Publications by authors named "Nannan Zhou"

59 Publications

ACE2 expression is regulated by AhR in SARS-CoV-2-infected macaques.

Cell Mol Immunol 2021 05 1;18(5):1308-1310. Epub 2021 Apr 1.

Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing, China.

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http://dx.doi.org/10.1038/s41423-021-00672-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015744PMC
May 2021

Preliminary proposal: a classification system for reconstruction with autologous femoral head after periacetabular tumors resection.

J Orthop Surg Res 2021 Feb 8;16(1):119. Epub 2021 Feb 8.

Department of Orthopedic Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, PR China.

Background: Although researchers have adopted various methods for the resection and reconstruction of periacetabular tumors, the total incidence rate of complications remains high. Aiming for preserving the acetabulum and reducing the risk of complications, we applied a surgery method using tumor-free autologous femoral head to reconstruct the defective acetabulum after resection of periacetabular tumors followed by performing a conventional total hip arthroplasty (THA). Moreover, we proposed a preliminary classification system for these surgery methods.

Methods: We retrospectively reviewed 6 patients treated with acetabulum reconstruction combined with autologous femoral head following peri-acetabulum resection between April 2010 and May 2018. All patients were diagnosed as periacetabular tumors including chondrosarcoma (n = 5) and chondroblastoma (n = 1). Clinical data such as age, diagnosis, complications, local recurrence or metastasis, and function (Musculoskeletal Tumor Society 1993, MSTS93) were documented. The average time of follow-up was 62.5 months (range, 17 to 106 months).

Results: A total of 5 patients survive with average MSTS93 score of 27.8 points (range, 26-30). One patient, suffering from multiple bone metastasis prior treatment, ended up dying. One who had received radiotherapy before surgery had poor incision healing. Further, a classification system was preliminary proposed in 2 patients involving the pubis (type A) and 4 patients involving ischium (type B).

Conclusions: Based on the results, we preliminary proposed a classification system for reconstruction with autologous femoral head after periacetabular low malignant tumors resection. The clinical results suggested that surgery methods involving pubis (type A) and ischium (Type B) are safe and feasible. However, further researches should be conducted to verify our classification system.
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http://dx.doi.org/10.1186/s13018-021-02275-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869519PMC
February 2021

IL-2 regulates tumor-reactive CD8 T cell exhaustion by activating the aryl hydrocarbon receptor.

Nat Immunol 2021 03 11;22(3):358-369. Epub 2021 Jan 11.

Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing, China.

CD8 T cell exhaustion dampens antitumor immunity. Although several transcription factors have been identified that regulate T cell exhaustion, the molecular mechanisms by which CD8 T cells are triggered to enter an exhausted state remain unclear. Here, we show that interleukin-2 (IL-2) acts as an environmental cue to induce CD8 T cell exhaustion within tumor microenvironments. We find that a continuously high level of IL-2 leads to the persistent activation of STAT5 in CD8 T cells, which in turn induces strong expression of tryptophan hydroxylase 1, thus catalyzing the conversion to tryptophan to 5-hydroxytryptophan (5-HTP). 5-HTP subsequently activates AhR nuclear translocation, causing a coordinated upregulation of inhibitory receptors and downregulation of cytokine and effector-molecule production, thereby rendering T cells dysfunctional in the tumor microenvironment. This molecular pathway is not only present in mouse tumor models but is also observed in people with cancer, identifying IL-2 as a novel inducer of T cell exhaustion.
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http://dx.doi.org/10.1038/s41590-020-00850-9DOI Listing
March 2021

B7-H3-Induced Signaling in Lung Adenocarcinoma Cell Lines with Divergent Epidermal Growth Factor Receptor Mutation Patterns.

Biomed Res Int 2020 24;2020:8824805. Epub 2020 Dec 24.

Department of Laboratory Medicine, Second Hospital of Anhui Medical University, 678 Furong Road, Hefei, Anhui 230601, China.

The cosignal molecule B7-H3 is gaining attention due to its abnormal expression and abundant signal transduction in many types of malignancies. B7-H3-induced signaling includes at least three cascades: PI3K/AKT, JAK2/STAT3, and Raf/MEK/ERK1/2, which are also involved in epidermal growth factor receptor- (EGFR-) triggered signaling in lung adenocarcinoma cells. However, the correlation between B7-H3-induced signaling and EGFR signaling, and between B7-H3-targeted immunotherapy and EGFR-targeted therapy in lung adenocarcinoma, remains to be elucidated. Herein we find that knockout of gene decreased cell survival and increased EGFR-tyrosine kinase inhibitor gefitinib susceptibility of both H3255 and HCC827 cells, two lung adenocarcinoma cell lines harboring EGFR L858R (exon 21) and Del E746-A750 (exon 19) mutations, respectively. deletion resulted in dramatic reduction of phosphorylation level of AKT and STAT3 in H3255 cells while having mild-to-moderate suppression on AKT, STAT3, and ERK1/2 in HCC827 cells. Gefitinib had similar effects with deletion both in H3255 and HCC827 cells. Furthermore, ablation had significant synergistic effects with gefitinib in HCC827 cells. Collectively, our study reveals B7-H3-induced signaling in lung adenocarcinoma cell lines with divergent EGFR mutations, and a translational potential of combined targeted therapy of B7-H3 and EGFR in lung adenocarcinoma with EGFR Del E746-A750 mutation.
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http://dx.doi.org/10.1155/2020/8824805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775133PMC
May 2021

Contribution of Connexin Hemichannels to the Pathogenesis of Acute Lung Injury.

Mediators Inflamm 2020 17;2020:8094347. Epub 2020 Nov 17.

Sepsis Laboratory, Center for Translational Medicine, Huaihe Hospital, Henan University, Kaifeng, Henan, China.

