postoperative Cognition in Elderly Patients Undergoing Laparoscopic Abdominal Surgery.

Anesthesiology 2021 03;134(3):381-394

Background: Delayed neurocognitive recovery after surgery is associated with poor outcome. Most surgeries require general anesthesia, of which sevoflurane and propofol are the most commonly used inhalational and intravenous anesthetics. The authors tested the primary hypothesis that patients with laparoscopic abdominal surgery under propofol-based anesthesia have a lower incidence of delayed neurocognitive recovery than patients under sevoflurane-based anesthesia. A second hypothesis is that there were blood biomarkers for predicting delayed neurocognitive recovery to occur.

Methods: A randomized, double-blind, parallel, controlled study was performed at four hospitals in China. Elderly patients (60 yr and older) undergoing laparoscopic abdominal surgery that was likely longer than 2 h were randomized to a propofol- or sevoflurane-based regimen to maintain general anesthesia. A minimum of 221 patients was planned for each group to detect a one-third decrease in delayed neurocognitive recovery incidence in propofol group compared with sevoflurane group. The primary outcome was delayed neurocognitive recovery incidence 5 to 7 days after surgery.

Results: A total of 544 patients were enrolled, with 272 patients in each group. Of these patients, 226 in the propofol group and 221 in the sevoflurane group completed the needed neuropsychological tests for diagnosing delayed neurocognitive recovery, and 46 (20.8%) in the sevoflurane group and 38 (16.8%) in the propofol group met the criteria for delayed neurocognitive recovery (odds ratio, 0.77; 95% CI, 0.48 to 1.24; P = 0.279). A high blood interleukin-6 concentration at 1 h after skin incision was associated with an increased likelihood of delayed neurocognitive recovery (odds ratio, 1.04; 95% CI, 1.01 to 1.07; P = 0.007). Adverse event incidences were similar in both groups.

Conclusions: Anesthetic choice between propofol and sevoflurane did not appear to affect the incidence of delayed neurocognitive recovery 5 to 7 days after laparoscopic abdominal surgery. A high blood interleukin-6 concentration after surgical incision may be an independent risk factor for delayed neurocognitive recovery.

Editor’s Perspective:
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http://dx.doi.org/10.1097/ALN.0000000000003680DOI Listing
March 2021

SARS-CoV-2-specific T cells are rapidly expanded for therapeutic use and target conserved regions of the membrane protein.

Blood 2020 12;136(25):2905-2917

National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD.

T-cell responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been described in recovered patients, and may be important for immunity following infection and vaccination as well as for the development of an adoptive immunotherapy for the treatment of immunocompromised individuals. In this report, we demonstrate that SARS-CoV-2-specific T cells can be expanded from convalescent donors and recognize immunodominant viral epitopes in conserved regions of membrane, spike, and nucleocapsid. Following in vitro expansion using a good manufacturing practice-compliant methodology (designed to allow the rapid translation of this novel SARS-CoV-2 T-cell therapy to the clinic), membrane, spike, and nucleocapsid peptides elicited interferon-γ production, in 27 (59%), 12 (26%), and 10 (22%) convalescent donors (respectively), as well as in 2 of 15 unexposed controls. We identified multiple polyfunctional CD4-restricted T-cell epitopes within a highly conserved region of membrane protein, which induced polyfunctional T-cell responses, which may be critical for the development of effective vaccine and T-cell therapies. Hence, our study shows that SARS-CoV-2 directed T-cell immunotherapy targeting structural proteins, most importantly membrane protein, should be feasible for the prevention or early treatment of SARS-CoV-2 infection in immunocompromised patients with blood disorders or after bone marrow transplantation to achieve antiviral control while mitigating uncontrolled inflammation.
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http://dx.doi.org/10.1182/blood.2020008488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746091PMC
December 2020

The Inhibition of H1N1 Influenza Virus-Induced Apoptosis by Surface Decoration of Selenium Nanoparticles with β-Thujaplicin through Reactive Oxygen Species-Mediated AKT and p53 Signaling Pathways.

ACS Omega 2020 Dec 16;5(47):30633-30642. Epub 2020 Nov 16.

Center Laboratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, No 318 Renminzhong Road, Yuexiu District, Guangzhou 510120, Guangdong, People's Republic of China.

