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  • 1
    Online Resource
    Online Resource
    Immune checkpoint inhibitors combined with chemotherapy for the treatment of advanced pancreatic cancer patients
    Springer Science and Business Media LLC ; 2020
    In:  Cancer Immunology, Immunotherapy Vol. 69, No. 3 ( 2020-03), p. 365-372
    Details
    In: Cancer Immunology, Immunotherapy, Springer Science and Business Media LLC, Vol. 69, No. 3 ( 2020-03), p. 365-372
    Type of Medium: Online Resource
    ISSN: 0340-7004 , 1432-0851
    URL: Article
    DOI: 10.1007/s00262-019-02452-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
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  • 2
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    Molecular basis of pH sensitivity of Orai1/stim1 channels
    Wiley ; 2015
    In:  The FASEB Journal Vol. 29, No. S1 ( 2015-04)
    Details
    In: The FASEB Journal, Wiley, Vol. 29, No. S1 ( 2015-04)
    Abstract: Changes of intracellular and extracellular pH are involved in a variety of physiological and pathological processes, in which regulation of the Ca 2+ release activated Ca 2+ channel (I CRAC ) by pH has been implicated. Ca 2+ entry mediated by I CRAC as well as native I CRAC currents have been shown to be regulated by acidic or alkaline pH. However, the mechanism by which the CRAC channel is regulated by internal pH (pH i ) and external pH (pH o ) has remained elusive. By generating a series of mutations in the channel pore region, intracellular and extracellular loops, transmembrane domains, and N‐ and C‐termini, we unexpectedly identified that the mutant E190D lost sensitivity to both acidic and alkaline pH o , and the mutant H155F markedly diminished the response to acidic and alkaline pH i . Thus, it appears that E190 in the TM3 is the external pH sensor, and H155 in the intracellular loop is the internal pH i sensor of Orai1/Stim1 channels. Our results provide a novel mechanism that changes of external and internal pH modulate I CRAC activity by directly regulating channel gating of the pore‐forming subunit Orai through residues E190 and H155. Given that pH changes can influence a variety of physiological/pathological functions, Orai/Stim channels may be an important mediator for various physiological and pathological processes associated with acidosis and alkalinization.
    Type of Medium: Online Resource
    ISSN: 0892-6638 , 1530-6860
    URL: Issue
    URL: Article
    DOI: 10.1096/fsb2.v29.S1
    DOI: 10.1096/fasebj.29.1_supplement.1021.8
    Language: English
    Publisher: Wiley
    Publication Date: 2015
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    detail.hit.zdb_id: 639186-2
    SSG: 12
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  • 3
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    A retrospective cohort study of anti-PD-1 therapy combined with chemotherapy in patients with advanced biliary tract cancer.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. e14100-e14100
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. e14100-e14100
    Abstract: e14100 Background: Biliary tract cancer (BTC) is highly aggressive with poor prognosis and few treatment options following progression on gemcitabine-based chemotherapy. Disappointing results from clinical trials for refractory BTC highlight the need for more effective therapies. Immune checkpoint inhibitor (ICI) has been hailed as a major breakthrough for cancer treatment. However, evidence for the efficacy of immunotherapy in biliary tract cancer (BTC) is limited and unsatisfactory. KEYNOTE-158 trial has merely shown a 5.8% of overall response rate with pembrolizumab monotherapy in advanced BTCs. Thus, combining other therapies with ICIs is becoming the researching focus. Herein, we constructed a cohort to evaluate the efficacy and safety of ICIs combined with chemotherapy in advanced BTCs. Methods: Chinese BTC patients receiving PD-1 inhibitors with chemotherapy, PD-1 inhibitors monotherapy or chemotherapy alone were retrospectively analyzed. The primary outcome was overall survival (OS). The key secondary outcome were progression-free survival (PFS) and safety. Patients previously treated with any agent targeting T-cell co-stimulation or immune checkpoints were excluded. Results: The study included 77 patients (PD-1 inhibitors plus chemotherapy, n = 38; PD-1 inhibitors monotherapy, n = 20; chemotherapy, n = 19). Median OS was 14.9 months with PD-1 inhibitors plus chemotherapy, 4.1 months with PD-1 inhibitors and 6.0 months with chemotherapy, with significantly longer for anti-PD-1 combination therapy than monotherapy (HR 0.37, 95% CI 0.17-0.80, P= 0.001) or chemotherapy (HR 0.63, 95% CI 0.42-0.94, P= 0.011). Median PFS was 5.1 months with PD-1 inhibitors plus chemotherapy, 2.2 months with PD-1 inhibitors and 2.4 months with chemotherapy, with significant difference for anti-PD-1 combination therapy versus anti-PD-1 monotherapy (HR 0.59, 95% CI 0.31-1.10, P= 0.014) or chemotherapy (HR 0.61, 95% CI 0.45-0.83, P= 0.003). Grade 3 or 4 treatment-related adverse events were similar between anti-PD-1 combination group and chemotherapy group (34.2% and 36.8%). Conclusions: PD-1 inhibitors plus chemotherapy is effective and tolerable for advanced BTC.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.e14100
