More, More, More: Reducing Thrombosis in Acute Coronary Syndromes Beyond Dual Antiplatelet Therapy-Current Data and Future Directions.

© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.Common to the pathogenesis of acute coronary syndromes (ACS) is the formation of arterial thrombus, which results from platelet activation and triggering of the coagulation cascade.1 To attenuate the risk of future thrombotic events, patients with ACS are treated with dual antiplatelet therapy (DAPT), namely, the combination of aspirin with a P2Y12 inhibitor, such as clopidogrel, ticagrelor, or prasugrel. Despite DAPT, some ≈10% of ACS patients experience recurrent major adverse cardiovascular events over the subsequent 30 days,2 driving the quest for more effective inhibition of thrombotic pathways. In this review, we provide an overview of studies to date and those ongoing that aim to deliver more effective combinations of antithrombotic agents to patients with recent ACS. We have chosen to confine the review to ACS patients without atrial fibrillation because those with atrial fibrillation have a clear indication for combination therapy that includes oral anticoagulation and should, we feel, be treated as a separate cohort. In this article, we discuss the limitations of the currently available clinical trial data and future directions, with suggestions for how practice might change to reduce the risk of coronary thrombosis in those at greatest risk, with minimal impact on bleeding.Peer reviewedFinal Published versio

Genomic structure and alterations of homeobox gene CDX2 in colorectal carcinomas

Expression of CDX2, a caudal-related homeobox gene, was found to be decreased in colorectal carcinomas. Heterozygous null mutant mice as to Cdx2 develop multiple intestinal adenomatous polyps. To clarify the role of CDX2 in colorectal carcinogenesis, we determined its genomic structure, and searched for mutations of CDX2 in 49 sporadic colorectal carcinomas and ten hereditary non-polyposis colorectal cancers (HNPCC) without microsatellite instability. None of them exhibited a mutation. We further examined 19 HNPCC carcinomas with microsatellite instability for mutations in a (G)7 repeat site within CDX2. One of them (5.3%) exhibited one G insertion. Loss of heterozygosity was observed in 2 of the 20 (10%) informative sporadic carcinomas, and in one of the three (33.3%) informative HNPCC cancers. These data indicate that CDX2 may play only a minor role in colorectal carcinogenesis. © 1999 Cancer Research Campaig

The 'Harmonizing Optimal Strategy for Treatment of coronary artery stenosis - sAfety & effectiveneSS of drug-elUting stents & antiplatelet REgimen' (HOST-ASSURE) trial: study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Second-generation drug-eluting stents (DES) have raised the bar of clinical performance. These stents are mostly made from cobalt chromium alloy. A newer generation DES has been developed from platinum chromium alloy, but clinical data regarding the efficacy and safety of the platinum chromium-based everolimus-eluting stent (PtCr-EES) is limited, with no comparison data against the cobalt chromium-based zotarolimus-eluting stent (CoCr-ZES). In addition, an antiplatelet regimen is an integral component of medical therapy after percutaneous coronary intervention (PCI). A 1-week duration of doubling the dose of clopidogrel (double-dose antiplatelet therapy (DDAT)) was shown to improve outcome at 1 month compared with conventional dose in acute coronary syndrome (ACS) patients undergoing PCI. However in Asia, including Korea, the addition of cilostazol (triplet antiplatelet therapy (TAT)) is used more commonly than doubling the dose of clopidogrel in high-risk patients.</p> <p>Methods</p> <p>In the 'Harmonizing Optimal Strategy for Treatment of coronary artery stenosis - sAfety & effectiveneSS of drug-elUting stents & antiplatelet REgimen' (HOST-ASSURE) trial, approximately 3,750 patients are being prospectively and randomly assigned in a 2 × 2 factorial design according to the type of stent (PtCr-EES vs CoCr-ZES) and antiplatelet regimen (TAT vs DDAT). The first primary endpoint is target lesion failure at 1 year for the stent comparison, and the second primary endpoint is net clinical outcome at 1 month for comparison of antiplatelet therapy regimen.</p> <p>Discussion</p> <p>The HOST-ASSURE trial is the largest study yet performed to directly compare the efficacy and safety of the PtCr-EES versus CoCr-ZES in an 'all-comers' population. In addition, this study will also compare the clinical outcome of TAT versus DDAT for 1-month post PCI.</p> <p>Trial registration</p> <p>ClincalTrials.gov number <a href="http://www.clinicaltrials.gov/ct2/show/NCT01267734">NCT01267734</a>.</p

