Publications by authors named "Yina Wang"

88 Publications

Mechanism of genome instability mediated by human DNA polymerase mu misincorporation.

Nat Commun 2021 06 18;12(1):3759. Epub 2021 Jun 18.

Institute of Biophysics, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China.

Pol μ is capable of performing gap-filling repair synthesis in the nonhomologous end joining (NHEJ) pathway. Together with DNA ligase, misincorporation of dGTP opposite the templating T by Pol μ results in a promutagenic T:G mispair, leading to genomic instability. Here, crystal structures and kinetics of Pol μ substituting dGTP for dATP on gapped DNA substrates containing templating T were determined and compared. Pol μ is highly mutagenic on a 2-nt gapped DNA substrate, with T:dGTP base pairing at the 3' end of the gap. Two residues (Lys438 and Gln441) interact with T:dGTP and fine tune the active site microenvironments. The in-crystal misincorporation reaction of Pol μ revealed an unexpected second dGTP in the active site, suggesting its potential mutagenic role among human X family polymerases in NHEJ.
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http://dx.doi.org/10.1038/s41467-021-24096-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213813PMC
June 2021

Adipocyte inducible 6-phosphofructo-2-kinase suppresses adipose tissue inflammation and promotes macrophage anti-inflammatory activation.

J Nutr Biochem 2021 May 6;95:108764. Epub 2021 May 6.

Department of Nutrition, Texas A&M University, College Station, Texas, USA. Electronic address:

Obesity-associated inflammation in white adipose tissue (WAT) is a causal factor of systemic insulin resistance. To better understand how adipocytes regulate WAT inflammation, the present study generated chimeric mice in which inducible 6-phosphofructo-2-kinase was low, normal, or high in WAT while the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (Pfkfb3) was normal in hematopoietic cells, and analyzed changes in high-fat diet (HFD)-induced WAT inflammation and systemic insulin resistance in the mice. Indicated by proinflammatory signaling and cytokine expression, the severity of HFD-induced WAT inflammation in WT → Pfkfb3 mice, whose Pfkfb3 was disrupted in WAT adipocytes but not hematopoietic cells, was comparable with that in WT → WT mice, whose Pfkfb3 was normal in all cells. In contrast, the severity of HFD-induced WAT inflammation in WT → Adi-Tg mice, whose Pfkfb3 was over-expressed in WAT adipocytes but not hematopoietic cells, remained much lower than that in WT → WT mice. Additionally, HFD-induced insulin resistance was correlated with the status of WAT inflammation and comparable between WT → Pfkfb3 mice and WT → WT mice, but was significantly lower in WT → Adi-Tg mice than in WT → WT mice. In vitro, palmitoleate decreased macrophage phosphorylation states of Jnk p46 and Nfkb p65 and potentiated the effect of interleukin 4 on suppressing macrophage proinflammatory activation. Taken together, these results suggest that the Pfkfb3 in adipocytes functions to suppress WAT inflammation. Moreover, the role played by adipocyte Pfkfb3 is attributable to, at least in part, palmitoleate promotion of macrophage anti-inflammatory activation.
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http://dx.doi.org/10.1016/j.jnutbio.2021.108764DOI Listing
May 2021

Renal outcomes of idiopathic and atypical membranous nephropathy in adult Chinese patients: a single center retrospective cohort study.

BMC Nephrol 2021 Apr 22;22(1):148. Epub 2021 Apr 22.

Department of Nephrology, Peking University People's Hospital, 11 Xizhimennan Street, Xicheng District, 100044, Beijing, China.

Background: Membranous nephropathy (MN) is mainly classified into idiopathic MN (iMN) and secondary MN in etiology. In recent years, a new kind of membranous nephropathy, atypical membranous nephropathy (aMN) which shows "full house" in immunofluorescence but without definite etiology was paid more attention. In a single center cohort, the renal outcomes of iMN and aMN were compared.

Methods: iMN and aMN patients were selected from renal pathology databank from January 2006 to December 2015. Patients' demographics, laboratory values, induction regimens and patients' responses were recorded. Specially, creatinine, eGFR, albumin and 24 h urinary protein excretion were recorded at 6th month after the induction of immunosuppressive (IS) treatment and at the end of follow up. Complete proteinuria remission was defined as urinary protein < 0.3 g/d, partial proteinuria remission was defined as urinary protein between 0.3 g/d ~ 3.5 g/d and decreased > 50 % from the baseline. The primary outcome was worsening renal function, defined as a 30 % or more decrease in eGFR or end-stage renal disease (eGFR < 15ml/min/1.73m). COX proportional hazard models were used to test if aMN was a risk factor of worsening renal function compared with iMN.

Results: There were 298 patients diagnosed with MN and followed in our center for 1 year or more, including 145 iMN patients with an average follow-up time of 4.5 ± 2.6 years, and 153 aMN patients with 4.1 ± 2.0 years (p = 0.109). The average age of iMN patients was older than aMN patients (56.1 ± 12.2 versus 47.2 ± 16.2 years old, p < 0.001). There were 99 iMN patients and 105 aMN patients with nephrotic range proteinuria and without previous immunosuppressive treatment. 93 (93.9 %) and 95 (90.5 %) patients underwent immunosuppressive treatment in iMN and aMN group, and there was no significant difference of the overall proteinuria remission rates at 6th month (59.1 % vs. 52.0 %, p = 0.334) and endpoint (73.7 % vs. 69.5 %, p = 0.505) between the two groups. 25 (25.3 %) patients in iMN group and 21 (20.0 %) patients in aMN group reached primary endpoint (X = 0.056, p = 0.812). Multivariate COX regression showed that after demographics, baseline laboratory values and remission status at 6th month were adjusted, aMN group had similar renal outcome compared with iMN group, the HR of primary outcome was 0.735 (95 % CI 0.360 ~ 1.503, p = 0.399).

Conclusions: The proteinuria remission rates and renal outcomes were similar in iMN and aMN patients after covariables were adjusted.
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http://dx.doi.org/10.1186/s12882-021-02348-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063350PMC
April 2021

Imaging Biomarkers to Predict and Evaluate the Effectiveness of Immunotherapy in Advanced Non-Small-Cell Lung Cancer.

Front Oncol 2021 19;11:657615. Epub 2021 Mar 19.

Department of Radiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, China.

Objective: We aimed to identify imaging biomarkers to assess predictive capacity of radiomics nomogram regarding treatment response status (responder/non-responder) in patients with advanced NSCLC undergoing anti-PD1 immunotherapy.