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
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    detail.hit.zdb_id: 604914-X
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  • 4
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    Anti-PD-1 therapy combined with chemotherapy in patients with advanced pancreas cancer in a real-world clinical setting.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. e14103-e14103
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. e14103-e14103
    Abstract: e14103 Background: Pancreatic cancer (PC) is a highly lethal disease and characterized by a strong resistance to current radiotherapy and chemotherapy. As PC has the presence of a microenvironment filled with immunosuppressive mediators and a dense stroma which involved in immune system control, the immune system has been hypothesized to play an important role in PC. However, there was no response in patients who received immune checkpoint inhibitors (ICIs) monotherapy. Though small sample studies revealed that ICIs combined with chemotherapy is effective, a head-to-head comparison of ICIs plus chemotherapy and chemotherapy is limited. Methods: Advanced PC patients treated with chemotherapy alone or plus ICIs were retrospectively screened for eligibility. Patients previously treated with any agent targeting T-cell co-stimulation or checkpoint pathways was excluded. The primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS), overall response rate (ORR) and safety. Results: In total, 58 patients were included (combination, n = 22; chemotherapy, n = 36). Combination group presented significantly longer OS than chemotherapy group (median, 18.1 vs 6.1 months, HR 0.46 [0.23-0.90], P = 0.021). Median PFS was 3.2 months in the combination group and 2.0 months in the chemotherapy group (HR 0.57 [0.32-0.99] , P = 0.041). The ORR was similar between the combination group and the chemotherapy group with no significant difference (18.2% vs 19.4%, P = 0.906). And all the patients, who reached partial response, accepted a two-chemotherapic-drugs regimen regardless of combinating with ICIs. Adverse events of grade 3 or higher occurred in 31.8% of the patients in the combination group and in 16.9% of those in the chemotherapy group. Though the incidence rate of serious treatment-related adverse events (TRAEs) was higher in the combination group than the chemotherapy group, no statistical significance existed (P = 0.183). Conclusions: Combination of ICIs plus chemotherapy is effective and tolerable for advanced PC. Accepting ICIs combined with a two-drug chemotherapy regimen might be the better choice.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.e14103
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
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    detail.hit.zdb_id: 604914-X
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  • 5
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    Online Resource
    Abstract P3129: Functional Coupling Of TRPM2 And Extrasynaptic NMDARs Exacerbates Excitotoxicity In Ischemic Stroke
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Circulation Research Vol. 131, No. Suppl_1 ( 2022-08-05)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 131, No. Suppl_1 ( 2022-08-05)