β-Thujaplicin possess a variety of biological activities. The use of modified biological nanoparticles (NPs) to develop novel anti-influenza drugs has increased in recent years. Selenium nanoparticles (SeNPs) with antiviral activity have attracted increasing attention for biomedical intervention. Functionalized SeNPs by β-thujaplicin ([email protected]) surface modified with superior antiviral activity were synthesized in this study. Compared to a virus group (43%), when treated with [email protected] (88%), the cell survival rate of MDCK cells was 45% higher. [email protected] could inhibit H1N1 from infecting Madin-Darby canine kidney (MDCK) cells and block chromatin condensation and DNA fragmentation. [email protected] obviously prevented MDCK cells from generating reactive oxygen species. Furthermore, [email protected] prevents lung injury in H1N1-infected mice through eosin staining and hematoxylin . Mechanistic investigation revealed that [email protected] inhibited H1N1 influenza virus from infecting MDCK cells through induction of apoptosis via suppressing AKT and p53 signaling pathways through immunohistochemical assay. Our results suggest that β-thujaplicin-modified SeNPs as carriers are an efficient way to achieve an antiviral pharmaceutical candidate for H1N1 influenza.
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http://dx.doi.org/10.1021/acsomega.0c04624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711941PMC
December 2020

The Change of Soluble Programmed Cell Death-Ligand 1 in Glioma Patients Receiving Radiotherapy and Its Impact on Clinical Outcomes.

Front Immunol 2020 30;11:580335. Epub 2020 Oct 30.

Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.

Background: The programmed cell death ligand 1 (PD-L1) plays a key role in glioma development. However, due to the specificity of glioma's anatomical position, the role of its expression as a tumor biomarker is limited. It has been proven that the levels of soluble programmed death-ligand 1 (sPD-L1) are associated with prognosis in many malignancies including glioma. However, the expression of sPD-L1 in glioma patients receiving radiotherapy (RT) remains unclear. The purpose of this study was to evaluate the concentration of sPD-L1 in the plasma of glioma patients before and after RT and to explore its relationship with clinical outcomes.

Methods: Between October 2017 and September 2018, glioma patients treated with RT (30 ± 10 Gy, 2 Gy/f) were enrolled, and blood samples were collected before and after RT. We quantified the sPD-L1 levels by enzyme-linked immunosorbent assay (ELISA). The isocitrate dehydrogenase-1 (IDH-1) mutational status and Ki-67 expression of tumors were evaluated by immunohistochemistry. Glioma murine model were used to address whether circulating sPD-L1 molecules are directly targeted by an anti-PD-L1 antibody. The associations between sPD-L1 and clinical features were assessed with Pearson's or Spearman's correlation analysis. The progression-free survival (PFS) and overall survival (OS) were determined by the Kaplan-Meier method.

Results: Sixty glioma patients were included, with a median age of 52 years. The proportions of grade I, II, III, and IV gliomas were 6.7%, 23.3%, 28.4%, and 41.6%, respectively. The baseline sPD-L1 levels were significantly associated with tumor grade, IDH-1 mutation status and Ki-67 expression. Using 14.35 pg/ml as the cutoff, significantly worse PFS and OS were both observed in patients with higher baseline levels of sPD-L1 ( = 0.027 and 0.008, respectively). RT significantly increased the mean level of sPD-L1 ( < 0.001). Further analysis showed that the level of sPD-L1 in IDH-1 mutation patients was higher than that in wild-type patients. Furthermore, an analysis of glioma murine model indicated that anti-PD-L1 antibody combine with RT can be a potentially powerful cancer therapy.

Conclusion: This study reported that sPD-L1 might be a potential biomarker to predict the outcome in glioma patients receiving RT. The elevated level of sPD-L1 after RT suggested that the strategy of a combination of immune checkpoint inhibitors and RT might be promising for glioma patients, especially for those with IDH-1 mutations.
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http://dx.doi.org/10.3389/fimmu.2020.580335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668030PMC
June 2021

SARS-CoV-2 specific T-cells Are Rapidly Expanded for Therapeutic Use and Target Conserved Regions of Membrane Protein.

Blood 2020 Oct 26. Epub 2020 Oct 26.

