Search

Recently, there have been many developments and improvements in portal hypertension surgery, but there are still many controversies regarding the surgical indications, the timing of surgery, and the choice of surgical procedures. Minimally invasive laparoscopy and robotics are the leading direction for the development of surgical techniques for portal hypertension. Surgical selection procedures should be based on evidence-based, but guidelines should not be blindly followed. Surgical development needs to strengthen multidisciplinary cooperation, and surgical reform is the driving force for surgical development.门静脉高压在外科手术近年有不少发展和进步，但手术适应证、手术时机及术式选择仍存在很多争议。微创腹腔镜及机器人是门静脉高压外科技术发展的引领方向。外科术式选择应以循证为依据，但不应盲从指南。外科发展需加强多学科合作，术式革新是外科发展的动力。.

To investigate effects of benzo(a)pyrene (BaP) on expressions of insulin-degrading enzyme (IDE) and neprilysin (NEP) which have the ability to degrade β-amyloid (Aβ) in neuroglia cells.Primary mix-neuroglia cells were cultured from newborn SD rats. After exposure to BaP, AβThe cell survival rate showed no significant differences after treatment with BaP (≤20.00 μmol/L), AβOn the premise of no significant change of cell survival rate, BaP pretreatment inhibited the up-regulated expressions of IDE in primary mixed neuroglia cells under cotreatment with Aβ oligomer, indicating that BaP may disturb degradation of Aβ oligomer and cause deposition of β-amyloid and further induce cognitive decline and acceleration of Alzheimer.

Lung cancer, especially non-small cell lung cancer (NSCLC), is the leading cause of cancer-related mortality in the world. Both microRNAs and epidermal growth factor receptor (EGFR) are important factors in NSCLC. In our study, the expression of miR-30b in 47 tumor tissues and paired normal tissues of NSCLC were detected by RT-PCR, and we found that miR-30b was down-regulated in NSCLC tumor tissues and was associated with TNM stage, differentiation, and lymph node metastases. Then we investigated the ability of miR-30b to regulate EGFR in several NSCLC cell lines, and found that miR-30b inhibited proliferation, migration and invasion, induced apoptosis and enhanced sensitivity of the NSCLC cells to EGFR tyrosine kinase inhibitors (EGFR-TKIs) by targeting EGFR and repressing EGFR signaling pathways. Overall, these results indicate that miR-30b may be a potential therapeutic target in NSCLC patients.

Human telomerase is absent in most normal tissues, but is abnormally activated in all major cancer cells. Telomerase enables tumor cells to maintain telomere length, allowing indefinite replicative capacity. Albeit not sufficient in itself to induce neoplasia, telomerase is believed to be necessary for cancer cells to grow without limit. Studies using an antisense oligonucleotide (ASODN) to the RNA component of telomerase or human telomerase reverse transcriptase (hTERT) demonstrate that telomerase in human tumor lines can be blocked in vivo. Inhibition of hTERT led to telomere shortening and cancer cell death, validating telomerase as a target for anticancer genetic therapy. Varieties of approaches for hTERT inhibition have been investigated. The aim of this study was to analyze the biological activity of ASODN to the hTERT mediated by retrovirus vector, which was used as therapy for ovarian tumor. We constructed and characterized a recombinant retrovirus vector with full-length hTERT antisense complementary DNA. The vector was introduced into ES-2 by lipofectamine-mediated gene transfection. The cellular proliferation and telomerase activity of the transformant cells were retarded. The hTERT gene expression and the telomerase activity of the transformant cells were both decreased. The transformant cells show partial reversion of the malignant phenotype. PT67 cells were also transfected with the recombinant vector and virus-producer cells were generated. The retrovirus-containing supernatant effectively inhibited the growth of human ovarian tumor xenografts in mouse models (subcutaneous tumor model), and enhanced the mouse survival time.

The objective of this study was to evaluate the effects of the different ratios of acetate and β-hydroxybutyrate (BHBA) on cell viability, triacylglycerol (TAG) content, and mRNA expression of the genes related to lipid and protein synthesis in bovine mammary epithelial cells (BMECs). Primary cells were isolated from the mammary glands of Holstein dairy cows and were passaged twice. Then, the cells were cul

Introduction The objective of the study was to assess the cost-effectiveness of EVE+EXE versus endocrine monotherapies in the treatment of postmenopausal women with HR + , HER2 − ABC after failure of treatment with nonsteroidal aromatase inhibitors from a US third-party payer perspective. Materials and Methods A Markov model was developed to evaluate the costs and effectiveness associated with EVE+EXE, exemestane (EXE), fulvestrant (FUL), and tamoxifen (TAM) over a 10-year time horizon. The model included 3 health states: responsive/stable disease, progression, or death. Monthly transition probabilities were estimated based on the BOLERO-2 (Breast cancer trials of OraL EveROlimus-2) data and network meta-analyses. Costs included drug acquisition and administration costs, medical costs associated health states, and costs for managing adverse events (AEs). Utilities for each health state and disutilities for AEs were derived from the literature. Incremental costs per quality-adjusted life year (QALY) were estimated by comparing EVE+EXE with each endocrine monotherapy. One-way and probabilistic sensitivity analyses were performed. Results In the base case, EVE+EXE was associated with 1.99 QALYs and total direct costs of $258,648 over 10 years. The incremental cost per QALY of EVE+EXE was $139,740 compared with EXE, $157,749 compared with FUL, and $115,624 compared with TAM. At a willingness-to-pay threshold of $130,000/QALY or above, EVE+EXE appeared to be the most cost-effective treatment among all drugs. Conclusions Everolimus with EXE demonstrated QALY improvements compared with 3 other endocrine monotherapies. Benchmarked by the economic value of other novel cancer therapies, EVE+EXE might be considered a cost-effective option compared with endocrine therapies for HR + /HER2 − ABC.