Methods: 197 eligible patients with histologically confirmed NSCLC were retrospectively enrolled from nine hospitals. We carried out a radiomics characterization from target lesions (TL) approach and largest target lesion (LL) approach on baseline and first follow-up (TP1) CT imaging data. Delta-radiomics feature was calculated as the relative net change in radiomics feature between baseline and TP1. Minimum Redundancy Maximum Relevance (mRMR) and Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression were applied for feature selection and radiomics signature construction.

Results: Radiomics signature at baseline did not show significant predictive value regarding response status for LL approach ( = 0.10), nor in terms of TL approach ( = 0.27). A combined Delta-radiomics nomogram incorporating Delta-radiomics signature with clinical factor of distant metastasis for target lesions had satisfactory performance in distinguishing responders from non-responders with AUCs of 0.83 (95% CI: 0.75-0.91) and 0.81 (95% CI: 0.68-0.95) in the training and test sets respectively, which was comparable with that from LL approach ( = 0.92, = 0.97). Among a subset of those patients with available pretreatment PD-L1 expression status (n = 66), models that incorporating Delta-radiomics features showed superior predictive accuracy than that of PD-L1 expression status alone (0.001).

Conclusion: Early response assessment using combined Delta-radiomics nomograms have potential advantages to identify patients that were more likely to benefit from immunotherapy, and help oncologists modify treatments tailored individually to each patient under therapy.
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http://dx.doi.org/10.3389/fonc.2021.657615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017283PMC
March 2021

Obstructive Sleep Apnea-hypopnea Syndrome as a Novel Potential Risk for Aging.

Authors:
Yayong Li Yina Wang

Aging Dis 2021 Apr 1;12(2):586-596. Epub 2021 Apr 1.

2Department of Geriatrics, The Second Xiangya Hospital of Central South University, Changsha, China.

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a common sleep disorder, negatively influencing individuals' quality of life and socioeconomic burden. In recent years, OSAHS has been reported in not only constituting an aging-associated disease, but also in accelerating and/or potentiating aging mechanisms. However, the negative impacts of OSAHS on aging are underestimated because of low level of public awareness about this disease and high rates of undiagnosed cases, which are more critical in developing countries or economically disadvantaged regions. Hence, reviewing previously reported observations may assist scholars to better indicate that OSAHS is likely a novel potential risk for aging. Further understanding of the pathophysiological mechanism of OSAHS and its role in procession of aging may markedly highlight the importance of this common sleep disorder.
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http://dx.doi.org/10.14336/AD.2020.0723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990365PMC
April 2021

Versatile Labeling and Detection of Endogenous Proteins Using Tag-Assisted Split Enzyme Complementation.

ACS Chem Biol 2021 04 18;16(4):671-681. Epub 2021 Mar 18.

Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94143, United States.

Recent advances in genome engineering have expanded our capabilities to study proteins in their natural states. In particular, the ease and scalability of knocking-in small peptide tags has enabled high throughput tagging and analysis of endogenous proteins. To improve enrichment capacities and expand the functionality of knock-ins using short tags, we developed the tag-assisted split enzyme complementation (TASEC) approach, which uses two orthogonal small peptide tags and their cognate binders to conditionally drive complementation of a split enzyme upon labeled protein expression. Using this approach, we have engineered and optimized the tag-assisted split HaloTag complementation system (TA-splitHalo) and demonstrated its versatile applications in improving the efficiency of knock-in cell enrichment, detection of protein-protein interaction, and isolation of biallelic gene edited cells through multiplexing.
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http://dx.doi.org/10.1021/acschembio.0c00925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115985PMC
April 2021

Yeast Fermentate Prebiotic Ameliorates Allergic Asthma, Associating with Inhibiting Inflammation and Reducing Oxidative Stress Level through Suppressing Autophagy.

Mediators Inflamm 2021 19;2021:4080935. Epub 2021 Jan 19.

Second Xiangya Hospital of Central South University, No. 139 Middle Renmin Road, Changsha City, Hunan Province, China.

Methods: Ovalbumin was used to induce allergic asthma following administration of YFP for one week in mice, to collect the lung tissues, bronchoalveolar lavage fluid (BLFA), and feces. The pathological state, tight-junction proteins, inflammatory and oxidative stress-associated biomarkers, and TLRs/NF-B signaling pathway of the lung tissues were evaluated by HE staining, immunofluorescence, ELISA, and WB, separately. RT-PCR was used to test oxidative stress-associated genes. Leukocyte counts of BLFA and intestinal microbiota were also analyzed using a hemocytometer and 16S rDNA-sequencing, separately.

Result: YFP ameliorated the lung injury of the mouse asthma model by inhibiting peribronchial and perivascular infiltrations of eosinophils and increasing tight-junction protein expression. YFP inhibited the decrease in the number of BALF leukocytes and expression of inflammatory-related genes and reversed OVA-induced TLRs/NF-B signaling pathway activation. YFP ameliorated the level of oxidative stress in the lung of the mouse asthma model by inhibiting MDA and promoting the protein level of GSH-PX, SOD, CAT, and oxidative-related genes. ATG5, Beclin1, and LC3BII/I were significantly upregulated in asthma mice, which were greatly suppressed by the introduction of YFP, indicating that YFP ameliorated the autophagy in the lung of the mouse asthma model. Lastly, the distribution of bacterial species was slightly changed by YFP in asthma mice, with a significant difference in the relative abundance of 6 major bacterial species between the asthma and YFP groups.

Conclusion: Our research showed that YFP might exert antiasthmatic effects by inhibiting airway allergic inflammation and oxidative stress level through suppressing autophagy.
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http://dx.doi.org/10.1155/2021/4080935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840264PMC
January 2021

Age-Specific Imbalance of Circulating Tfh Cell Subsets and Its Association With Gout-Targeted Kidney Impairment.

Front Immunol 2020 11;11:625458. Epub 2021 Jan 11.

Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.

Objective: Gout is a chronic disease characterized by the deposition of monosodium urate (MSU) crystals in tissue. Study with a focus on adaptive immune response remains to be understood although innate immune response has been reported extensively in gout etiology. Our study attempted to investigate the association of gout-related immune cell imbalance with clinical features and comorbidity with renal impairment and the implicated pathogenesis the assessment of T and B cell subsets in different activity phases or with immune effects combined with the analyses of clinical parameters.

Methods: Fifty-eight gout patients and 56 age- and sex-matched healthy individuals were enrolled. To learn the roles of circulating T cells, a lymphocyte profile incorporating 32 T cell subsets was tested from isolated freshly peripheral blood monocyte cells (PBMCs) with multiple-color flow cytometry. Furthermore, the collected clinical features of participants were used to analyze the characteristics of these differential cell subsets. Stratified on the basis of the level of creatinine (Cr, enzymatic method), all patients were categorized into Cr (Cr ≤ 116 μmol/L) and Cr (Cr > 116 μmol/L) groups to exploit whether these gout-associated T cell subsets were functional in gout-targeted kidney dysfunction. The differentiation of B cells was investigated in gout patients.