    Abstract: Introduction: Ischemic stroke caused a heavy burden on public health. NMDA receptor (NMDAR) mediated excitotoxicity was thought to be the culprit for neuronal death during ischemic stroke. However, NMDAR antagonists all failed to show protective effects in human patients. The heat-sensitive ion channel TRPM2 is Ca 2+ -permeable and usually activated under oxidative stress conditions. TRPM2 is abundantly expressed in the brain and promotes neuronal death during ischemic stroke, whereas the underlying mechanisms remain elusive. Hypothesis: Oxidative stress is a hallmark of brain damage during ischemic stroke. We hypothesized that TRPM2 is important in magnifying NMDAR-mediated excitotoxicity. Methods: Neuron specific TRPM2 knockout was achieved by crossing nestin-cre mice with Trpm2 fl/fl mice. Middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation (OGD) were performed to mimic ischemic stroke in vivo and in vitro, respectively. Co-immunoprecipitation and direct binding assay were used to examine protein-protein interaction. Subcloning and mutagenesis were used to identify interaction details. Interfering peptide specifically disrupting TRPM2-NMDAR interaction was designed and synthesized. Cortical neurons were isolated and cultured, Fura-2-AM and Rhodamine-123 imaging were used to examine Ca 2+ overload and mitochondrial dysfunction, respectively. Synaptic and extrasynaptic NMDAR mediated responses were separated, and synaptosome was isolated to examine the influence of TRPM2 on NMDAR and expression of TRPM2 in neurons at different sites, respectively. Results: Neuron specific TRPM2 knockout alleviates ischemic stroke in mice. TRPM2 physically and functionally interacts with extrasynaptic NMDAR, which enhances excitotoxity. The EE 3 motif in TRPM2 directly associates with the KKR motif in NMDAR. Uncoupling of TRPM2-NMDAR association using a disrupting peptide TAT-EE 3 prevents OGD-induced Ca 2+ overload and mitochondrial dysfunction in neurons, and protects mice against MCAO-induced brain injury. Conclusion: Therapeutic interfering peptide TAT-EE 3 attenuates ischemic stroke. Targeting the TRPM2-NMDAR coupling could be a promising strategy for screening more effective therapies for ischemic stroke.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/res.131.suppl_1.P3129
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
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    detail.hit.zdb_id: 1467838-X
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  • 6
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    Online Resource
    Role of TRP channels in the cardiovascular system
    American Physiological Society ; 2015
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 308, No. 3 ( 2015-02-01), p. H157-H182
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 308, No. 3 ( 2015-02-01), p. H157-H182
    Abstract: The transient receptor potential (TRP) superfamily consists of a large number of nonselective cation channels with variable degree of Ca 2+ -permeability. The 28 mammalian TRP channel proteins can be grouped into six subfamilies: canonical, vanilloid, melastatin, ankyrin, polycystic, and mucolipin TRPs. The majority of these TRP channels are expressed in different cell types including both excitable and nonexcitable cells of the cardiovascular system. Unlike voltage-gated ion channels, TRP channels do not have a typical voltage sensor, but instead can sense a variety of other stimuli including pressure, shear stress, mechanical stretch, oxidative stress, lipid environment alterations, hypertrophic signals, and inflammation products. By integrating multiple stimuli and transducing their activity to downstream cellular signal pathways via Ca 2+ entry and/or membrane depolarization, TRP channels play an essential role in regulating fundamental cell functions such as contraction, relaxation, proliferation, differentiation, and cell death. With the use of targeted deletion and transgenic mouse models, recent studies have revealed that TRP channels are involved in numerous cellular functions and play an important role in the pathophysiology of many diseases in the cardiovascular system. Moreover, several TRP channels are involved in inherited diseases of the cardiovascular system. This review presents an overview of current knowledge concerning the physiological functions of TRP channels in the cardiovascular system and their contributions to cardiovascular diseases. Ultimately, TRP channels may become potential therapeutic targets for cardiovascular diseases.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00457.2014
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2015
    detail.hit.zdb_id: 603838-4
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 7
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    Online Resource
    Transient Receptor Potential (TRP) Channels and Cardiac Fibrosis
    Bentham Science Publishers Ltd. ; 2013
    In:  Current Topics in Medicinal Chemistry Vol. 13, No. 3 ( 2013-03-01), p. 270-282
    Details
    In: Current Topics in Medicinal Chemistry, Bentham Science Publishers Ltd., Vol. 13, No. 3 ( 2013-03-01), p. 270-282
    Type of Medium: Online Resource
    ISSN: 1568-0266
    URL: Article
    DOI: 10.2174/1568026611313030005
    Language: English
    Publisher: Bentham Science Publishers Ltd.
