Regulation of core clock genes in human islets

Nearly all mammalian cells express a set of genes known as clock genes. These regulate the circadian rhythm of cellular processes by means of negative and positive autoregulatory feedback loops of transcription and translation. Recent genomewide association studies have demonstrated an association between a polymorphism near the circadian clock gene CRY2 and elevated fasting glucose. To determine whether clock genes could play a pathogenetic role in the disease, we examined messenger RNA (mRNA) expression of core clock genes in human islets from donors with or without type 2 diabetes mellitus. Microarray and quantitative real-time polymerase chain reaction analyses were used to assess expression of the core clock genes CLOCK, BMAL-1, PER1 to 3, and CRY1 and 2 in human islets. Insulin secretion and insulin content in human islets were measured by radioimmunoassay. The mRNA levels of PER2, PER3, and CRY2 were significantly lower in islets from donors with type 2 diabetes mellitus. To investigate the functional relevance of these clock genes, we correlated their expression to insulin content and glycated hemoglobin levels: mRNA levels of PER2 (ρ = 0.33, P =.012), PER3 (ρ = 0.30, P =.023), and CRY2 (ρ = 0.37, P =.0047) correlated positively with insulin content. Of these genes, expression of PER3 and CRY2 correlated negatively with glycated hemoglobin levels (ρ = -0.44, P =.0012; ρ = -0.28, P =.042). Furthermore, in an in vitro model mimicking pathogenetic conditions, the PER3 mRNA level was reduced in human islets exposed to 16.7 mmol/L glucose per 1 mmol/L palmitate for 48 hours (P =.003). Core clock genes are regulated in human islets. The data suggest that perturbations of circadian clock components may contribute to islet pathophysiology in human type 2 diabetes mellitus

Expression of matrix metalloproteinases (MMPs) in primary human breast cancer and breast cancer cell lines: New findings and review of the literature

<p>Abstract</p> <p>Background</p> <p>Matrix metalloproteinases (MMPs) are a family of structural and functional related endopeptidases. They play a crucial role in tumor invasion and building of metastatic formations because of their ability to degrade extracellular matrix proteins. Under physiological conditions their activity is precisely regulated in order to prevent tissue disruption. This physiological balance seems to be disrupted in cancer making tumor cells capable of invading the tissue. In breast cancer different expression levels of several MMPs have been found.</p> <p>Methods</p> <p>To fill the gap in our knowledge about MMP expression in breast cancer, we analyzed the expression of all known human MMPs in a panel of twenty-five tissue samples (five normal breast tissues, ten grade 2 (G2) and ten grade 3 (G3) breast cancer tissues). As we found different expression levels for several MMPs in normal breast and breast cancer tissue as well as depending on tumor grade, we additionally analyzed the expression of MMPs in four breast cancer cell lines (MCF-7, MDA-MB-468, BT 20, ZR 75/1) commonly used in research. The results could thus be used as model for further studies on human breast cancer. Expression analysis was performed on mRNA and protein level using semiquantitative RT-PCR, Western blot, immunohistochemistry and immunocytochemistry.</p> <p>Results</p> <p>In summary, we identified several MMPs (MMP-1, -2, -8, -9, -10, -11, -12, -13, -15, -19, -23, -24, -27 and -28) with a stronger expression in breast cancer tissue compared to normal breast tissue. Of those, expression of MMP-8, -10, -12 and -27 is related to tumor grade since it is higher in analyzed G3 compared to G2 tissue samples. In contrast, MMP-7 and MMP-27 mRNA showed a weaker expression in tumor samples compared to healthy tissue. In addition, we demonstrated that the four breast cancer cell lines examined, are constitutively expressing a wide variety of MMPs. Of those, MDA-MB-468 showed the strongest mRNA and protein expression for most of the MMPs analyzed.</p> <p>Conclusion</p> <p>MMP-1, -2, -8, -9, -10, -11, -12, -13, -15, -19, -23, -24, -27 and -28 might thus be associated with breast cancer development and tumor progression. Therefore, these MMPs are proper candidates for further functional analysis of their role in breast cancer.</p

Search for a high-mass dimuon resonance produced in association with b quark jets at s\sqrt{s}=13 TeV

International audienceA search for high-mass dimuon resonance production in association with one or more b quark jets is presented. The study uses proton-proton collision data collected with the CMS detector at the LHC corresponding to an integrated luminosity of 138 fb$^{-1}$ at a center-of-mass energy of 13 TeV. Model-independent limits are derived on the number of signal events with exactly one or more than one b quark jet. Results are also interpreted in a lepton-flavor-universal model with Z$'$ boson couplings to a bb quark pair ($g_\mathrm{b}$), an sb quark pair ($g_\mathrm{b}\delta_\mathrm{bs}$), and any same-flavor charged lepton ($g_\ell$) or neutrino pair ($g_\nu$), with $\left|g_{\nu}\right|=\left|g_\ell\right|$. For a Z$'$ boson with a mass $m_{\mathrm{Z}'}$ = 350 GeV (2 TeV) and $\left|\delta_\mathrm{bs}\right| \lt$ 0.25, the majority of the parameter space with 0.0057 $\lt \left|g_\ell\right| \lt$ 0.35 (0.25 $\lt \left|g_\ell\right| \lt$ 0.43) and 0.0079 $\lt \left|g_\mathrm{b}\right| \lt$ 0.46 (0.34 $\lt \left|g_\mathrm{b}\right| \lt$ 0.57) is excluded at 95% confidence level. Finally, constraints are set on a Z$'$ model with parameters consistent with low-energy b $\to$ s$\ell\ell$ measurements. In this scenario, most of the allowed parameter space is excluded for a Z$'$ boson with 350 $\lt m_{\mathrm{Z}'}\lt$ 500 GeV, while the constraints are less stringent for higher $m_{\mathrm{Z}'}$ hypotheses. This is the first dedicated search at the LHC for a high-mass dimuon resonance produced in association with multiple b quark jets, and the constraints obtained on models with this signature are the most stringent to date

