Displaying publications 81 - 100 of 277 in total

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  1. Search for Narrow Hγ Resonances in Proton-Proton Collisions at sqrt[s]=13  TeV
    Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, et al.
    Phys Rev Lett, 2019 Mar 01;122(8):081804.
    PMID: 30932612 DOI: 10.1103/PhysRevLett.122.081804
    A search for heavy, narrow resonances decaying to a Higgs boson and a photon (Hγ) has been performed in proton-proton collision data at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 35.9  fb^{-1} collected with the CMS detector at the LHC in 2016. Events containing a photon and a Lorentz-boosted hadronically decaying Higgs boson reconstructed as a single, large-radius jet are considered, and the γ+jet invariant mass spectrum is analyzed for the presence of narrow resonances. To increase the sensitivity of the search, events are categorized depending on whether or not the large-radius jet can be identified as a result of the merging of two jets originating from b quarks. Results in both categories are found to agree with the predictions of the standard model. Upper limits on the production rate of Hγ resonances are set as a function of their mass in the range of 720-3250 GeV, representing the most stringent constraints to date.
  2. Search for Low-Mass Quark-Antiquark Resonances Produced in Association with a Photon at sqrt[s]=13  TeV
    Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Bergauer T, Brandstetter J, et al.
    Phys Rev Lett, 2019 Dec 06;123(23):231803.
    PMID: 31868480 DOI: 10.1103/PhysRevLett.123.231803
    A search for narrow low-mass resonances decaying to quark-antiquark pairs is presented. The search is based on proton-proton collision events collected at 13 TeV by the CMS detector at the CERN LHC. The data sample corresponds to an integrated luminosity of 35.9  fb^{-1}, recorded in 2016. The search considers the case where the resonance has high transverse momentum due to initial-state radiation of a hard photon. To study this process, the decay products of the resonance are reconstructed as a single large-radius jet with two-pronged substructure. The signal would be identified as a localized excess in the jet invariant mass spectrum. No evidence for such a resonance is observed in the mass range 10 to 125 GeV. Upper limits at the 95% confidence level are set on the coupling strength of resonances decaying to quark pairs. The results obtained with this photon trigger strategy provide the first direct constraints on quark-antiquark resonance masses below 50 GeV obtained at a hadron collider.
  3. Search for Low Mass Vector Resonances Decaying to Quark-Antiquark Pairs in Proton-Proton Collisions at sqrt[s]=13  TeV
    Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, et al.
    Phys Rev Lett, 2017 Sep 15;119(11):111802.
    PMID: 28949210 DOI: 10.1103/PhysRevLett.119.111802
    A search is reported for a narrow vector resonance decaying to quark-antiquark pairs in proton-proton collisions at sqrt[s]=13  TeV, collected with the CMS detector at the LHC. The data sample corresponds to an integrated luminosity of 2.7   fb^{-1}. The vector resonance is produced at large transverse momenta, with its decay products merged into a single jet. The resulting signature is a peak over background in the distribution of the invariant mass of the jet. The results are interpreted in the framework of a leptophobic vector resonance and no evidence is found for such particles in the mass range of 100-300 GeV. Upper limits at 95% confidence level on the production cross section are presented in a region of mass-coupling phase space previously unexplored at the LHC. The region below 140 GeV has not been explored by any previous experiments.
  4. Search for Long-Lived Particles Decaying in the CMS End Cap Muon Detectors in Proton-Proton Collisions at sqrt[s]=13  TeV
    Tumasyan A, Adam W, Andrejkovic JW, Bergauer T, Chatterjee S, Dragicevic M, et al.
    Phys Rev Lett, 2021 Dec 24;127(26):261804.