The aim of the study is to study the correlation of genetic polymorphism of vascular endothelial growth factor (VEGF) gene with susceptibility to primary lung cancer. A total of 414 patients with primary lung cancer and 338 healthy volunteers were enrolled in this case-control study from September 2008 to October 2011. Gene identification with PCR-RFLP (polymerase chain reaction-based restriction fragment length polymorphism) was used to detect in white blood cells from the subjects the single-nucleotide polymorphisms (SNP) of VEGF gene, including +405G/C, -460 T/C, -1154G/A, -2578C/A sites. Association of genotypes or haplotypes with susceptibility of lung cancer was analyzed with unconditional logistic regression adjusted by gender and age. Smoking was significantly associated with increased risk of lung cancer. Gene phenotypic analysis demonstrated that C allele of +405G/C in VEGF gene was significantly associated increased risk of lung cancer in males (P=0.0094, odds ratio=1.634.3), as that with carrying GCTC haplotype (odds ratio=1.349), whereas carrying GACG had decreased risk for lung cancer (odds ratio=0.044). No relationship existed between 460 T/C, -1154G/A, -2578C/A alleles of VEGF gene and risk of lung cancer. VEGF gene polymorphism may have a role in the development of lung cancer.

The Daya Bay Experiment consists of eight identically designed detectors located in three underground experimental halls named as EH1, EH2, EH3, with 250, 265 and 860 meters of water equivalent vertical overburden, respectively. Cosmic muon events have been recorded over a two-year period. The underground muon rate is observed to be positively correlated with the effective atmospheric temperature and to follow a seasonal modulation pattern. The correlation coefficient $\alpha$, describing how a variation in the muon rate relates to a variation in the effective atmospheric temperature, is found to be $\alpha_{\text{EH1}} = 0.362\pm0.031$, $\alpha_{\text{EH2}} = 0.433\pm0.038$ and $\alpha_{\text{EH3}} = 0.641\pm0.057$ for each experimental hall., Comment: Updated to be identical to the published version

Imaging the surface topography and elasticity of a living cell can provide new insights into the roles played by its volumetric and elastic properties in its functions and disease. Atomic force microscopy (AFM) would be a natural means to this end, but is designed for operation in air and does not function well in a liquid biological environment. The authors develop a technique for noncontact viscoelastic imaging of live cells using AFM with a long glass probe. This method opens the door to studying a wide range of interesting problems in the nanomechanics of soft matter and the mechanobiology of living cells and tissues.

γ-Tubulin ring complexes (γTuRCs) initiate microtubule growth and mediate microtubule attachment at microtubule-organizing centers, such as centrosomes and the Golgi complex. However, the mechanisms that control γTuRC-mediated microtubule nucleation have remained mostly unknown. Here, we show that the DNA polymerase δ catalytic subunit (PolD1) binds directly to γTuRCs and potently inhibits γTuRC-mediated microtubule nucleation. Whereas PolD1 depletion through RNA interference does not influence centrosome-based microtubule growth, the depletion augments microtubule nucleation at the Golgi complex. Conversely, PolD1 overexpression inhibits Golgi-based microtubule nucleation. Golgi-derived microtubules are required for the assembly and maintenance of the proper Golgi structure, and we found that alteration of PolD1 levels affects Golgi structural organization. Moreover, suppression of PolD1 expression impairs Golgi reassembly after nocodazole-induced disassembly and causes defects in Golgi reorientation and directional cell migration. Collectively, these results reveal a mechanism that controls noncentrosomal γTuRC activity and regulates the organization of Golgi-derived microtubules., Microtubule organization requires γ-tubulin ring complexes (γTuRCs), but the mechanisms that control γTuRC-mediated microtubule nucleation are unclear. Here the authors show that the DNA polymerase δ catalytic subunit controls noncentrosomal γTuRC activity and regulates the organization of Golgi-derived microtubules.

To evaluate 3DVHTM as a patient dose-verification and analysis tool through multiple institutional studies. Virtual patient doses were measured and compared among different vendors' treatment planning systems (TPS) and delivered by different vendors' LINACS so that we better understand the uncertainty of entire process within a patient undergone radiotherapy.One head-and-neck (HN) and one lung patient were selected in this study. The DICOM images/RT structures along with clinical protocols including prescription doses (59.4Gy for HN and 70.2Gy for lung) and normalhyphen;tissues tolerances were distributed to six institutions. Based on the same criteria, each institution generated their IMRT plans for the patients. Four different TPS and six different LINACS were used. The conventional perhyphen;beam IMRT QA using MapCHECK was performed by all participants. All the measured and calculated data were sent back to one institution for 3DVH analysis. Through the use of planned-dose-perturbation (PDP)TM algorithm (Sun Nuclear Corp.), the 'actual-DVHs' were generated and then compared to the 'reference-DVHs' from plans. Their differences represented errors induced from the combination of TPS dose-calculation algorithm and beam-delivery systems.All plans in the study have met the clinical criteria. The 3D matching rates for 3%global/3mm (DD/DTA) ranged from 95.8-99.9% for HN and 93.5-100% for lung. The dose-difference-histogram for PTV had a mean of 0.67% [0-2%] for HN cases and 1% [0.6-2.8%] for lung cases. The QA tool was able to spot the doses outside 3%/3mm criteria for critical structures much easier than conventional planar QA methods. In addition, the hot/cold spots at the boundaries of collimators are attributed to the uncertainty of collimator-positioning greater than 1-mm.The analysis of IMRT plans in this study has shown that 3DVH is a vital QA tool for assessing clinically relevant doses as well as diagnosing potential systematic errors from both TPS and delivery systems.

A typical maloperation case of the differential protection utilized in the ultra-high voltage (UHV) voltage-regulating transformer (VRT) under inrush conditions is investigated in this paper. It indicates that the second harmonic restraint principle cannot identify the inrush current reliably under such conditions. This paper proposes a normalized equivalent instantaneous inductance (NEII)-based inrush blocking method, which improves the equivalent instantaneous inductance (EII)-based method in the UHV VRT protection. Although the EII-based method is capable of discriminating inrush currents and internal faults, some factors constrain its application, such as the field limitation of measuring the terminal voltage of the transformer and the difficulty of determining a reasonable threshold due to the diversity of transformer magnetizing characteristics. The proposed NEII-based method overcomes limitations of the EII-based method and can be adopted in UHVVRT protection. A number of simulation tests have verified the effectiveness of the proposed method.

