Water-pipe smoking promotes epithelial-mesenchymal transition and invasion of human breast cancer cells via ERK1/ERK2 pathways.

With the increasing popularity of water-pipe smoking (WPS), it is critical to comprehend how WPS may affect women's health. The main goal of this study is to identify the potential outcome of WPS on human breast cancer progression. Two breast cancer cell lines, MCF7 and BT20, were used in this investigation. We explored the outcome of WPS on cell morphology and cell invasion using inverted microscope and Biocoat Matrigel invasion chambers. On the other hand, Western blot was employed to study the expression patterns of key control genes of cell adhesion and invasion. Our data reveal that WPS induces epithelial-mesenchymal transition (EMT) of MCF7 and BT20 breast cancer cell lines; thus, WPS enhances cell invasion ability of both cell lines in comparison with their matched controls. More significantly, WPS provokes a down- and up-regulation of E-cadherin and focal adhesion kinase (FAK), respectively, which are important key regulators of cancer progression genes. Finally, our data point out that WPS incites the activation of Erk1/Erk2, which could be behind the stimulation of EMT and invasion as well as the deregulation of E-cadherin and FAK expression. Our data show, for the first time, that WPS initiates EMT and stimulates cell invasion of breast cancer cells, which could incite metastatic development in breast cancer patients. Thus, we believe that further studies, both in vitro and in vivo, are required to elucidate the pathogenic outcome of WPS on cancer progression of several human carcinomas including breast

Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial

Background Post-partum haemorrhage is the leading cause of maternal death worldwide. Early administration of tranexamic acid reduces deaths due to bleeding in trauma patients. We aimed to assess the effects of early administration of tranexamic acid on death, hysterectomy, and other relevant outcomes in women with post-partum haemorrhage. Methods In this randomised, double-blind, placebo-controlled trial, we recruited women aged 16 years and older with a clinical diagnosis of post-partum haemorrhage after a vaginal birth or caesarean section from 193 hospitals in 21 countries. We randomly assigned women to receive either 1 g intravenous tranexamic acid or matching placebo in addition to usual care. If bleeding continued after 30 min, or stopped and restarted within 24 h of the first dose, a second dose of 1 g of tranexamic acid or placebo could be given. Patients were assigned by selection of a numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Participants, care givers, and those assessing outcomes were masked to allocation. We originally planned to enrol 15 000 women with a composite primary endpoint of death from all-causes or hysterectomy within 42 days of giving birth. However, during the trial it became apparent that the decision to conduct a hysterectomy was often made at the same time as randomisation. Although tranexamic acid could influence the risk of death in these cases, it could not affect the risk of hysterectomy. We therefore increased the sample size from 15 000 to 20 000 women in order to estimate the effect of tranexamic acid on the risk of death from post-partum haemorrhage. All analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN76912190 (Dec 8, 2008); ClinicalTrials.gov, number NCT00872469; and PACTR201007000192283. Findings Between March, 2010, and April, 2016, 20 060 women were enrolled and randomly assigned to receive tranexamic acid (n=10 051) or placebo (n=10 009), of whom 10 036 and 9985, respectively, were included in the analysis. Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1·5%] of 10 036 patients vs 191 [1·9%] of 9985 in the placebo group, risk ratio [RR] 0·81, 95% CI 0·65–1·00; p=0·045), especially in women given treatment within 3 h of giving birth (89 [1·2%] in the tranexamic acid group vs 127 [1·7%] in the placebo group, RR 0·69, 95% CI 0·52–0·91; p=0·008). All other causes of death did not differ significantly by group. Hysterectomy was not reduced with tranexamic acid (358 [3·6%] patients in the tranexamic acid group vs 351 [3·5%] in the placebo group, RR 1·02, 95% CI 0·88–1·07; p=0·84). The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid (534 [5·3%] deaths or hysterectomies in the tranexamic acid group vs 546 [5·5%] in the placebo group, RR 0·97, 95% CI 0·87-1·09; p=0·65). Adverse events (including thromboembolic events) did not differ significantly in the tranexamic acid versus placebo group. Interpretation Tranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no adverse effects. When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset. Funding London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation

Sequential therapeutic targeting of ovarian cancer harboring dysfunctional BRCA1

Ovarian cancer (OC) remains the leading cause of death from gynecological malignancies. This cancer is typically diagnosed in advanced stages and still represents a challenge due to poor overall survival. Among all subtypes of OC, High-Grade Serous Ovarian Cancer (HGSOC) is the most common subtype (70%) and is characterized by having genomic instability represented by 50% of defective homologous recombination DNA repair pathways (HRD) and in 23% are mutated for BRCA1 and BRCA2. Today, the majority of HGSOC show a significant, but transient response to debulking surgery followed by platinum-based chemotherapy, however most patients will relapse and eventually develop platinum-resistant disease with a poor overall survival. For HGSC, the only successful and currently approved targeted therapy is the inhibition of poly (ADP-ribose) polymerase (PARP). PARP inhibitors (PARPi) are mostly used in BRCA1-mutated and non-mutated recurrent ovarian cancer patients with a known vulnerability in the HRD pathway.Previously, our research group described a significant reduction in PARP1 protein levels in patients treated with standard carbo-platinum-paclitaxel chemotherapy that affected the efficacy of PARPi in clinical trials. Also we showed that by using PARPi as a first line of therapy followed by standard chemotherapy might improve patient response rates. To understand this finding, in the current study, we have studied PARPi as a first line of treatment followed by standard chemotherapy on different ovarian cancer cell-lines (having wild-type, mutated and methylated BRCA1). Interestingly, we observed that this treatment regimen sensitized ovarian cancer cells to lower doses of chemotherapy. Moreover we found that PARPi as a first line of treatment is more efficient in growth inhibition and induction of apoptosis in comparison with the administration of standard chemotherapy followed by PARPi. Altogether provide new evidence and the basis for future pre-clinical work involving PARPi to be used as first line of treatment in HGSOC patients carrying functional or dysfunctional BRCA1.Le cancer de l'ovaire (CO) est la principale cause de décès attribuables aux cancers gynécologiques. Ce cancer est généralement diagnostiqué à un stade avancé et demeure un défi en raison d'un faible taux de survie globale des patientes. Parmi tous les sous-types de CO, le carcinome séreux de haut grade (CSHG) est le sous-type le plus fréquent (70%). Il se caractérise par une instabilité génomique illustrée par 50% de défaut dans les voies de réparation l'ADN par recombinaison homologue. Ces défauts s'expliquent à 23% par une mutation des gènes BRCA1 et BRCA2. Aujourd'hui, la majorité des CSHG répondent de manière significative, mais transitoire, à la chirurgie de réduction suivie d'une chimiothérapie à base de platine, mais la plupart des patientes rechuteront et finiront par développer une résistance aux dérivés de platine avec une survie globale médiocre. Dans le cas du CSHG, le seul traitement ciblé, efficace et actuellement approuvé est l'inhibition de la poly (ADP-ribose) polymérase (PARP). Les inhibiteurs de la PARP (iPARP) sont principalement utilisés chez les patientes dont le carcinome est récurrent, associé ou non avec une mutation du gène BRCA1, et qui présentent une déficience dans la voie de réparation d'ADN par recombinaison homologue. Notre groupe de recherche a précédemment démontré qu'une réduction significative des niveaux protéiques de PARP1 chez les patientes traitées par chimiothérapie carbo-platine-paclitaxel standard a affecté l'efficacité des iPARP dans des essais cliniques. En outre, nous avons démontré que l'utilisation des iPARP en première ligne de traitement suivie par une chimiothérapie standard pourrait améliorer les taux de réponse des patientes. Pour élaborer ces conclusions, dans la présente étude, nous avons étudié l'effet des iPARP en première ligne de traitement suivie d'une chimiothérapie standard sur différentes lignées cellulaires de CO (ayant un BRCA1 de type sauvage, muté et méthylé). Fait intéressant, nous avons observé que ce régime de traitement a sensibilisé les cellules cancéreuses de l'ovaire à des doses plus faibles de chimiothérapie. En outre, nous démontrons qu'en première ligne de traitement, les iPARP sont plus efficaces dans l'inhibition de la croissance cellulaire et l'induction de l'apoptose en comparaison au régime d'administration de la chimiothérapie standard suivie d'iPARP. En résumé, ces données nouvelles pourraient représenter la base pour des futurs travaux précliniques impliquant l'utilisation des iPARP en première ligne de traitement chez les patientes atteintes de CSHG porteuses de BRCA1 fonctionnel ou dysfonctionnel