Connexin (Cx) family members form hemichannels (HCs) and gap junctions (GJs). Biological functions of Cx HCs have not been adequately characterized due to the inability to selectively target HCs or GJs. Recently, we developed a 6-mer peptide mimetic (P5) of the first extracellular loop of Cx43 and showed that it can block the permeability of HCs but not GJs formed by Cx43. In this study, we further characterized the HC blocking property of P5 and investigated the role of Cx HCs in acute lung injury (ALI). We found that P5 administration decreased HC permeability, in pulmonary microvascular endothelial cells, HepG2 cells, and even Cx43-deficient astrocytes, which express different sets of Cxs, suggesting that P5 is a broad spectrum Cx HC blocker. In addition, P5 reduced HC permeability of alveolar cells . Moreover, P5 decreased endotoxin-induced release, by vascular endothelial cells , of high mobility group box protein 1 (HMGB1), a critical mediator of acute lung injury (ALI), and reduced HMGB1 accumulation in bronchoalveolar lavage fluid (BALF) of mice subjected to intratracheal endotoxin instillation. Furthermore, P5 administration resulted in a significant decrease in the concentrations of ALT, AST, and LDH in the BALF, the accumulation of leukocytes in alveoli, and the mortality rate of mice subjected to ALI. Wright-Giemsa staining showed that P5 caused similar reductions of both neutrophils and monocytes in BALF of ALI mice. Together, these results suggest that Cx HCs mediate HMGB1 release, augment leukocyte recruitment, and contribute to ALI pathology.
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http://dx.doi.org/10.1155/2020/8094347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688369PMC
November 2020

Cell softness regulates tumorigenicity and stemness of cancer cells.

EMBO J 2021 01 4;40(2):e106123. Epub 2020 Dec 4.

Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing, China.

Identifying and sorting highly tumorigenic and metastatic tumor cells from a heterogeneous cell population is a daunting challenge. Here, we show that microfluidic devices can be used to sort marker-based heterogeneous cancer stem cells (CSC) into mechanically stiff and soft subpopulations. The isolated soft tumor cells (< 400 Pa) but not the stiff ones (> 700 Pa) can form a tumor in immunocompetent mice with 100 cells per inoculation. Notably, only the soft, but not the stiff cells, isolated from CD133 , ALDH , or side population CSCs, are able to form a tumor with only 100 cells in NOD-SCID or immunocompetent mice. The Wnt signaling protein BCL9L is upregulated in soft tumor cells and regulates their stemness and tumorigenicity. Clinically, BCL9L expression is correlated with a worse prognosis. Our findings suggest that the intrinsic softness is a unique marker of highly tumorigenic and metastatic tumor cells.
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http://dx.doi.org/10.15252/embj.2020106123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809788PMC
January 2021

Susceptibility of global HIV-1 clinical isolates to fostemsavir using the PhenoSense® Entry assay.

J Antimicrob Chemother 2021 02;76(3):648-652

ViiV Healthcare, Discovery, 36 East Industrial Road, Branford, CT 06405, USA.

Background: Fostemsavir is a prodrug of a first-in-class HIV-1 attachment inhibitor, temsavir, that binds to gp120 and blocks attachment to the host-cell CD4 receptor, preventing entry and infection of the target cell. Previous studies using a limited number of clinical isolates showed that there was intrinsic variability in their susceptibility to temsavir.

Objectives: Here, an analysis was performed using all clinical isolates analysed in the Monogram Biosciences PhenoSense® Entry assay as part of the development programme.

Methods: In total, 1337 individual envelopes encompassing 20 different HIV-1 subtypes were examined for their susceptibility to temsavir. However, only seven subtypes (B, C, F1, A, [B, F1], BF and A1) were present more than five times, with subtype B (881 isolates) and subtype C (156 isolates) having the largest numbers.

Results: As expected, variability in susceptibility was observed within all subtypes. However, for the great majority of these viruses, temsavir was highly potent, with most viruses exhibiting IC50s <10 nM. One exception was CRF01_AE viruses, where all five isolates exhibited IC50s >100 nM. For the 607 isolates where tropism data were available, geometric mean temsavir IC50 values were remarkably similar for CCR5-, CXCR4- and dual mixed-tropic envelopes from infected individuals.

Conclusions: These data show that HIV-1 viruses from most subtypes are highly susceptible to temsavir and that temsavir susceptibility is independent of tropism.
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http://dx.doi.org/10.1093/jac/dkaa474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879148PMC
February 2021

Cell Softness Prevents Cytolytic T-cell Killing of Tumor-Repopulating Cells.

Cancer Res 2021 01 9;81(2):476-488. Epub 2020 Nov 9.

Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing, China.

Biomechanics is a fundamental feature of a cell. However, the manner by which actomysin tension affects tumor immune evasion remains unclear. Here we show that although cytotoxic T lymphocytes (CTL) can effectively destroy stiff differentiated tumor cells, they fail to kill soft tumor-repopulating cells (TRC). TRC softness prevented membrane pore formation caused by CTL-released perforin. Perforin interacting with nonmuscle myosin heavy-chain 9 transmitted forces to less F-actins in soft TRC, thus generating an inadequate contractile force for perforin pore formation. Stiffening TRC allowed perforin the ability to drill through the membrane, leading to CTL-mediated killing of TRC. Importantly, overcoming mechanical softness in human TRC also enhanced TRC cell death caused by human CTL, potentiating a mechanics-based immunotherapeutic strategy. These findings reveal a mechanics-mediated tumor immune evasion, thus potentially providing an alternative approach for tumor immunotherapy. SIGNIFICANCE: Tumor-repopulating cells evade CD8 cytolytic T-cell killing through a mechanical softness mechanism, underlying the impediment of perforin pore formation at the immune synapse site.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2569DOI Listing
January 2021

Mucus production stimulated by IFN-AhR signaling triggers hypoxia of COVID-19.

Cell Res 2020 12 6;30(12):1078-1087. Epub 2020 Nov 6.

Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing, 100005, China.

Silent hypoxia has emerged as a unique feature of coronavirus disease 2019 (COVID-19). In this study, we show that mucins are accumulated in the bronchoalveolar lavage fluid (BALF) of COVID-19 patients and are upregulated in the lungs of severe respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected mice and macaques. We find that induction of either interferon (IFN)-β or IFN-γ upon SARS-CoV-2 infection results in activation of aryl hydrocarbon receptor (AhR) signaling through an IDO-Kyn-dependent pathway, leading to transcriptional upregulation of the expression of mucins, both the secreted and membrane-bound, in alveolar epithelial cells. Consequently, accumulated alveolar mucus affects the blood-gas barrier, thus inducing hypoxia and diminishing lung capacity, which can be reversed by blocking AhR activity. These findings potentially explain the silent hypoxia formation in COVID-19 patients, and suggest a possible intervention strategy by targeting the AhR pathway.
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http://dx.doi.org/10.1038/s41422-020-00435-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646495PMC
December 2020

The Occurrence of Valvular Atrial Fibrillation: Involvement of NGF/TrKA Signaling Pathway.

