Downregulation of uPAR and Cathepsin B Induces Apoptosis via Regulation of Bcl-2 and Bax and Inhibition of the PI3K/Akt Pathway in Gliomas

Glioma is the most commonly diagnosed primary brain tumor and is characterized by invasive and infiltrative behavior. uPAR and cathepsin B are known to be overexpressed in high-grade gliomas and are strongly correlated with invasive cancer phenotypes.In the present study, we observed that simultaneous downregulation of uPAR and cathepsin B induces upregulation of some pro-apoptotic genes and suppression of anti-apoptotic genes in human glioma cells. uPAR and cathepsin B (pCU)-downregulated cells exhibited decreases in the Bcl-2/Bax ratio and initiated the collapse of mitochondrial membrane potential. We also observed that the broad caspase inhibitor, Z-Asp-2, 6-dichlorobenzoylmethylketone rescued pCU-induced apoptosis in U251 cells but not in 5310 cells. Immunoblot analysis of caspase-9 immunoprecipitates for Apaf-1 showed that uPAR and cathepsin B knockdown activated apoptosome complex formation in U251 cells. Downregulation of uPAR and cathepsin B also retarded nuclear translocation and interfered with DNA binding activity of CREB in both U251 and 5310 cells. Further western blotting analysis demonstrated that downregulation of uPAR and cathepsin B significantly decreased expression of the signaling molecules p-PDGFR-β, p-PI3K and p-Akt. An increase in the number of TUNEL-positive cells, increased Bax expression, and decreased Bcl-2 expression in nude mice brain tumor sections and brain tissue lysates confirm our in vitro results.In conclusion, RNAi-mediated downregulation of uPAR and cathepsin B initiates caspase-dependent mitochondrial apoptosis in U251 cells and caspase-independent mitochondrial apoptosis in 5310 cells. Thus, targeting uPAR and cathepsin B-mediated signaling using siRNA may serve as a novel therapeutic strategy for the treatment of gliomas

SPARC Overexpression Inhibits Cell Proliferation in Neuroblastoma and Is Partly Mediated by Tumor Suppressor Protein PTEN and AKT

Secreted protein acidic and rich in cysteine (SPARC) is also known as BM-40 or Osteonectin, a multi-functional protein modulating cell–cell and cell–matrix interactions. In cancer, SPARC is not only linked with a highly aggressive phenotype, but it also acts as a tumor suppressor. In the present study, we sought to characterize the function of SPARC and its role in sensitizing neuroblastoma cells to radio-therapy. SPARC overexpression in neuroblastoma cells inhibited cell proliferation in vitro. Additionally, SPARC overexpression significantly suppressed the activity of AKT and this suppression was accompanied by an increase in the tumor suppressor protein PTEN both in vitro and in vivo. Restoration of neuroblastoma cell radio-sensitivity was achieved by overexpression of SPARC in neuroblastoma cells in vitro and in vivo. To confirm the role of the AKT in proliferation inhibited by SPARC overexpression, we transfected neuroblastoma cells with a plasmid vector carrying myr-AKT. Myr-AKT overexpression reversed SPARC-mediated PTEN and increased proliferation of neuroblastoma cells in vitro. PTEN overexpression in parallel with SPARC siRNA resulted in decreased AKT phosphorylation and proliferation in vitro. Taken together, these results establish SPARC as an effector of AKT-PTEN-mediated inhibition of proliferation in neuroblastoma in vitro and in vivo

Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families.

Discovery of most autosomal recessive disease-associated genes has involved analysis of large, often consanguineous multiplex families or small cohorts of unrelated individuals with a well-defined clinical condition. Discovery of new dominant causes of rare, genetically heterogeneous developmental disorders has been revolutionized by exome analysis of large cohorts of phenotypically diverse parent-offspring trios. Here we analyzed 4,125 families with diverse, rare and genetically heterogeneous developmental disorders and identified four new autosomal recessive disorders. These four disorders were identified by integrating Mendelian filtering (selecting probands with rare, biallelic and putatively damaging variants in the same gene) with statistical assessments of (i) the likelihood of sampling the observed genotypes from the general population and (ii) the phenotypic similarity of patients with recessive variants in the same candidate gene. This new paradigm promises to catalyze the discovery of novel recessive disorders, especially those with less consistent or nonspecific clinical presentations and those caused predominantly by compound heterozygous genotypes

Search for CP violation in D0 → KS0KS0 decays in proton-proton collisions at √s=13TeV