National Institute of Dental and Craniofacial Research, Bethesda, Maryland, United States.

T-cell responses to SARS-CoV-2 have been described in recovered patients, and may be important for immunity following infection and vaccination as well as for the development of an adoptive immunotherapy for the treatment of immunocompromised individuals. In this report, we demonstrate that SARS-CoV-2-specific T-cells can be expanded from convalescent donors, and recognize immunodominant viral epitopes in conserved regions of membrane, spike, and nucleocapsid. Following in vitro expansion using a GMP-compliant methodology (designed to allow the rapid translation of this novel SARS-CoV-2 T-cell therapy to the clinic), membrane, spike, and nucleocapsid peptides elicited IFN-γ production, in 27 (59%), 12 (26%), and 10 (22%) convalescent donors (respectively), as well as in 2 of 15 unexposed controls. We identified multiple polyfunctional CD4-restricted T-cell epitopes within a highly conserved region of membrane protein, which induced polyfunctional T cell responses, which may be critical for the development of effective vaccine and T cell therapies. Hence, our study shows that SARS-CoV-2 directed T-cell immunotherapy targeting structural proteins, most importantly membrane protein, should be feasible for the prevention or early treatment of SARS-CoV-2 infection in immunocompromised patients with blood disorders or after bone marrow transplantation to achieve anti-viral control while mitigating uncontrolled inflammation.
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http://dx.doi.org/10.1182/blood.2020008488DOI Listing
October 2020

Liraglutide protects against high-fat diet-induced kidney injury by ameliorating apoptosis.

Endocr Connect 2020 Oct;9(9):946-954

Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.

Background: Obesity is associated with the development and progression of chronic kidney disease. Emerging evidence suggests that glucagon-like peptide-1 receptor agonist could reduce renal damage and albuminuria. Sirtuin 1 (SIRT1) was considered as a crucial regulator in metabolism-related kidney disease. Herein, the role of SIRT1 in liraglutide-ameliorated high-fat diet (HFD)-induced kidney injury was illustrated.

Methods: Male C57BL/6 mice were fed HFD for 20 weeks to induce kidney injury that was then treated with liraglutide for 8 weeks to estimate its protective effect on the kidney. Also, the mechanism of the drug in SV40 MES 13 (SV40) mouse mesangial cells was elucidated.

Results: Liraglutide treatment ameliorated HFD-induced metabolic disorders, including hyperglycemia, increasing body weight, and insulin resistance. In addition, kidney weight, urine albumin-to-creatinine, and kidney morphological changes such as vacuolated tubules, glomerulomegaly, thickened glomerular basement membrane, and tubulointerstitial fibrosis were also significantly ameliorated. Furthermore, apoptotic cells and apoptosis markers were downregulated in the kidney of liraglutide-treated mice. In addition, the expression of SIRT1 protein was upregulated, whereas thioredoxin-interacting protein (TXNIP), which serves as a mediator of oxidative stress and apoptosis in metabolism disease, was downregulated by liraglutide. In SV40 cells, the effect of liraglutide on reversing the upregulation of cleaved caspase-3 induced by high glucose (30 mM) was hampered when SIRT1 was knocked down; also, the downregulation of TXNIP by liraglutide was blocked.

Conclusions: Liraglutide might have a beneficial effect on metabolism-related kidney damage by inhibiting apoptosis via activation of SIRT1 and suppression of TXNIP pathway.
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http://dx.doi.org/10.1530/EC-20-0294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583131PMC
October 2020

Protective role of histone deacetylase 4 from ultraviolet radiation-induced DNA lesions.

Mol Carcinog 2020 11 13;59(11):1292-1301. Epub 2020 Sep 13.

Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

Ultraviolet B (UVB) exposure is a core factor that leads to skin disease or carcinogenesis through the insufficient repair of DNA lesions. UVB-induced DNA lesions are mainly removed by the nucleotide excision repair (NER) mechanism. The expression of histone deacetylase 4 (HDAC4) is altered in the skin upon UVB exposure, indicating its possible implication in UVB-induced DNA lesions repair. Here, we investigated the role of HDAC4 in the NER removal of the main classes of UVB-induced DNA lesions consisting of cyclobutane pyrimidine dimers and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs). We found that UVB irradiation increased HDAC4 expression at both the mRNA and protein levels. HDAC4 interacted with NER factor XPC, which played an important role in effectively removing the UVB-induced DNA lesions. This study provides an understanding of the HDAC4 function in DNA repair, which will allow the development of efficient strategies to protect the skin from UVR-induced diseases.
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http://dx.doi.org/10.1002/mc.23257DOI Listing
November 2020

PNPLA3 I148M is involved in the variability in anti-NAFLD response to exenatide.