Introduction: FLT3 is a frequently mutated gene in approximately one-third of AML cases and is associated with a poor prognosis. Few effective therapeutic options exist for patients with R/R FLT3mut+ AML. In 2018, gilteritinib was approved in the US as the first targeted therapy indicated for R/R FLT3mut+ AML. The efficacy of gilteritinib was established in the ADMIRAL trial, a phase 3 randomized trial, in comparison with SC (i.e., low-dose cyctarbine [LDAC], azacitidine, mitoxantrone + etoposide + cytarabine [MEC], and fludarabine + cytarabine + granulocyte colony stimulating factor + idarubicin [FLAG-IDA]). The results from the trial indicated that gilteritinib significantly improved overall survival (OS) compared to SC with 1-year survival rates of 37% vs. 17%. To inform the value of gilteritinib, this study aimed to assess the cost-effectiveness of gilteritinib for the treatment of R/R FLT3mut+ AML from a US third-party payer's perspective. Methods: A cost-effectiveness analysis (CEA) model was developed using monthly cycles and a 3% discount rate to assess the incremental cost effectiveness of gilteritinib compared to SC over a lifetime horizon. The model structure comprised a decision tree followed by two three-state partitioned survival models. The decision tree component stratified patients based on whether they received allogeneic hematopoietic stem cell transplantation (HSCT) following treatment initiation. The partitioned survival components included three health states: event-free survival (EFS), alive and post-event, and death. The selected model structure was chosen because HSCT is a key clinical event that has a significant impact on treatment outcomes for the target population. The efficacy inputs (OS and EFS) varied by HSCT status. The efficacy inputs for OS and EFS without HSCT were estimated based on the ADMIRAL trial. The efficacy inputs for OS and EFS with HSCT were assumed to be the same for both gilteritinib and SC and were based on available literature (Evers 2018). Parametric survival models or HRs were used to predict probabilities of being in different health states until year 3. Afterwards, all patients who remained alive were considered long-term survivors and their mortality risk was twice that of the general population based on literature. Treatment costs (drug, administration, and hospitalization), adverse event (AE) costs, subsequent HSCT costs, medical costs for each health state, FLT3 mutation testing, post-progression treatment, and terminal care costs were obtained from public databases and literature. For SC, the same regimen composition (i.e., LDAC, azacitidine, MEC, and FLAG-IDA) as the ADMIRAL trial was considered to estimate the treatment costs. All costs were inflated to 2018 US dollar (USD). Utilities for each health state were derived from the ADMIRAL trial and disutilities for AEs were derived from the literature. Total incremental costs, total incremental LYs, and total incremental QALYs were calculated. Incremental cost-effectiveness ratios (ICERs), defined as the incremental cost per additional gain in health effect (i.e., LY and QALY), were used to assess the economic value of gilteritinib relative to SC. Deterministic sensitivity analyses (DSA) and probabilistic sensitivity analyses (PSA) were also performed to test the robustness of the base-case results. Results: Over a lifetime horizon, the base-case model estimated that treatment with gilteritinib led to an increase of 1.55 discounted LYs and an increase of 1.29 discounted QALYs at an additional cost of $141,097 relative to SC; the corresponding incremental cost per LY gained was $90,761, and incremental cost per QALY gained was $109,741. Cost-effectiveness was most sensitive to gilteritinib cost, HSCT rate, and discount rate. In the PSA, the estimated probability that gilteritinib is cost-effective was 93.5% at an acceptable willingness-to-pay threshold of $150,000/QALY. Conclusions: Gilteritinib demonstrated greater LY and QALY improvements compared with SC. With an ICER of $109,741/QALY, gilteritinib is a cost-effective strategy from a US third-party payer's perspective, based on the $150,000/QALY threshold recommended by the US Institute for Clinical and Economic Review. Compared to SC, gilteritinib represents a new active treatment option for R/R FLT3mut+ AML patients that provides better health outcomes with a favorable cost-effectiveness profile. Disclosures Zeidan: Trovagene: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Ariad: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Daiichi Sankyo: Honoraria; Cardinal Health: Honoraria; Seattle Genetics: Honoraria; BeyondSpring: Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Agios: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria. Qi:Astellas: Other: I am an employee of Analysis Group, Inc., which provided paid consulting services to Astellas for the conduct of this study; Analysis Group, Inc.: Employment. Pandya:Astellas Pharmaceuticals: Employment. Garnham:Astellas: Employment. Yang:Analysis Group, Inc.: Employment; Astellas: Other: I am an employee of Analysis Group, Inc., which provided paid consulting services to Astellas for the conduct of this study. Shah:Astellas: Employment.