A search is reported for charge-parity CP violation in D0 → K0 SK0 S decays, using data collected in proton– proton collisions at √s = 13 TeV recorded by the CMS experiment in 2018. The analysis uses a dedicated data set that corresponds to an integrated luminosity of 41.6 fb−1 , which consists of about 10 billion events containing a pair of b hadrons, nearly all of which decay to charm hadrons. The flavor of the neutral D meson is determined by the pion charge in the reconstructed decays D∗+ → D0 π+ and D∗− → D0 π−. The CP asymmetry in D0 → K0 SK0 S is measured to be ACP(K0 SK0 S) = (6.2 ± 3.0 ± 0.2 ± 0.8)%, where the three uncertainties represent the statistical uncertainty, the systematic uncertainty, and the uncertainty in the measurement of theCP asymmetry in the D0 → K0 Sπ+π− decay. This is the first CP asymmetry measurement by CMS in the charm sector as well as the first to utilize a fully hadronic final state

Search for the production of W^{\pm} W^{\pm} W^{\mp} events at \sqrt{s} = 13 TeV

A search for the production of events containing three W bosons predicted by the standard model is reported. The search is based on a data sample of proton-proton collisions at a center-of-mass energy of 13 TeV recorded by the CMS experiment at the CERN LHC and corresponding to a total integrated luminosity of 35.9 fb^{-1}. The search is performed in final states with three leptons (electrons or muons), or with two same-charge leptons plus two jets. The observed (expected) significance of the signal for W^{\pm} W^{\pm} W^{\mp} production is 0.60 (1.78) standard deviations, and the ratio of the measured signal yield to that expected from the standard model is 0.34_{-0.34}^{+0.62}. Limits are placed on three anomalous quartic gauge couplings and on the production of massive axionlike particles

Measurement of energy correlators inside jets and determination of the strong coupling αS(mZ)

A preprint version of this article is available at arXiv:2402.13864v2 [hep-ex], https://arxiv.org/abs/2402.13864 . Comments: Replaced with the published version. Added the journal reference and the DOI. All the figures and tables can be found at https://cms-results.web.cern.ch/cms-results/public-results/publications/SMP-22-015 (CMS Public Pages). Report number: CMS-SMP-22-015, CERN-EP-2024-010 .Energy correlators that describe energy-weighted distances between two or three particles in a hadronic jet are measured using an event sample of √ = 13  TeV proton-proton collisions collected by the CMS experiment and corresponding to an integrated luminosity of 36.3  fb^−1. The measured distributions are consistent with the trends in the simulation that reveal two key features of the strong interaction: confinement and asymptotic freedom. By comparing the ratio of the measured three- and two-particle energy correlator distributions with theoretical calculations that resum collinear emissions at approximate next-to-next-to-leading-logarithmic accuracy matched to a next-to-leading-order calculation, the strong coupling is determined at the boson mass: ⁡() = 0.122⁢9+0.0040 −0.0050, the most precise ⁡() value obtained using jet substructure observables.SCOAP3

Search for new Higgs bosons via same-sign top quark pair production in association with a jet in proton-proton collisions at √s = 13 TeV

Data availability: Release and preservation of data used by the CMS Collaboration as the basis for publications is guided by the CMS policy as stated in “CMS data preservation, re-use and open access policy” available online at: https://cms-docdb.cern.ch/cgi-bin/PublicDocDB/RetrieveFile?docid=6032&filename=CMSDataPolicyV1.2.pdf&version=2 .A preprint of this article is available online at arXiv:2311.03261v2 [hep-ex] https://arxiv.org/abs/2311.03261v2 . Comments: Replaced with the published version. Added the journal reference and the DOI. All the figures and tables can be found at https://cms-results.web.cern.ch/cms-results/public-results/publications/TOP-22-010 (CMS Public Pages)A search is presented for new Higgs bosons in proton-proton (pp) collision events in which a same-sign top quark pair is produced in association with a jet, via the pp → tH/A → tt¯c and pp → tH/A → tt¯u processes. Here, H and A represent the extra scalar and pseudoscalar boson, respectively, of the second Higgs doublet in the generalized two-Higgs-doublet model (g2HDM). The search is based on pp collision data collected at a center-of-mass energy of 13 TeV with the CMS detector at the LHC, corresponding to an integrated luminosity of 138 fb−1. Final states with a same-sign lepton pair in association with jets and missing transverse momentum are considered. New Higgs bosons in the 200-1000 GeV mass range and new Yukawa couplings between 0.1 and 1.0 are targeted in the search, for scenarios in which either H or A appear alone, or in which they coexist and interfere. No significant excess above the standard model prediction is observed. Exclusion limits are derived in the context of the g2HDM.SCOAP3

Energy-scaling behavior of intrinsic transverse-momentum parameters in Drell-Yan simulation