Results: Our results show that CD 4 T cells, Th2 cells, and Tc2 cells were upregulated, whereas Tc17 cells were downregulated. Tfh cells skewed toward the polarization of Tfh2 cells. Specifically, Tfh2 cells increased, but Tfh1 cells decreased, accompanied with aging for gout patients, suggesting that age might trigger the skewing of Tfh1/Tfh2 cell subsets to influence gout development. Moreover, Tfh2 cells were connected to renal dysfunction as well. No alterations of B cell subsets were observed in patients when compared to controls.

Conclusions: Our data demonstrate age-specific dysfunctions of Tfh1/2 cells in gout occurrence, and Tfh2 cell upregulation is associated with gout-targeted renal dysfunction. However, Tfh2 cells may function in auto-inflammatory gout independent of helping B differentiation, and an in-depth study remains to be conducted.
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http://dx.doi.org/10.3389/fimmu.2020.625458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829215PMC
June 2021

MicroRNA-374b inhibits breast cancer progression through regulating CCND1 and TGFA genes.

Carcinogenesis 2021 Apr;42(4):528-536

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA.

Emerging evidence indicates that microRNAs (miRNAs) play a critical role in breast cancer development. We recently reported that a higher expression of miR-374b in tumor tissues was associated with a better disease-free survival of triple-negative breast cancer (TNBC). However, the functional significance and molecular mechanisms underlying the role of miR-374b in breast cancer are largely unknown. In this current study, we evaluated the biological functions and potential mechanisms of miR-374b in both TNBC and non-TNBC. We found that miR-374b was significantly downregulated in breast cancer tissues, compared to adjacent tissues. MiR-374b levels were also lower in breast cancer cell lines, as compared to breast epithelial cells. In vitro and in vivo studies demonstrated that miR-374b modulates the malignant behavior of breast cancer cells, such as cell proliferation in 2D and 3D, cell invasion ability, colony-forming ability and tumor growth in mice. By using bioinformatics tools, we predicted that miR-374b plays a role in breast cancer cells through negatively regulating cyclin D1 (CCND1) and transforming growth factor alpha (TGFA). We further confirmed that CCND1 and TGFA contribute to the malignant behavior of breast cancer cells in vitro and in vivo. Our rescue experiments showed that overexpressing CCND1 or TGFA reverses the phenotypes caused by miR-374b overexpression. Taken together, our studies suggest that miR-374b modulates malignant behavior of breast cancer cells by negatively regulating CCND1 and TGFA genes. The newly identified miR-374b-mediated CCND1 and TGFA gene silencing may facilitate a better understanding of the molecular mechanisms of breast cancer progression.
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http://dx.doi.org/10.1093/carcin/bgab005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086770PMC
April 2021

Adipose tissue inflammation and systemic insulin resistance in mice with diet-induced obesity is possibly associated with disruption of PFKFB3 in hematopoietic cells.

Lab Invest 2021 03 18;101(3):328-340. Epub 2021 Jan 18.

Department of Nutrition, Texas A&M University, College Station, TX, USA.

Obesity-associated inflammation in white adipose tissue (WAT) is a causal factor of systemic insulin resistance; however, precisely how immune cells regulate WAT inflammation in relation to systemic insulin resistance remains to be elucidated. The present study examined a role for 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in hematopoietic cells in regulating WAT inflammation and systemic insulin sensitivity. Male C57BL/6J mice were fed a high-fat diet (HFD) or low-fat diet (LFD) for 12 weeks and examined for WAT inducible 6-phosphofructo-2-kinase (iPFK2) content, while additional HFD-fed mice were treated with rosiglitazone and examined for PFKFB3 mRNAs in WAT stromal vascular cells (SVC). Also, chimeric mice in which PFKFB3 was disrupted only in hematopoietic cells and control chimeric mice were also fed an HFD and examined for HFD-induced WAT inflammation and systemic insulin resistance. In vitro, adipocytes were co-cultured with bone marrow-derived macrophages and examined for adipocyte proinflammatory responses and insulin signaling. Compared with their respective levels in controls, WAT iPFK2 amount in HFD-fed mice and WAT SVC PFKFB3 mRNAs in rosiglitazone-treated mice were significantly increased. When the inflammatory responses were analyzed, peritoneal macrophages from PFKFB3-disrputed mice revealed increased proinflammatory activation and decreased anti-inflammatory activation compared with control macrophages. At the whole animal level, hematopoietic cell-specific PFKFB3 disruption enhanced the effects of HFD feeding on promoting WAT inflammation, impairing WAT insulin signaling, and increasing systemic insulin resistance. In vitro, adipocytes co-cultured with PFKFB3-disrupted macrophages revealed increased proinflammatory responses and decreased insulin signaling compared with adipocytes co-cultured with control macrophages. These results suggest that PFKFB3 disruption in hematopoietic cells only exacerbates HFD-induced WAT inflammation and systemic insulin resistance.
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http://dx.doi.org/10.1038/s41374-020-00523-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897240PMC
March 2021

An In Situ Reflectance Spectroscopic Investigation to Monitor Two-Dimensional MoS Flakes on a Sapphire Substrate.

Materials (Basel) 2020 Dec 18;13(24). Epub 2020 Dec 18.

School of Control Science and Engineering, Shandong University, Jingshi Road, Jinan 250061, China.

In this work, we demonstrate the application of differential reflectance spectroscopy (DRS) to monitor the growth of molybdenum disulfide (MoS) using chemical vapor deposition (CVD). The growth process, optical properties, and structure evolution of MoS were recorded by in-situ DRS. Indeed, blue shifts of the characteristic peak B were discussed with the decrease of temperature. We also obtained the imaginary part of the MoS dielectric constant according to reflectance spectra. This method provides an approach for studying the change of two-dimensional (2D) materials' dielectric constant with temperature. More importantly, our work emphasizes that the DRS technique is a non-destructive and effective method for in-situ monitoring the growth of 2D materials, which is helpful in guiding the preparation of 2D materials.
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http://dx.doi.org/10.3390/ma13245794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766002PMC
December 2020

Bazedoxifene exhibits anti-inflammation and anti-atherosclerotic effects via inhibition of IL-6/IL-6R/STAT3 signaling.

Eur J Pharmacol 2021 Feb 23;893:173822. Epub 2020 Dec 23.

Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

Atherosclerosis is regarded as chronic inflammatory disease. The IL-6/STAT3 pathway plays an important role in inflammation. We previously described a small-molecule compound, Bazedoxifene, which target IL-6/STAT3 pathway and has been approved for clinical use for osteoporosis in postmenopausal women. The aim of this study is to evaluate the effect of Bazedoxifene in the progression of atherosclerosis in apolipoprotein E-deficient (ApoE-/-) mice. Five-week-old male ApoE-/- mice were fed with High-fat diet (HFD) containing 5 mg/kg Bazedoxifene or a matching control for 12 weeks. Oil red O (ORO) staining was used to detect plaque size; immunohistochemical staining was used to detect the presence of endothelial cells, vascular muscle cells and phosphorylated STAT3 (P-STAT3) in localized plaques. The potential underlying mechanisms in human umbilical vein endothelial cells (HUVECs) and vascular muscle cells (VSMCs) was detected by Western blot analysis, Wound healing assay and Elisa assay. In the ApoE-/- mice fed with HFD, daily Bazedoxifene administration effectively attenuated atherosclerotic plaque area (P < 0.01), down-regulated IL-6 levels (P < 0.01), decreased STAT3 phosphorylation, reduced VSMCs proliferation and increased endothelial coverage in aortic vessels. Interestingly, we found HUVECs lack of membrane IL-6 receptor (IL-6R) compared to VSMCs (P < 0.01). Furthermore, we found that the soluble IL-6 receptor (sIL6R) participates in the activation of STAT3 induced by IL-6 or TNF-α in HUVECs and primary HUVECs. Bazedoxifene did not inhibit the growth of HUVECs while suppressing the proliferation of VSMCs. Bazedoxifene is an attractive novel therapeutic reagent for atherosclerosis diseases. This mechanism may be partially attributed to regulating IL-6/IL-6R/STAT3 signaling pathway.
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http://dx.doi.org/10.1016/j.ejphar.2020.173822DOI Listing
February 2021

Efficacy and Biomarker Analysis of Camrelizumab in Combination with Apatinib in Patients with Advanced Nonsquamous NSCLC Previously Treated with Chemotherapy.

Clin Cancer Res 2021 Mar 15;27(5):1296-1304. Epub 2020 Dec 15.

Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University, Shanghai, P.R. China.

Purpose: Our preclinical work suggests that appropriate angiogenesis inhibition could potentiate PD-1/PD-L1 blockade via alleviating hypoxia, increasing infiltration of CD8 T cells and reducing recruitment of tumor-associated macrophages. We hereby conducted a clinical trial to evaluate this combination in pretreated patients with advanced non-small cell lung cancer (NSCLC).

Patients And Methods: The study included phase Ib apatinib dose-escalation and phase II expansion cohorts. Patients received apatinib at doses of 250-500 mg orally once daily, in combination with camrelizumab 200 mg intravenously every 2 weeks.

Results: From March 2017 to October 2018, 105 chemotherapy-pretreated patients with nonsquamous NSCLC were enrolled and received apatinib 250 mg (recommended phase II dose) and camrelizumab. Among them, one (1.0%) complete response, 28 (26.7%) partial responses, and 48 (45.7%) stable diseases were observed. In the efficacy-evaluable population ( = 94), objective response rate (ORR) was 30.9% [95% confidence interval (CI), 21.7-41.2]. The median progression-free survival was 5.7 months (95% CI, 4.5-8.8) and overall survival was 15.5 months (95% CI, 10.9-24.5). Efficacy of combination therapy was evident across all PD-L1 and tumor mutation burden subgroups, and appeared to be improved in patients with STK11/KEAP1 mutation (mutant vs. wild-type, ORR: 42.9% vs. 28.1%; 1-year survival rate: 85.1% vs. 53.1%). No unexpected adverse events were observed.

Conclusions: Combined apatinib and camrelizumab showed encouraging antitumor activity and acceptable toxicity in chemotherapy-pretreated patients with advanced nonsquamous NSCLC. Patients with STK11/KEAP1 mutation might derive more benefits from this combination. We will validate these results in an ongoing phase III trial (NCT04203485).
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3136DOI Listing
March 2021

A novel HIP1-ALK fusion variant in lung adenocarcinoma showing resistance to Crizotinib.

Lung Cancer 2021 01 23;151:98-100. Epub 2020 Nov 23.

Department of Medical Oncology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. Electronic address:

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http://dx.doi.org/10.1016/j.lungcan.2020.11.014DOI Listing
January 2021

sp. nov., isolated from the Jiulong River Estuary in PR China.

Int J Syst Evol Microbiol 2020 Dec;70(12):6220-6225

College of Ocean and Earth Sciences, Xiamen University, Xiamen, PR China.

A novel Gram-stain-negative, rod-shaped, aerobic, oxidase-positive and catalase-positive bacterium of the genus , designated strain E2-1, was isolated from surface water of Jiulong River Estuary, PR China. Cells of strain E2-1 grew in medium containing 0.5-12 % NaCl (w/v; optimum, 2-4 %), at 15-45 °C (optimum, 28-33 °C) and at pH 7.0-9.0 (optimum, pH 7.0-8.0). Comparative analyses of the 16S rRNA gene sequence revealed that strain E2-1 had the highest similarity to JLT1210 (97.3 %) and HTCC2597 (97.1 %), and had less than 97.0 % 16S rRNA gene sequence similarity to other type strains within the genus . The DNA G+C content of strain E2-1 was 65.7 mol%. The average nucleotide identity and digital DNA-DNA hybridization relatedness values between E2-1 and related type strains were 75.0 and 20.1 % with JLT1210 and 75.6 and 20.4 % with HTCC2597, respectively. The sole isoprenoid quinone was Q-10; the predominant polar lipids were diphosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, three unidentified phospholipids and six unidentified lipids; the major cellular fatty acids were C (17.5 %), C cyclo 8 (22.7 %) and summed feature 8 (C 7C 6; 10.1 %). According to the phylogenetic and genotypic results, strain E2-1 represents a novel species in the genus , for which the name sp. nov. is proposed. The type strain is E2-1 (=MCCC 1K03742=KCTC 72107).
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http://dx.doi.org/10.1099/ijsem.0.004520DOI Listing
December 2020

ctDNA Concentration, MIKI67 Mutations and Hyper-Progressive Disease Related Gene Mutations Are Prognostic Markers for Camrelizumab and Apatinib Combined Multiline Treatment in Advanced NSCLC.

Front Oncol 2020 4;10:1706. Epub 2020 Sep 4.

Department of Oncology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.