Endocrine 2020 12 30;70(3):517-525. Epub 2020 Aug 30.

Department of Endocrinology and Metabolism, Third Affiliated Hospital of Sun Yat-Sen University, and Guangdong Provincial Key Laboratory of Diabetology, Guangzhou, China.

Purpose: GLP-1 receptor agonists, such as exenatide, have been proven to attenuate nonalcoholic fatty liver disease (NAFLD) in vivo and in vitro. However, the efficiency of exenatide had interindividual differences. PNPLA3 is a major susceptibility gene for NAFLD and its I148M polymorphism increases the risk of all disorders of the NAFLD spectrum. Whether this variant contributes to variability in exenatide response is still unclear.

Methods: PNPLA3 148I knockin HepG2 cells were constructed using the Cas9/sgRNA system. Oil Red O staining combined with TG quantification was used to evaluate lipid accumulation. Western blotting and qRT-qPCR were conducted, respectively, to measure the protein and mRNA expression of lipid metabolic and endoplasmic reticulum (ER) stress-related inflammatory markers. PNPLA3 I148M was genotyped in type 2 diabetics using Sanger sequencing. The exenatide-induced changes in liver fat content and other clinical parameters were compared between PNPLA3 I148M genotypes.

Results: Lipid deposition increased in both PNPLA3 148I/I and 148M/M HepG2 cells treated with palmitoleic acid, while cells with 148M/M had a higher TG content than those with 148I/I. Exendin-4 treatment was showed to be more significant in 148I/I cells than in 148M/M cells in terms of reducing the intrahepatic fat content, inhibiting SREBP-1c and ER stress-related inflammation, and activating AMPK-ACC lipid oxidation pathway. In patients with type 2 diabetes, 24-week treatment with exenatide improved liver fat content in patients carrying PNPLA3 148I/I better than in patients with 148M/M.

Conclusions: PNPLA3 I148M might modify the anti-NAFLD response to exenatide.
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http://dx.doi.org/10.1007/s12020-020-02470-7DOI Listing
December 2020

[Retroauricular teratoma with congenital microtia and ankylotia: a case report].

Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2020 Apr;34(4):372-373

Teratoma is a germ cell tumor, which is rare behind the ear. We described a rare case of retroauricular teratoma accompanied with congenital malformation of external and middle ear and cholesteatoma of middle ear in a 13-years-old girl. Congenital microtia and ankylotia of right ear was found since childhood, suppuration occurred repeatedly behind the right ear 1 year ago. Temporal bone CT and MRI scan revealed congenital malformation of middle ear and cholesteatoma of middle ear. Cystic mass containing a tooth was found intraoperatively. The pathological results showed that it was benign cystic teratoma. It showed no evidence of recurrence on the patient during 3 months follow-up.
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http://dx.doi.org/10.13201/j.issn.2096-7993.2020.04.021DOI Listing
April 2020

Cyr61 Promotes Inflammation of a Gouty Arthritis Model in Rats.

Mediators Inflamm 2020 24;2020:8298615. Epub 2020 Jul 24.

Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.

Background: Cyr61 is considered a novel proinflammatory factor. Gouty arthritis (GA) is a self-limited inflammatory reaction caused by monosodium urate (MSU) crystals. In this study, we assessed the role of Cyr61 in the inflammatory process of GA.

Methods: We investigated the expression of Cyr61 in MSU-induced rat gout models and MSU-stimulated rat fibroblast-like synovial (FLS) cells. After inhibiting the expression of Cyr61, levels of IL-1, TNF-, and IL-6 were detected by ELISA, qPCR, western blot, and immunohistochemical methods. We probed the downstream NF-B signaling pathway using the NF-B inhibitor PDTC, and levels of NF-B and p-NF-B were detected by western blot and qPCR.