INTRODUCTION: Acute lymphoblastic leukemia (ALL) is a hematological malignancy that primarily affects children, adolescents, and young adults. Patients with refractory disease or in second or later relapse have a poor prognosis and are less likely to achieve long-term disease remission. In August 2017, tisagenlecleucel, a Chimeric antigen receptor T-cell (CAR-T) therapy, received approval from the US Food and Drug Administration (FDA) for the treatment of pediatric and young adult patients with B-cell ALL that is refractory or in second or later relapse based on data from the pivotal Phase II trial ELIANA. Since the launch of tisagenlecleucel in ALL, there has been discussion on the expected health resource use (HRU) and costs associated with the treatment beyond the cost of the drug and procedure. The current study aimed to estimate the total costs of tisagenlecleucel for the treatment of pediatric and young adult patients with relapsed or refractory (r/r) ALL from a US hospital's perspective using the HRU and safety data from the ELIANA trial. METHODS: An economic model was developed to assess the total costs associated with tisagenlecleucel treatment among pediatric and young patients with r/r ALL from a US hospital's perspective. The total costs were estimated from the time of leukapheresis to 2 months post-infusion, which is the timeframe when HRU related to the tisagenlecleucel infusion would likely occur. The model was developed using a fee-for-service approach, which estimated costs based on the HRU and safety data from the ELIANA trial. The model considered costs of leukapheresis, lymphodepleting chemotherapy, tisagenlecleucel infusion and hospital administration, inpatient and intensive care unit (ICU) admission, medical professional visits, lab tests and procedures, and additional medication and HRU for the management of major adverse events (AEs) (e.g., cytokine release syndrome [CRS]). Medication costs were estimated using the wholesale acquisition cost from the Truven Redbook. Unit costs for medication administration, medical professional visits, and lab test and procedures were obtained from the Centers for Medicare & Medicaid Services Physician Fee Schedule. Unit costs for AE were derived from the Healthcare Cost and Utilization Project. The daily inpatient and ICU costs were obtained from the literature. All costs were inflation-adjusted to 2019 USD. The base-case model estimated the total costs using the observed hospitalization, ICU and AE data from all patients receiving tisagenlecleucel infusion in the ELIANA trial. Scenario analyses were conducted varying key assumptions related to AEs and hospitalization. RESULTS: The overall costs associated with the tisagenlecleucel treatment from leukapheresis to 2-months post infusion in r/r ALL patients were estimated at $612,779. Considering a list price of tisagenlecleucel at $475,000, the model calculated additional cost of care to be $137,636, which included $70,968 (51.5%) for AE management, $57,952 (42.1%) for inpatient and ICU not attributing to AEs, $5,209 (3.8%) for lab tests and procedures, $1,780 (1.3%) for medical professional visits, and $1,727 (1.3%) for lymphodepleting drug and administration. In the sensitivity analyses, the total costs ranged from $483,169 (no AEs, no hospitalization) to $672,373 (CRS and other AEs, hospitalization). CONCLUSIONS: This is the first US-focused study that comprehensively evaluated the cost associated with tisagenlecleucel treatment based on HRU data from clinical trial observation. The total costs within 2 months of tisagenlecleucel administration was estimated at $612,779, on average. Compared to the cost of tisagenlecleucel procedure, the non-drug cost is relatively small. Further research with estimates based on real-world clinical use of tisagenlecleucel is warranted. Disclosures Yang: Astellas: Other: I am an employee of Analysis Group, Inc., which provided paid consulting services to Astellas for the conduct of this study; Analysis Group, Inc.: Employment. Hao:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Qi:Astellas: Other: I am an employee of Analysis Group, Inc., which provided paid consulting services to Astellas for the conduct of this study; Analysis Group, Inc.: Employment. Chai:Analysis Group, Inc.: Employment; Novartis: Other: I am an employee of Analysis Group, Inc., which provided paid consulting services to Novartis for the conduct of this study. Wu:Novartis: Other: I am an employee of Analysis Group, Inc., which provided paid consulting services to Novartis for the conduct of this study.

Introduction: AML is an aggressive hematopoietic malignancy, and ~30% of patients have mutations in the FLT3 gene. Historically, patients with R/R FLT3mut+ AML experienced dismal survival outcomes. The approval of FLT3-targeted agents has resulted in a paradigm change in the management of these patients. In 2018, gilteritinib was approved as the first targeted agent for R/R FLT3mut+ AML based on results of the phase 3 ADMIRAL trial, showing significantly improved median overall survival (OS) of 9.3 months. Historically, due to limited effective options and tolerability concerns, 11-40% of patients with R/R FLT3mut+ AML received BSC (defined as no active leukemia-directed therapy). Patients managed by BSC still incur substantial resource use and have poor outcomes. The estimated median OS was 2-3 months, with the majority of patients (> 90%) dying within one year. To quantify the incremental benefit and economic value of gilteritinib over BSC, a cost-effectiveness analysis (CEA) model was constructed to model disease trajectory, quality of life impact, and economic impact. Methods: A CEA was developed to compare the costs and effectiveness of gilteritinib and BSC from a US third-party payer's perspective over a lifetime horizon. The model used a 1-month cycle and 3% discount rate and comprised a decision tree followed by a three-stage partitioned survival model. In the decision tree stage, patients were first classified based on whether they received allogeneic hematopoietic stem cell transplantation (HSCT). Following stratification, patients were distributed among three health states: event-free survival (EFS), alive and post-event, and death. Due to the palliative nature of BSC, all patients in the BSC arm were assumed to start in the alive and post-event state and were not eligible to receive subsequent HSCT based on clinical inputs. For patients in the gilteritinib arm, the efficacy inputs were based on the ADMIRAL trial for patients without HSCT or literature (Evers 2018) for those with HSCT. For patients in the BSC arm, the efficacy inputs were based on available literature (Sarkozy 2013). Parametric survival models or hazard ratios were used to predict probabilities in different health states until year 3. After year 3, all patients who remained alive were considered cured with a two-fold increase in mortality risk compared to the general population. Treatment costs (drug, administration, and hospitalization), adverse event (AE) costs, subsequent HSCT costs, medical costs for health states, FLT3 testing, post-progression treatment, and terminal care costs were obtained from public databases and literature. Patients managed by BSC were assumed not to incur any costs related to treatment, AEs, or HSCT. All costs were inflated to 2018 US dollar (USD). Utilities for each health state were derived from the ADMIRAL trial and disutilities for AEs were derived from the literature. The model calculated total costs, and total effectiveness measured by life years (LYs) and quality-adjusted life years (QALYs) for gilteritinib and BSC, respectively. Incremental cost-effectiveness ratios (ICERs), defined as the incremental cost per additional gain in health effect (i.e., LY and QALY), were estimated comparing gilteritinib to BSC. To test the robustness of the results, deterministic sensitivity analyses (DSA) and probabilistic sensitivity analyses (PSA) were performed. Results: Over a lifetime horizon, treatment with gilteritinib, compared to BSC, was associated with an incremental LY gain of 2.82 and QALY gain of 2.32, respectively. With an additional cost of $239,623 relative to BSC, the ICER per one LY gained was $84,922, and ICER per one QALY gained was $103,110. The results were most sensitive to discount rate, cure assumptions, and gilteritinib cost. PSA showed 100% probability of being cost-effective at an acceptable willingness-to-pay threshold of $150,000/QALY in the US. Conclusions: Gilteritinib led to substantial clinical benefit compared to BSC for treatment of R/R FLT3mut+ AML. Despite the large cost difference, the ICER is still within a reasonable range of less than $150,000/QALY, as established by the US Institute for Clinical and Economic Review. Gilteritinib fulfills an important unmet need in the treatment landscape and represents a potential paradigm shift in the current management of R/R FLT3mut+ AML for patients who otherwise would not have received active therapy. Disclosures Zeidan: BeyondSpring: Honoraria; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Cardinal Health: Honoraria; Otsuka: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Ariad: Honoraria; Agios: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Daiichi Sankyo: Honoraria; Medimmune/AstraZeneca: Research Funding; Seattle Genetics: Honoraria. Pandya:Astellas Pharmaceuticals: Employment. Qi:Astellas: Other: I am an employee of Analysis Group, Inc., which provided paid consulting services to Astellas for the conduct of this study; Analysis Group, Inc.: Employment. Garnham:Astellas: Employment. Yang:Analysis Group, Inc.: Employment; Astellas: Other: I am an employee of Analysis Group, Inc., which provided paid consulting services to Astellas for the conduct of this study. Shah:Astellas: Employment.