    PMID: 35029469 DOI: 10.1103/PhysRevLett.127.261804
    A search for long-lived particles (LLPs) produced in decays of standard model (SM) Higgs bosons is presented. The data sample consists of 137  fb^{-1} of proton-proton collisions at sqrt[s]=13  TeV, recorded at the LHC in 2016-2018. A novel technique is employed to reconstruct decays of LLPs in the end cap muon detectors. The search is sensitive to a broad range of LLP decay modes and to masses as low as a few GeV. No excess of events above the SM background is observed. The most stringent limits to date on the branching fraction of the Higgs boson to LLPs subsequently decaying to quarks and τ^{+}τ^{-} are found for proper decay lengths greater than 6, 20, and 40 m, for LLP masses of 7, 15, and 40 GeV, respectively.
  5. Search for Leptoquarks Coupled to Third-Generation Quarks in Proton-Proton Collisions at sqrt[s]=13  TeV
    Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, et al.
    Phys Rev Lett, 2018 Dec 14;121(24):241802.
    PMID: 30608761 DOI: 10.1103/PhysRevLett.121.241802
    Three of the most significant measured deviations from standard model predictions, the enhanced decay rate for B→D^{(*)}τν, hints of lepton universality violation in B→K^{(*)}ℓℓ decays, and the anomalous magnetic moment of the muon, can be explained by the existence of leptoquarks (LQs) with large couplings to third-generation quarks and masses at the TeV scale. The existence of these states can be probed at the LHC in high energy proton-proton collisions. A novel search is presented for pair production of LQs coupled to a top quark and a muon using data at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 35.9  fb^{-1}, recorded by the CMS experiment. No deviation from the standard model prediction has been observed and scalar LQs decaying exclusively into tμ are excluded up to masses of 1420 GeV. The results of this search are combined with those from previous searches for LQ decays into tτ and bν, which excluded scalar LQs below masses of 900 and 1080 GeV. Vector LQs are excluded up to masses of 1190 GeV for all possible combinations of branching fractions to tμ, tτ and bν. With this analysis, all relevant couplings of LQs with an electric charge of -1/3 to third-generation quarks are probed for the first time.
  6. Search for Inelastic Dark Matter in Events with Two Displaced Muons and Missing Transverse Momentum in Proton-Proton Collisions at sqrt[s]=13  TeV
    Hayrapetyan A, Tumasyan A, Adam W, Andrejkovic JW, Bergauer T, Chatterjee S, et al.
    Phys Rev Lett, 2024 Jan 26;132(4):041802.
    PMID: 38335361 DOI: 10.1103/PhysRevLett.132.041802
    A search for dark matter in events with a displaced nonresonant muon pair and missing transverse momentum is presented. The analysis is performed using an integrated luminosity of 138  fb^{-1} of proton-proton (pp) collision data at a center-of-mass energy of 13 TeV produced by the LHC in 2016-2018. No significant excess over the predicted backgrounds is observed. Upper limits are set on the product of the inelastic dark matter production cross section σ(pp→A^{'}→χ_{1}χ_{2}) and the decay branching fraction B(χ_{2}→χ_{1}μ^{+}μ^{-}), where A^{'} is a dark photon and χ_{1} and χ_{2} are states in the dark sector with near mass degeneracy. This is the first dedicated collider search for inelastic dark matter.
  7. Search for Higgs Boson and Observation of Z Boson through Their Decay into a Charm Quark-Antiquark Pair in Boosted Topologies in Proton-Proton Collisions at sqrt[s]=13  TeV
    Tumasyan A, Adam W, Andrejkovic JW, Bergauer T, Chatterjee S, Damanakis K, et al.
    Phys Rev Lett, 2023 Jul 28;131(4):041801.
    PMID: 37566854 DOI: 10.1103/PhysRevLett.131.041801
    A search for the standard model (SM) Higgs boson (H) produced with transverse momentum (p_{T}) greater than 450 GeV and decaying to a charm quark-antiquark (cc[over ¯]) pair is presented. The search is performed using proton-proton collision data collected at sqrt[s]=13  TeV by the CMS experiment at the LHC, corresponding to an integrated luminosity of 138  fb^{-1}. Boosted H→cc[over ¯] decay products are reconstructed as a single large-radius jet and identified using a deep neural network charm tagging technique. The method is validated by measuring the Z→cc[over ¯] decay process, which is observed in association with jets at high p_{T} for the first time with a signal strength of 1.00_{-0.14}^{+0.17}(syst)±0.08(theo)±0.06(stat), defined as the ratio of the observed process rate to the SM expectation. The observed (expected) upper limit on σ(H)B(H→cc[over ¯]) is set at 47 (39) times the SM prediction at 95% confidence level.
