Evaluation of menopausal status among breast cancer patients with chemotherapy-induced amenorrhea

Objective： In patients with chemotherapy-induced amenorrhea （CIA）, the menopausal status is ambiguous anddifficult to evaluate. This study aimed to establish a discriminative model to predict and classify the menopausalstatus of breast cancer patients with CIA.Methods： This is a single center hospital-based study from 2013 to 2016. The menopausal age distribution andaccumulated incidence rate of CIA are described. Multivariate models were adjusted for established and potentialconfounding factors including age, serum concentration of estradiol （E2） and follicle-stimulating hormone （FSH）,feeding, pregnancy, parity, abortions, and body mass index （BMI）. The odds ratio （OR） and 95% confidenceinterval （95% CI） of different risk factors were estimated.Results： A total of 1,796 breast cancer patients were included in this study, among whom, 1,175 （65.42%） werepremenopausal patients and 621 （34.58%） were post-menopause patients. Five hundred and fifty patients wereincluded in CIA analysis, and a cumulative CIA rate of 81.64% was found in them. Age （OR： 1.856, 95% CI：1.732-1.990）, serum concentration of E2 （OR： 0.976, 95% CI： 0.972-0.980） and FSH （OR： 1.060, 95% CI：1.053-i.066）, and menarche age （OR： 1.074, 95% CI： 1.009-1.144） were found to be associated with the patients＇menopausal status. According to multivariate analysis, the discriminative model to predict the menopausal status isLogit （P）=-28.396＋0.536Age-0.014E2＋0.031FSH. The sensitivities for this model were higher than 85%, and itsspecificities were higher than 89%.Conclusions： The discriminative model obtained from this study for predicting menstrual state is important forpremenopausal patients with CIA. This model has high specificity and sensitivity and should be prudently used.

EGFR改变图谱及其潜在的临床意义:综合泛癌分析研究

背景与目的人表皮生长因子受体(human epidermal growth factor receptor,EGFR)是癌基因,是EGFR突变型肺癌精准治疗的主要靶点之一。虽然有许多关于单一肿瘤的报道,但尚无关于EGFR突变、过表达、扩增、DNA甲基化及其在多种不同癌症中并存的临床相关性的综合分析。本研究旨在深入探讨EGFR改变谱图及其治疗和预后意义,填补该领域空白。方法我们分析了癌症基因组计划(The Cancer Genome Atlas,TCGA)数据库中涉及的32种癌症类型、11,314例患者的EGFR基因改变(突变和扩增/缺失)、异常表达和DNA甲基化情况。比较了不同肿瘤类型间的突变频率、基因组位置分布、功能影响和临床靶向治疗的意义,并分析了它们与患者生存期的关系。结果在不同肿瘤中,EGFR改变率、功能域的突变位点、扩增、过表达和DNA甲基化模式均有很大差异。在所有肿瘤中,总体突变率相对较低。多发于肺癌,可靶向治疗的突变主要在Pkinase_Tyr结构域中。改变频率最高的是多形性胶质母细胞瘤,但主要为基因扩增和靶向治疗效果较差的Furin-like结构域内突变。脑低级别胶质瘤通常为EGFR基因扩增和表达增加,且预后不良。虽然结肠和胰腺癌的EGFR突变很少,然而EGFR高表达与患者生存期短显著相关。鳞状细胞癌(无论发生在头颈部、肺部或食管)均表现出相似的特征,改变率为5.0%,以基因扩增为主,EGFR表达增加,且与患者的生存期短相关。在某些癌症中,DNA甲基化与EGFR表达和患者预后密切相关。结论EGFR改变类型、频率、在功能域的分布和表达因癌症类型而异。虽然Pkinase_Tyr结构域突变对于治疗选择更为重要,但扩增或失调引起的表达增加会影响更多类型的肿瘤,并导致预后更差,因此需要对EGFR驱动的肿瘤采取新的治疗策略。

Thymidylate synthase confers pemetrexed resistance of non-small cell lung cancer cells by EGFR/PI3K/AKT pathway