Nickel-cobalt bimetallic sulfide NiCo2S4nanostructures for a robust hydrogen evolution reaction in acidic media

There are many challenges associated with the fabrication of efficient, inexpensive, durable and very stable nonprecious metal catalysts for the hydrogen evolution reaction (HER). In this study, we have designed a facile strategy by tailoring the concentration of precursors to successfully obtain nickel-cobalt bimetallic sulfide (NiCo2S4) using a simple hydrothermal method. The morphology of the newly prepared NiCo2S4comprised a mixture of microparticles and nanorods, which were few microns in dimension. The crystallinity of the composite sample was found to be excellent with a cubic phase. The sample that contained a higher amount of cobalt compared to nickel and produced single-phase NiCo2S4exhibited considerably improved HER performance. The variation in the salt precursor concentration during the synthesis of a material is a simple methodology to produce a scalable platinum-free catalyst for HER. The advantageous features of the multiple active sites of cobalt in the CN-21 sample as compared to that for pristine CoS and NiS laid the foundation for the provision of abundant active edges for HER. The composite sample produced a current density of 10 mA cm−2at an overpotential of 345 mV. Also, it exhibited a Tafel value of 60 mV dec−1, which predominantly ensured rapid charge transfer kinetics during HER. CN-21 was highly durable and stable for 30 hours. Electrochemical impedance spectroscopy showed that the charge transfer resistance was 21.88 ohms, which further validated the HER polarization curves and Tafel results. CN-21 exhibited a double layer capacitance of 4.69 μF cm−2and a significant electrochemically active surface area of 134.0 cm2, which again supported the robust efficiency for HER. The obtained results reveal that our developed NiCo2S4catalyst has a high density of active edges, and it is a non-noble metal catalyst for the hydrogen evolution reaction. The present findings provide an alternative strategy and an active nonprecious material for the development of energy-related applications

Sequential therapeutic targeting of ovarian Cancer harboring dysfunctional BRCA1

Abstract Background Poly (ADP-ribose) polymerase inhibitors (PARPi) have become the first targeted therapies available in the treatment of patients with high-grade serous ovarian cancer (HGSOC). We recently described a significant reduction in PARP1 protein levels in vitro and in vivo in patients treated with standard carboplatinum-paclitaxel chemotherapy, raising the question whether the sequence of treatment used today with chemotherapy followed by PARPi is optimal. In this study, we aim to evaluate if the sequence of PARPi followed by chemotherapy could be more beneficial. Methods BRCA1-mutated (UWB1.287, SNU-251), epigenetically-silenced (OVCAR8), and wild-type (SKOV3, A2780PAR & A2780CR) ovarian cancer cell lines were exposed to clinically relevant doses of PARPi followed by different doses of standard chemotherapy and compared to the inverse treatment. The therapeutic efficacy was assessed using colony formation assays. Flow cytometry was used to evaluate cell apoptosis rate and the changes in cell cycle. Finally, apoptotic and cell cycle protein expression was immunodetected using western blot. Results Exposure to PARPi prior to standard chemotherapy sensitized BRCA1-mutated or epigenetically-silenced BRCA1 cell lines to lower doses of chemotherapy. Similar results were observed in BRCA1 wild-type and cell lines in which BRCA1 functionality was restored. Moreover, this treatment increased the apoptotic rate in these cell lines. Conclusion Pre-treatment with PARPi followed by standard chemotherapy in vitro is more efficient in growth inhibition and induction of apoptosis compared to the administration of standard chemotherapy followed by PARPi

Biguanides in combination with olaparib limits tumorigenesis of drug‐resistant ovarian cancer cells through inhibition of Snail