  8. Search for Higgs Boson Decay to a Charm Quark-Antiquark Pair in Proton-Proton Collisions at sqrt[s]=13  TeV
    Tumasyan A, Adam W, Andrejkovic JW, Bergauer T, Chatterjee S, Damanakis K, et al.
    Phys Rev Lett, 2023 Aug 11;131(6):061801.
    PMID: 37625071 DOI: 10.1103/PhysRevLett.131.061801
    A search for the standard model Higgs boson decaying to a charm quark-antiquark pair, H→cc[over ¯], produced in association with a leptonically decaying V (W or Z) boson is presented. The search is performed with proton-proton collisions at sqrt[s]=13  TeV collected by the CMS experiment, corresponding to an integrated luminosity of 138  fb^{-1}. Novel charm jet identification and analysis methods using machine learning techniques are employed. The analysis is validated by searching for Z→cc[over ¯] in VZ events, leading to its first observation at a hadron collider with a significance of 5.7 standard deviations. The observed (expected) upper limit on σ(VH)B(H→cc[over ¯]) is 0.94 (0.50_{-0.15}^{+0.22})pb at 95% confidence level (C.L.), corresponding to 14 (7.6_{-2.3}^{+3.4}) times the standard model prediction. For the Higgs-charm Yukawa coupling modifier, κ_{c}, the observed (expected) 95% C.L. interval is 1.1
  9. Search for Heavy Neutral Leptons in Events with Three Charged Leptons in Proton-Proton Collisions at sqrt[s]=13  TeV
    Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, et al.
    Phys Rev Lett, 2018 Jun 01;120(22):221801.
    PMID: 29906166 DOI: 10.1103/PhysRevLett.120.221801
    A search for a heavy neutral lepton N of Majorana nature decaying into a W boson and a charged lepton is performed using the CMS detector at the LHC. The targeted signature consists of three prompt charged leptons in any flavor combination of electrons and muons. The data were collected in proton-proton collisions at a center-of-mass energy of 13 TeV, with an integrated luminosity of 35.9  fb^{-1}. The search is performed in the N mass range between 1 GeV and 1.2 TeV. The data are found to be consistent with the expected standard model background. Upper limits are set on the values of |V_{eN}|^{2} and |V_{μN}|^{2}, where V_{ℓN} is the matrix element describing the mixing of N with the standard model neutrino of flavor ℓ. These are the first direct limits for N masses above 500 GeV and the first limits obtained at a hadron collider for N masses below 40 GeV.
  10. Search for Exotic Higgs Boson Decays H→AA→4γ with Events Containing Two Merged Diphotons in Proton-Proton Collisions at sqrt[s]=13  TeV
    Tumasyan A, Adam W, Andrejkovic JW, Bergauer T, Chatterjee S, Damanakis K, et al.
    Phys Rev Lett, 2023 Sep 08;131(10):101801.
    PMID: 37739361 DOI: 10.1103/PhysRevLett.131.101801
    We present the first direct search for exotic Higgs boson decays H→AA, A→γγ in events with two photonlike objects. The hypothetical particle A is a low-mass spin-0 particle decaying promptly to a merged diphoton reconstructed as a single photonlike object. We analyze the data collected by the CMS experiment at sqrt[s]=13  TeV corresponding to an integrated luminosity of 136  fb^{-1}. No excess above the estimated background is found. We set upper limits on the branching fraction B(H→AA→4γ) of (0.9-3.3)×10^{-3} at 95% confidence level for masses of A in the range 0.1-1.2 GeV.
  11. Search for Evidence of the Type-III Seesaw Mechanism in Multilepton Final States in Proton-Proton Collisions at sqrt[s]=13  TeV
    Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, et al.