Immunotherapy by immune checkpoint inhibitors (ICIs) has showed outstanding efficacy in the treatment of advanced non-small cell lung cancer (NSCLC). The combination of immunotherapy with anti-angiogenic therapy exhibited enhanced efficacy in multiline treatment. However, the potential biomarkers for predicting and monitoring the therapeutic response of the combined therapy remain undefined. In this study, we performed a pilot study by prospectively recruiting 22 advanced NSCLC patients who failed to previous lines of chemotherapy, chemoradiotherapy, TKI therapy, surgery, or any combination of the therapies, and investigated the prognostic factors for patients who received anti-PD-1 (Camrelizumab) and anti-angiogenic (Apatinib) combined therapy. The objective response rate (ORR) assessed by an independent radiology review was 22.7%, and the median progression-free survival (PFS) was 5.25 months. We found that high concentration of circulating-free DNA (cfDNA) (HR = 27.75, = 0.003), MIKI67 mutation (HR = 114.11, = 0.009) and gene variations related to hyper-progressive disease (HPD) (HR = 36.85, = 0.004) were independent risk factors and exhibited significant correlation with PFS. Circulating tumor DNA (ctDNA) mutational status was also a predicting indicator for PFS. In contrast, the blood tumor mutational burden (bTMB) could not stratify the clinical benefit in this combined therapy (HR = 0.81, = 0.137). Furthermore, we found that the variant allele fraction (VAF) of mutations in ctDNA was sensitive indicators of therapeutic response and therefore can be used to monitor the tumor relief or progression. In conclusion, cfDNA concentration, MIKI67 mutations and HPD-related mutations were independent risk factors and PFS predictors for multiline combined anti-angiogenic/ICI combined therapy. ctDNA may be a novel monitoring biomarker for therapeutic response and predicting biomarker for prognosis in future combined therapy involving PD-1 blockade.
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http://dx.doi.org/10.3389/fonc.2020.01706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509428PMC
September 2020

Electrocardiogram analysis of patients with different types of COVID-19.

Ann Noninvasive Electrocardiol 2020 11 20;25(6):e12806. Epub 2020 Sep 20.

Division of Cardiology and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background: Severe acute respiratory syndrome coronavirus 2 causes acute myocardial damage and arrhythmia in coronavirus disease 2019 (COVID-19) patients. Studying the changes of electrocardiogram is of great significance for the diagnosis of patients with COVID-19.

Methods: A retrospective analysis method was adopted to compare the electrocardiogram changes between COVID-19 critically severe and severe patients. Univariate and multivariate logistic regression were used to analyze the correlation of the levels of serum indexes and past medical history with ST-T changes and atrial fibrillation. And the correlation of ECG parameters with in-hospital death and ventilator use were investigated by using the same methods.

Results: The incidence of male, stroke, elevated cardiac troponin I (cTnI), N-terminal of the prohormone brain natriuretic peptide (NT-proBNP), d-dimer, high-sensitivity C-reactive protein (hs-CRP), hyperkalemia, and hypocalcemia in the critically ill patients was higher than that in severe patients. There were differences in ST-T changes, sinus tachycardia, atrial fibrillation, and atrial tachycardia between the two groups. Multivariate logistic regression analysis showed that elevated cTnI and NT-proBNP were the independent risk factors of ST-T changes. Elevated NT-proBNP and age were the independent risk factors of atrial fibrillation. Sinus tachycardia and atrial fibrillation were the independent risk factors of in-hospital death and ventilator use.

Conclusion: ST-T changes, sinus tachycardia, and atrial fibrillation are with great significance in the diagnosis of the severity, myocardia injury, and cardiac insufficiency of COVID-19 patients. Sinus tachycardia and atrial fibrillation could be used as independent variables predicting in-hospital death and ventilator use.
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http://dx.doi.org/10.1111/anec.12806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536962PMC
November 2020

Coronavirus disease 2019 in the elderly: Clinical characteristics, diagnosis and treatment strategies.

Authors:
Yayong Li Yina Wang

Zhong Nan Da Xue Xue Bao Yi Xue Ban 2020 May;45(5):549-554

Department of Geriatrics, Second Xiangya Hospital, Central South University, Changsha 410011, China.

Many countries in the world have faced with coronavirus disease 2019 (COVID-19) epidemic since December 2019, while the proportion of elderly patients with COVID-19 in severe and death cases is relatively high. At present, China is in the rapid development stage of population aging, and the demand of the elderly for medical care, health care, nursing and life services far exceeds that of other people. Especially in the period of COVID-19, it is particularly urgent to summarize more experience and methods in time to reduce the infection rate, the incidence of critical illness, and the mortality rate. Therefore, this review combines the existing research results with clinic experience of diagnosis and treatment for senile infectious diseases, summarizes the clinical characteristics and puts forward the prevention strategies of elderly COVID-19 patients, which provide evidence for effective prevention and treatment of COVID-19 in elderly patients, improvement of cure rate, and reduction of severe incidence rate and mortality.
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http://dx.doi.org/10.11817/j.issn.1672-7347.2020.200264DOI Listing
May 2020

Raloxifene inhibits IL-6/STAT3 signaling pathway and protects against high-fat-induced atherosclerosis in ApoE mice.

Life Sci 2020 Nov 20;261:118304. Epub 2020 Aug 20.

Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

Aims: The signal transducer and activator of transcription 3 (STAT3) pathway plays an important role in inflammatory cascade process. Our previous studies found that Raloxifene targeted against IL-6/GP130 protein-protein interface and inhibited STAT3 phosphorylation induced by IL-6 in cancer cells. However, whether Raloxifene could suppress IL-6/STAT3 signaling pathway and attenuate atherosclerosis in high-fat diet (HFD)-induced mice remains unknown. The objective of this study was to explore the potential effect of Raloxifene on the prevention of atherosclerosis.

Main Methods: HFD-induced atherosclerosis was established in apoliprotein E-deficient (ApoE ) mice. Mice by daily intragastric gavage with Raloxifene or vehicle as controls were provided. The human umbilical vein endothelial cells (HUVEC), Rat VSMC and RAW264.7 cell lines were used to evaluate the effect of Raloxifene in vitro.

Key Findings: We demonstrated that Raloxifene was effective in ameliorating HFD- induced atherosclerosis plaque burden and size. Histological analysis showed that the expression of IL-6, P-STAT3, ICAM-1, VCAM-1, CD68 and α-SMA were significantly decreased in the Raloxifene intervention group compared to HFD group. Moreover, we observed that IL-6 increased migration and cell viability of VSMCs and RAW264.7 cells, while Raloxifene treatment decreased migration and reduced cell viability of VSMCs and RAW264.7 cells stimulated by IL-6. Furthermore, this effect was related to blocking IL-6/STAT3 pathway.