J Invest Surg 2020 Aug 12:1-8. Epub 2020 Aug 12.

Department of Geriatric Cardiology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, PR China.

Objective: Nerve growth factor (NGF) and tropomyosin kinase receptors A (TrKA) exert a crucial effect on the regulation of autonomic nervous system which contributes to the progress of atrial fibrillation (AF). Valvular heart disease (VHD) patients are more easily to induce the AF. We investigated whether NGF/TrKA could impact the occurrence of AF in VHD patients.

Materials And Methods: Atrial tissues were resected from 30 VHD patients with chronic AF ( = 15, AF >6 months) or sinus rhythm (SR,  = 15). The expression of NGF, TrKA, protein kinase B (PKB/Akt), beta-isoforms of glycogen synthase kinase-3 (GSK3β), Serine473 phosphorylation of Akt (p-Ser473 Akt), Serine9 phosphorylation of GSK-3β (p-Ser9 GSK3β) in right atrial tissues and peripheral blood lymphocyte were quantified by Western blot. The localization of those genes expression was measured by immunohistochemistry. Double sandwich enzyme-linked immunosorbent assay was used to observe the trace changes of NGF-β in peripheral plasma.

Results: Our results revealed that the NGF expression was markedly elevated in the tissue of right atrial appendage and peripheral blood lymphocytes from AF patients compared with the SR patients. But, the expression of TrKA, GSK3β, p-Akt and p-GSK3β were decreased. There was no difference about the expression of Akt from the AF patients and the SR patients. The NGF-β level in peripheral blood plasma of patients with AF and SR was not statistical difference.

Conclusion: Thus, we thought that NGF/TrKA signaling pathway may be involved in the AF in the patients with VHD, inactivation of GSK3β could increase the incidence of AF, but not relevant to phosphorylation.
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http://dx.doi.org/10.1080/08941939.2020.1798570DOI Listing
August 2020

Methotrexate-loaded tumour-cell-derived microvesicles can relieve biliary obstruction in patients with extrahepatic cholangiocarcinoma.

Nat Biomed Eng 2020 07 6;4(7):743-753. Epub 2020 Jul 6.

Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Most patients with cholangiocarcinoma (CCA) develop extrahepatic malignant biliary obstructions, which require palliative drainage to normalize bilirubin levels and to improve the patients' overall survival. Here, we report that the infusion of methotrexate-containing plasma-membrane microvesicles derived from apoptotic human tumour cells into the bile-duct lumen of patients with extrahepatic CCA mobilized and activated neutrophils and relieved biliary obstruction in 25% of the patients. Neutrophil recruitment by the microvesicles was associated with an increase in uridine diphosphate glucose and complement C5, and led to the degradation of the stromal barrier of CCA. The microvesicles induced pyroptosis of CCA cells through a gasdermin E-dependent pathway, and their intracellular contents released upon CCA-cell death activated patient-derived macrophages into producing proinflammatory cytokines, which attracted a secondary wave of neutrophils to the tumour site. Our findings suggest a possible treatment for the alleviation of obstructive extrahepatic CCA with few adverse effects, and highlight the potential of tumour-cell-derived microvesicles as drug carriers for antitumour therapies.
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http://dx.doi.org/10.1038/s41551-020-0583-0DOI Listing
July 2020

Piezoelectric Performance of a Symmetrical Ring-Shaped Piezoelectric Energy Harvester Using PZT-5H under a Temperature Gradient.

Micromachines (Basel) 2020 Jun 29;11(7). Epub 2020 Jun 29.

Department of Machine Design, School of Mechatronics Engineering, Harbin Institute of Technology, Harbin 150001, China.

With the rapid development of microelectronics technology, low-power electronic sensors have been widely applied in many fields, such as Internet of Things, aerospace, and so on. In this paper, a symmetrical ring-shaped piezoelectric energy harvester (SR-PEH) is designed to provide energy for the sensor to detect the ambient temperature. The finite element method is used by utilizing software COMSOL 5.4, and the electromechanical coupling model of the piezoelectric cantilever is established. The output performance equations are proposed; the microelectromechanical system (MEMS) integration process of the SR-PEH, circuit, and sensor is stated; and the changing trend of the output power density is explained from an energy perspective. In the logarithmic coordinate system, the results indicate that the output voltage and output power are approximately linear with the temperature when the resistance is constant. In addition, the growth rate of the output voltage and output power decreases with an increase of resistance under the condition of constant temperature. In addition, with an increase of temperature, the growth rate of the output power is faster than that of the output voltage. Furthermore, resistance has a more dramatic effect on the output voltage, whereas temperature has a more significant effect on the output power. More importantly, the comparison with the conventional cantilever-shaped piezoelectric energy harvester (CC-PEH) shows that the SR-PEH can improve the output performance and broaden the frequency band.
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http://dx.doi.org/10.3390/mi11070640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408445PMC
June 2020

Gasdermin E-mediated target cell pyroptosis by CAR T cells triggers cytokine release syndrome.

Sci Immunol 2020 01;5(43)

Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing 100005, China.

Cytokine release syndrome (CRS) counteracts the effectiveness of chimeric antigen receptor (CAR) T cell therapy in cancer patients, but the mechanism underlying CRS remains unclear. Here, we show that tumor cell pyroptosis triggers CRS during CAR T cell therapy. We find that CAR T cells rapidly activate caspase 3 in target cells through release of granzyme B. The latter cleaves gasdermin E (GSDME), a pore-forming protein highly expressed in B leukemic and other target cells, which results in extensive pyroptosis. Consequently, pyroptosis-released factors activate caspase 1 for GSDMD cleavage in macrophages, which results in the release of cytokines and subsequent CRS. Knocking out GSDME, depleting macrophages, or inhibiting caspase 1 eliminates CRS occurrence in mouse models. In patients, GSDME and lactate dehydrogenase levels are correlated with the severity of CRS. Notably, we find that the quantity of perforin/granzyme B used by CAR T cells rather than existing CD8 T cells is critical for CAR T cells to induce target cell pyroptosis.
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http://dx.doi.org/10.1126/sciimmunol.aax7969DOI Listing
January 2020

Impact of Preexisting Hepatitis C Virus Genotype 6 NS3, NS5A, and NS5B Polymorphisms on the Potency of Direct-Acting Antiviral Agents.