    Publication Date: 2013
    detail.hit.zdb_id: 2064823-6
    SSG: 15,3
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  • 8
    Online Resource
    Online Resource
    Anti-PD-1 therapy combined with chemotherapy in patients with advanced biliary tract cancer
    Springer Science and Business Media LLC ; 2019
    In:  Cancer Immunology, Immunotherapy Vol. 68, No. 9 ( 2019-09), p. 1527-1535
    Details
    In: Cancer Immunology, Immunotherapy, Springer Science and Business Media LLC, Vol. 68, No. 9 ( 2019-09), p. 1527-1535
    Abstract: Evidence for the efficacy of immunotherapy in biliary tract cancer (BTC) is limited and unsatisfactory. Methods Chinese BTC patients receiving a PD-1 inhibitor with chemotherapy, PD-1 inhibitor monotherapy or chemotherapy alone were retrospectively analyzed. The primary outcome was overall survival (OS). The key secondary outcomes were progression-free survival (PFS) and safety. Patients previously treated with any agent targeting T cell costimulation or immune checkpoints were excluded. Results The study included 77 patients (a PD-1 inhibitor plus chemotherapy, n  = 38; PD-1 inhibitor monotherapy, n  = 20; chemotherapy alone, n  = 19). The median OS was 14.9 months with a PD-1 inhibitor plus chemotherapy, significantly longer than the 4.1 months with PD-1 inhibitor monotherapy (HR 0.37, 95% CI 0.17–0.80, P  = 0.001) and the 6.0 months with chemotherapy alone (HR 0.63, 95% CI 0.42–0.94, P  = 0.011). The median PFS was 5.1 months with a PD-1 inhibitor plus chemotherapy, significantly longer than the 2.2 months with PD-1 inhibitor monotherapy (HR 0.59, 95% CI 0.31–1.10, P  = 0.014) and the 2.4 months with chemotherapy alone (HR 0.61, 95% CI 0.45–0.83, P  = 0.003). Grade 3 or 4 treatment-related adverse events were similar between the anti-PD-1 combination group and the chemotherapy alone group (34.2% and 36.8%, respectively). Conclusions Anti-PD-1 therapy plus chemotherapy is an effective and tolerable approach for advanced BTC.
    Type of Medium: Online Resource
    ISSN: 0340-7004 , 1432-0851
    URL: Article
    DOI: 10.1007/s00262-019-02386-w
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 1458489-X
    detail.hit.zdb_id: 195342-4
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  • 9
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    Functional coupling of TRPM2 and extrasynaptic NMDARs exacerbates excitotoxicity in ischemic brain injury
    Elsevier BV ; 2022
    In:  Neuron Vol. 110, No. 12 ( 2022-06), p. 1944-1958.e8
    Details
    In: Neuron, Elsevier BV, Vol. 110, No. 12 ( 2022-06), p. 1944-1958.e8
    Type of Medium: Online Resource
    ISSN: 0896-6273
    URL: Article
    DOI: 10.1016/j.neuron.2022.03.021
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 808167-0
    SSG: 12
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  • 10
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    Combinational analysis of linkage and exome sequencing identifies the causative mutation in a Chinese family with congenital cataract
    Springer Science and Business Media LLC ; 2013
    In:  BMC Medical Genetics Vol. 14, No. 1 ( 2013-12)
    Details
    In: BMC Medical Genetics, Springer Science and Business Media LLC, Vol. 14, No. 1 ( 2013-12)
    Abstract: Congenital cataract is a Mendelian disorder that frequently causes blindness in infants. To date, various cataract-associated loci have been mapped; more than 30 genes have been identified by linkage analysis. However, the pathogenic loci in some affected families are still unknown, and new research strategies are needed. In this study, we used linkage-exome combinational analysis to further investigate the pedigree of a four-generation Chinese family with autosomal dominant coralliform cataract. Methods We combined whole exome sequencing and linkage analysis to identify the causative mutation. The exome capture and next-generation sequencing were used to sequence the protein-coding regions in the genome of the proband to identify rare mutations, which were further screened for candidate mutations in linkage regions. Candidate mutations were independently verified for co-segregation in the whole pedigree using Sanger sequencing. Results We identified a C to A transversion at nucleotide position c.70 in exon 2 of CRYGD , a cataract-associated gene. This mutation resulted in a threonine substitution for proline at amino acid residue 24. Conclusions We identified a missense P24T mutation in CRYGD that was responsible for coralliform cataract in our studied family. Our findings suggest that the combination of exome sequencing and linkage analysis is a powerful tool for identifying Mendelian disease mutations that might be missed by the classic linkage analysis strategy.
    Type of Medium: Online Resource
    ISSN: 1471-2350
    URL: Article
    DOI: 10.1186/1471-2350-14-107
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2013
    detail.hit.zdb_id: 2041359-2
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