SiCf/SiC composites have attracted wide attention as thermo-structural materials owing to its extraordinary properties at elevated temperature. To further improve the toughness of SiCf/SiC, Ti3SiC2 is used as the reinforcement of SiC matrix. In this study, the effect of Si content on the formation of Ti3SiC2 was discussed. The melt Si infiltration method was used to prepare the SiC matrix, whichTi3SiC2phase was in-situ formed from the reaction between TiC, C and Si during the infiltration process. X-ray diffractometry (XRD), scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS) were determined to characterize the phase constitution and microstructure of the matrix. The results demonstrate that the synthesis of Ti3SiC2 was depended on the amount of Si during the molten Si infiltration. The small amount of Si could resulted in the incomplete infiltration reaction. TiSi2 was obtained at the presence of excessive Si. Thus appropriate amount of Si promotes the formation of Ti3SiC2 and improves the purity.

Background Neoadjuvant studies in breast cancer (BC) patients have well-demonstrated that attaining pathological complete response (pCR) is associated with improved event-free survival (EFS) and overall survival (OS); and the association is strong in triple negative BC (TNBC) subtype. This study aimed to comprehensively evaluate the association of pCR and survival outcomes in TNBC by incorporating most recent studies; and to explore the impact of different study settings, thresholds of hormone receptor positivity defining TNBC and adjuvant chemotherapy usage on this association. Methods A literature search of neoadjuvant studies in TNBC was conducted up to October 2018. Clinical trials (CTs), real-world evidence (RWE) studies and meta-analyses (MA) with EFS/OS reported by pCR outcome were included. Main analyses were restricted to pCR definition of absence of tumor in the breast and axillary nodes, which is aligned with FDA guidance. Hazard ratios (HRs) evaluating the association between pCR and EFS/OS were derived from meta-analyses using fixed-effect and random-effects models. To further quantify the association, meta-analyses were conducted to synthesize the published survival curves by pCR outcome. A random-effects frailty model was utilized to account for between-study variation. Results Four randomized CTs, 2 single-arm CTs, 18 RWE studies and 1 MA for a total of 4,330 patients with TNBC were included in this study. Achieving pCR was strongly associated with improved survival outcomes (HR of EFS: 0.26, 95% CI: 0.22-0.30; and HR of OS: 0.20, 95% CI: 0.16-0.25). HR results were similar across study settings of CTs, RWE and MA. TNBC definition and adjuvant chemotherapy use did not have significant impact on HR results. The meta-analyses showed numerically longer survival in studies that reported adjuvant chemotherapy usage compared with those which did not, irrespective of attainment of pCR. Conclusions This study confirms the strong association between pCR and survival outcomes in TNBC based on evidence synthesis from both clinical and real-world settings. In addition, this study suggests potential survival benefit of subsequent adjuvant therapy for TNBC patients who received neoadjuvant therapy. Legal entity responsible for the study Merck & Co., Inc. Funding Merck & Co., Inc. Disclosure P.A. Fasching: Advisory / Consultancy: Merck & Co., Inc. M. Huang: Full / Part-time employment: Merck & Co., Inc. J. Cortes: Advisory / Consultancy: Merck & Co., Inc. J. Zhao: Full / Part-time employment: Merck & Co., Inc. J. O’Shaughnessy: Advisory / Consultancy: Merck & Co., Inc. P. Hu: Full / Part-time employment: Merck & Co., Inc. A. Haiderali: Full / Part-time employment: Merck & CO., Inc. V. Karantza: Full / Part-time employment: Merck & Co., Inc. G. Aktan: Full / Part-time employment: Merck & Co., Inc. A. Briggs: Advisory / Consultancy: Merck & Co., Inc. S. Ramsey: Advisory / Consultancy: Merck & Co., Inc. C.Z. Qi: Advisory / Consultancy, Employee of Analysis Group, Inc., which has received consulting fees from Merck & Co., Inc.: Merck & Co., Inc. J. Xie: Advisory / Consultancy, Employee of Analysis Group, Inc., which has received consulting fees from Merck & Co., Inc.: Merck & Co., Inc. C. Gu: Advisory / Consultancy, Employee of Analysis Group, Inc., which has received consulting fees from Merck & Co., Inc.: Merck & Co., Inc. K. Qian: Advisory / Consultancy, Employee of Analysis Group, Inc., which has received consulting fees from Merck & Co., Inc.: Merck & Co., Inc. M. Yuan: Advisory / Consultancy, Employee of Analysis Group, Inc., which has received consulting fees from Merck & Co., Inc.: Merck & Co., Inc. E.Q. Wu: Advisory / Consultancy, Employee of Analysis Group, Inc., which has received consulting fees from Merck & Co., Inc.: Merck & Co., Inc.

The γ-tubulin ring complex (γTuRC) is the primary microtubule nucleator in animal cells. NME7 possesses an intrinsic kinase activity that is involved in the stimulation of the γTuRC., As the primary microtubule nucleator in animal cells, the γ-tubulin ring complex (γTuRC) plays a crucial role in microtubule organization, but little is known about how the activity of the γTuRC is regulated. Recently, isolated γTuRC was found to contain NME7, a poorly characterized member of the NME family. Here we report that NME7 is a γTuRC component that regulates the microtubule-nucleating activity of the γTuRC. NME7 contains two putative kinase domains, A and B, and shows autophosphorylating activity. Whereas domain A is involved in the autophosphorylation, domain B is inactive. NME7 interacts with the γTuRC through both A and B domains, with Arg-322 in domain B being crucial to the binding. In association with the γTuRC, NME7 localizes to centrosomes throughout the cell cycle and to mitotic spindles during mitosis. Suppression of NME7 expression does not affect γTuRC assembly or localization to centrosomes, but it does impair centrosome-based microtubule nucleation. Of importance, wild-type NME7 promotes γTuRC-dependent nucleation of microtubules, but kinase-deficient NME7 does so only poorly. These results suggest that NME7 functions in the γTuRC in a kinase-dependent manner to facilitate microtubule nucleation.