Antimicrob Agents Chemother 2019 04 27;63(4). Epub 2019 Mar 27.

Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.

HCV genotype 6 (GT-6) is found predominantly in East and Southeast Asia. Clinical studies have focused on patients infected with hepatitis C virus (HCV) GT-6a, where high sustained virologic response (SVR) rates to direct-acting antivirals (DAAs) have been achieved. However, GT-6 is highly diverse, with 29 reported subtypes. We explored the diversity of GT-6 polymorphisms at residues associated with DAA resistance, their impact on DAA potency when evaluated in a GT-6a consensus replicon, and their association with specific GT-6 subtypes. GT-6 sequences from 25 patient-derived samples and 105 sequences from the U.S. HCV database were compared, and substitutions at resistance-associated residue positions were phenotyped against different DAAs. Preexisting resistance-associated substitutions (RASs) to NS3 protease (A156V and D168E) and NS5B nucleotide (L159F and S282C) inhibitors were rare (<4%). Preexisting RASs to NS5A inhibitors were common, especially at L28 (A/F/G/M/T/V) and R30 (E/N/S). susceptibilities of NS5A-L28A and -L28T were dramatically reduced against all tested NS5A drugs (90% effective concentration [EC] range, 119 to 2,032 nM) compared with susceptibilities against a GT-6a consensus replicon (EC range, 0.1 to 19 nM). These L28 RASs preexisted in combination with R30S (EC [L28A-R30S] of ≥720 nM or EC [L28T-R30S] of ≥128 nM against tested DAAs) or as L28T-L31I (EC [tested DAAs] of >5,000 nM) and were detected in evaluated GT-6b and -6f sequences. NS5A-L28A-R30A, observed in GT-6r, did not replicate. In conclusion, HCV GT-6b, GT-6f, and GT-6r sequences harbored highly resistant RASs to all evaluated NS5A drugs. Therefore, monitoring SVR in patients infected with these GT-6 subtypes treated with NS5A drug-containing regimens is suggested to confirm any association between noted NS5A polymorphisms and treatment failure.
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http://dx.doi.org/10.1128/AAC.02205-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437522PMC
April 2019

Visualization of perforin/gasdermin/complement-formed pores in real cell membranes using atomic force microscopy.

Cell Mol Immunol 2019 06 3;16(6):611-620. Epub 2018 Oct 3.

Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China.

Different types of pores ubiquitously form in cell membranes, leading to various types of cell death that profoundly influence the fate of inflammation and the disease status. However, these pores have never truly been visualized to date. Atomic force microscopy (AFM), which is emerging as a powerful tool to analyze the mechanical properties of biomolecules and cells, is actually an excellent imaging platform that allows biological samples to be visualized by probing surface roughness at the level of atomic resolution. Here, membrane pore structures were clearly visualized using AFM. This visualization not only describes the aperture and depth of the pore complexes but also highlights differences among the pores formed by perforin and gasdermins in tumor cell membranes and by complement in immune cell membranes. Additionally, this type of visualization also reveals the dynamic process of pore formation, fusion, and repair.
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http://dx.doi.org/10.1038/s41423-018-0165-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804747PMC
June 2019

Discovery of the Novel Entecavir-Resistant Hepatitis B Virus Reverse Transcriptase A181C Substitution From an Integrated Genotypic Analysis.

Hepatol Commun 2018 Sep 21;2(9):1123-1135. Epub 2018 Aug 21.

Bristol-Myers Squibb Pharmaceutical Research and Development Wallingford CT.

Entecavir (ETV) is a first-line therapy for chronic hepatitis B virus (HBV), demonstrating potent suppression of HBV DNA and a high barrier to viral resistance. Previous studies revealed that ETV-resistant (ETVr) HBV DNA resulted from substitutions in the HBV reverse transcriptase (RT) at positions rtT184, rtS202, or rtM250 in combination with lamivudine resistance (LVDr) substitutions rtM204I/V±rtL180M. , viral variants exhibit varying degrees of ETV susceptibility and replication capacity depending on specific resistance substitutions. To explore the potential for additional pathways to ETVr, HBV RT sequences from 982 evaluable patients enrolled in 17 ETV clinical studies were analyzed. Thirty novel emergent substitutions at amino acid positions not previously associated with HBV nucleos(t)ide drug resistance were observed in at least 2 patients and were identified in patient-derived HBV with a wild-type, LVDr, or ETVr RT sequence. Phenotypic analysis of these substitutions indicated that they had no effect on ETV susceptibility. Phenotypic analysis was also performed on patient-derived HBV RT sequences from 10 LVD-naive and 13 LVD-experienced patients with virologic breakthrough and emergent novel substitutions while on ETV treatment. One LVD-experienced patient-derived HBV RT harboring LVDr substitutions rtL180M+rtM204V with rtA181C displayed reduced ETV susceptibility (122-fold greater than wild-type HBV) and remained susceptible to adefovir and tenofovir. HBV harboring the rtA181C substitution without LVDr substitutions rtL180M+rtM204V remained susceptible to inhibition by ETV, adefovir, and tenofovir, although cross-resistance to LVD and telbivudine was observed. An integrated genotypic analysis of HBV RT sequences from patients with chronic HBV treated with ETV led to the discovery of the novel ETVr substitution rtA181C. This substitution was always detected in combination with LVDr substitutions rtL180M+rtM204V in ETV-treated patients.
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http://dx.doi.org/10.1002/hep4.1231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128232PMC
September 2018

Sex Hormone Contributes to Sexually Dimorphic Susceptibility in CVB3-Induced Viral Myocarditis via Modulating IFN-γ NK Cell Production.

Can J Cardiol 2018 04 6;34(4):492-501. Epub 2018 Jan 6.

Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Science, Soochow University, Suzhou, People's Republic of China. Electronic address:

Background: Viral myocarditis is a widespread cardiac disease associated with inflammation and myocardial injury and is predominantly caused by coxsackievirus B3 (CVB3) infection in humans as well as in mice. CVB3-induced myocarditis shows sexually dimorphic sensitivity and is more prevalent in male mice. Our previous studies showed that natural killer (NK) cells played an indispensable role in CVB3-induced myocarditis, and female mice exhibited less pathological cardiac interferon gamma (IFN-γ) NK cell infiltration than did male mice. However, the precise mechanisms were not well elucidated.

Methods: We investigated the influence of estrogen on cardiac IFN-γ NK cell enrichment in CVB3-induced myocarditis and explored the underlying molecular mechanism.

Results: In this study, we found that CVB3 stimulation could clearly induce IFN-γ expression by NK cells; however, this trend could be blunted by estrogen treatment. Consistently, ovariectomized female mice with decreased estrogen levels exhibited substantially increased enrichment of cardiac IFN-γ NK cells and displayed significantly aggravated myocarditis. Similarly, estrogen-treated male mice showed less cardiac IFN-γ NK cell infiltration, accompanied by significantly alleviated viral myocarditis. In sharp contrast, sexually immature female and male mice (with similar estrogen levels) showed comparable levels of cardiac IFN-γ NK cell infiltration and similar levels of myocarditis severity. Upon further exploration of the underlying mechanisms, we found that estrogen could downregulate expression of Th1-specific T box transcription factor (T-bet), the key transcription factor associated with IFN-γ production, in CVB3-stimulated NK cells.

Conclusions: Overall, this study might help us understand the mechanism of increased cardiac infiltration by IFN-γ NK cells in CVB3-infected male mice compared with that in female mice and might provide new clues for the sex bias in CVB3-induced myocarditis.
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http://dx.doi.org/10.1016/j.cjca.2018.01.002DOI Listing
April 2018

Viral Drug Resistance Through 48 Weeks, in a Phase 2b, Randomized, Controlled Trial of the HIV-1 Attachment Inhibitor Prodrug, Fostemsavir.

J Acquir Immune Defic Syndr 2018 03;77(3):299-307

Currently, Research and Development, ViiV Healthcare, Wallingford, CT.

Background: Fostemsavir is a prodrug of temsavir, an attachment inhibitor that binds to HIV-1 gp120, blocking viral attachment to host CD4 T-cells. The phase 2b trial AI438011 investigated the safety, efficacy, and dose-response of fostemsavir vs ritonavir-boosted atazanavir (ATV/r) in treatment-experienced, HIV-1-infected subjects.

Methods: Two hundred fifty-one treatment-experienced subjects with baseline (BL) susceptibility to study drugs [temsavir half-maximal inhibitory concentration (IC50) <100 nM, PhenoSense Entry assay] received fostemsavir or ATV/r, each with tenofovir disoproxil fumarate + raltegravir. Subjects meeting resistance-testing criteria were assessed for emergent viral drug resistance. Changes in temsavir IC50 from BL was given a conservative technical cutoff (>3-fold increase).

Results: 66/200 fostemsavir and 14/51 ATV/r subjects had resistance testing performed; 44/66 and 9/14 were successfully tested using the PhenoSense GT assay. No subjects had emergent tenofovir disoproxil fumarate or ATV resistance. Six fostemsavir-treated subjects developed emergent raltegravir resistance. 29/66 fostemsavir-treated subjects had an evaluable phenotype using PhenoSense Entry (which tests for viral susceptibility to temsavir) and 13/29 exhibited >3-fold increase in temsavir IC50 from BL. gp120 population sequencing was successful in 11/13 subjects and 7 had emergent substitutions in gp120 associated with reduced temsavir susceptibility (S375, M426, or M434). However, 5/13 fostemsavir-treated subjects achieved subsequent suppression to <50 copies/mL before the week 48 database lock, regardless of key gp120 substitutions.

Conclusions: Response rates remained similar across study arms regardless of BL nucleoside reverse transcriptase inhibitor, nonnucleoside reverse transcriptase inhibitor, and protease inhibitor resistance-associated mutations. Emergent changes in viral susceptibility occurred more frequently with fostemsavir compared with ATV/r. However, the full impact of temsavir IC50 changes and emergent HIV-1 gp120 substitutions, and thus appropriate clinical cutoffs, requires further study. Fostemsavir is being evaluated in a phase 3 trial in heavily treatment-experienced subjects.
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http://dx.doi.org/10.1097/QAI.0000000000001602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815643PMC
March 2018

Knockdown of Long Noncoding RNA Small Nucleolar RNA Host Gene 12 Inhibits Cell Growth and Induces Apoptosis by Upregulating miR-138 in Nonsmall Cell Lung Cancer.

DNA Cell Biol 2017 Nov 5;36(11):892-900. Epub 2017 Sep 5.

Department of Pneumology, Huaihe Hospital of Henan University , Kaifeng, China .

Small nucleolar RNA host gene 12 (SNHG12) is a novel long noncoding RNA identified to be upregulated and functions as an oncogene in several cancers. However, the function of SNHG12 and its target genes in modulating nonsmall cell lung cancer (NSCLC) development are rarely reported. In the present study, we validated that SNHG12 was overexpressed, while miR-138 was low-expressed, in NSCLC cells compared with normal human lung epithelial cells. SNHG12 harbored the binding site of miR-138 and inversely regulated the expression miR-138. Knockdown of SNHG12 inhibited proliferation and colony-forming ability, induced apoptosis, and increased caspase-3 activity of NSCLC cells, whereas miR-138 downregulation restored these effects. Furthermore, SNHG12 knockdown decreased volumes and weight of xenograft tumors in a NSCLC mouse model. Taken together, these findings suggested that knockdown of SNHG12 suppressed cell growth and induced apoptosis by upregulating miR-138 in NSCLC.
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http://dx.doi.org/10.1089/dna.2017.3830DOI Listing
November 2017

Pooled analysis of HCV genotype 1 resistance-associated substitutions in NS5A, NS3 and NS5B pre-and post-treatment with 12 weeks of daclatasvir, asunaprevir and beclabuvir.

