One of greatest challenges to the successful treatment of cancer is drug resistance. An exciting approach is the eradication of cancer stem cells (CSCs). However, little is known about key signals ...regulating the formation and expansion of CSCs. Moreover, lack of a reliable predictive preclinical model has been a major obstacle to discover new cancer drugs and predict their clinical activity. Here, in ovarian cancer, a highly chemoresistant tumor that is rapidly fatal, we provide the first evidence demonstrating the causal involvement of mechanical stimulus in the CSC phenotype using a customizable microfluidic platform and three-dimensional spheroids, which most closely mimic tumor behavior. We found that ovarian cancer cells significantly acquired the expression of epithelial-to-mesenchymal transition and CSC markers and a remarkable chemoresistance to clinically relevant doses of frontline chemotherapeutic drugs cisplatin and paclitaxel when grown under fluid shear stress, which corroborates with the physiological attainable levels in the malignant ascites, but not under static condition. Furthermore, we uncovered a new link of microRNA-199a-3p, phosphatidylinositol 3-kinase/Akt, and multidrug transporter activation in shear stress-induced CSC enrichment. Our findings shed new light on the significance of hydrodynamics in cancer progression, emphasizing the need of a flow-informed framework in the development of therapeutics.
Organ-specific colonization suggests that specific cell–cell recognition is essential. Yet, very little is known about this particular interaction. Moreover, tumor cell lodgement requires binding ...under shear stress, but not static, conditions. Here, we successfully isolate the metastatic populations of cancer stem/tumor-initiating cells (M-CSCs). We show that the M-CSCs tether more and roll slower than the non-metastatic (NM)-CSCs, thus resulting in the preferential binding to the peritoneal mesothelium under ascitic fluid shear stress. Mechanistically, this interaction is mediated by P-selectin expressed by the peritoneal mesothelium. Insulin-like growth factor receptor-1 carrying an uncommon non-sulfated sialyl-Lewisx (sLex) epitope serves as a distinct P-selectin binding determinant. Several glycosyltransferases, particularly α1,3-fucosyltransferase with rate-limiting activity for sLex synthesis, are highly expressed in M-CSCs. Tumor xenografts and clinical samples corroborate the relevance of these findings. These data advance our understanding on the molecular regulation of peritoneal metastasis and support the therapeutic potential of targeting the sLex-P-selectin cascade.Tumor cell in the peritoneum are often exposed to shear forces generated by ascitic flow during metastasis. Here, the authors show that metastatic cancer stem cells tether more and roll slower than the non-metastatic counterparts, and that sialyl-Lewisx -P-selectin axis mediates peritoneal metastasis.
•The e-commerce internal order processing flow is streamlined and re-designed.•A GA-rule-based system for efficient e-commerce order fulfilment is proposed.•An optimal order processing plan is ...generated by genetic algorithm technique.•A system implementation shows a significant order processing time reduction.
In today's world of digitization, the rise of the e-commerce business around the globe has brought a tremendous change not only in our purchasing habits, but also to the entire retail and logistics industry. Given the irregular e-commerce order arrival patterns, limited time for order processing in e-fulfilment centres, and the guaranteed delivery schedules offered by e-retailers, such as same-day or next-day delivery upon placing an order, logistics service providers (LSPs) must be extremely efficient in handling outsourced e-commerce logistics orders. Without re-engineering the order fulfilment processes, the LSPs are found to have difficulties in executing the order fulfilment process due to the tight handling requirements. This, in turn, delays the subsequent processes in the supply chain, such as last-mile delivery operations, consequently affecting customer satisfaction towards both the retailer and the LSP. In view of the need to improve the efficiency in handling e-commerce orders, this study aims at re-engineering the fulfilment process of e-commerce orders in distribution centres. The concept of warehouse postponement is embedded into a new cloud-based e-order fulfilment pre-processing system (CEPS), by incorporating the genetic algorithm (GA) approach for e-commerce order grouping decision support and a rule-based inference engine for generating operating guidelines and suggesting the use of appropriate handling equipment. Through a case study conducted in a logistics company, the CEPS provides order handling solutions for processing e-commerce logistics orders very efficiently, with a significant reduction in order processing time and traveling distance. In turn, improved operating efficiency in e-commerce order handling allows LSPs to better align strategically with online retailers, who provide customers with aggressive, guaranteed delivery dates.