Efficacy, Tolerability, and Biomarker Analyses of Once-Every-2-Weeks Cetuximab Plus First-Line FOLFOX or FOLFIRI in Patients With KRAS or All RAS Wild-Type Metastatic Colorectal Cancer: The Phase 2 APEC Study

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MicroRNA profiling of cisplatinresistant oral squamous cell carcinoma cell lines enriched withcancer-stem-cell-like and epithelial-mesenchymal transition-type features

Oral cancer is of major public health problem in India. Current investigation was aimed to identify the specific deregulated miRNAs which are responsible for development of resistance phenotype through regulating their resistance related target gene expression in oral squamous cell carcinoma (OSCC). Cisplatin-resistant OSCC cell lines were developed from their parental human OSCC cell lines and subsequently characterised. The resistant cells exhibited enhanced proliferative, clonogenic capacity with significant up-regulation of P-glycoprotein (ABCB1), c-Myc, survivin, β-catenin and a putative cancer-stem-like signature with increased expression of CD44, whereas the loss of E-cadherin signifies induced EMT phenotype. A comparative analysis of miRNA expression profiling in parental and cisplatin-resistant OSCC cell lines for a selected sets (deregulated miRNAs in head and neck cancer) revealed resistance specific signature. Moreover, we observed similar expression pattern for these resistance specific signature miRNAs in neoadjuvant chemotherapy treated and recurrent tumours compared to those with newly diagnosed primary tumours in patients with OSCC. All these results revealed that these miRNAs play an important role in the development of cisplatin-resistance mainly through modulating cancer stem-cell-like and EMT-type properties in OSCC

Efficacy of an Educational Material on Second Primary Cancer Screening Practice for Cancer Survivors: A Randomized Controlled Trial

<div><h3>Background</h3><p>Cancer surivors have limited knowledge about second primary cancer (SPC) screening and suboptimal rates of completion of screening practices for SPC. Our objective was to test the efficacy of an educational material on the knowledge, attitudes, and screening practices for SPC among cancer survivors.</p> <h3>Methods</h3><p>Randomized, controlled trial among 326 cancer survivors from 6 oncology care outpatient clinics in Korea. Patients were randomized to an intervention or an attention control group. The intervention was a photo-novel, culturally tailored to increase knowledge about SPC screening. Knowledge and attitudes regarding SPC screening were assessed two weeks after the intervention, and screening practices were assessed after one year.</p> <h3>Results</h3><p>At two weeks post-intervention, the average knowledge score was significantly higher in the intervention compared to the control group (0.81 vs. 0.75, P<0.01), with no significant difference in their attitude scores (2.64 vs. 2.57, P = 0.18). After 1 year of follow-up, the completion rate of all appropriate cancer screening was 47.2% in both intervention and control groups.</p> <h3>Conclusion</h3><p>While the educatinal material was effective for increasing knowledge of SPC screening, it did not promote cancer screening practice among cancer survivors. More effective interventions are needed to increase SPC screening rates in this population.</p> <h3>Trial Registration</h3><p>ClinicalTrial.gov <a href="http://clinicaltrials.gov/ct2/show/NCT00948337">NCT00948337</a></p> </div