Significance: Raloxifene has effects on inhibiting atherosclerosis development, the underlying mechanisms might involve in inhibiting inflammation-related IL-6/STAT3 signaling pathway.
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http://dx.doi.org/10.1016/j.lfs.2020.118304DOI Listing
November 2020

Lung adenocarcinoma with a novel SRBD1-ALK Fusion responding to crizotinib.

Lung Cancer 2020 08 4;146:370-372. Epub 2020 May 4.

Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, China.

Objectives: Anaplastic lymphoma kinase (ALK) rearrangements account for approximately 3-5% in non-small-cell lung cancer (NSCLC) patients who tend to be young and never/light-smokers. Echinoderm microtubule-associated protein like 4 (EML4) is the most common partner for ALK fusion, while more than 90 other partners have been reported in NSCLC. Majority of the ALK actionable rearrangements were sensitive to crizotinib, yet some rare fusion types may less benefit than EML4-ALK. Here, we reported a case of lung adenocarcinoma harboring a novel S1 RNA binding domain 1 (SRBD1)-ALK fusion which the breakpoints was (S6,A20). To our knowledge, this case is the first report showed clinical evidence of SRBD1-ALK fusion responding to crizotinib.

Materials And Methods: Immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) examination and next-generation sequencing (NGS) based on a 425-gene panel was performed on the biopsy sample.

Results: The IHC analysis revealed positive expression of ALK and atypical FISH signals were detected. Further NGS detected a novel SRBD1-ALK fusion. The patient received crizotinib (250 mg, twice a day) as first-line treatment and partial response was observed. The progression-free survival (PFS) is already over than 10 months up to today.

Conclusion: To our knowledge, our case is the first case of SRBD1-ALK fusion with excellent response to crizotinib. This case merits further follow-up and provides valuable information on the response to crizotinib of NSCLC patients with SRBD1-ALK fusion.
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http://dx.doi.org/10.1016/j.lungcan.2020.04.031DOI Listing
August 2020

Females with Type 2 Diabetes Mellitus Are Prone to Diabetic Retinopathy: A Twelve-Province Cross-Sectional Study in China.

J Diabetes Res 2020 21;2020:5814296. Epub 2020 Apr 21.

Department of Endocrinology & Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.

Aims: To investigate the distribution of diabetic retinopathy (DR) by sex in patients with type 2 diabetes mellitus (T2DM) in a twelve-province cross-sectional study in China.

Methods: Patients with T2DM, whose ages were ≥18 years, were recruited from 76 cities/counties in 12 provinces in mainland China between January 2015 and December 2018. All participants received a standardized interview, eye examinations, and digital fundus photography. The presence and severity of DR were diagnosed and classified by retina specialists according to the DR domestic typing method.

Results: A total of 12,766 participants (5963 males and 6803 females) were eligible for this study. The total prevalence of DR was 30.1%. Females exhibited a significantly higher prevalence of DR than males (31.1% vs. 29.0%, = 0.011). A multivariate logistic regression analysis confirmed that female sex was an independent predictor for a higher prevalence of DR after adjusting for age, the duration of diabetes, economic status, and the presence of hypertension (OR: 1.096, 95% CI: 1.013-1.186, = 0.023). Even after stratification by the diabetic duration, age, and economic status, female sex was still independently associated with the presence of DR in patients whose T2DM history was more than 10 years, whose ages were over 60 years, or who were in a relatively intermediate economic area.

Conclusion: Females had a higher prevalence of DR than males in T2DM patients with a diabetic history of more than 10 years, ages over 60 years, or a relatively intermediate economic status.
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http://dx.doi.org/10.1155/2020/5814296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191394PMC
February 2021

BMPR2 promotes fatty acid oxidation and protects white adipocytes from cell death in mice.

Commun Biol 2020 04 29;3(1):200. Epub 2020 Apr 29.

The Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, and Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, 200032, Shanghai, China.

Adipocyte cell death is pathologically involved in both obesity and lipodystrophy. Inflammation and pro-inflammatory cytokines are generally regarded as inducers for adipocyte apoptosis, but whether some innate defects affect their susceptibility to cell death has not been extensively studied. Here, we found bone morphogenetic protein receptor type 2 (BMPR2) knockout adipocytes were prone to cell death, which involved both apoptosis and pyroptosis. BMPR2 deficiency in adipocytes inhibited phosphorylation of perilipin, a lipid-droplet-coating protein, and impaired lipolysis when stimulated by tumor necrosis factor (TNFα), which lead to failure of fatty acid oxidation and oxidative phosphorylation. In addition, impaired lipolysis was associated with mitochondria-mediated apoptosis and pyroptosis as well as elevated inflammation. These results suggest that BMPR2 is important for maintaining the functional integrity of adipocytes and their ability to survive when interacting with inflammatory factors, which may explain why adipocytes among individuals show discrepancy for death responses in inflammatory settings.
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http://dx.doi.org/10.1038/s42003-020-0928-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190840PMC
April 2020

Activation of Meiotic Genes Mediates Ploidy Reduction during Cryptococcal Infection.

Curr Biol 2020 04 27;30(8):1387-1396.e5. Epub 2020 Feb 27.

Department of Microbiology, University of Georgia, Athens, GA 30602, USA; Department of Plant Biology, University of Georgia, Athens, GA 30602, USA. Electronic address:

Cryptococcus neoformans is a global human fungal pathogen that causes fatal meningoencephalitis in mostly immunocompromised individuals. During pulmonary infection, cryptococcal cells form large polyploid cells that exhibit increased resistance to host immune attack and are proposed to contribute to the latency of cryptococcal infection. These polyploid titan cells can generate haploid and aneuploid progeny that may result in systemic infection. What triggers cryptococcal polyploidization and how ploidy reduction is achieved remain open questions. Here, we discovered that Cryptococcus cells polyploidize in response to genotoxic stresses that cause DNA double-strand breaks. Intriguingly, meiosis-specific genes are activated in C. neoformans and contribute to ploidy reduction, both in vitro and during infection in mice. Cryptococcal cells that activated their meiotic genes in mice were resistant to specific genotoxic stress compared to sister cells recovered from the same host tissue but without activation of meiotic genes. Our findings support the idea that meiotic genes, in addition to their conventional roles in classic sexual reproduction, contribute to adaptation of eukaryotic cells that undergo dramatic genome changes in response to genotoxic stress. The discovery has additional implications for evolution of sexual reproduction and the paradox of the presence of meiotic machinery in asexual species. Finally, our findings in this eukaryotic microbe mirror the revolutionary discoveries of the polyploidization and meiosis-like ploidy reduction process in cancer cells, suggesting that the reversible ploidy change itself could provide a general mechanism for rejuvenation to promote individual survival in response to stress.
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http://dx.doi.org/10.1016/j.cub.2020.01.081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228024PMC
April 2020

A Mechanosensitive Channel Governs Lipid Flippase-Mediated Echinocandin Resistance in Cryptococcus neoformans.

mBio 2019 12 10;10(6). Epub 2019 Dec 10.

Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA

Echinocandins show fungicidal activity against common invasive mycoses but are ineffective against cryptococcosis. The underlying mechanism for echinocandin resistance in remains poorly understood but has been shown to involve Cdc50, the regulatory subunit of lipid flippase. In a forward genetic screen for Δ suppressor mutations that are caspofungin resistant, we identified Crm1 (aspofungin esistant utation ), a homolog of mechanosensitive channel proteins, and showed that Δ restored caspofungin resistance in Δ cells. Caspofungin-treated Δ cells exhibited abnormally high intracellular calcium levels ([Ca]c) and heightened activation of the calcineurin pathway. Deletion of in the Δ background normalized the abnormally high [Ca]c. Cdc50 interacts with Crm1 to maintain cellular calcium homeostasis. Analysis of chitin/chitosan content showed that deleting reversed the decreased chitosan production of Δ cells. Together, these results demonstrate that Cdc50 and Crm1 regulation of the calcineurin pathway and cytoplasmic calcium homeostasis may underlie caspofungin resistance in is the leading cause of fungal meningitis, accounting for ∼15% of HIV/AIDS-related deaths, but treatment options for cryptococcosis are limited. Echinocandins are the newest fungicidal drug class introduced but are ineffective in treating cryptococcosis. Our previous study identified the lipid flippase subunit Cdc50 as a contributor to echinocandin resistance in Here, we further elucidated the mechanism of Cdc50-mediated caspofungin drug resistance. We discovered that Cdc50 interacts with the mechanosensitive calcium channel protein Crm1 to regulate calcium homeostasis and caspofungin resistance via calcium/calcineurin signaling. These results provide novel insights into echinocandin resistance in this pathogen, which may lead to new treatment options, as well as inform echinocandin resistance mechanisms in other fungal organisms and, hence, advance our understanding of modes of antifungal drug susceptibility and resistance.
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http://dx.doi.org/10.1128/mBio.01952-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904872PMC
December 2019

Generation of an induced pluripotent stem cell line (SYSUi002-A) from a patient with coronary slow flow phenomenon.

Stem Cell Res 2019 12 2;41:101646. Epub 2019 Nov 2.

Cardiovascular Department, The Eighth Affiliated Hospital, Sun Yat-sen University, Shennan Middle Road 3025#, Shenzhen 518033, China. Electronic address:

The coronary slow flow phenomenon (CSFP) is characterized by delayed progression of the injected contrast medium through the coronary tree during coronary angiography due to unknown mechanisms. Here, a human induced pluripotent stem cell (iPSC) line (SYSUi002-A) was established using the Sendai-virus delivery system from dermal fibroblasts of a CSFP patient. This cell line may represent a valuable tool for investigating the pathogenesis and therapeutic strategies of CSFP.
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http://dx.doi.org/10.1016/j.scr.2019.101646DOI Listing
December 2019

A Heat-Killed Mutant Strain Induces Host Protection against Multiple Invasive Mycoses in a Murine Vaccine Model.

mBio 2019 11 26;10(6). Epub 2019 Nov 26.

Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA

is a fungal pathogen that infects the lungs and then often disseminates to the central nervous system, causing meningitis. How is able to suppress host immunity and escape the antifungal activity of macrophages remains incompletely understood. We reported that the F-box protein Fbp1, a subunit of the SCF(Fbp1) E3 ligase, promotes virulence by regulating host- interactions. Our recent studies demonstrated that the Δ mutant elicited superior protective Th1 host immunity in the lungs and that the enhanced immunogenicity of heat-killed Δ yeast cells can be harnessed to confer protection against a subsequent infection with the virulent parental strain. We therefore examined the use of heat-killed Δ cells in several vaccination strategies. Interestingly, the vaccine protection remains effective even in mice depleted of CD4 T cells. This finding is particularly important in the context of HIV/AIDS-induced immune deficiency. Moreover, we observed that vaccinating mice with heat-killed Δ induces significant cross-protection against challenge with diverse invasive fungal pathogens, including , , and , as well as partial protection against Thus, our data suggest that the heat-killed strain has the potential to be a suitable vaccine candidate against cryptococcosis and other invasive fungal infections in both immunocompetent and immunocompromised populations. Invasive fungal infections kill more than 1.5 million people each year, with limited treatment options. There is no vaccine available in clinical use to prevent and control fungal infections. Our recent studies showed that a mutant of the F-box protein Fbp1, a subunit of the SCF(Fbp1) E3 ligase in , elicited superior protective Th1 host immunity. Here, we demonstrate that the heat-killed Δ cells (HK-fbp1) can be harnessed to confer protection against a challenge by the virulent parental strain, even in animals depleted of CD4 T cells. This finding is particularly important in the context of HIV/AIDS-induced immune deficiency. Moreover, we observed that HK-fbp1 vaccination induces significant cross-protection against challenge with diverse invasive fungal pathogens. Thus, our data suggest that HK-fbp1 has the potential to be a broad-spectrum vaccine candidate against invasive fungal infections in both immunocompetent and immunocompromised populations.
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http://dx.doi.org/10.1128/mBio.02145-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879717PMC
November 2019

Direct Observation of Monolayer MoS Prepared by CVD Using In-Situ Differential Reflectance Spectroscopy.

Nanomaterials (Basel) 2019 Nov 19;9(11). Epub 2019 Nov 19.

School of Control Science and Engineering, Shandong University, Jinan 250061, China.

The in-situ observation is of great significance to the study of the growth mechanism and controllability of two-dimensional transition metal dichalcogenides (TMDCs). Here, the differential reflectance spectroscopy (DRS) was performed to monitor the growth of molybdenum disulfide (MoS) on a SiO/Si substrate prepared by chemical vapor deposition (CVD). A home-built in-situ DRS setup was applied to monitor the growth of MoS in-situ. The formation and evolution of monolayer MoS are revealed by differential reflectance (DR) spectra. The morphology, vibration mode, absorption characteristics and thickness of monolayer MoS have been confirmed by optical microscopy, Raman spectroscopy, ex-situ DR spectra, and atomic force microscopy (AFM) respectively. The results demonstrated that DRS was a powerful tool for in-situ observations and has great potential for growth mechanism and controllability of TMDCs prepared by CVD. To the best of the authors' knowledge, it was the first report in which the CVD growth of two-dimensional TMDCs has been investigated in-situ by reflectance spectroscopy.
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http://dx.doi.org/10.3390/nano9111640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915464PMC
November 2019

Prediction and Analysis of Hub Genes in Renal Cell Carcinoma based on CFS Gene Selection Method Combined with Adaboost Algorithm.