    Phys Rev Lett, 2017 Dec 01;119(22):221802.
    PMID: 29286783 DOI: 10.1103/PhysRevLett.119.221802
    A search for a signal consistent with the type-III seesaw mechanism in events with three or more electrons or muons is presented. The data sample consists of proton-proton collisions at sqrt[s]=13  TeV collected by the CMS experiment at the LHC in 2016 and corresponds to an integrated luminosity of 35.9  fb^{-1}. Selection criteria based on the number of leptons and the invariant mass of oppositely charged lepton pairs are used to distinguish the signal from the standard model background. The observations are consistent with the expectations from standard model processes. The results are used to place limits on the production of heavy fermions of the type-III seesaw model as a function of the branching ratio to each lepton flavor. In the scenario of equal branching fractions to each lepton flavor, heavy fermions with masses below 840 GeV are excluded. This is the most sensitive probe to date of the type-III seesaw mechanism.
  12. Fulltext Search for Dark Matter and Supersymmetry with a Compressed Mass Spectrum in the Vector Boson Fusion Topology in Proton-Proton Collisions at sqrt[s]=8  TeV
    Khachatryan V, Sirunyan AM, Tumasyan A, Adam W, Asilar E, Bergauer T, et al.
    Phys Rev Lett, 2017 Jan 13;118(2):021802.
    PMID: 28128610 DOI: 10.1103/PhysRevLett.118.021802
    A first search for pair production of dark matter candidates through vector boson fusion in proton-proton collisions at sqrt[s]=8  TeV is performed with the CMS detector. The vector boson fusion topology enhances missing transverse momentum, providing a way to probe supersymmetry, even in the case of a compressed mass spectrum. The data sample corresponds to an integrated luminosity of 18.5  fb^{-1}, recorded by the CMS experiment. The observed dijet mass spectrum is consistent with the standard model expectation. In an effective field theory, dark matter masses are explored as a function of contact interaction strength. The most stringent limit on bottom squark production with mass below 315 GeV is also reported, assuming a 5 GeV mass difference with respect to the lightest neutralino.
  13. Search for Dark Matter Particles Produced in Association with a Top Quark Pair at sqrt[s]=13  TeV
    Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, et al.
    Phys Rev Lett, 2019 Jan 11;122(1):011803.
    PMID: 31012697 DOI: 10.1103/PhysRevLett.122.011803
    A search is performed for dark matter particles produced in association with a top quark pair in proton-proton collisions at sqrt[s]=13  TeV. The data correspond to an integrated luminosity of 35.9  fb^{-1} recorded by the CMS detector at the LHC. No significant excess over the standard model expectation is observed. The results are interpreted using simplified models of dark matter production via spin-0 mediators that couple to dark matter particles and to standard model quarks, providing constraints on the coupling strength between the mediator and the quarks. These are the most stringent collider limits to date for scalar mediators, and the most stringent for pseudoscalar mediators at low masses.
  14. Search for Charged Higgs Bosons Produced via Vector Boson Fusion and Decaying into a Pair of W and Z Bosons Using pp Collisions at sqrt[s]=13  TeV
    Sirunyan AM, Tumasyan A, Adam W, Asilar E, Bergauer T, Brandstetter J, et al.
    Phys Rev Lett, 2017 Oct 06;119(14):141802.
    PMID: 29053305 DOI: 10.1103/PhysRevLett.119.141802
    A search for charged Higgs bosons produced via vector boson fusion and decaying into W and Z bosons using proton-proton collisions at sqrt[s]=13  TeV is presented. The data sample corresponds to an integrated luminosity of 15.2  fb^{-1} collected with the CMS detector in 2015 and 2016. The event selection requires three leptons (electrons or muons), two jets with large pseudorapidity separation and high dijet mass, and missing transverse momentum. The observation agrees with the standard model prediction. Limits on the vector boson fusion production cross section times branching fraction for new charged physical states are reported as a function of mass from 200 to 2000 GeV and interpreted in the context of Higgs triplet models.