The Daya Bay Reactor Neutrino Experiment was designed to achieve a sensitivity on the value of sin^2 2θ_(13) to better than 0.01 at 90% CL. The experiment consists of eight antineutrino detectors installed underground at different baselines from six nuclear reactors. With data collected with six antineutrino detectors for 55 days, Daya Bay announced the discovery of a non-zero value for sin^2 2θ_(13) with a significance of 5.2 standard deviations in March 2012. The most recent analysis with 139 days of data acquired in a six-detector configuration yields sin^2 2θ_(13) = 0.089 ± 0.010 (stat.) ± 0.005 (syst.), which is the most precise measurement of sin^2 2θ_(13) to date.

This article aimed to investigate the value of α-fetoprotein (AFP) for the diagnosis of hepatocellular carcinoma (HCC) and to evaluate the relationship between AFP and various clinical variables of HCC comprehensively. A retrospective study of postoperative patients diagnosed with liver neoplasm from two Chinese centers was enrolled in our study.A total of 3050 patients were included. The best cut-off point of AFP for the diagnosis of HCC was 20ng/ml with ideal sensitivity (69.74%), specificity (91.18%), LR (4.12) and YI (0.61). Non-HBV infection patients showed the highest specificity (94.44%) but lowest sensitivity (60.13%). In HBV infection. Patients, HBsAg, HBeAb, and HBcAb positive patients had the highest sensitivity (79.55%) and specificity (58.49%). AFP levels increased significantly in symptomatic patients (p=0.011). Those patients with tumor sizes ≥10cm had much higher serum AFP level compared with smaller tumors ones (p=0.014). AFP levels increased remarkably in patients with vascular invasion (p=0.015). Stepwise logistic regression showed tumor size (≥10cm) was an independent predictor of elevated AFP (OR=2.743, 95%CI: 1.167-6.447, P=0.021). The best discriminating AFP value for the diagnosis of HCC is 20ng/ml; HBsAg, HBeAb and HBcAb positive patients have the optimal sensitivity and specificity; tumor size ≥ 10cm is an independent predictor of elevated AFP.

To compare outcomes of metastatic renal cell carcinoma (mRCC) patients treated with everolimus, temsirolimus, and sorafenib following initial treatment with a tyrosine kinase inhibitor (TKI) in community and academic practices throughout the US.Medical records of mRCC patients who received everolimus, temsirolimus or sorafenib as their second therapy following a TKI were retrospectively reviewed from a nationally representative panel of oncologists. Overall survival (OS) and progression-free survival (PFS) of second targeted therapies were compared using multivariable Cox proportional hazard models, with adjustment for demographics, disease severity and prior treatments.A total of 233, 178, and 123 mRCC patients receiving everolimus, temsirolimus, and sorafenib, respectively, as second targeted therapies were included. Eighty-six percent used sunitinib and the remainder used sorafenib or pazopanib as their initial TKI. After adjusting for baseline characteristics, everolimus was associated with significantly prolonged OS (hazard ratio [HR] 0.60; CI 0.42-0.85; p = 0.004) and PFS (HR 0.73; CI 0.54-0.97; p = 0.032) compared to temsirolimus. Everolimus was associated with significantly longer OS (HR 0.66; CI 0.44-0.99; p = 0.045) and numerically longer PFS compared to sorafenib. No significant differences were observed between temsirolimus and sorafenib.Despite adjustment for multiple patient characteristics, comparisons between treatment groups may be confounded by unobserved factors in this retrospective observational study. Tolerability outcomes were not collected.In this retrospective, non-randomized study of mRCC patients with prior TKI treatment, everolimus was associated with significantly prolonged OS and PFS compared to temsirolimus and significantly prolonged OS compared to sorafenib.

Relative permeability modifier (RPM) is proven to be effective to control water production. In this study, the static adsorption and disproportionate permeability reduction of RPM were investigated. Experimental results indicate that the static adsorption of RPM on quartz sands and reservoir sands, which is in line with Langmuir adsorption isotherm, is affected by electrostatic interactions and wettability of solid surface. Adsorption on reservoir sands is far less than that on quartz sands and RPM can render the oil-wet quartz plate to be weakly water-wet plate. Physical simulation results show that RPM has good disproportionate permeability reduction effect to control water production.

A genome-wide microscopy screen identifies proteins localized to Cajal bodies, paraspeckles, and other known and previously uncharacterized nuclear subcompartments., The nucleus is a unique organelle that contains essential genetic materials in chromosome territories. The interchromatin space is composed of nuclear subcompartments, which are defined by several distinctive nuclear bodies believed to be factories of DNA or RNA processing and sites of transcriptional and/or posttranscriptional regulation. In this paper, we performed a genome-wide microscopy-based screening for proteins that form nuclear foci and characterized their localizations using markers of known nuclear bodies. In total, we identified 325 proteins localized to distinct nuclear bodies, including nucleoli (148), promyelocytic leukemia nuclear bodies (38), nuclear speckles (27), paraspeckles (24), Cajal bodies (17), Sam68 nuclear bodies (5), Polycomb bodies (2), and uncharacterized nuclear bodies (64). Functional validation revealed several proteins potentially involved in the assembly of Cajal bodies and paraspeckles. Together, these data establish the first atlas of human proteins in different nuclear bodies and provide key information for research on nuclear bodies.

