Network Biology of Tumor Stem-like Cells Identified a Regulatory Role of CBX5 in Lung Cancer

Mounting evidence links cancers possessing stem-like properties with worse prognosis. Network biology with signal processing mechanics was explored here using expression profiles of a panel of tumor stem-like cells (TSLCs). The profiles were compared to their parental tumor cells (PTCs) and the human embryonic stem cells (hESCs), for the identification of gene chromobox homolog 5, CBX5, as a potential target for lung cancer. CBX5 was found to regulate the stem-like properties of lung TSLCs and was predictive of lung cancer prognosis. The investigation was facilitated by finding target genes based on modeling epistatic signaling mechanics via a predictive and scalable network-based survival model. Topologically-weighted measurements of CBX5 were synchronized with those of BIRC5, DNMT1, E2F1, ESR1, MLH1, MSH2, RB1, SMAD1 and TAF5. We validated our findings in another Taiwanese lung cancer cohort, as well as in knockdown experiments using sh-CBX5 RNAi both in vitro and in vivo.National Science Council (China) (NSC grant 100-2325-B-010-010-MY3/98-2314-B-010-024-MY2/97-3111-B075-001-MY3/ 96-2314-075-056-MY3)National Yang-Ming University (Ministry of Education, Aim for the Top University Plan: 96ADD122, 96ADD125, 96ADT191, 97ACD113, 97ACT302, 98ACT302, 98ACD107, 98ACT192 and Brain Research Center-3T-MRI project)))Taipei Veterans General Hospital (98-C1-099/E1-003/ER3-001)Taipei Veterans General Hospital (Joint Projects of VGHUST (98-G6-6/ 98-P1-01/99-P6-39)Chi Mei Medical Center (CMYM9801)Yen-Tjing-Ling Medical Foundation (96/97/98)Taipei City Hospital (96-002-62-092)Technology Development Program for Academia (TDPA; 98-EC-17-A-19-S2-0107)Taiwan. Department of Industrial Technology, Ministry of Economic AffairsNational Science Council (China) (NSC 101-2325-B-010 -009)Taiwan. Department of Health. Cancer Research Center of Excellence (DOH101-TD-C-111-007

Resistance to Ag(I) Cations in Bacteria: Environments, Genes and Proteins

Bacterial resistance to Ag(I) has been reported periodically with isolates from many environments where toxic levels of silver might be expected to occur, but initial reports were limited to the occurrence of resistant bacteria. The availability of silver-resistance conferring DNA sequences now allow genetic and mechanistic studies that had basically been missing. The genes determining Ag(I) resistance were sequenced from a plasmid found in a burn ward isolate. The 14.2 kb determinant contains seven recognized genes, arranged in three mRNA transcriptional units. The silE gene determines an extracellular (periplasmic space) metal-binding protein of 123 amino acids, including ten histidine residues implicated in Ag(I) binding. SilE is homologous to PcoE, of copper resistance. The next two genes, silR and silS, determine a two protein, histidine-kinase membrane sensor and aspartyl phosphate transcriptional responder, similar to other two component systems such as CzcR and CzcS (for cadmium, zinc and cobalt resistance) and PcoR and PcoS (for copper resistance). The remaining four genes, silCBAP, are co-transcribed and appear to determine Ag+ efflux, with SilCBA homologous to CzcCBA, a three component cation/proton antiporter, and SilP a novel P-type ATPase with a amino-terminal histidine-rich cation-specificity region. The effects of increasing Ag+ concentrations and growth medium halides (Cl-, Br- and I-) have been characterized, with lower Cl- concentrations facilitating resistance and higher concentrations toxicity. The properties of this unique Ag(I)-binding SilE protein are being characterized. Sequences similar to the silver-resistance DNA are being characterized by Southern blot DNA/DNA hybridization, PCR in vitro DNA synthesis and DNA sequencing. More than 25 additional closely related sequences have been identified in bacteria from diverse sources. Initial DNA sequencing results shows approximately 5-20% differences in DNA sequences

Elimination of head and neck cancer initiating cells through targeting glucose regulated protein78 signaling