Chemotherapy drug resistance is the main cause leading to the relapse and metastasis of non-small cell lung cancer(NSCLC)patients.Our study aimed to investigate the mechanism of pemetrexed resistance in NSCLC.Firstly,the pemetrexed(PEM)-resistant PC-9 and A549 lung adenocarcinoma cell lines(PC-9/PEM and A549/PEM)were established.The expression of thymidylate synthase(TS)in PC-9/PEM,A549/PEM,A549,and PC-9 cells were analyzed by qRT-PCR and western blot.Then,cell viability,colony formation,migration,and invasion were performed on PEM-resistant cells transfected with TS siRNA.The role of EGFR in PEM resistance of PEM-resistant cells was investigated using EGFR siRNA.The effects of gefitinib and EGFR siRNA on EGFR/PI3K/AKT pathway and downstream signaling Cyclin D1 and E2F1 in PEM-resistant cells were analyzed.Results showed that the protein level of TS was significantly increased in A549/PEM and PC-9/PEM.TS knockdown inhibited the potency of proliferation,colony-forming potential,migration,and invasion in PEM-resistant cells.EGFR knockdown abrogated the resistance to PEM of PEM-resistant cells and suppressed the migration and invasion of PEM-resistant cells.Gefitinib treatment and EGFR knockdown respectively inhibited the EGFR/PI3K/AKT pathway and downregulated Cyclin D1 and E2F1 in PEM-resistant cells.Thus,TS might be a predictive marker for PEM resistance in NSCLC.Inhibition of the EGFR pathway abrogated the resistance to PEM and inhibited the EGFR/PI3K/AKT and downstream signaling of PEM-resistant NSCLC cell lines.

Spectrum of EGFR aberrations and potential clinical implications:insights from integrative pan-cancer analysis

Background:Human epidermal growth factor receptor(EGFR)is an oncogenic gene and one of top targets of precision therapy in lung cancer with EGFR mutations.Although there are many reports for some individual cancers,comprehensive profiling of EGFR mutations,overexpression,amplification,DNA methylation,and their clinical associations across many different cancers simultaneously was not available.This study aimed to fill the gap and provide insights to the alteration spectrum of EGFR and its therapeutic and prognostic implications.Methods:The Cancer Genome Atlas(TCGA)datasets for 32 cancer types involving 11,314 patients were analyzed for alterations(mutations and amplification/deletion),abnormal expression and DNA methylation in EGFR gene.Mutation frequency,genomic location distribution,functional impact,and clinical targeted therapy implication were compared among different cancer types,and their associations with patient survival were analyzed.Results:EGFR alteration frequency,mutation sites across functional domains,amplification,overexpression,and DNA methylation patterns differed greatly among different cancer types.The overall mutation frequency in all cancers combined was relatively low.Targetable mutations,mainly in lung cancer,were primarily found in the Pkinase_Tyr domain.Glioblastoma multiforme had the highest rate of alterations,but it was dominated by gene amplification and most mutations were in the Furin-like domain where targeted therapy was less effective.Low-grade glioma often had gene amplification and increased EGFR expression which was associated with poor outcome.Colon and pancreatic adenocarcinoma had very few EGFR mutations;however,high EGFR expression was significantly associated with short patient survival.Squamous cell carcinoma regardless of their sites(the head and neck,lung,or esophagus)exhibited similar characteristics with an alteration frequency of about 5.0%,was dominated by gene amplification,and had increased EGFR expression generally associated with short patient survival.DNA methylation was highly associated with EGFR expression and patient outcomes in some cancers.Conclusions:EGFR aberration type,frequency,distribution in functional domains,and expression vary from cancer to cancer.While mutations in the Pkinase_Tyr domain are more important for treatment selection,increased expression from amplification or deregulation affects more tumor types and leads to worse outcome,which calls for new treatment strategies for these EGFR-driven tumors.

Highly active porous nickel-film electrode via polystyrene microsphere template-assisted composite electrodeposition for hydrogen-evolution reaction in alkaline medium

A highly porous nickel-film electrode with satisfactory mechanical strength was prepared by a facile vertical template-assisted composite electrodeposition method using polystyrene(PS) microspheres templates, with the aim of improving the electrocatalytic activity for the hydrogen-evolution reaction(HER). During the composite electrodeposition process, the hydrophobic PS microspheres were highly dispersed in the electrolyte with the help of a surfactant, and then co-deposited with Ni to form the film electrode. After removing the PS templates by annealing, a porous Ni film containing large amount of uniformly dispersed pores with narrow size distribution was obtained, and then applied as the electrode for the HER in an alkaline medium. As evidenced by the electrochemical analysis, the porous Ni film electrode exhibits higher catalytic activity as compared to a dense Ni film electrode and is superior to a Ni/Ru O2/Ce O2 commercial electrode. The effect of temperature on the catalytic properties of the porous Ni film electrode was also investigated; the activation energy was calculated as 17.26 k J/mol. The enhanced activity toward the HER was attributed to the improved electrochemical surface area and mass transportation facilitated by the high porosity of the synthesized Ni film electrode.