  15. Fulltext Safety and efficacy of tocotrienol supplementation for bone health in postmenopausal women: protocol for a dose-response double-blinded placebo-controlled randomised trial
    Shen CL, Mo H, Yang S, Wang S, Felton CK, Tomison MD, et al.
    BMJ Open, 2016 12 23;6(12):e012572.
    PMID: 28011809 DOI: 10.1136/bmjopen-2016-012572
    INTRODUCTION: Osteoporosis is a major health concern in postmenopausal women, and oxidative stress contributes to the development of bone loss. Cellular studies and ovariectomised rat model mimicking bone loss in postmenopausal women show the bone-protective effect of tocotrienols (TTs) with antioxidant capability. We aim to access the safety and efficacy of TT consumption for bone health in postmenopausal women.

    METHODS AND ANALYSIS: In this 12-week randomised double-blinded placebo-controlled trial for the effects of dietary TT supplementation in postmenopausal women, postmenopausal women aged 45 years and older with at least 1 year after menopause and bone mineral density T-score at the spine and/or hip 2.5 or more below the reference values will be randomly assigned to 3 daily supplements: (1) placebo group receiving 860 mg olive oil, (2) low TT group receiving 430 mg of 70% pure TTs (containing 300 mg TT) and (3) high TT group receiving 860 mg of 70% pure TTs (600 mg TT). The primary outcome measure will be urinary N-terminal telopeptide. The secondary outcome measures will be serum bone-specific alkaline phosphatase, receptor activator of nuclear factor-κB ligand, osteoprotegerin, urinary 8-hydroxy-2'-deoxyguanosine and quality of life. At 0, 6 and 12 weeks, the following will be assessed: (1) primary and secondary outcome measures; (2) serum TT and tocopherol concentrations; (3) physical activity and food frequency questionnaires. Liver function will be monitored every 6 weeks for safety. 'Intent-to-treat' principle will be employed for data analysis. A model of repeated measurements with random effect error terms will be applied. Analysis of covariance, χ2 analysis and regression will be used for comparisons.

    ETHICS AND DISSEMINATION: This study was approved by the Bioethics Committee of the Texas Tech University Health Sciences Center. The findings of this trial will be submitted to a peer-reviewed journal in the areas of bone or nutrition and international conferences.

    TRIAL REGISTRATION NUMBER: NCT02058420; results.

  16. Fulltext SARS-CoV-2 detection by targeting four loci of viral genome using graphene oxide and gold nanoparticle DNA biosensor
    Babadi AA, Rahmati S, Fakhlaei R, Heidari R, Baradaran S, Akbariqomi M, et al.
    Sci Rep, 2022 Nov 12;12(1):19416.
    PMID: 36371566 DOI: 10.1038/s41598-022-23996-y
    The current COVID-19 pandemic outbreak poses a serious threat to public health, demonstrating the critical need for the development of effective and reproducible detection tests. Since the RT-qPCR primers are highly specific and can only be designed based on the known sequence, mutation sensitivity is its limitation. Moreover, the mutations in the severe acute respiratory syndrome β-coronavirus (SARS-CoV-2) genome led to new highly transmissible variants such as Delta and Omicron variants. In the case of mutation, RT-qPCR primers cannot recognize and attach to the target sequence. This research presents an accurate dual-platform DNA biosensor based on the colorimetric assay of gold nanoparticles and the surface-enhanced Raman scattering (SERS) technique. It simultaneously targets four different regions of the viral genome for detection of SARS-CoV-2 and its new variants prior to any sequencing. Hence, in the case of mutation in one of the target sequences, the other three probes could detect the SARS-CoV-2 genome. The method is based on visible biosensor color shift and a locally enhanced electromagnetic field and significantly amplified SERS signal due to the proximity of Sulfo-Cyanine 3 (Cy3) and AuNPs intensity peak at 1468 cm-1. The dual-platform DNA/GO/AuNP biosensor exhibits high sensitivity toward the viral genome with a LOD of 0.16 ng/µL. This is a safe point-of-care, naked-eye, equipment-free, and rapid (10 min) detection biosensor for diagnosing COVID-19 cases at home using a nasopharyngeal sample.