Search for scalar leptoquarks produced in lepton-quark collisions and coupled to τ\tau leptons

The first search for scalar leptoquarks produced in lepton-quark collisions and coupled to $\tau$ leptons is presented. It is based on a set of proton-proton collision data recorded with the CMS detector at the LHC at a center-of-mass energy of 13 TeV corresponding to an integrated luminosity of 138 fb$^{-1}$. The reconstructed final state consists of a jet, significant missing transverse momentum, and a $\tau$ lepton reconstructed through its hadronic or leptonic decays. Limits are set on the product of the leptoquark production cross section and branching fraction and interpreted as exclusions in the plane of the leptoquark mass and the leptoquark-$\tau$-quark coupling strength

Observation of WWγ\gamma production and search for Hγ\gamma production in proton-proton collisions at s\sqrt{s} = 13 TeV

The observation of WW$\gamma$ production in proton-proton collisions at a center-of-mass energy of 13 TeV with an integrated luminosity of 138 fb$^{-1}$ is presented. The observed (expected) significance is 5.6 (4.7) standard deviations. Events are selected by requiring exactly two leptons (one electron and one muon) of opposite charge, moderate missing transverse momentum, and a photon. The measured fiducial cross section for WW$\gamma$ is 6.0 $\pm$ 0.8 (stat) $\pm$ 0.7 (syst) $\pm$ 0.6 (modeling) fb, in agreement with the next-to-leading order quantum chromodynamics prediction. The analysis is extended with a search for the associated production of the Higgs boson and a photon, which is generated by a coupling of the Higgs boson to light quarks. The result is used to constrain the Higgs boson couplings to light quarks

Search for a high-mass dimuon resonance produced in association with b quark jets at s\sqrt{s} = 13 TeV

A search for high-mass dimuon resonance production in association with one or more b quark jets is presented. The study uses proton-proton collision data collected with the CMS detector at the LHC corresponding to an integrated luminosity of 138 fb$^{-1}$ at a center-of-mass energy of 13 TeV. Model-independent limits are derived on the number of signal events with exactly one or more than one b quark jet. Results are also interpreted in a lepton-flavor-universal model with Z$'$ boson couplings to a bb quark pair ($g_\mathrm{b}$), an sb quark pair ($g_\mathrm{b}\delta_\mathrm{bs}$), and any same-flavor charged lepton ($g_\ell$) or neutrino pair ($g_\nu$), with $\left|g_{\nu}\right|=\left|g_\ell\right|$. For a Z$'$ boson with a mass $m_{\mathrm{Z}'}$ = 350 GeV (2 TeV) and $\left|\delta_\mathrm{bs}\right| \lt$ 0.25, the majority of the parameter space with 0.0057 $\lt \left|g_\ell\right| \lt$ 0.35 (0.25 $\lt \left|g_\ell\right| \lt$ 0.43) and 0.0079 $\lt \left|g_\mathrm{b}\right| \lt$ 0.46 (0.34 $\lt \left|g_\mathrm{b}\right| \lt$ 0.57) is excluded at 95% confidence level. Finally, constraints are set on a Z$'$ model with parameters consistent with low-energy b $\to$ s$\ell\ell$ measurements. In this scenario, most of the allowed parameter space is excluded for a Z$'$ boson with 350 $\lt m_{\mathrm{Z}'}\lt$ 500 GeV, while the constraints are less stringent for higher $m_{\mathrm{Z}'}$ hypotheses. This is the first dedicated search at the LHC for a high-mass dimuon resonance produced in association with multiple b quark jets, and the constraints obtained on models with this signature are the most stringent to date

Search for a third-generation leptoquark coupled to a τ\tau lepton and a b quark through single, pair, and nonresonant production in proton-proton collisions at s\sqrt{s} = 13 TeV

A search is presented for a third-generation leptoquark (LQ) coupled exclusively to a $\tau$ lepton and a b quark. The search is based on proton-proton collision data at a center-of-mass energy of 13 TeV recorded with the CMS detector, corresponding to an integrated luminosity of 138 fb$^{-1}$. Events with $\tau$ leptons and a varying number of jets originating from b quarks are considered, targeting the single and pair production of LQs, as well as nonresonant $t$-channel LQ exchange. An excess is observed in the data with respect to the background expectation in the combined analysis of all search regions. For a benchmark LQ mass of 2 TeV and an LQ-b-$\tau$ coupling strength of 2.5, the excess reaches a local significance of up to 2.8 standard deviations. Upper limits at the 95% confidence level are placed on the LQ production cross section in the LQ mass range 0.5-2.3 TeV, and up to 3 TeV for $t$-channel LQ exchange. Leptoquarks are excluded below masses of 1.22-1.88 TeV for different LQ models and varying coupling strengths up to 2.5. The study of nonresonant $\tau\tau$ production through $t$-channel LQ exchange allows lower limits on the LQ mass of up to 2.3 TeV to be obtained