Neoadjuvant Chemotherapy with FOLFOX4 Regimen to Treat Advanced Gastric Cancer Improves Survival without Increasing Adverse Events: A Retrospective Cohort Study from a Chinese Center

Background/Aim. To evaluate the clinical efficacy of FOLFOX4 (5-fluomumcil/leucovorin combined and oxaliplatin) neoadjuvant chemotherapy for advanced gastric cancer (AGC). Patients and Methods. Fifty-eight AGC patients were enrolled in this retrospective cohort study, 23 in the neoadjuvant group and 35 in the adjuvant group. R0 resection, survival, and adverse events were compared. Results. The two groups were well-matched, with no significant differences in R0 resection rate (82.6% versus 82.0%) and number of lymph nodes dissection (16 (0–49) versus 13 (3–40)) between the two groups (P>0.05). The number of lymph node metastases in the neoadjuvant group (3 (0–14)) was significantly fewer than that in the adjuvant group (6 (0–27)) (P=0.04). The neoadjuvant group had significantly better median overall survival (29.0 versus 22.0 months) and 3-year survival rate (73.9% versus 40.0%) than the adjuvant group (P=0.013). The positive expression rate of Ki-67 in the neoadjuvant group (40.0%, 8/20) was lower than that in the adjuvant group (74.2%, 23/31; P=0.015). Conclusion. The FOLFOX4 neoadjuvant chemotherapy could improve survival without increasing adverse events in patients with AGC

Tet and TDG Mediate DNA Demethylation Essential for Mesenchymal-to-Epithelial Transition in Somatic Cell Reprogramming

SummaryTet-mediated DNA oxidation is a recently identified mammalian epigenetic modification, and its functional role in cell-fate transitions remains poorly understood. Here, we derive mouse embryonic fibroblasts (MEFs) deleted in all three Tet genes and examine their capacity for reprogramming into induced pluripotent stem cells (iPSCs). We show that Tet-deficient MEFs cannot be reprogrammed because of a block in the mesenchymal-to-epithelial transition (MET) step. Reprogramming of MEFs deficient in TDG is similarly impaired. The block in reprogramming is caused at least in part by defective activation of key miRNAs, which depends on oxidative demethylation promoted by Tet and TDG. Reintroduction of either the affected miRNAs or catalytically active Tet and TDG restores reprogramming in the knockout MEFs. Thus, oxidative demethylation to promote gene activation appears to be functionally required for reprogramming of fibroblasts to pluripotency. These findings provide mechanistic insight into the role of epigenetic barriers in cell-lineage conversion

28-Day Oral Chronic Toxicity Study of Arctigenin in Rats

Arctium lappa (burdock) is the most popular daily edible vegetable in China and Japan because of its general health tonic effects. Previous studies focused on the beneficial role of Arctigenin but neglected its potential side-effects and toxicities. In the present study, the sub-chronic toxicity profile of Arctigenin following 28 days of consecutive exposure was investigated in rats. The results showed that during the drug exposure period, Arctigenin-12 mg/kg administration resulted in focal necrosis and lymphocytes infiltration of heart ventricular septal muscle cells. In the kidney cortical zone, the renal tubular epithelial cells were swollen, mineralized, and lymphocyte infiltrated. In the liver, the partial hepatocyte cytoplasm showed vacuolation and fatty changes, focal necrosis, and interstitial lymphocyte infiltration. In the rats that underwent 36 mg/kg/day administration, there was bilateral testis and epididymis atrophy. In the lung and primary bronchus, erythrocytes and edema fluid were observed. Changes of proestrus or estrus were observed in the uterus, cervix, and vagina intimal epithelial cells. Lymphocytic focal infiltration occurred in the prostate mesenchyme. The high dosage of Arctigenin only decreased the body weight at day 4. At the end of the recovery period, histopathological changes were irreversible, even after withdrawal of the drug for 28 days. Focal necrosis still existed in the heart ventricular septal muscle cells and hepatocytes. Lymphocyte infiltrations were observed in the heart, renal cortex, hepatocyte, and pancreas exocrine gland. Meanwhile, atrophy occurred in the testicles and pancreas. In addition, in the Arctigenin-12 mg/kg group, creatinine (CREA) and brain weight were both significantly increased. The toxicokinetical study demonstrated that Arctigenin accumulated in the organs of rats. The food consumption, hematological, and biochemical parameters were not associated with the above results. These contradictory results might result from the lesions induced by Arctigenin, which were not sufficiently serious to change the parameters. These results suggest that Arctium lappa should be consumed daily with caution because of the potential toxicity induced by Arctigenin. According to all results, the lowest observed adverse effect level (LOAEL) was induced by 12 mg/kg daily exposure to Arctigenin, and the No-observed-adverse-effect-level (NOAEL) should be lower than 12 mg/kg

Oxidation of trimethylamine to trimethylamine N-oxide facilitates high hydrostatic pressure tolerance in a generalist bacterial lineage

High hydrostatic pressure (HHP) is a characteristic environmental factor of the deep ocean. However, it remains unclear how piezotolerant bacteria adapt to HHP. Here, we identify a two-step metabolic pathway to cope with HHP stress in a piezotolerant bacterium. Myroides profundi D25T, obtained from a deep-sea sediment, can take up trimethylamine (TMA) through a previously unidentified TMA transporter, TmaT, and oxidize intracellular TMA into trimethylamine N-oxide (TMAO) by a TMA monooxygenase, MpTmm. The produced TMAO is accumulated in the cell, functioning as a piezolyte, improving both growth and survival at HHP. The function of the TmaT-MpTmm pathway was further confirmed by introducing it into Escherichia coli and Bacillus subtilis. Encoded TmaT-like and MpTmm-like sequences extensively exist in marine metagenomes, and other marine Bacteroidetes bacteria containing genes encoding TmaT-like and MpTmm-like proteins also have improved HHP tolerance in the presence of TMA, implying the universality of this HHP tolerance strategy in marine Bacteroidetes