Antivir Ther 2018 ;23(1):53-66

Toranomon Hospital, Tokyo, Japan.

Background: Daclatasvir (DCV; non-structural [NS]5A inhibitor) plus asunaprevir (ASV; NS3 inhibitor) plus beclabuvir (BCV; non-nucleoside NS5B inhibitor) is an approved regimen for hepatitis C virus (HCV) genotype (GT)-1 treatment in Japan. A comprehensive analysis of pre-treatment and treatment-emergent HCV resistance to this regimen ± ribavirin (RBV) was performed.

Methods: Data were pooled from five Phase 2/3 studies of DCV+ASV+BCV±RBV given for 12 weeks to GT-1a- or GT-1b-infected patients. The prevalence and impact of pre-treatment resistance-associated substitutions (RAS) in NS5A, NS3, and NS5B on sustained virological response (SVR) was assessed, as were emergent RAS and their post-treatment persistence.

Results: Baseline NS5A RAS (GT-1a: M28T, Q30H/L/R/S, L31M, Y93C/H; GT-1b: L31I/M, Y93C/H) were present in 5% (26/561) of GT-1a and 16% (85/537) of GT-1b sequences. SVR12 for GT-1b without RBV was 100% (82/82) with RAS and >99% (427/428) without RAS. For GT-1a, SVR12 without RAS was 97% (85/88) with RBV and 92% (410/447) without RBV; SVR12 with RAS was 100% (2/2) with RBV and 54% (13/24) without RBV. Baseline NS3 (at R155 or D168) and NS5B (at P495) RAS were rare (≤1%). Treatment-emergent NS5A RAS (mostly Q30E/H/K/R±Y93H/N) in GT-1a persisted 60 weeks post-treatment, while NS3 RAS (mostly R155K) and NS5B-P495L/S were no longer detected after 48 or 24 weeks, respectively.

Conclusions: DCV+ASV+BCV±RBV was highly efficacious in HCV GT-1 infection, including HCV GT-1b with NS5A RAS. The fitness of treatment-emergent RAS post-treatment was NS5A > NS3 > NS5B; NS3 and NS5B RAS were generally replaced by wild-type sequence within 48 weeks.
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http://dx.doi.org/10.3851/IMP3177DOI Listing
September 2019

Leucine-rich repeats and immunoglobulin-like domains protein 1 and fascin actin-bundling protein 1 expression in nonsmall cell lung cancer.

J Cancer Res Ther 2016 Dec;12(Supplement):C248-C251

Department of Respiratory, Henan University Huaihe Hospital, Kaifeng, Henan, China.

Objective: To assess the clinical significance of leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) and fascin actin-bundling protein 1 (Fascin-1) expression in nonsmall cell lung cancer (NSCLC).

Materials And Methods: Six-one NSCLC patients were included in this study. The expression of LRIG1 and Fascin-1 was assayed in the tumor tissue and relative normal lung tissue of the 61 NSCLC patients by immunohistochemistry. The relationship between LRIG1, Fascin-1 expression pattern and lung cancer patients' clinical pathology characteristics was evaluated.

Results: The positive expression rate of Fascin-1 in cancer tissue and normal tissue was 70.5% (43/61) and 13.1% (8/61), respectively, which indicated cancer tissue much higher than normal tissue (P < 0.05); for LRIG1, the positive expression rate was 54.1% (33/61) and 82.0% (50/61) for tumor tissue and normal tissue with statistical difference (P < 0.05); Fascin-1-positive expression was associated with tumor diameter (P < 0.05) and mediastinal lymph node metastasis (P < 0.05). Moreover, LRIG1-positive expression was correlated with pathology type (P < 0.05), clinical stage (P < 0.05), and mediastinal lymph node metastasis (P < 0.05).

Conclusion: LRIG1 and Fascin-1 were differently expressed in cancer and normal lung tissue in patients with NSCLC, which could be a biomarker for mediastinal lymph node metastasis in NSCLC patients.
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http://dx.doi.org/10.4103/0973-1482.200749DOI Listing
December 2016

Effect of minor populations of NS5A and NS5B resistance-associated variants on HCV genotype-3 response to daclatasvir plus sofosbuvir, with or without ribavirin.

Antivir Ther 2017 23;22(3):237-246. Epub 2016 Dec 23.

Bristol-Myers Squibb Research and Development, Wallingford, CT, USA.

Background: Treatment of hepatitis C virus (HCV) genotype 3 (GT3) is a medical priority. All-oral treatment of HCV GT3 with daclatasvir (DCV) and sofosbuvir (SOF), with or without ribavirin (RBV), is recommended by several treatment guidelines. The impact of HCV minority populations at amino acid positions in NS5A and NS5B associated with drug resistance on response to DCV+SOF±RBV was assessed in SOF-naive and SOF-experienced HCV patients.

Methods: The presence of baseline NS5A or NS5B polymorphisms was assessed in 227 and 167 HCV-GT3-infected patients, respectively, from four clinical studies of DCV+SOF±RBV. Polymorphisms were identified at a sequencing detection threshold of ≥10%, and at ≥1% by next-generation sequencing (NGS) for a subset.

Results: No SOF resistance-associated polymorphisms were detected at baseline. Among 58 patients with prospective baseline sequencing data at ≥10% and ≥1%, detectable NS5A substitutions at A30 (A30K/R/S/T/V), S62 (S62A/F/K/L/T) or Y93H were 38% more prevalent at ≥1% compared with ≥10% (55% [32/58] versus 41% [24/58] of patients), although sustained virological response (SVR) in patients with these substitutions remained the same at both sequencing thresholds (88%). Only one additional Y93H was detected at ≥1%; the patient achieved SVR. In two virological failures with baseline Y93H, a minority S62L substitution at baseline was enriched from <20% to ≥95% at failure. Treatment-emergent minority populations (at A30, L31, P32, P58 and E92) observed by NGS in four virological failures became undetectable by week 24 post-treatment.

Conclusions: Sequencing at a depth of ≥10% appears to be sufficient to predict HCV GT3 response to DCV+SOF±RBV.
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http://dx.doi.org/10.3851/IMP3120DOI Listing
March 2018

Protease Serine S1 Family Member 8 (PRSS8) Inhibits Tumor Growth In Vitro and In Vivo in Human Non-Small Cell Lung Cancer.