Abstract Ovarian cancer is the most lethal gynecological malignancy. Currently, new chemotherapeutic strategies are required to improve patient outcome and survival. Biguanides, classic anti‐diabetic drugs, have gained importance for theiri antitumor potency demonstrated by various studies. Olaparib is a PARP inhibitor approved for maintenance therapy following platinum‐based chemotherapy. Furthermore, Snai1, a transcription factor that works as a master regulator of the epithelial/mesenchymal transition process (EMT) is involved in ovarian cancer resistance and progression. Here we aimed to demonstrate the possible cross talk between biguanides and Snail in response to olaparib combination therapy. In this study, we have shown that while in A2780CR cells biguanides reduced cell survival (single treatments ~20%; combined treatment ~44%) and cell migration (single treatments ~45%; biguanide‐olaparib ~80%) significantly, A2780PAR exhibited superior efficacy with single (~60%) and combined treatments (~80%). Moreover, our results indicate that knock‐down of Snail further enhances the attenuation of migration, inhibits EMT related‐proteins (~90%) and induces a synergistic effect in biguanide‐olaparib treatment. Altogether, this work suggests a novel treatment strategy against drug‐resistant or recurrent ovarian cancer

The chemically reduced CuO-Co3O4 composite as a highly efficient electrocatalyst for oxygen evolution reaction in alkaline media

The fabrication of efficient, alkaline-stable and nonprecious electrocatalysts for the oxygen evolution reaction is highly needed; however, it is a challenging task. Herein, we report a noble metal-free advanced catalyst, i.e. the chemically reduced mixed transition metal oxide CuO-Co3O4 composite, with outstanding oxygen evolution reaction activity in alkaline media. Sodium borohydride (NaBH4) was used as a reducing agent for the mixed transition metal oxide CuO-Co3O4. The chemically reduced composite carried mixed valence states of Cu and Co, which played a dynamic role in driving an excellent oxygen evolution reaction process. The X-ray photo-electron spectroscopy (XPS) study confirmed high density of active sites in the treated sample with a large number of oxygen vacancies. The developed electrocatalyst showed the lowest overpotential of 144.5 mV vs. the reversible hydrogen electrode (RHE) to achieve the current density of 40 mA cm-2 and remained stable for 40 hours throughout the chronoamperometry test at the constant potential of 1.39 V vs. RHE. Moreover, the chemically reduced composite was highly durable. Electrochemical impedance spectroscopy (EIS) confirmed the low charge transfer resistance of 13.53 ohms for the chemically reduced composite, which was 50 and 26 times smaller than that of Co3O4 and untreated CuO-Co3O4, respectively. The electrochemically active surface area for the chemically reduced composite was found to be greater than that for pristine CuO, Co3O4 and untreated pristine CuO-Co3O4. These findings reveal the possibility of a new gateway for the capitalization of a chemically reduced sample into diverse energy storage and conversion systems such as lithium-ion batteries and supercapacitors

Two step synthesis of TiO2–Co3O4 composite for efficient oxygen evolution reaction

For an active hydrogen gas generation through water dissociation, the sluggish oxygen evolution reaction (OER) kinetics due to large overpotential is a main hindrance. Herein, a simple approach is used to produce composite material based on TiO2/Co3O4 for efficient OER and overpotential is linearly reduced with increasing amount of TiO2. The scanning electron microscopy (SEM) and high resolution transmission electron microscopy (HRTEM) investigations reveal the wire like morphology of composite materials, formed by the self-assembly of nanoparticles. The titania nanoparticles were homogenously distributed on the larger Co3O4 nanoparticles. The powder x-ray diffraction revealed a tetragonal phase of TiO2 and the cubic phase of Co3O4 in the composite materials. Composite samples with increasing TiO2 content were obtained (18%, 33%, 41% and 65% wt.). Among the composites, cobalt oxide-titanium oxide with the highest TiO2 content (CT-20) possesses the lowest overpotential for OER with a Tafel slope of 60 mV dec−1 and an exchange current density of 2.98 × 10−3A/cm2. The CT-20 is highly durable for 45 h at different current densities of 10, 20 and 30 mA/cm2. Electrochemical impedance spectroscopy (EIS) confirmed the fast charge transport for the CT-20 sample, which potentially accelerated the OER kinetics. These results based on a two-step methodology for the synthesis of TiO2/Co3O4 material can be useful and interesting for various energy storage and energy conversion systems