Med Chem 2020 ;16(5):654-663

Department of VIP Medical Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.

Background: Renal cell carcinoma (RCC) is the most common malignant tumor of the adult kidney.

Objective: The aim of this study was to identify key genes signatures during RCC and uncover their potential mechanisms.

Methods: Firstly, the gene expression profiles of GSE53757 which contained 144 samples, including 72 kidney cancer samples and 72 controls, were downloaded from the GEO database. And then differentially expressed genes (DEGs) between the kidney cancer samples and the controls were identified. After that, GO and KEGG enrichment analyses of DEGs were performed by DAVID. Furthermore, the correlation-based feature subset (CFS) method was applied to the selection of key genes of DEGs. In addition, the classification model between the kidney cancer samples and the controls was built by Adaboost based on the selected key genes.

Results: 213 DEGs including 80 up-regulated and 133 down-regulated genes were selected as the feature genes to build the classification model between the kidney cancer samples and the controls by CFS method. The accuracy of the classification model by using 5-folds cross-validation test and independent set test is 84.4% and 83.3%, respectively. Besides, TYROBP, CD4163, CAV1, CXCL9, CXCL11 and CXCL13 also can be found in the top 20 hub genes screened by proteinprotein interaction (PPI) network.

Conclusion: It indicated that CFS is a useful tool to identify key genes in kidney cancer. Besides, we also predicted genes such as TYROBP, CD4163, CAV1, CXCL9, CXCL11 and CXCL13 that might target genes to diagnose the kidney cancer.
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http://dx.doi.org/10.2174/1573406415666191004100744DOI Listing
April 2021

A Phase I Comparative Pharmacokinetic and Safety Study of Two Intravenous Formulations of Vinorelbine in Patients With Advanced Non-Small Cell Lung Cancer.

Front Pharmacol 2019 11;10:774. Epub 2019 Jul 11.

Research Center of Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.

The aim of this study was to compare the pharmacokinetics and safety between two vinorelbine formulations [a new oil-in-water emulsion formulation (ANX) versus a previously marketed solution formulation (Navelbine)] in Chinese patients with advanced non-small cell lung cancer (NSCLC). This was a single-center, randomized, open-label study. Eligible patients aged 18-70 years who had histologically or cytologically confirmed NSCLC were enrolled. In cycle 1, the patients alternatively received the two formulations (30 mg/m, given as a 10-min infusion) with a 7-day interval. Samples for pharmacokinetic analysis were taken during cycle 1. For all subsequent 21-day cycles (maximum four cycles), ANX was administered on days 1 and day 8. Bioequivalence analysis was performed on C, AUC, and AUC. The safety profiles and anti-tumor effects were also determined. From March 2013 to January 2015, 24 patients were enrolled and 20 were eligible for pharmacokinetic evaluation. The 20 subjects in the pharmacokinetic analysis set had a median age of 61 years (range, 37-70 years), and 15 patients were male (75%). Mean vinorelbine C values for ANX and Navelbine were 1,317.40 and 1,446.30 ng/mL, respectively. Corresponding AUC values were 797.08 and 924.26 ng·h/mL, respectively. AUC values were 830.14 and 957.16 ng·h/mL, respectively. Treatment ratios of the geometric means were 90.00% (90% CI, 83.22-99.07%) for C, 86.92% (90% CI, 80.91-93.37%) for AUC, and 87.44% (90% CI, 82.08-93.16%) for AUC. These results met the required 80-125% bioequivalence criteria. The most frequently reported adverse events after vinorelbine administration were neutropenia, leucopenia, neutropenic fever, and constipation. At therapeutic dosage levels, pharmacokinetic behavior and safety profiles were similar for both formulations. Chinese National Registry Code: ChiCTR-IPR-15005856.
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http://dx.doi.org/10.3389/fphar.2019.00774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637297PMC
July 2019

Identification of Pathogen Genomic Differences That Impact Human Immune Response and Disease during Cryptococcus neoformans Infection.

mBio 2019 07 16;10(4). Epub 2019 Jul 16.

Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USA

Patient outcomes during infection are due to a complex interplay between the quality of medical care, host immunity factors, and the infecting pathogen's characteristics. To probe the influence of pathogen genotype on human survival, immune response, and other parameters of disease, we examined isolates collected during the Cryptococcal Optimal Antiretroviral Therapy (ART) Timing (COAT) Trial in Uganda. We measured human participants' survival, meningitis disease parameters, immunologic phenotypes, and pathogen growth characteristics. We compared those clinical data to whole-genome sequences from 38  isolates of the most frequently observed sequence type (ST), ST93, in our Ugandan participant population and to sequences from an additional 18 strains of 9 other sequence types representing the known genetic diversity within the Ugandan clinical isolates. We focused our analyses on 652 polymorphisms that were variable among the ST93 genomes, were not in centromeres or extreme telomeres, and were predicted to have a fitness effect. Logistic regression and principal component analysis identified 40 candidate genes and 3 hypothetical RNAs associated with human survival, immunologic response, or clinical parameters. We infected mice with 17 available KN99α gene deletion strains for these candidate genes and found that 35% (6/17) directly influenced murine survival. Four of the six gene deletions that impacted murine survival were novel. Such bedside-to-bench translational research identifies important candidate genes for future studies on virulence-associated traits in human infections. Even with the best available care, mortality rates in cryptococcal meningitis range from 20% to 60%. Disease is often due to infection by the fungus and involves a complex interaction between the human host and the fungal pathogen. Although previous studies have suggested genetic differences in the pathogen impact human disease, it has proven quite difficult to identify the specific genes that impact the outcome of the human infection. Here, we take advantage of a Ugandan patient cohort infected with closely related strains to examine the role of pathogen genetic variants on several human disease characteristics. Using a pathogen whole-genome sequencing approach, we showed that 40  genes are associated with human disease. Surprisingly, many of these genes are specific to and have unknown functions. We also show deletion of some of these genes alters disease in a mouse model of infection, confirming their role in disease. These findings are particularly important because they are the first to identify genes associated with human cryptococcal meningitis and lay the foundation for future studies that may lead to new treatment strategies aimed at reducing patient mortality.
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http://dx.doi.org/10.1128/mBio.01440-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635531PMC
July 2019
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