Efficacy, Safety, and Immunogenicity of an Escherichia coliProduced Bivalent Human Papillomavirus Vaccine: An Interim Analysis of a Randomized Clinical Trial

HPV是一种常见的生殖道感染病毒，高危型HPV持续性感染能够导致几乎所有的宫颈癌，其中HPV 16型和18型危害最大，可导致约70%的宫颈癌。预防性HPV疫苗有望减少甚至最终消灭由疫苗型别导致的宫颈癌，降低HPV相关的疾病负担。该研究是在全国4个中心5个现场的18-45岁健康女性中进行的多中心、随机、双盲、对照（戊肝疫苗）的三期临床试验，该研究结果证实我校自主研发的双价人乳头瘤病毒疫苗（大肠杆菌）具有良好的安全性、免疫原性和免疫持久性，可有效地预防HPV 16型和/或18型相关的宫颈高度癌前病变及持续性感染。 该论文报告了我校和厦门万泰沧海生物技术有限公司自主研发的双价人乳头瘤病毒疫苗（大肠杆菌）三期临床试验的期中分析结果。这是第一个进入临床试验并提交药品注册申请的国产人乳头瘤病毒疫苗（HPV疫苗），有望成为世界上第四个上市的HPV疫苗，受到世界卫生组织和盖茨基金会等国际组织的高度关注。 中国医学科学院肿瘤医院乔友林教授、我校吴婷教授、广西壮族自治区疾病预防控制中心李荣成主任医师、江苏省疾病预防控制中心胡月梅主任医师、北京大学人民医院魏丽惠教授、中国食品药品检定研究院李长贵研究员、中国医学科学院肿瘤医院陈汶教授为该论文的共同第一作者，我校张军教授、夏宁邵教授和中国医学科学院肿瘤医院乔友林教授为该论文的共同通讯作者。【Abstract】Background The high cost and insufficient supply of human papillomavirus (HPV) vaccines have slowed the pace of controlling cervical cancer. A phase 3 clinical trial was conducted to evaluate the efficacy, safety and immunogenicity of a novel Escherichia coli-produced bivalent HPV-16/18 vaccine. Methods A multi-centre, randomized, double-blind trial started on November 22, 2012, in China. In total, 7372 eligible women aged 18-45 years were age-stratified and randomly assigned to receiving 3 doses of the test or control (hepatitis E) vaccine at months 0, 1 and 6. Co-primary endpoints included high-grade genital lesions and persistent infection (over 6 months) associated with HPV-16/18. The primary analysis was performed on a per-protocol susceptible population of individuals who were negative for relevant HPV type-specific neutralizing antibodies (at day 0) and DNA (at day 0 through month 7) and who received 3 doses of the vaccine. This report presents data from a pre-specified interim analysis used for regulatory submission. Results In the per-protocol cohort, the efficacies against high-grade genital lesions and persistent infection were 100.0% (95% confidence interval [CI] = 55.6% to 100.0%, 0/3306 in the vaccine group vs. 10/3296 in the control group) and 97.8% (95% CI = 87.1% to 99.9%, 1/3240 vs. 45/3246), respectively. The side effects were mild. No vaccine-related serious adverse events were noted. Robust antibody responses for both types were induced and persisted for at least 42 months. Conclusions The Escherichia coli-produced HPV-16/18 vaccine is well tolerated and highly efficacious against HPV-16/18 associated high-grade genital lesions and persistent infection in women.This work was supported by grants from the Chinese National High-tech R&D Program (863 program, 2012AA02A408), the Chinese National Major Scientific and Technological Special Project for “Significant New Drug Development” (2018ZX09308010 and 2012ZX09101316), the National Natural Science Foundation of China (81673240 and U1705283), the Fujian Provincial Major Scientific and Technological Project (2015YZ0002), the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (CIFMS, 2017-I2M-B&R-03, and 2016-I2M-1-019) and Xiamen Innovax. 该研究获得了国家高技术研究发展计划（863计划）、新药创制国家科技重大专项、国家自然科学基金、福建省科技重大专项、中国医学科学院医学与健康科技创新工程基金以及厦门万泰沧海生物技术有限公司的资助

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Search for heavy resonances decaying to two Higgs bosons in final states containing four b quarks

A search is presented for narrow heavy resonances X decaying into pairs of Higgs bosons (H) in proton-proton collisions collected by the CMS experiment at the LHC at root s = 8 TeV. The data correspond to an integrated luminosity of 19.7 fb(-1). The search considers HH resonances with masses between 1 and 3 TeV, having final states of two b quark pairs. Each Higgs boson is produced with large momentum, and the hadronization products of the pair of b quarks can usually be reconstructed as single large jets. The background from multijet and t (t) over bar events is significantly reduced by applying requirements related to the flavor of the jet, its mass, and its substructure. The signal would be identified as a peak on top of the dijet invariant mass spectrum of the remaining background events. No evidence is observed for such a signal. Upper limits obtained at 95 confidence level for the product of the production cross section and branching fraction sigma(gg -> X) B(X -> HH -> b (b) over barb (b) over bar) range from 10 to 1.5 fb for the mass of X from 1.15 to 2.0 TeV, significantly extending previous searches. For a warped extra dimension theory with amass scale Lambda(R) = 1 TeV, the data exclude radion scalar masses between 1.15 and 1.55 TeV