  17. Fulltext Research on an innovative design and evaluation method of Chinese tea sets based on GT-AHP-FCE
    Zhao Y, Hamat B, Wang T, Wang S, Pang LLL
    PLoS One, 2024;19(4):e0302005.
    PMID: 38603676 DOI: 10.1371/journal.pone.0302005
    AIMS: In order to explore new consumer demands for Chinese tea set products, propose an innovative tea set product design and evaluation method to improve the user experience and satisfaction of the produced tea sets, thereby promoting the development of the tea set market and the promotion of tea culture.

    METHODS: Firstly, grounded theory (GT) was used to analyze interview data to extract consumer demand indicators and construct a design evaluation hierarchical model. Secondly, the Analytical Hierarchy Process (AHP) was used to calculate the weights of the indicators, determine their priority of importance, and obtain several indicators that have a greater impact on the tea set design to guide innovative design practice. Lastly, the tea set design schemes were evaluated using the fuzzy comprehensive evaluation method to select the optimal design scheme and also to act as a guideline for further design optimization.

    CONCLUSION: This study explores the innovative design and evaluation method for tea set products based on GT-AHP-FCE and validates the feasibility of this approach through a practical example of tea set design inspired by "The Classic of Mountains and Seas.". It provides innovative theoretical and practical guidance for designers of subsequent tea set products and also provides a new path for the inheritance and innovation of traditional culture.

  18. Fulltext Relative Modification of Prompt ψ(2S) and J/ψ Yields from pp to PbPb Collisions at sqrt[s_{NN}]=5.02  TeV
    Sirunyan AM, Tumasyan A, Adam W, Asilar E, Bergauer T, Brandstetter J, et al.
    Phys Rev Lett, 2017 Apr 21;118(16):162301.
    PMID: 28474955 DOI: 10.1103/PhysRevLett.118.162301
    The relative modification of the prompt ψ(2S) and J/ψ yields from pp to PbPb collisions, at the center-of-mass energy of 5.02 TeV per nucleon pair, is presented. The analysis is based on pp and PbPb data samples collected by the CMS experiment at the LHC in 2015, corresponding to integrated luminosities of 28.0  pb^{-1} and 464  μb^{-1}, respectively. The double ratio of measured yields of prompt charmonia reconstructed through their decays into muon pairs, (N_{ψ(2S)}/N_{J/ψ})_{PbPb}/(N_{ψ(2S)}/N_{J/ψ})_{pp}, is determined as a function of PbPb collision centrality and charmonium transverse momentum p_{T}, in two kinematic intervals: |y|<1.6 covering 6.5
  19. Relationship Between Post-Traumatic Stress Symptoms and Caregiver Burden In Breast Cancer Patients: The Mediating Role of Anxiety and Depression
    Wang S, Zhang Q, Goh PH, Hu J, Liu X, Du J, et al.
    J Clin Psychol Med Settings, 2023 Sep;30(3):645-653.
    PMID: 36385422 DOI: 10.1007/s10880-022-09927-z
    Breast cancer impacts not only the physical and mental health of patients but also the people around them-especially their caregivers. This study examined the relationship between post-traumatic stress symptoms (PTSS) and caregiver burden in breast cancer patients through the mediating pathway of anxiety and depression.

    METHODS: A total of 236 breast cancer patients from China completed the Chinese Version of the Posttraumatic Stress Disorder Symptom Scale (PSS), the Chinese version of the Patient Health Questionnaire (PHQ-9), the Chinese version of the General Anxiety Symptoms Scale (GAD-7). In addition, caregivers of these breast cancer patients were surveyed by the Caregiver Self-Assessment Questionnaire (CSAQ).

