Rociletinib (CO-1686) enhanced the efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells in vitro and in vivo

Overexpression of adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) in cancer cells is known to cause multidrug resistance (MDR), which severely limits the clinical efficacy of chemotherapy. Currently, there is no FDA-approved MDR modulator for clinical use. In this study, rociletinib (CO-1686), a mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was found to significantly improve the efficacy of ABCG2 substrate chemotherapeutic agents in the transporter-overexpressing cancer cells in vitro and in MDR tumor xenografts in nude mice, without incurring additional toxicity. Mechanistic studies revealed that in ABCG2-overexpressing cancer cells, rociletinib inhibited ABCG2-mediated drug efflux and increased intracellular accumulation of ABCG2 probe substrates. Moreover, rociletinib, inhibited the ATPase activity, and competed with [¹²⁵I] iodoarylazidoprazosin (IAAP) photolabeling of ABCG2. However, ABCG2 expression at mRNA and protein levels was not altered in the ABCG2-overexpressing cells after treatment with rociletinib. In addition, rociletinib did not inhibit EGFR downstream signaling and phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK). Our results collectively showed that rociletinib reversed ABCG2-mediated MDR by inhibiting ABCG2 efflux function, thus increasing the cellular accumulation of the transporter substrate anticancer drugs. The findings advocated the combination use of rociletinib and other chemotherapeutic drugs in cancer patients with ABCG2-overexpressing MDR tumors.     

Chronic inflammation and risk of lung cancer in older adults in the health,aging and body composition cohort study

Objectives

We examined the association between three inflammatory markers (Interleukin (IL)-6, C-reactive protein (CRP), tumor necrosis factor (TNF)-α) and incident lung cancer using baseline, updated, and averaged inflammatory measures in older adults.

心房颤动患者预后评分系统的构建和比较

目的构建心房颤动人群预后预测工具,并对其预测能力进行比较评估。方法连续性纳入275例新发心房颤动患者,随访终点包括卒中和全因死亡。收集相关基线资料,检测患者基线血浆N末端B型利钠肽原(N-terminal pro B-type natriuretic peptide,NT-proBNP)、高敏肌钙蛋白T(high-sensitivity cardiac troponin T,hs-cTnT)、生长分化因子15(growth differentiation factor-15,GDF-15)浓度。运用Cox比例风险模型构建卒中和死亡风险评分系统。应用C-统计量和校准图比较评分系统的预测能力。结果多因素Cox回归显示,糖尿病、短暂性脑缺血发作(transient ischemic attack,TIA)、卒中史、血浆NT-proBNP浓度与心房颤动患者卒中风险独立相关;年龄、心衰史、血浆hs-cTnT和GDF-15浓度与心房颤动患者全因死亡风险独立相关。我们构建的卒中风险评分系统预测能力与国外年龄、生物标志物和临床病史(age,biomarker,clinical history,ABC)卒中评分以及CHA2DS2-VASc评分相当,死亡风险评分系统与国外ABC死亡评分相当,优于CHA2DS2-VASc评分。结论本研究构建的心房颤动患者卒中和死亡风险预测评分系统表现出较好的预测性能,此评分系统的列线图可望作为临床决策的辅助工具。     

Multifaceted ABC transporters associated to microcin and bacteriocin export

Microcins and bacteriocins are ribosomally-synthesized defence peptides produced by Gram-negative and -positive bacteria to target competitors in their niche. Some of them carry posttranslational modifications established by dedicated enzymes. To protect themselves from their own toxic peptides, bacteria use dedicated immunity proteins or expel the toxin using ATP-binding cassette (ABC) transporters. In this last case, this immunity function is associated to export of the antimicrobial peptide out of the producing cells for targeting their competitors. Here we review the characteristics of these ABC-exporters and the mechanisms they use that unexpectedly cover from high promiscuity to high specificity or ensure another function concomitantly.     

Roles of FtsEX in cell division

FtsEX is a member of a small subclass of ABC transporters that uses mechano-transmission to perform work in the periplasm. FtsEX controls periplasmic peptidoglycan (PG) hydrolase activities in many Gram negative and positive organisms to ensure the safe separation of daughter cells during division. In these organisms FtsEX localizes to the Z ring and uses its ATPase activity to regulate its periplasmic effectors. In Escherichia coli, FtsEX also participates in building the divisome and coordinates PG synthesis with PG hydrolysis. This review discusses studies that are beginning to elucidate the mechanisms of FtsEX's various roles in cell division.     

Effects of Various Pharmaceutical Excipients on the Intestinal Transport and Absorption of Sulfasalazine,a Typical Substrate of Breast Cancer Resistance Protein Transporter

Breast cancer resistance protein (BCRP) transporter is an efflux transporter that utilizes energy from adenosine triphosphate hydrolysis to push its substrates, regardless of the concentration gradient. Its presence on the apical membrane of the intestinal mucosa is a major obstacle for the intestinal absorption of its substrates. In this study, we examined the effects of various pharmaceutical excipients on the intestinal transport and absorption of sulfasalazine, a BCRP substrate. Four excipients, including 0.05% and 0.075% BL-9EX, 0.01% and 0.05% Brij 97, 0.075% Labrasol, and 0.05% and 0.1% Tween 20 decreased the secretory transport of sulfasalazine in an in vitro diffusion chamber. Further investigation in an in situ closed loop experiment in rats showed that 0.05% and 0.1% BL-9EX and 0.1% Brij 97 effectively enhanced the intestinal absorption of sulfasalazine while maintaining minimal toxicity to the intestinal mucosa. However, 0.1% Brij 97 also increased the intestinal absorption of 5(6)-carboxyfluorescein, a paracellular marker compound. These findings suggest that BL-9EX might effectively inhibit the BCRP-mediated efflux of sulfasalazine in vivo, indicating that BL-9EX could improve the intestinal absorption of sulfasalazine and other BCRP substrates.     

Impact of individual behaviour change on the spread of emerging infectious diseases

Human behaviour plays an important role in the spread of emerging infectious diseases, and understanding the influence of behaviour changes on epidemics can be key to improving control efforts. However, how the dynamics of individual behaviour changes affects the development of emerging infectious disease is a key public health issue. To develop different formula for individual behaviour change and introduce how to embed it into a dynamic model of infectious diseases, we choose A/H1N1 and Ebola as typical examples, combined with the epidemic reported cases and media related news reports. Thus, the logistic model with the health belief model is used to determine behaviour decisions through the health belief model constructs. Furthermore, we propose 4 candidate infectious disease models without and with individual behaviour change and use approximate Bayesian computation based on sequential Monte Carlo method for model selection. The main results indicate that the classical compartment model without behaviour change and the model with average rate of behaviour change depicted by an exponential function could fit the observed data best. The results provide a new way on how to choose an infectious disease model to predict the disease prevalence trend or to evaluate the influence of intervention measures on disease control. However, sensitivity analyses indicate that the accumulated number of hospital notifications and deaths could be largely reduced as the rate of behaviour change increases. Therefore, in terms of mitigating emerging infectious diseases, both media publicity focused on how to guide people's behaviour change and positive responses of individuals are critical.