Expression of thymidylate synthase in gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection

We evaluated the expression of thymidylate synthase (TS) in locally advanced gastric cancer patients treated with adjuvant chemotherapy after curative resection and investigated the association between TS expression and clinicopathologic characteristics including prognosis of the patients. TS expression was evaluated by immunohistochemical staining using TS106 monoclonal antibody in 103 locally advanced gastric cancer patients (stage IB–IV) who underwent 5-fluorouracil (5-FU) and doxorubicin-based adjuvant chemotherapy after curative resection. 65 patients (63%) had primary tumours with high TS expression (≥ 25% of tumour cells positive), and 38 patients (37%) demonstrated low TS expression (< 25% of tumour cells positive or no staining). High TS expression was associated with male gender (P = 0.002), poorly differentiated histology (P = 0.015), and mixed type in Lauren’s classification (P = 0.027). There were no statistically significant differences in 4-year disease-free survival (60.0% vs 57.2%, P = 0.548) and overall survival (59.6% vs 59.3%, P = 0.792) between high-TS group and low-TS group. In conclusion, although high TS expression was associated with poorly differentiated histology and mixed type in Lauren's classification, it did not predict poor disease-free and overall survival in gastric cancer patients treated with 5-FU and doxorubicin-based adjuvant chemotherapy after curative resection. Further prospective studies including the evaluation of other biological markers associated with the resistance to 5-FU and doxorubicin are necessary. © 2001 Cancer Research Campaign http://www.bjcancer.co

Constitutive activation of T cells by γ2-herpesviral GPCR through the interaction with cellular CXCR4

Members of the herpesviral family use multiple strategies to hijack infected host cells and exploit cellular signaling for their pathogenesis and latent infection. Among the most intriguing weapons in the arsenal of pathogenic herpesviruses are the constitutively active virally-encoded G protein-coupled receptors (vGPCRs). Even though vGPCRs contribute to viral pathogenesis such as immune evasion and proliferative disorders, the molecular details of how vGPCRs continuously activate cellular signaling are largely unknown. Here, we report that the vGPCR of Herpesvirus saimiri (HVS), an oncogenic gamma 2-herpesvirus, constitutively activates T cells via a heteromeric interaction with cellular CXCR4. Constitutive T cell activation also occurs with expression of the vGPCR of Kaposi&apos;s sarcoma-associated herpesvirus (KSHV), but not the vGPCR of Epstein-Barr virus. Expression of HVS vGPCR down-regulated the surface expression of CXCR4 but did not induce the degradation of the chemokine receptor, suggesting that vGPCR/CXCR4 signaling continues in cytosolic compartments. The physical association of vGPCR with CXCR4 was demonstrated by proximity ligation assay as well as immunoprecipitation. Interestingly, the constitutive activation of T cells by HVS vGPCR is independent of proximal T cell receptor (TCR) signaling molecules, such as TcR beta, Lck, and ZAP70, whereas CXCR4 silencing by shRNA abolished T cell activation by vGPCRs of HVS and KSHV. Furthermore, previously identified inactive vGPCR mutants failed to interact with CXCR4. These findings on the positive cooperativity of vGPCR with cellular CXCR4 in T cell activation extend our current understanding of the molecular mechanisms of vGPCR function and highlight the importance of heteromerization for GPCR activity. (C) 2016 Elsevier B.V. All rights reserved.1111Ysciescopu

Production of Prompt Charmonia in e+e−e^+e^- Annihilation at s≈10.6\sqrt{s}\approx 10.6 GeV

The production of prompt $J/\psi$, $\psi(2S)$, $\chi_{c1}$ and $\chi_{c2}$ is studied using a $32.4 fb^{-1}$ data sample collected with the Belle detector at the $\Upsilon(4S)$ and 60 MeV below the resonance. The yield of prompt $J/\psi$ mesons in the $\Upsilon(4S)$ sample is compatible with that of continuum production; we set an upper limit ${\cal B}(\Upsilon(4S) \to J/\psi X) < 1.9 \times 10^{-4}$ at the 95% confidence level, and find $\sigma(e^{+}e^{-} \to J/\psi X)=1.47\pm 0.10 \pm 0.13$ pb. The cross-sections for prompt $\psi(2S)$ and direct $J/\psi$ are measured. The $J/\psi$ momentum spectrum, production angle distribution and polarization are studied.Comment: submitted to Phys. Rev. Let

Observation of Double cc bar Production in e+ e- Annihilation at sqrt{s} ~ 10.6 GeV

We report the observation of prompt J/psi via double ccbar production from the e+e- continuum. In this process one ccbar pair fragments into a J/psi meson while the remaining pair either produces a bound charmonium state or fragments into open charm. Both cases have been observed: the first by studying the mass spectrum of the system recoiling against the J/psi, and the second by reconstructing the J/psi together with a charmed meson. We find cross-sections of \sigma(e+ e- -> J/psi eta_c (gamma)) * BR (eta_c -> >=4 charged) = 0.033 (+0.007 -0.006)(stat) \pm 0.009(syst)pb and \sigma(e+ e- -> J/psi D*+ X) = 0.53 (+0.19 -0.15)(stat) \pm 0.14(syst) pb, and infer \sigma(e+ e- -> J/psi c cbar) / \sigma(e+ e- -> J/psi X) = 0.59 (+0.15 -0.13)(stat) \pm 0.12(syst). These results are obtained from a 46.2/fb data sample collected near the Upsilon(4S) resonance, with the Belle detector at the KEKB asymmetric energy e+ e- collider.Comment: 7 pages, 2 figures, to be submitted to Physical Review Letter

Belle II Technical Design Report

The Belle detector at the KEKB electron-positron collider has collected almost 1 billion Y(4S) events in its decade of operation. Super-KEKB, an upgrade of KEKB is under construction, to increase the luminosity by two orders of magnitude during a three-year shutdown, with an ultimate goal of 8E35 /cm^2 /s luminosity. To exploit the increased luminosity, an upgrade of the Belle detector has been proposed. A new international collaboration Belle-II, is being formed. The Technical Design Report presents physics motivation, basic methods of the accelerator upgrade, as well as key improvements of the detector.Comment: Edited by: Z. Dole\v{z}al and S. Un

Molecular pathogenesis of spondylocheirodysplastic Ehlers-Danlos syndrome caused by mutant ZIP13 proteins.