Oncol Res 2017 May 27;25(5):781-787. Epub 2016 Oct 27.

Protease serine S1 family member 8 (PRSS8), a membrane-anchored serine protease, has been reported to be involved in the development of several human cancers. However, the role of PRSS8 in non-small cell lung cancer (NSCLC) pathogenesis remains unclear. The objective of this study was to investigate PRSS8 expression, biological function, and its related molecular mechanism in NSCLC. Our results showed that PRSS8 was expressed in a low amount in NSCLC cell lines. Ectopic expression of PRSS8 inhibited tumor growth in vitro and in vivo. Furthermore, ectopic expression of PRSS8 inhibited the migration and invasion of NSCLC cells. It also suppressed the EMT process in A549 cells. Mechanistically, we found that the ectopic expression of PRSS8 downregulated the protein expression levels of p-JAK1, p-JAK2, and p-STAT3 in A549 cells. Taken together, our study showed that PRSS8 plays an important role in the growth and metastasis of NSCLC. Thus, PRSS8 may be a novel therapeutic target for NSCLC.
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http://dx.doi.org/10.3727/096504016X14772417575982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841066PMC
May 2017

Hetrombopag, a Thrombopoietin Receptor Agonist, Protects Cardiomyocyte Survival from Oxidative Stress Damage as an Enhancer of Stem Cells.

Cardiovasc Drugs Ther 2016 Dec;30(6):567-577

Department of Cardiovascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, People's Republic of China.

Purpose: Current human umbilical cord blood stem cell therapy faces the great challenges, because the stem cells are scarce and cannot survive for a long time. Here we describe how hetrombopag, an orally-active TPO receptor agonists, enhanced ex vivo expansion of human UCB stem cells, and protected cardiac myocytes from the damage caused by oxidative stress.

Methods: Ex vivo expansion of stem cells were performed in serum-free medium supplemented with rhSCF and rhFL plus hetrombopag for 7 days. The percentage and number of stem cell subsets were determined by flow cytometry. Rat cardiac myocytes, ex vivo expanded stem cells, or cardiac myocytes plus ex vivo expanded stem cells were serum starved for 24 hours, and were then subjected to HO, hetrombopag or both for 12 hours at the indicated concentrations. Cell viability assays, protein microarrays and western blots were then performed in each group.

Results: Our studies first revealed that the combination of hetrombopag and rhTPO manifested additive effect on ex vivo expansion of human UCB stem cells. Besides, hetrombopag dose-dependently enhanced the beneficial effects of ex vivo expanded human UCB MNCs in increasing the survival of injured cardiomyocytes during free oxygen radical stress.

Conclusion: These data, for the first time, uncovered a novel function of non-peptide small molecular TPO receptor agonists as enhancers of stem cells in protecting cardiac myocyte survival from oxidative stress damage, which might provide a new therapeutic avenue for the treatment of oxidative stress-related cardiovascular disease. Graphical abstract ᅟ.
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http://dx.doi.org/10.1007/s10557-016-6696-8DOI Listing
December 2016

Anaerobic co-metabolic biodegradation of tetrabromobisphenol A using a bioelectrochemical system.

J Hazard Mater 2017 Jan 29;321:791-800. Epub 2016 Sep 29.

College of Material Science and Engineering, Nanjing Tech University, Nanjing 210009, China.

Tetrabromobisphenol A(TBBPA), a pollutant in industrial wastewaters, needs to be removed due to its high toxicity and persistence. The main biodegradation pathway for TBBPA has been studied, and bisphenol A(BPA), which is toxic to the environment, is recognized as the general terminal product. In this study, we explored a new approach for the anaerobic biodegradation of TBBPA in a bioelectrochemical system (BES) through co-metabolic degradation of TBBPA with glucose. The half-life of TBBPA was significantly reduced to 13.5h at 25μg/l of TBBPA. With an increase in the concentration of TBBPA, the removal rates of TBBPA rose to more than eighty percent. Based on the analysis of the products, we found that the degradation products of TBBPA were 2,6-dibromo-4-(1-methyl-1-phenylethyl) phenol, (double-benzenes product) and 2,6-dibromo-4-(prop-1-en-2-yl) phenol (single-benzene product), rather than BPA. Simultaneously, we proposed two degradation pathways for TBBPA in a BES system. According to the microbial diversity analysis of the anode biofilm, we speculated that the microorganism responsible for the biodegradation of TBBPA was Azoarcus. Additionally, we briefly analyzed the effect of TBBPA on the performance of BES system to pave the way for the further analysis of the interaction between the TBBPA and the BES system.
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http://dx.doi.org/10.1016/j.jhazmat.2016.09.068DOI Listing
January 2017

Characterization of NS5A polymorphisms and their impact on response rates in patients with HCV genotype 2 treated with daclatasvir-based regimens.

J Antimicrob Chemother 2016 12 7;71(12):3495-3505. Epub 2016 Sep 7.

Bristol-Myers Squibb R&D, Wallingford, CT 06492, USA

Objective: Daclatasvir (DCV) is a pan-genotypic non-structural protein 5A (NS5A) inhibitor that is approved for treatment of hepatitis C virus (HCV) genotype (GT)1 and GT3 in the USA and GT1, GT3 and GT4 in Europe. We set out to examine the impact of daclatasvir-based regimens on the sustained virologic response (SVR) in patients with GT2 infection with respect to GT2 subtype and NS5A polymorphisms at amino acid positions associated with daclatasvir resistance.

Methods: Analyses were performed on 283 GT2 NS5A sequences from five daclatasvir regimen-based clinical trials (ClinicalTrials.gov: NCT-01257204, NCT-01359644, NCT-02032875, NCT-02032888 and NCT-01616524) and 143 NS5A sequences from the Los Alamos HCV database. Susceptibility analyses of substitutions at amino acid positions associated with daclatasvir resistance and patient-derived NS5A sequences were performed using an in vitro HCV replication assay.