MiR-200c Regulates Noxa Expression and Sensitivity to Proteasomal Inhibitors

The pro-apoptotic p53 target Noxa is a BH3-only protein that antagonizes the function of selected anti-apoptotic Bcl-2 family members. While much is known regarding the transcriptional regulation of Noxa, its posttranscriptional regulation remains relatively unstudied. In this study, we therefore investigated whether Noxa is regulated by microRNAs. Using a screen combining luciferase reporters, bioinformatic target prediction analysis and microRNA expression profiling, we identified miR-200c as a negative regulator of Noxa expression. MiR-200c was shown to repress basal expression of Noxa, as well as Noxa expression induced by various stimuli, including proteasomal inhibition. Luciferase reporter experiments furthermore defined one miR-200c target site in the Noxa 3′UTR that is essential for this direct regulation. In spite of the miR-200c:Noxa interaction, miR-200c overexpression led to increased sensitivity to the clinically used proteasomal inhibitor bortezomib in several cell lines. This apparently contradictory finding was reconciled by the fact that in cells devoid of Noxa expression, miR-200c overexpression had an even more pronounced positive effect on apoptosis induced by proteasomal inhibition. Together, our data define miR-200c as a potentiator of bortezomib-induced cell death. At the same time, we show that miR-200c is a novel negative regulator of the pro-apoptotic Bcl-2 family member Noxa

The Beneficial Effects of Antifreeze Proteins in the Vitrification of Immature Mouse Oocytes

Antifreeze proteins (AFPs) are a class of polypeptides that permit organismal survival in sub-freezing environments. The purpose of this study was to investigate the effect of AFP supplementation on immature mouse oocyte vitrification. Germinal vesicle-stage oocytes were vitrified using a two-step exposure to equilibrium and vitrification solution in the presence or absence of 500 ng/mL of AFP III. After warming, oocyte survival, in vitro maturation, fertilization, and embryonic development up to the blastocyst stage were assessed. Spindle and chromosome morphology, membrane integrity, and the expression levels of several genes were assessed in in vitro matured oocytes. The rate of blastocyst formation was significantly higher and the number of caspase-positive blastomeres was significantly lower in the AFP-treated group compared with the untreated group. The proportion of oocytes with intact spindles/chromosomes and stable membranes was also significantly higher in the AFP group. The AFP group showed increased Mad2, Hook-1, Zar1, Zp1, and Bcl2 expression and lower Eg5, Zp2, Caspase6, and Rbm3 expression compared with the untreated group. Supplementation of the vitrification medium with AFP has a protective effect on immature mouse oocytes, promoting their resistance to chilling injury. AFPs may preserve spindle forming ability and membrane integrity at GV stage. The fertilization and subsequent developmental competence of oocytes may be associated with the modulation of Zar1, Zp1/Zp2, Bcl2, Caspase6, and Rbm3

Baifuzi reduces transient ischemic brain damage through an interaction with the STREX domain of BKCa channels

Stroke is a long-term disability and one of the leading causes of death. However, no successful therapeutic intervention is available for the majority of stroke patients. In this study, we explored a traditional Chinese medicine Baifuzi (Typhonium giganteum Engl.). We show, at first, that the ethanol extract of Baifuzi exerts neuroprotective effects against brain damage induced by transient global or focal cerebral ischemia in rats and mice. Second, the extract activated large-conductance Ca2+-activated K+ channel (BKCa) channels, and BKCa channel blockade suppressed the neuroprotection of the extract, suggesting that the BKCa is the molecular target of Baifuzi. Third, Baifuzi cerebroside (Baifuzi-CB), purified from its ethanol extract, activated BKCa channels in a manner similar to that of the extract. Fourth, the stress axis hormone-regulated exon (STREX) domain of the BKCa channel directly interacted with Baifuzi-CB, and its deletion suppressed channel activation by Baifuzi-CB. These results indicate that Baifuzi-CB activated the BKCa channel through its direct interaction with the STREX domain of the channel and suggests that Baifuzi-CB merits exploration as a potential therapeutic agent for treating brain ischemia