The zinc transporter protein ZIP13 plays critical roles in bone, tooth, and connective tissue development, and its dysfunction is responsible for the spondylocheirodysplastic form of Ehlers-Danlos syndrome (SCD-EDS, OMIM 612350). Here, we report the molecular pathogenic mechanism of SCD-EDS caused by two different mutant ZIP13 proteins found in human patients: ZIP13(G64D), in which Gly at amino acid position 64 is replaced by Asp, and ZIP13(ΔFLA), which contains a deletion of Phe-Leu-Ala. We demonstrated that both the ZIP13(G64D) and ZIP13(ΔFLA) protein levels are decreased by degradation via the valosin-containing protein (VCP)-linked ubiquitin proteasome pathway. The inhibition of degradation pathways rescued the protein expression levels, resulting in improved intracellular Zn homeostasis. Our findings uncover the pathogenic mechanisms elicited by mutant ZIP13 proteins. Further elucidation of these degradation processes may lead to novel therapeutic targets for SCD-EDS

Pharmacogenomic analysis of patient-derived tumor cells in gynecologic cancers

Background Gynecologic malignancy is one of the leading causes of mortality in female adults worldwide. Comprehensive genomic analysis has revealed a list of molecular aberrations that are essential to tumorigenesis, progression, and metastasis of gynecologic tumors. However, targeting such alterations has frequently led to treatment failures due to underlying genomic complexity and simultaneous activation of various tumor cell survival pathway molecules. A compilation of molecular characterization of tumors with pharmacological drug response is the next step toward clinical application of patient-tailored treatment regimens. Results Toward this goal, we establish a library of 139 gynecologic tumors including epithelial ovarian cancers (EOCs), cervical, endometrial tumors, and uterine sarcomas that are genomically and/or pharmacologically annotated and explore dynamic pharmacogenomic associations against 37 molecularly targeted drugs. We discover lineage-specific drug sensitivities based on subcategorization of gynecologic tumors and identify TP53 mutation as a molecular determinant that elicits therapeutic response to poly (ADP-Ribose) polymerase (PARP) inhibitor. We further identify transcriptome expression of inhibitor of DNA biding 2 (ID2) as a potential predictive biomarker for treatment response to olaparib. Conclusions Together, our results demonstrate the potential utility of rapid drug screening combined with genomic profiling for precision treatment of gynecologic cancers

A Lithium-ion Battery Using Partially Lithiated Graphite Anode and Amphi-redox LiMn2O4 Cathode

Delithiation followed by lithiation of Li+-occupied (n-type) tetrahedral sites of cubic LiMn2O4 spine! (LMO) at similar to 4V(Li/Li+). (delivering-100 mAhg(LMO)-1) has been used for energy storage by lithium ion batteries (LIBs). In this work, we utilized unoccupied (p-type) octahedral sites of LMO available for lithiation at -3V(Li/Li). (delivering additional -100 mAh gLmo(-1)) that have never been used for LI Bs in full cell configuration. The whole capacity of amphi-redox LMO, including both oxidizable n-type and reducible p-type redox sites, at -200 mAh g(LMO)-1 was realized by using the reactions both at 4 VLi/Li+ and 3 VLi/Li+. Durable reversibility of the 3 V reaction was achieved by graphene-wrapping LMO nanoparticles (LMO@Gn). Prelithiated graphite (LinC6,, n &lt; 1) was used as anodes to lithiate the unoccupied octahedral sites of LMO for the 3V reactio

Atomic Layer Deposition of 2D Metal Dichalcogenides for Electronics, Catalysis, Energy Storage, and Beyond

2D transition metal dichalcogenides (TMDCs) are among the most exciting materials of today. Their layered crystal structures result in unique and useful electronic, optical, catalytic, and quantum properties. To realize the technological potential of TMDCs, methods depositing uniform films of controlled thickness at low temperatures in a highly controllable, scalable, and repeatable manner are needed. Atomic layer deposition (ALD) is a chemical gas-phase thin film deposition method capable of meeting these challenges. In this review, the applications evaluated for ALD TMDCs are systematically examined, including electronics and optoelectonics, electrocatalysis and photocatalysis, energy storage, lubrication, plasmonics, solar cells, and photonics. This review focuses on understanding the interplay between ALD precursors and deposition conditions, the resulting film characteristics such as thickness, crystallinity, and morphology, and ultimately device performance. Through rational choice of precursors and conditions, ALD is observed to exhibit potential to meet the varying requirements of widely different applications. Beyond the current state of ALD TMDCs, the future prospects, opportunities, and challenges in different applications are discussed. The authors hope that the review aids in bringing together experts in the fields of ALD, TMDCs, and various applications to eventually realize industrial applications of ALD TMDCs.Peer reviewe