Chemical water control technique has been successfully used to improve oil recovery of mature waterflooding reservoirs. However, for high-temperature and low-permeability sandstone reservoirs, not many options are available. An inorganic gel composed of aluminum chloride hexahydrate as gelling agent and urea as an activator was developed. Based on the proper gelation time and degree of syneresis, the optimum mass ratio of aluminum chloride and urea was 1:0.625. According to the gel strength and economical cost, the reasonable concentration of aluminum chloride should range from 3.0% to 6.0%. Gel compatibility with various formation brines showed that the gel could tolerate sodium chloride concentrations up to 80 g·L −1 and calcium chloride concentrations up to 40 g·L −1. Long-term thermal stability and sandpack flow results showed that after aging for 60 days at 110°C, the gel showed approximately 82% permeability reduction when about 16% syneresis was observed in bulk samples.

We measure spontaneous imbibition of aqueous (deionized water and KCl solutions of various concentrations) and oleic (kerosene and iso-octane) phases in several dry organic shale samples selected from two wells drilled in the Horn River basin. We find that the imbibition rate of aqueous phases is much higher than that of oleic phases even when plotted versus scaling dimensionless time, contrary to capillary-driven imbibition models. The observed difference is more pronounced in samples with higher clay content. The results suggest that the excess water intake is due to (1) the additional driving force provided through water adsorption by clay minerals, and (2) the enhancement of sample permeability through adsorption-induced microfractures.

Due to the features of strong heterogeneity, difficult early diagnosis, poor prognosis, and high fatality rate, hepatocellular carcinoma (HCC) has become an important disease which threatens the health of the Chinese population. Accurate early diagnosis is crucial to improving the success rate of liver cancer resection and reducing postoperative recurrence and metastasis, and its core is the screening and validation of biomarkers for early diagnosis. Isobaric tags for relative and absolute quantitation (iTRAQ) and stable isotope labeling with amino acids in cell culture are important parts of proteomics technology, and iTRAQ has become the most important technique in quantitative proteomics technology due to its advantages of high throughput, high quantitative accuracy, and no limitation by sample source. This article reviews the research advances in molecular mechanism of the development and progression of HCC and screening of markers, in order to establish a theoretical foundation for in-depth understanding of the molecular mechanisms of the development and progression of HCC and the development of new biomarkers.

A new measurement of the reactor antineutrino flux and energy spectrum by the Daya Bay reactor neutrino experiment is reported. The antineutrinos were generated by six 2.9~GW$_{\mathrm{th}}$ nuclear reactors and detected by eight antineutrino detectors deployed in two near (560~m and 600~m flux-weighted baselines) and one far (1640~m flux-weighted baseline) underground experimental halls. With 621 days of data, more than 1.2 million inverse beta decay (IBD) candidates were detected. The IBD yield in the eight detectors was measured, and the ratio of measured to predicted flux was found to be $0.946\pm0.020$ ($0.992\pm0.021$) for the Huber+Mueller (ILL+Vogel) model. A 2.9~$\sigma$ deviation was found in the measured IBD positron energy spectrum compared to the predictions. In particular, an excess of events in the region of 4-6~MeV was found in the measured spectrum, with a local significance of 4.4~$\sigma$. A reactor antineutrino spectrum weighted by the IBD cross section is extracted for model-independent predictions., Comment: version published in Chinese Physics C

Like many complex human diseases, esophageal squamous cell carcinoma (ESCC) is known to cluster in families. Familial ESCC cases often show early onset and worse prognosis than the sporadic cases. However, the molecular genetic basis underlying the development of familial ESCC is mostly unknown. We reported that SLC22A3 is significantly down-regulated in nontumor esophageal tissues from patients with familial ESCC compared with tissues from patients with sporadic ESCCs. A-to-I RNA editing of the SLC22A3 gene results in its reduced expression in the nontumor esophageal tissues of familial ESCCs and is significantly correlated with lymph node metastasis. The RNA-editing enzyme ADAR2, a familial ESCC susceptibility gene identified by our post hoc genome-wide association study, is positively correlated with the editing level of SLC22A3 Moreover, functional studies showed that SLC22A3 is a metastasis suppressor in ESCC, and deregulation of SLC22A3 facilitates cell invasion and filopodia formation by reducing its direct association with α-actinin-4 (ACTN4), leading to the increased actin-binding activity of ACTN4 in normal esophageal cells. Collectively, we now show that A-to-I RNA editing of SLC22A3 contributes to the early development and progression of familial esophageal cancer in high-risk individuals.

Penicillium expansum produces large amounts of lipase, which is widely used in laundry detergent and leather industry. We isolated the glyceraldehyde-3-phosphate dehydrogenase gene (PeGPD) from P. expansum PE-12 through reverse transcriptase PCR and 5'-3' rapid amplification of cDNA ends (RACE-PCR). The gene is 1266 bp long, including an ORF of 1014 bp, encoding a polypeptide chain of 337 amino acids. A phylogenetic tree based on GPD proteins showed that P. expansum is close to Aspergillus species, but comparatively distant from P. marneffei. Southern blot results revealed a single copy of PeGPD, and expression analysis gave evidence of high expression levels. PeGPD genes have potential for genetic engineering of P. expansum for industrial lipase production.

Microtubules are polar cytoskeleton filaments that extend via growth at their plus ends. Microtubule plus-end-tracking proteins (+TIPs) accumulate at these growing plus ends to control microtubule dynamics and attachment. The +TIP end-binding protein 1 (EB1) and its homologs possess an autonomous plus-end-tracking mechanism and interact with other known +TIPs, which then recruit those +TIPs to the growing plus ends. A major +TIP class contains the SXIP (Ser-X-Ile-Pro, with X denoting any amino acid residue) motif, known to interact with EB1 and its homologs for plus-end tracking, but the role of SXIP in regulating EB1 activities is unclear. We show here that an interaction of EB1 with the SXIP-containing +TIP CDK5 regulatory subunit-associated protein 2 (CDK5RAP2) regulates several EB1 activities, including microtubule plus-end tracking, dynamics at microtubule plus ends, microtubule and α/β-tubulin binding, and microtubule polymerization. The SXIP motif fused with a dimerization domain from CDK5RAP2 significantly enhanced EB1 plus-end-tracking and microtubule-polymerizing and bundling activities, but the SXIP motif alone failed to do so. An SXIP-binding-deficient EB1 mutant displayed significantly lower microtubule plus-end tracking than the wild-type protein in transfected cells. These results suggest that EB1 cooperates with CDK5RAP2 and perhaps other SXIP-containing +TIPs in tracking growing microtubule tips. We also generated plus-end-tracking chimeras of CDK5RAP2 and the adenomatous polyposis coli protein (APC) and found that overexpression of the dimerization domains interfered with microtubule plus-end tracking of their respective SXIP-containing chimeras. Our results suggest that disruption of SXIP dimerization enables detailed investigations of microtubule plus-end-associated functions of individual SXIP-containing +TIPs.