Results: Our results demonstrate that Cyr61 plays a potent role in the formation of local inflammation in vitro and in vivo. Cyr61 was highly expressed in synovial tissues of gout models, and the expression of Cyr61 protein was also significantly increased in MSU-stimulated FLS cells. Cyr61 promoted MSU-induced acute inflammation via the NF-B signaling pathway.

Conclusions: Our study has revealed that Cyr61 is an important regulatory factor for the initiation of inflammation in GA. The high expression of Cyr61 protein can induce synovial cells to produce many inflammatory cytokines, such as IL-1, TNF-, and IL-6, partly in an NF-B-dependent manner. Thus, inhibition of Cyr61 could be a new target and strategy for the prevention and treatment of GA.
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http://dx.doi.org/10.1155/2020/8298615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396108PMC
June 2021

Recognition of maturity-onset diabetes of the young in China.

J Diabetes Investig 2021 Apr 9;12(4):501-509. Epub 2020 Sep 9.

Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou, China.

Aims/introduction: Given that mutations related to maturity-onset diabetes of the young (MODY) are rarely found in Chinese populations, we aim to characterize the mutation spectrum of MODY pedigrees.

Materials And Methods: Maturity-onset diabetes of the young candidate gene- or exome-targeted capture sequencing was carried out in 76 probands from unrelated families fulfilling the clinical diagnostic criteria for MODY. MAF <0.01 in the GnomAD or ExAC database was used to filter significant variants. Sanger sequencing was then carried out to validate findings. Function prediction by SIFT, PolyPhen-2 and PROVEAN or CADD was carried out in missense mutations.

Results: A total of 32 mutations in six genes were identified in 31 families, accounting for 40.79% of the potential MODY families. The MODY subtype detection rate was 18.42% for GCK, 15.79% for HNF1A, 2.63% for HNF4A, and 1.32% for KLF11, PAX4 and NEUROG3. Seven nonsense/frameshift mutations and four missense mutations with damaging prediction were newly identified novel mutations. The clinical features of MODY2, MODY3/1 and MODYX are similar to previous reports. Clinical phenotype of NEUROG3 p.Arg55Glufs*23 is characterized by hyperglycemia and mild intermittent abdominal pain.

Conclusions: This study adds to the emerging pattern of MODY epidemiology that the proportion of MODY explained by known pathogenic genes is higher than that previously reported, and found NEUROG3 as a new causative gene for MODY.
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http://dx.doi.org/10.1111/jdi.13378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015824PMC
April 2021

Independent risk factors for axillary lymph node metastasis in breast cancer patients with one or two positive sentinel lymph nodes.

BMC Womens Health 2020 07 9;20(1):143. Epub 2020 Jul 9.

Department of Breast Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Rd., Xi'an, 710061, Shaanxi, China.

Background: The benefit of axillary lymph node dissection (ALND) in breast cancer patients with one or two positive sentinel lymph nodes (SLNs) remains inconclusive. The purpose of this study was to identify risk factors independently associated with axillary lymph node (ALN) metastasis.

Methods: We retrospectively analyzed data from 389 Chinese breast cancer patients with one or two positive SLNs who underwent ALND. Univariate and multivariate logistic regression analyses were performed to identify ALN metastasis-associated risk factors.

Results: Among the 389 patients, 174 (44.7%) had ALN metastasis, while 215 (55.3%) showed no evidence of ALN metastasis. Univariate analysis revealed significant differences in age (< 60 or ≥ 60 years), human epidermal growth factor receptor-2 (Her-2) status, and the ratio of positive to total SLNs between the ALN metastasis and non-metastasis groups (P < 0.05). The multivariate analysis indicated that age, the ratio of positive to total SLNs, and occupations were significantly different between the two groups. Lastly, younger age (< 60 years), a higher ratio of positive to total SLNs, and manual labor jobs were independently associated with ALN metastasis (P < 0.05).

Conclusions: The risk of ALN metastasis in breast cancer patients with one or two positive SLNs can be further increased by younger age, manual labor jobs, and a high ratio of positive to total SLNs. Our findings may also aid in identifying which patients with one or two positive SLNs may not require ALND.
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http://dx.doi.org/10.1186/s12905-020-01004-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350751PMC
July 2020
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