DNA repair and synthetic lethality

Tumors often have DNA repair defects, suggesting additional inhibition of other DNA repair pathways in tumors may lead to synthetic lethality. Accumulating data demonstrate that DNA repair-defective tumors, in particular homologous recombination (HR), are highly sensitive to DNA-damaging agents. Thus, HR-defective tumors exhibit potential vulnerability to the synthetic lethality approach, which may lead to new therapeutic strategies. It is well known that poly (adenosine diphosphate (ADP)-ribose) polymerase (PARP) inhibitors show the synthetically lethal effect in tumors defective in BRCA1 or BRCA2 genes encoded proteins that are required for efficient HR. In this review, we summarize the strategies of targeting DNA repair pathways and other DNA metabolic functions to cause synthetic lethality in HR-defective tumor cells

Constraints on Spin-Independent Nucleus Scattering with sub-GeV Weakly Interacting Massive Particle Dark Matter from the CDEX-1B Experiment at the China Jin-Ping Laboratory

We report results on the searches of weakly interacting massive particles (WIMPs) with sub-GeV masses ($m_{\chi}$) via WIMP-nucleus spin-independent scattering with Migdal effect incorporated. Analysis on time-integrated (TI) and annual modulation (AM) effects on CDEX-1B data are performed, with 737.1 kg$\cdot$day exposure and 160 eVee threshold for TI analysis, and 1107.5 kg$\cdot$day exposure and 250 eVee threshold for AM analysis. The sensitive windows in $m_{\chi}$ are expanded by an order of magnitude to lower DM masses with Migdal effect incorporated. New limits on $\sigma_{\chi N}^{\rm SI}$ at 90\% confidence level are derived as $2\times$10$^{-32}\sim7\times$10$^{-35}$ $\rm cm^2$ for TI analysis at $m_{\chi}\sim$ 50$-$180 MeV/$c^2$, and $3\times$10$^{-32}\sim9\times$10$^{-38}$ $\rm cm^2$ for AM analysis at $m_{\chi}\sim$75 MeV/$c^2-$3.0 GeV/$c^2$.Comment: 5 pages, 4 figure

Search for Light Weakly-Interacting-Massive-Particle Dark Matter by Annual Modulation Analysis with a Point-Contact Germanium Detector at the China Jinping Underground Laboratory

We present results on light weakly interacting massive particle (WIMP) searches with annual modulation (AM) analysis on data from a 1-kg mass $p$-type point-contact germanium detector of the CDEX-1B experiment at the China Jinping Underground Laboratory. Datasets with a total live time of 3.2 yr within a 4.2 yr span are analyzed with analysis threshold of 250 eVee. Limits on WIMP-nucleus (${\chi}$-$N$) spin-independent cross sections as function of WIMP mass ($m_{\chi}$) at 90\% confidence level (C.L.) are derived using the dark matter halo model. Within the context of the standard halo model, the 90\% C.L. allowed regions implied by the DAMA/LIBRA and CoGeNT AM-based analysis are excluded at $>$99.99\% and 98\% C.L., respectively. These results correspond to the best sensitivity at $m_{\chi}$$<$6$~{\rm GeV}/c^2$ among WIMP AM measurements to date.Comment: 5 pages, 4 figure

A multi-targeted approach to suppress tumor-promoting inflammation

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes

Clinical and molecular characterization of Wilson's disease in China: identification of 14 novel mutations