Results: Of 13 GT2 subtypes identified from 426 NS5A sequences, the most prevalent were GT2a (32%), GT2b (48%) and GT2c (10%). The most prevalent NS5A polymorphism was L31M (GT2a = 88%; GT2b = 59%; GT2c = 10%). Substitutions identified in 96% of GT2 NS5A sequences exhibited daclatasvir EC values ranging from 0.005 to 20 nM when tested in vitro. A similar range in daclatasvir EC values was observed for 16 diverse GT2 patient-derived NS5A sequences (EC = 0.005-60 nM). Depending on the daclatasvir-based regimen studied (daclatasvir/interferon-based or daclatasvir/sofosbuvir-based), SVR rates ranged from 90% to 100% in GT2 patients with the most prevalent baseline NS5A-L31M polymorphism, compared with from 96% to 100% without this polymorphism.

Conclusions: High SVR rates were achieved in patients infected with GT2 treated with daclatasvir-based regimens irrespective of GT2 subtype or baseline NS5A polymorphisms.
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http://dx.doi.org/10.1093/jac/dkw336DOI Listing
December 2016

Effect of bedtime administration of blood-pressure lowering agents on ambulatory blood pressure monitoring results: A meta-analysis.

Cardiol J 2016 14;23(4):473-81. Epub 2016 Jun 14.

Department of Cardiology, Shandong Provincial Hospital affiliated to Shandong University, China.

Background: Bedtime administration of antihypertensive drugs currently receives more at-tention, but no clear consensus has been reached on the blood pressure (BP)-lowering effect of this strategy.

Methods: We systematically searched literature for clinical trials of ingestion time of anti-hypertensive drugs evaluated by ambulatory blood pressure monitoring (ABPM) to perform a meta-analysis which aimed at determining the difference in diurnal, nocturnal, and 24-h mean of systolic BP (SBP) and diastolic BP (DBP), absolute BP reduction from baseline between bedtime administration group (experimental group) and morning (awaking) administration group (control group).

Results: The synthesis analysis showed that the level of BP in bedtime administration group was lower than the morning administration group, which reduced diurnal SBP/DBP by 1.67/1.13 mm Hg (p = 0.36/0.48), 24-h SBP/DBP by 2.78/0.36 mm Hg (p = 0.09/0.62), nocturnal SBP/DBP by 6.32/3.17 mm Hg (p = 0.03/0.007). Furthermore, there was lack of statistically significant differences in the diurnal mean of SBP/DBP reduction from baseline between the two groups (p = 0.94/0.85), but bedtime administration resulted in significant reduction from baseline in the nocturnal mean of SBP/DBP, by -4.72/-3.57 mm Hg (p = 0.01/0.05). Funnel plot demonstrated that there was no evidence of publication bias.

Conclusions: Administration of ≥ 1 antihypertensive drugs at bedtime or evening results in a greater reduction of nocturnal hypertension than dosing in the morning without loss of efficacy of diurnal and 24 h mean BP reduction.
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http://dx.doi.org/10.5603/CJ.a2016.0027DOI Listing
March 2017

[Calpain-2 and calcineurin protein expression in right atrial appendages from patients underwent valve replacement with or without atrial fibrillation].

Zhonghua Xin Xue Guan Bing Za Zhi 2015 Aug;43(8):705-8

Objective: To investigate the relationship between the protein expression of calpain-2 and calcineurin (CaN) and atrial fibrillation (AF) in patient with valvular heart disease (VHD).

Methods: A total of 40 patients who underwent valve replacement surgery in our hospital from March 2013 to March 2014, right atrial appendages were excised during operation and patients were divided into sinus rhythm (SR) group (n = 17) and AF group (n = 23). The protein expression of calpain-2 and the α-isoform of CaN catalytic subunit (CnA) in the right atrial appendages were determined by Western blot.

Results: The protein levels of the full-length CnAa (60,000), the 45,000 fragment of CnAa without autoinhibitory domain, and calpain-2 were significantly upregulated in the AF group compared to the SR group (1.25 ± 0.51 vs. 0.76 ± 0.37, 1.08 ± 0.37 vs. 0.76 ± 0.25, and 0.82 ± 0.44 vs. 0.51 ± 0.19, respectively, all P < 0.05).

Conclusion: Activated calpain-2-CaN signal pathway might be involved in the pathogenesis of AF.
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August 2015

Heterogeneity, Inequity Aversion, and Group Performance.

Soc Choice Welfare 2016 Feb 28;46(2):263-286. Epub 2015 Aug 28.

University of Cologne.

We investigate the effects of inequality in wealth on the incentives to contribute to a group output when agents are inequity averse and may differ in ability. We show that equality may lead to a reduction of contributions below levels generated by purely selfish agents. But introducing inequality motivates more productive agents to exert higher efforts and help the group to coordinate on equilibria with less free-riding. As a result, less able agents may benefit from initially disadvantageous inequality. Moreover, the more inequity averse the agents, the more inequality should be imposed even by an egalitarian social planner.
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http://dx.doi.org/10.1007/s00355-015-0912-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772919PMC
February 2016

A Genetic Algorithm Based Support Vector Machine Model for Blood-Brain Barrier Penetration Prediction.

Biomed Res Int 2015 4;2015:292683. Epub 2015 Oct 4.

Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.

Blood-brain barrier (BBB) is a highly complex physical barrier determining what substances are allowed to enter the brain. Support vector machine (SVM) is a kernel-based machine learning method that is widely used in QSAR study. For a successful SVM model, the kernel parameters for SVM and feature subset selection are the most important factors affecting prediction accuracy. In most studies, they are treated as two independent problems, but it has been proven that they could affect each other. We designed and implemented genetic algorithm (GA) to optimize kernel parameters and feature subset selection for SVM regression and applied it to the BBB penetration prediction. The results show that our GA/SVM model is more accurate than other currently available log BB models. Therefore, to optimize both SVM parameters and feature subset simultaneously with genetic algorithm is a better approach than other methods that treat the two problems separately. Analysis of our log BB model suggests that carboxylic acid group, polar surface area (PSA)/hydrogen-bonding ability, lipophilicity, and molecular charge play important role in BBB penetration. Among those properties relevant to BBB penetration, lipophilicity could enhance the BBB penetration while all the others are negatively correlated with BBB penetration.
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http://dx.doi.org/10.1155/2015/292683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4609370PMC
August 2016
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