NO ABSTRACT Keywords: goose parvovirus; Yan goose; isolation; characterization.

To retrospectively analyze the prognosis and its related factor in stage Ⅲ thoracic esophageal carcinoma after surgery.504 patients with stage Ⅲ thoracic esophageal cancer after resection were included in this study. There were 388 males and 116 females. The median age was 60 years. 476 cases were treated with two-field and 28 with three-field lymphadenectomy. There were 44 cases of upper-, 334 of middle-, and 126 of lower-thoracic esophageal cancer. There were 292 patients with stage Ⅲa, 128 with stage Ⅲb and 84 with stage Ⅲc esophageal cancer. 137 patients were treated with surgery alone, 264 had postoperative chemotherapy (CT), 64 had radiotherapy (RT) and 39 had CT plus RT.The follow-up was ended on September 31, 2014. The 1-, 3-, and 5-year overall survival (OS) rates and median survival were 73.0%, 34.4%, 26.7% and 22 months, respectively. Univariate analysis showed that mode of surgery, site of lesion, N and TNM stages, and postoperative adjuvant therapy were significantly associated with OS (P0.05 for all). Multivariate analysis showed that TNM and adjuvant therapy were independent factors for OS (P0.05 for both). The 1-, 3-, 5-years progression-free survival (PFS) rates of patients undergoing postoperative adjuvant therapy were 57.3%, 32.0% and 27.0%, respectively, higher than those of the patients treated by surgery alone (P0.05). Further analysis showed that postoperative chemotherapy and/or radiotherapy could mainly improve OS in the patients with cancer in the upper- or middle-thoracic segment and well- or moderately differentiated squamous cell carcimoma (P0.05). Univariate analysis showed that site of lesion, N and TNM stage, R0/R1 and adjuvant therapy were significantly related to PFS (P0.05). Multivariate analysis showed that site of lesion, R0/R1 resection, TNM stage and postoperative adjuvant therapy were independent factors for PFS (P0.05 for all). Patients with severe adhesion at surgery or R1 resection had a lower PFS rate (P0.05).The prognosis of stage Ⅲ esophageal carcinoma after two-field surgery is poor. TNM stage and postoperative adjuvant therapy are independent factors for OS and PFS. Postoperative chemotherapy and/or radiotherapy can improve OS and PFS. Site of lesion is also associated with prognosis. The risk of disease progression could be increased in patients with severe adhesion at surgery or R1 resection.

We describe the upgrade of the L3 detector for running at LHC. The principle goals are the precise measurement of electrons, photons and muons.

Searches for a light sterile neutrino have been performed independently by the MINOS and the Daya Bay experiments using the muon (anti)neutrino and electron antineutrino disappearance channels, respectively. In this Letter, results from both experiments are combined with those from the Bugey-3 reactor neutrino experiment to constrain oscillations into light sterile neutrinos. The three experiments are sensitive to complementary regions of parameter space, enabling the combined analysis to probe regions allowed by the LSND and MiniBooNE experiments in a minimally extended four-neutrino flavor framework. Stringent limits on $\sin^2 2\theta_{\mu e}$ are set over 6 orders of magnitude in the sterile mass-squared splitting $\Delta m^2_{41}$. The sterile-neutrino mixing phase space allowed by the LSND and MiniBooNE experiments is excluded for $\Delta m^2_{41} < 0.8$ eV$^2$ at 95% CL$_s$., Comment: 8 pages, 4 figures, published in Physical Review Letters. Data release found at http://www-numi.fnal.gov/PublicInfo/forscientists.html and at https://wiki.bnl.gov/dayabay/index.php?title=Daya_Bay%27s_Sterile_Neutrino_Results_in_2016

Relaxin (RLX) has demonstrated diverse pharmacological effects in various scientific and clinical studies. The emergence of porcine relaxin (pRLX) has raised concerns on the doping potential of pRLX. There have also been speculations in the horseracing industry on its covert use. To control the abuse of pRLX in equine sports, a method to detect pRLX effectively and to provide its unequivocal identification in equine biological samples is required. This paper reports on the detection and confirmation of pRLX in equine plasma by liquid chromatography-high resolution mass spectrometry. pRLX was isolated from equine plasma by immunoaffinity purification using anti-pRLX antibody-coated magnetic beads. Anti-pRLX antibody was generated in-house by purifying antisera from rabbits immunized with pRLX. The isolated pRLX was subjected to reduction of their disulfide bonds to obtain their respective A- and B-chains. The extracts were then further purified and concentrated prior to reversed-phase LC separation and high resolution accurate mass measurement. As detection of the A-chains was far more sensitive than that of the B-chains, the A-chain of pRLX was set as the targets for detection and confirmation. The limit of detection for pRLX was around 0.005 ng/mL (~ 0.86 fM) and the limit of confirmation was around 0.02 ng/mL (~ 3.4 fM). It was observed that method sensitivity was improved at least 5-fold by using an EASY-spray column and emitter in place of the conventional ESI source. The applicability of this method was demonstrated by the identification of pRLX and its metabolites in equine plasma obtained after subcutaneous administration. To our knowledge, this is the first report of a validated mass spectrometry method for the unequivocal confirmation of pRLX in any biological fluid. Copyright © 2016 John WileySons, Ltd.

This paper presents a novel steering control method for 4-Wheel Independent Drive and Independent Steering (4-WIDIS) electric mobility scooter for disabled people and elderlies, in which steering of all four wheels are coordinated to minimise the turning radius of the scooter to zero. A full-scale prototype is built for experiment on mobility pathway, which demonstrated the manoeuvrability advantage of such steering control in a scooter application.