<p>Abstract</p> <p>Background</p> <p>Wilson's disease (WND) is a rare autosomal recessive disorder. Here we have evaluated 62 WND cases (58 probands) from the Chinese Han population to expand our knowledge of <it>ATP7B </it>mutations and to more completely characterize WND in China.</p> <p>Methods</p> <p>The coding and promoter regions of the <it>ATP7B </it>gene were analyzed by direct sequencing in 62 Chinese patients (58 probands) with WND (male, n = 37; female, n = 25; age range, 2 ~ 61 years old).</p> <p>Results</p> <p>Neurologic manifestations were associated with older age at diagnosis (p < 0.0001) and longer diagnostic delay (p < 0.0001). Age at diagnosis was also correlated with urinary copper concentration (r = 0.58, p < 0.001). Forty different mutations, including 14 novel mutations, were identified in these patients. Common mutations included p.Arg778Leu (31.9%) and p.Pro992Leu (11.2%). Homozygous p.Arg778Leu and nonsense mutation/frameshift mutations were more often associated with primary hepatic manifestations (p = 0.0286 and p = 0.0383, respectively) and higher alanine transaminase levels at diagnosis (p = 0.0361 and p = 0.0047, respectively). Nonsense mutation/frameshift mutations were also associated with lower serum ceruloplasmin (p = 0.0065).</p> <p>Conclusions</p> <p>We identified 14 novel mutations and found that the spectrum of mutations of <it>ATP7B </it>in China is quite distinct from that of Western countries. The mutation type plays a role in predicting clinical manifestations. Genetic testing is a valuable tool to detect WND in young children, especially in patients younger than 8 years old. Four exons (8, 12, 13, and 16) and two mutations (p.Arg778Leu, p.Pro992Leu) should be considered high priority for cost-effective testing in China.</p

Constraints on Sub-GeV Dark Matter--Electron Scattering from the CDEX-10 Experiment

We present improved germanium-based constraints on sub-GeV dark matter via dark matter--electron ($\chi$-$e$) scattering using the 205.4 kg$\cdot$day dataset from the CDEX-10 experiment. Using a novel calculation technique, we attain predicted $\chi$-$e$ scattering spectra observable in high-purity germanium detectors. In the heavy mediator scenario, our results achieve 3 orders of magnitude of improvement for $m_{\chi}$ larger than 80 MeV/c$^2$ compared to previous germanium-based $\chi$-$e$ results. We also present the most stringent $\chi$-$e$ cross-section limit to date among experiments using solid-state detectors for $m_{\chi}$ larger than 90 MeV/c$^2$ with heavy mediators and $m_{\chi}$ larger than 100 MeV/c$^2$ with electric dipole coupling. The result proves the feasibility and demonstrates the vast potential of a new $\chi$-$e$ detection method with high-purity germanium detectors in ultralow radioactive background.Comment: 6 pages, 3 figures. Version updated to match PRL versio

Exotic Dark Matter Search with CDEX-10 Experiment at China Jinping Underground Laboratory

A search for exotic dark matter (DM) in the sub-GeV mass range has been conducted using 205 kg$\cdot$day data taken from a p-type point contact germanium detector of CDEX-10 experiment at China Jinping underground laboratory. New low-mass dark matter searching channels, neutral current fermionic DM absorption ($\chi+A\rightarrow \nu+A$) and DM-nucleus 3$\rightarrow$2 scattering ($\chi+\chi+A\rightarrow \phi+A$), have been analyzed with an energy threshold of 160 eVee. No significant signal was found. Thus new limits on the DM-nucleon interaction cross section are set for both models at sub-GeV DM mass region. A cross section limit for the fermionic DM absorption is set to be $\rm 2.5\times 10^{-46} cm^2$(90\% C.L.) at DM mass of 10 MeV/c$^2$. For the DM-nucleus 3$\rightarrow$2 scattering scenario, limits are extended to DM mass of 5 MeV/c$^2$ and 14 MeV/c$^2$ for the massless dark photon and bound DM final state, respectively.Comment: 5 pages, 7 figure

Search for exotic neutrino interactions using solar neutrinos in the CDEX-10 experiment

We investigate the exotic neutrino interactions using the 205.4 kg day exposure dataset of the CDEX-10 experiment at the China Jinping Underground Laboratory. New constraints on the mass and couplings of extra gauge boson are presented. The results are interpreted in two physics scenarios including an $U(1)_{B-L}$ gauge boson induced interaction between active neutrinos and electron/nucleus, and a dark photon induced the interaction between sterile neutrino and electron/nucleus where the dark photon couples to the Standard Model particles through kinetic mixing with the photon. This work probes new parameter space involving sterile neutrino coupling with dark photon with masses below 1 eV$/c^2$ at some typical choice of $\Delta m_{41}^{2}$ and $g^{\prime2}{\rm{sin}}^{2}2\theta_{14}$, which was previously unexplored by dark matter direct detection experiments and neutrino experiments.Comment: 6 pages, 3 figure