Abstract
Bisphenol A (BPA) is a ubiquitous environmental xenobiotic impacting millions of people worldwide. BPA has long been proposed to promote ovarian carcinogenesis, but the detrimental ...mechanistic target remains unclear. Cancer stem cells (CSCs) are considered as the trigger of tumour initiation and progression. Here, we show for the first time that nanomolar (environmentally relevant) concentration of BPA can markedly increase the formation and expansion of ovarian CSCs concomitant. This effect is observed in both oestrogen receptor (ER)‐positive and ER‐defective ovarian cancer cells, suggesting that is independent of the classical ERs. Rather, the signal is mediated through alternative ER G‐protein‐coupled receptor 30 (GPR30), but not oestrogen‐related receptor α and γ. Moreover, we report a novel role of BPA in the regulation of Exportin‐5 that led to dysregulation of microRNA biogenesis through miR‐21. The use of GPR30 siRNA or antagonist to inhibit GPR30 expression or activity, respectively, resulted in significant inhibition of ovarian CSCs. Similarly, the CSCs phenotype can be reversed by expression of Exportin‐5 siRNA. These results identify for the first time non‐classical ER and microRNA dysregulation as novel mediators of low, physiological levels of BPA function in CSCs that may underlie its significant tumour‐promoting properties in ovarian cancer.
Sex differences in the pathogenesis of hypertension exist. While gut microbiota (GM) has been associated with hypertension, it is unclear whether there are sex-linked differences in the association ...between GM and hypertension.
We conducted a cross-sectional study to investigate the sex differences in associations between GM characterized by shotgun sequencing, GM-derived short-chain fatty acids, and 24-hour ambulatory blood pressure in 241 Hong Kong Chinese (113 men and 128 women; mean age, 54±6 years).
The hypertensive group was associated with GM alterations; however, significant differences in β-diversity and GM composition in hypertensive versus normotensive groups were only observed in women and not in men under various statistical models adjusting for the following covariates: age, sex, body mass index, sodium intake estimated by spot urine analysis, blood glucose, triglycerides, low- and high-density lipoprotein cholesterol, smoking, menopause, and fatty liver status. Specifically,
,
, and
were significantly more abundant in the hypertensive women, whereas
was more abundant in the normotensive women. No bacterial species were found to be significantly associated with hypertension in men. Furthermore, total plasma short-chain fatty acids and propionic acid were independent predictors of systolic and diastolic blood pressure in women but not men.
GM dysregulation was strongly associated with 24-hour ambulatory blood pressure in women but not men, which may be mediated through propionic acid. Our work suggests that sex differences may be an important consideration while assessing the role of GM in the development and treatment of hypertension.
Background. Informed consent forms (ICFs) are used to obtain consent from participants. However the complexity and comprehensiveness of these forms may not be appropriate. Readability can be ...quantified by formulas in Microsoft (MS) Word, such as the Flesch Reading Ease test. The South African (SA) ethics guidelines suggest that the MS Word Flesch-Kincaid Reading Grade score should be used to assess the complexity of ICFs and should be the equivalent of grade 8 level, or lower. Objectives. To use readability formulas to determine whether current SA ICFs are appropriate for the general population. Methods. This was a descriptive study of a sample of English ICFs (solicited from our studies, as well as from local researchers) which received approval from local ethical review boards during the past 5 years, for prospective (≥6 months) drug studies that explored treatment and prevention of HIV, tuberculosis, diabetes or cardiovascular disease. ICFs were evaluated in MS Word for Flesch Reading Ease and Flesch-Kincaid Reading Grade, with the Simple Measure of Gobbledygook (SMOG) index calculated using www.readabilityformulas.com. Recommended targets for easy readability are above 60 for the Flesch Reading Ease score, and less than or equal to a grade 8 reading level for the Flesch-Kincaid Reading Grade and SMOG. Results. A total of 75 consent forms from 35 individual research studies conducted in SA over the last 5 years were included. The consent forms had been approved by six ethics committees across seven of the SA provinces. The median (interquartile range (IQR)) Flesch Reading Ease score was 55.8 (48.7 - 59.7) and 18 (25.0%) of the ICFs had easy or standard readability, while the median (IQR) Flesch-Kincaid Grade was 10.2 (8.8 - 11.4), with 23 (30.6%) at least a grade 8 level or lower. The median (IQR) SMOG index was 9.8 (9.0 - 11.1) and 4 (5.3%) scored below grade 8 level. Conclusions. Two-thirds of the ICFs from this study fail to meet the SA readability standard, a result matched by using alternative readability formulas. Readability can be improved with simple techniques and by actively monitoring readability metrics.
The p70 S6 kinase (p70(S6K)) is frequently active in ovarian and a wide range of cancer types, and it has a crucial role in several processes considered hallmarks of cancer. Therefore, blocking ...p70(S6K) expression or activity may present a promising strategy for anticancer treatment.