<p>Abstract</p> <p>Background</p> <p>Head and neck squamous cell carcinoma (HNSCC) is a highly lethal cancer that contains cellular and functional heterogeneity. Previously, we enriched a subpopulation of highly tumorigenic head and neck cancer initiating cells (HN-CICs) from HNSCC. However, the molecular mechanisms by which to govern the characteristics of HN-CICs remain unclear. GRP78, a stress-inducible endoplasmic reticulum chaperone, has been reported to play a crucial role in the maintenance of embryonic stem cells, but the role of GRP78 in CICs has not been elucidated.</p> <p>Results</p> <p>Initially, we recognized GRP78 as a putative candidate on mediating the stemness and tumorigenic properties of HN-CICs by differential systemic analyses. Subsequently, cells with GRP78 anchored at the plasma membrane (^memGRP78⁺) exerted cancer stemness properties of self-renewal, differentiation and radioresistance. Of note, xenotransplantation assay indicated merely 100 ^memGRP78⁺HNSCCs resulted in tumor growth. Moreover, knockdown of GRP78 significantly reduced the self-renewal ability, side population cells and expression of stemness genes, but inversely promoted cell differentiation and apoptosis in HN-CICs. Targeting GRP78 also lessened tumorigenicity of HN-CICs both <it>in vitro </it>and <it>in vivo</it>. Clinically, co-expression of GRP78 and Nanog predicted the worse survival prognosis of HNSCC patients by immunohistochemical analyses. Finally, depletion of GRP78 in HN-CICs induced the expression of Bax, Caspase 3, and PTEN.</p> <p>Conclusions</p> <p>In summary, ^memGRP78 should be a novel surface marker for isolation of HN-CICs, and targeting GRP78 signaling might be a potential therapeutic strategy for HNSCC through eliminating HN-CICs.</p

A Combined DNA-Affinic Molecule and N-Mustard Alkylating Agent Has an Anti-Cancer Effect and Induces Autophagy in Oral Cancer Cells

Although surgery or the combination of chemotherapy and radiation are reported to improve the quality of life and reduce symptoms in patients with oral cancer, the prognosis of oral cancer remains generally poor. DNA alkylating agents, such as N-mustard, play an important role in cancer drug development. BO-1051 is a new 9-anilinoacridine N-mustard-derivative anti-cancer drug that can effectively target a variety of cancer cell lines and inhibit tumorigenesis in vivo. However, the underlying mechanism of BO-1051-mediated tumor suppression remains undetermined. In the present study, BO-1051 suppressed cell viability with a low IC50 in oral cancer cells, but not in normal gingival fibroblasts. Cell cycle analysis revealed that the tumor suppression by BO-1051 was accompanied by cell cycle arrest and downregulation of stemness genes. The enhanced conversion of LC3-I to LC3-II and the formation of acidic vesicular organelles indicated that BO-1501 induced autophagy. The expression of checkpoint kinases was upregulated as demonstrated with Western blot analysis, showing that BO-1051 could induce DNA damage and participate in DNA repair mechanisms. Furthermore, BO-1051 treatment alone exhibited a moderate tumor suppressive effect against xenograft tumor growth in immunocompromised mice. Importantly, the combination of BO-1051 and radiation led to a potent inhibition on xenograft tumorigenesis. Collectively, our findings demonstrated that BO-1051 exhibited a cytotoxic effect via cell cycle arrest and the induction of autophagy. Thus, the combination of BO-1051 and radiotherapy may be a feasible therapeutic strategy against oral cancer in the future

Measurements of the pp → ZZ production cross section and the Z → 4ℓ branching fraction, and constraints on anomalous triple gauge couplings at √s = 13 TeV

Four-lepton production in proton-proton collisions, pp -> (Z/gamma*)(Z/gamma*) -> 4l, where l = e or mu, is studied at a center-of-mass energy of 13 TeV with the CMS detector at the LHC. The data sample corresponds to an integrated luminosity of 35.9 fb(-1). The ZZ production cross section, sigma(pp -> ZZ) = 17.2 +/- 0.5 (stat) +/- 0.7 (syst) +/- 0.4 (theo) +/- 0.4 (lumi) pb, measured using events with two opposite-sign, same-flavor lepton pairs produced in the mass region 60 4l) = 4.83(-0.22)(+0.23) (stat)(-0.29)(+0.32) (syst) +/- 0.08 (theo) +/- 0.12(lumi) x 10(-6) for events with a four-lepton invariant mass in the range 80 4GeV for all opposite-sign, same-flavor lepton pairs. The results agree with standard model predictions. The invariant mass distribution of the four-lepton system is used to set limits on anomalous ZZZ and ZZ. couplings at 95% confidence level: -0.0012 < f(4)(Z) < 0.0010, -0.0010 < f(5)(Z) < 0.0013, -0.0012 < f(4)(gamma) < 0.0013, -0.0012 < f(5)(gamma) < 0.0013