Data Availability: Release and preservation of data used by the CMS Collaboration as the basis for publications is guided by the CMS data preservation, re-use, and open access policy https://dx.doi.org/10.7483/OPENDATA.CMS.7347.JDWH .A preprint version of the article is available on arXiv, arXiv:2409.17770v2 [hep-ph] (https://arxiv.org/abs/2409.17770). [v2] Tue, 8 Apr 2025 23:23:48 UTC (450 KB). Comments: Replaced with the published version. Added the journal reference and the DOI. All the figures and tables can be found at https://cms-results.web.cern.ch/cms-results/public-results/publications/GEN-22-001 (CMS Public Pages). Subjects: High Energy Physics - Phenomenology (hep-ph); High Energy Physics - Experiment (hep-ex). Report numbers: CMS-GEN-22-001, CERN-EP-2024-216An analysis is presented based on models of the intrinsic transverse momentum (intrinsic ) of partons in nucleons by studying the dilepton transverse momentum in Drell-Yan events. Using parameter tuning in event generators and existing data from fixed-target experiments and from hadron colliders, our investigation spans 3 orders of magnitude in center-of-mass energy and 2 orders of magnitude in dilepton invariant mass. The results show an energy-scaling behavior of the intrinsic parameters, independent of the dilepton invariant mass at a given center-of-mass energy.We congratulate our colleagues in the CERN accelerator departments for the excellent performance of the LHC and thank the technical and administrative staffs at CERN and at other CMS institutes for their contributions to the success of the CMS effort. In addition, we gratefully acknowledge the computing centers and personnel of the Worldwide LHC Computing Grid and other centers for delivering so effectively the computing infrastructure essential to our analyses. Finally, we acknowledge the enduring support for the construction and operation of the LHC, the CMS detector, and the supporting computing infrastructure provided by the following funding agencies: SC (Armenia), BMBWF and FWF (Austria); FNRS and FWO (Belgium); CNPq, CAPES, FAPERJ, FAPERGS, and FAPESP (Brazil); MES and BNSF (Bulgaria); CERN; CAS, MoST, and NSFC (China); MINCIENCIAS (Colombia); MSES and CSF (Croatia); RIF (Cyprus); SENESCYT (Ecuador); ERC PRG, RVTT3 and MoER TK202 (Estonia); Academy of Finland, MEC, and HIP (Finland); CEA and CNRS/IN2P3 (France); SRNSF (Georgia); BMBF, DFG, and HGF (Germany); GSRI (Greece); NKFIH (Hungary); DAE and DST (India); IPM (Iran); SFI (Ireland); INFN (Italy); MSIP and NRF (Republic of Korea); MES (Latvia); LMTLT (Lithuania); MOE and UM (Malaysia); BUAP, CINVESTAV, CONACYT, LNS, SEP, and UASLP-FAI (Mexico); MOS (Montenegro); MBIE (New Zealand); PAEC (Pakistan); MES and NSC (Poland); FCT (Portugal); MESTD (Serbia); MCIN/AEI and PCTI (Spain); MOSTR (Sri Lanka); Swiss Funding Agencies (Switzerland); MST (Taipei); MHESI and NSTDA (Thailand); TUBITAK and TENMAK (Turkey); NASU (Ukraine); STFC (United Kingdom); DOE and NSF (USA)

Search for physics beyond the standard model in top quark production with additional leptons in the context of effective field theory

A preprint version of the article is available at arXiv:2307.15761v2 [hep-ex], https://arxiv.org/abs/2307.15761v2 . Comments: Replaced with the published version. Added the journal reference and the DOI. All the figures and tables can be found at https://cms-results.web.cern.ch/cms-results/public-results/publications/TOP-22-006 (CMS Public Pages). Report number: CMS-TOP-22-006, CERN-EP-2023-124.A search for new physics in top quark production with additional final-state leptons is performed using data collected by the CMS experiment in proton-proton collisions at √s = 13 TeV at the LHC during 2016-2018. The data set corresponds to an integrated luminosity of 138 fb−1. Using the framework of effective field theory (EFT), potential new physics effects are parametrized in terms of 26 dimension-six EFT operators. The impacts of EFT operators are incorporated through the event-level reweighting of Monte Carlo simulations, which allows for detector-level predictions. The events are divided into several categories based on lepton multiplicity, total lepton charge, jet multiplicity, and b-tagged jet multiplicity. Kinematic variables corresponding to the transverse momentum (pT) of the leading pair of leptons and/or jets as well as the pT of on-shell Z bosons are used to extract the 95% confidence intervals of the 26 Wilson coefficients corresponding to these EFT operators. No significant deviation with respect to the standard model prediction is found.SCOAP3