The current understanding of the molecular mechanisms that govern p70(S6K) regulation as well as its tumorigenic effects, which are involved in the initiation and progression in ovarian cancer, in particular the emerging new role of p70(S6K) in cell migration, which is a prerequisite of tumor metastasis. The p70(S6K) cellular substrates and/or interacting proteins. The current state of drugs that target this kinase, either alone or in combination with other targeted agents.
Targeting p70(S6K) through the use of small-molecule inhibitors, microRNAs and natural compounds may represent a beneficial new avenue for cancer therapy and opens new areas of investigation in p70(S6K) biology.
•A new study that forecasts the daily arrival pattern of e-commerce orders.•An AR-ANFIS model for e-order arrival prediction is proposed.•A two-stage model performance validation is ...introduced.•Experimental results indicate that the proposed model outperforms ARIMA model.
The complexity of today's e-commerce logistics environment compels practitioners to achieve a higher level of operating efficiency. As it is infeasible for operators to process a large number of discrete e-orders individually, warehouse postponement, that is, delaying the execution of a logistics process until the last possible moment, is essential. Yet the question remains as to how one can accurately identify the timing for consolidating e-orders, and subsequently releasing the grouped e-orders for batch order picking. This is a subject, lacking previous research, but is fundamentally crucial in today's e-commerce logistics environment. This paper introduces an integrated autoregressive-adaptive neuro-fuzzy inference system (AR-ANFIS) approach for forecasting e-commerce order arrivals. Two AR-ANFIS models are built for evaluating their prediction ability against ARIMA models. The experimental results confirm the suitability of the hybrid model for forecasting e-order arrivals. To make use of the model output, an algorithm is formulated to convert e-order arrival figures into cut-off time of order grouping. In this sense, this total solution, packaged as a decision support system, namely the E-order arrival prediction system, assists logistics practitioners in judging when to release the grouped e-orders for batch processing, and essentially improves their order handling capability.
Mammalian stanniocalcin-2 (STC2) is a secreted glycoprotein hormone with a putative role in unfolded protein response and apoptosis. Here we reported that STC2 expression was sporadically abrogated ...in human cancer cells by transcriptional silencing associated with CpG island promoter hypermethylation. Direct sequencing of bisulfite-modified DNA from a panel of seven human cancer cell lines revealed that CpG dinucleotides in STC2 promoter was methylated in human ovarian epithelial cancer (SKOV3, OVCAR3 and CaOV3), pancreatic cancer (BxP3), colon adenoma (HT29), and leukemia (Jurkat cells). STC2 CpG island hypermethylation was accompanied with a low basal STC2 expression level. Treatment of these cancer cells with 5-aza-2′-deoxycytidine (5-aza-CdR), an inhibitor of DNA methylation significantly induced STC2 expression. Using SKOV3 cells as a model, the link between DNA demethylation and STC2 expression was consistently demonstrated with hydralazine treatment, which was shown to reduce the protein level of DNA methyltransferase 1 (DNMT1) but stimulated STC2 expression. Two human normal surface ovarian cell-lines (i.e. IOSE 29 and 398) showed no methylation at CpG dinucleotides in the examined promoter region and were accompanied with high basal STC2 levels. Hypoxia stimulated STC2 expression in SKOV3 cells was markedly increased in 5-aza-CdR pretreated cells, showing that DNA methylation may hinder the HIF-1 mediated activation. To elucidate this possibility, RNA interference studies confirmed that endogenous HIF-1α was a key factor for STC2 gene activation as well as in the synergistic induction of STC2 expression in 5-aza-CdR pretreated cells. Chromatin immunoprecipitation (ChIP) assay demonstrated the binding of HIF-1α to STC2 promoter. The binding was increased in 5-aza-CdR pretreated cells. Collectively, this is the first report to show that STC2 was aberrantly hypermethylated in human cancer cells. The findings demonstrated that STC2 epigenetic inactivation may interfere with HIF-1 mediated activation of STC2 expression.
Ovarian cancer is characterized by extensive peritoneal metastasis, with tumor spheres commonly found in the malignant ascites. This is associated with poor clinical outcomes and currently lacks ...effective treatment. Both the three-dimensional (3D) environment and the dynamic mechanical forces are very important factors in this metastatic cascade. However, traditional cell cultures fail to recapitulate this natural tumor microenvironment. Thus, in vivo-like models that can emulate the intraperitoneal environment are of obvious importance. In this study, a new microfluidic platform of the peritoneum was set up to mimic the situation of ovarian cancer spheroids in the peritoneal cavity during metastasis. Ovarian cancer spheroids generated under a non-adherent condition were cultured in microfluidic channels coated with peritoneal mesothelial cells subjected to physiologically relevant shear stress. In summary, this dynamic 3D ovarian cancer-mesothelium microfluidic platform can provide new knowledge on basic cancer biology and serve as a platform for potential drug screening and development.
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