Active Component of Antrodia cinnamomea

Head and neck squamous cell carcinoma (HNSCC) is a highly lethal cancer. Previously, we identify head and neck cancer initiating cells (HN-CICs), which are highly tumorigenic and resistant to conventional therapy. Therefore, development of drug candidates that effectively target HN-CICs would benefit future head and neck cancer therapy. In this study, we first successfully screened for an active component, named YMGKI-1, from natural products of Antrodia cinnamomea Mycelia (ACM), which can target the stemness properties of HNSCC. Treatment of YMGKI-1 significantly downregulated the aldehyde dehydrogenase (ALDH) activity, one of the characteristics of CIC in HNSCC cells. Additionally, the tumorigenic properties of HNSCC cells were attenuated by YMGKI-1 treatment in vivo. Further, the stemness properties of HN-CICs, which are responsible for the malignancy of HNSCC, were also diminished by YMGKI-1 treatment. Strikingly, YMGKI-1 also effectively suppressed the cell viability of HN-CICs but not normal stem cells. Finally, YMGKI-1 induces the cell death of HN-CICs by dysregulating the exaggerated autophagic signaling pathways. Together, our results indicate that YMGKI-1 successfully lessens stemness properties and tumorigenicity of HN-CICs. These findings provide a new drug candidate from purified components of ACM as an alternative therapy for head and neck cancer in the future

Development and validation of HERWIG 7 tunes from CMS underlying-event measurements

This paper presents new sets of parameters (“tunes”) for the underlying-event model of the HERWIG7 event generator. These parameters control the description of multiple-parton interactions (MPI) and colour reconnection in HERWIG7, and are obtained from a fit to minimum-bias data collected by the CMS experiment at s=0.9, 7, and 13Te. The tunes are based on the NNPDF 3.1 next-to-next-to-leading-order parton distribution function (PDF) set for the parton shower, and either a leading-order or next-to-next-to-leading-order PDF set for the simulation of MPI and the beam remnants. Predictions utilizing the tunes are produced for event shape observables in electron-positron collisions, and for minimum-bias, inclusive jet, top quark pair, and Z and W boson events in proton-proton collisions, and are compared with data. Each of the new tunes describes the data at a reasonable level, and the tunes using a leading-order PDF for the simulation of MPI provide the best description of the dat

Search for top squark pair production using dilepton final states in pp collision data collected at root s=13TeV

A search is presented for supersymmetric partners of the top quark (top squarks) in final states with two oppositely charged leptons (electrons or muons), jets identified as originating from bquarks, and missing transverse momentum. The search uses data from proton-proton collisions at root s = 13 TeV collected with the CMS detector, corresponding to an integrated luminosity of 137 fb(-1). Hypothetical signal events are efficiently separated from the dominant top quark pair production background with requirements on the significance of the missing transverse momentum and on transverse mass variables. No significant deviation is observed from the expected background. Exclusion limits are set in the context of simplified supersymmetric models with pair-produced lightest top squarks. For top squarks decaying exclusively to a top quark and a lightest neutralino, lower limits are placed at 95% confidence level on the masses of the top squark and the neutralino up to 925 and 450 GeV, respectively. If the decay proceeds via an intermediate chargino, the corresponding lower limits on the mass of the lightest top squark are set up to 850 GeV for neutralino masses below 420 GeV. For top squarks undergoing a cascade decay through charginos and sleptons, the mass limits reach up to 1.4 TeV and 900 GeV respectively for the top squark and the lightest neutralino.Peer reviewe

Measurement of the t(t)over-barb(b)over-bar production cross section in the all-jet final state in pp collisions at root s=13 TeV

A measurement of the production cross section of top quark pairs in association with two b jets (t (t) over barb (b) over bar) is presented using data collected in proton-proton collisions at root s=13 TeV by the CMS detector at the LHC corresponding to an integrated luminosity of 35.9 fb(-1). The cross section is measured in the all-jet decay channel of the top quark pair by selecting events containing at least eight jets, of which at least two are identified as originating from the hadronization of b quarks. A combination of multivariate analysis techniques is used to reduce the large background from multijet events not containing a top quark pair, and to help discriminate between jets originating from top quark decays and other additional jets. The cross section is determined for the total phase space to be 5.5 +/- 0.3 (stat)(-1.3)(+)(1.6) (syst)pb and also measured for two fiducial t (t) over barb (b) over bar, definitions. The measured cross sections are found to be larger than theoretical predictions by a factor of 1.5-2.4, corresponding to 1-2 standard deviations. (C) 2020 The Author. Published by Elsevier B.V.Peer reviewe