    RESULTS: Structural equation model showed that our model fitted well [χ2 /df = 1.966, TLI = 0.959, CFI = 0.994, RMSEA (90% CI) = 0.065 (0-0.12)] and revealed that anxiety, but not depression, mediated the relationship between PTSS in breast cancer patients and caregiver burden.

    CONCLUSION: The level of PTSS was positively correlated with anxiety and depression in breast cancer patients, and the level of anxiety and depression was positively related to caregiver burden. The PTSS of patients positively predicted caregiver burden and this relationship appears to be mediated by the patient's anxiety.

  20. Fulltext Regulation of Hippo/YAP signaling and Esophageal Squamous Carcinoma progression by an E3 ubiquitin ligase PARK2
    Zhou X, Li Y, Wang W, Wang S, Hou J, Zhang A, et al.
    Theranostics, 2020;10(21):9443-9457.
    PMID: 32863938 DOI: 10.7150/thno.46078
    Objective: Esophageal squamous cell carcinoma (ESCC) is one of the most commonly diagnosed cancer types in China. Recent genomic sequencing analysis indicated the over-activation of Hippo/YAP signaling might play important roles for the carcinogenic process and progression for ESCC patients. However, little is known about the molecular mechanisms that controls Hippo signaling activity in ESCC. Our previous studies indicated that PLCE1-an important risk factor for ESCC-linked to ESCC progression through snail signaling, during this period, we found PARK2 was an important downstream target of PLCE1-snail axis. PARK2 was decreased in ESCC human samples, and correlated with good prognosis in ESCC patients. Further research showed that PARK2 could inhibit YAP, which functions as key downstream effectors of the Hippo pathway. Here, we aim to reveal the molecular mechanisms of PARK2 modulated Hippo pathway in ESCC. Methods: To evaluate the function of PARK2 in ESCC, we used a tissue microarray (TMA) of 223 human ESCC patients and immunohistochemistry to analyze the correlation between PARK2 expression and clinicopathologic variables. Depletion of endogenous PARK2 and YAP from ESCC cells using CRISPR/Cas9 technologies. Flow cytometry and EdU cell proliferation assay were used to detect proliferation of ESCC cells. Nude mice subcutaneous injection and Ki-67 staining were used to evaluate tumor growth in vivo. Migration and invasion assays were performed. In addition, lung metastasis models in mice were used to validate the function of PARK2 in vivo. Identification of PARK2 involved in hippo pathway was achieved by expression microarray screening, double immunofluorescence staining and co-immunoprecipitation assays. The RNA-seq analysis results were validated through quantitative real-time PCR (qRT-PCR) analysis. The protein half-life of YAP was analyzed by Cycloheximide assay, and the TEAD activity was detected by Luciferase reporter assays. Results: Clinical sample of ESCC revealed that low PARK2 expression correlated with late tumor stage (P < 0.001), poor differentiation (P < 0.04), lymph node (P < 0.001) and distant metastasis (P = 0.0087). Multivariate Cox proportional regression analysis further revealed that PARK2 expression (P = 0.032) is an independent prognostic factor for the overall survival of ESCC patients. Besides, the immunohistochemistry results showed that PARK2 negatively correlated with YAP protein level (P < 0.001). PARK2 depletion promotes ESCC progression both through Hippo/YAP axis, while PARK2 overexpression suppresses ESCC tumor progression by Hippo signaling. Co-IP and ubiquitination assays revealed that PARK2 could interact with YAP in the cytosol and promotes YAP K48-linked ubiquitination at K90 sites. Conclusion: Clinical sample analysis and mechanistic study have validated PARK2 as a tumor suppressor for ESCC. Multivariate Cox proportional regression analysis further revealed that PARK2 is an independent prognostic factor for the overall survival of ESCC patients. Cellular and molecular mechanisms in this study showed that PARK2 associated with YAP protein in the cytosol, promoted YAP ubiquitination and proteasome-dependent degradation in ESCC cells. Therefore, as a novel modulator for Hippo signaling, modulation of PARK2 activity or gene expression level could be an appealing strategy to treat esophageal.
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