Synthesis of MXene-Epoxy Nanocomposites

This thesis explores the synthesis of MXene-epoxy nanocomposites. MXenes are a family of two-dimensional materials which display versatile chemistries that allow the material to be tuned for applications that include electrochemical storage devices, electromagnetic interference shielding devices, and catalysts, to name a few. Composites of MXenes with a variety of polymers have been produced, and they show enhanced mechanical and electrical properties. In this work, epoxy composites with MXenes are synthesized, because the use of a platelet-like filler allows property enhancements such as 2D stress transfer, and the formation of diffusion barriers and percolating thresholds. Complete exfoliation of the multilayered MXenes into their 2D sheets is desired in order to realize these property improvements. Two different techniques of producing MXene-epoxy composites are evaluated. The first is a tradition in situ polymerization technique, which involves the dispersion of the filler in a volatile solvent. Acetone was used to disperse Ti3CNTx into single layers, before the dispersion was mixed with epoxy. The other technique involves the application of laminar shear stress on multilayered Ti3C2Tx particles, in order to exfoliate them into single layers dispersed in the epoxy matrix. In this system, a room temperature ionic liquid (RTIL) is used as the dispersant for the filler and the initiator for epoxy cure. The problems associated with MXene exfoliation, nanoparticle dispersion, and nanocomposite synthesis are considered while evaluating these methods of synthesizing these composites. It was found that while a few single layers of Ti3CNTx were successfully exfoliated, a majority of the particles were still multilayered. The physical performance of the composite was lackluster as a result of this poor exfoliation and dispersion. The lack of covalent bonding between Ti3CNTx and epoxy, and the lack of wettability of the filler are also areas of concern. In the Ti3C2Tx-epoxy-RTIL composites, the exfoliation of single layers was also not accomplished. Despite approximate shear stresses experienced by the particles being higher than the theoretically predicted interlayer coupling, stacked Ti3C2Tx particles were observed. Instead, the Ti3C2Tx particles had undergone swelling, which resulted from the intercalation of the RTIL. Upon application of sufficient shear stress, intercalation of bigger molecules was observed. Better properties were also obtained, leading us to hypothesize that epoxy intercalation has occurred. The reasons for poor exfoliation and poor dispersion are detailed, and future areas of study for better understanding of the MXene-epoxy system are proposed.M.S., Materials Science and Engineering -- Drexel University, 201

Carbon isotopic evidence for microbial control of carbon supply to Orca Basin at the seawater–brine interface

© The Author(s), 2013. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Biogeosciences 10 (2013): 3175-3183, doi:10.5194/bg-10-3175-2013.Orca Basin, an intraslope basin on the Texas-Louisiana continental slope, hosts a hypersaline, anoxic brine in its lowermost 200 m in which limited microbial activity has been reported. This brine contains a large reservoir of reduced and aged carbon, and appears to be stable at decadal time scales: concentrations and isotopic composition of dissolved inorganic (DIC) and organic carbon (DOC) are similar to measurements made in the 1970s. Both DIC and DOC are more "aged" within the brine pool than in overlying water, and the isotopic contrast between brine carbon and seawater carbon is much greater for DIC than DOC. While the stable carbon isotopic composition of brine DIC points towards a combination of methane and organic carbon remineralization as its source, radiocarbon and box model results point to the brine interface as the major source region for DIC, allowing for only limited oxidation of methane diffusing upwards from sediments. This conclusion is consistent with previous studies that identify the seawater–brine interface as the focus of microbial activity associated with Orca Basin brine. Isotopic similarities between DIC and DOC suggest a different relationship between these two carbon reservoirs than is typically observed in deep ocean basins. Radiocarbon values implicate the seawater–brine interface region as the likely source region for DOC to the brine as well as DIC.This work was funded by the WHOI Postdoctoral Scholar program, NSF Cooperative Agreement for the Operation of a National Ocean Sciences Accelerator Mass Spectrometry Facility (OCE-0753487), and the US National Science Foundation’s Emerging Frontiers program (award 0801741 to SBJ)

Design and Evaluation of Tumor‐Specific Dendrimer Epigenetic Therapeutics

Histone deacetylase inhibitors (HDACi) are promising therapeutics for cancer. HDACi alter the epigenetic state of tumors and provide a unique approach to treat cancer. Although studies with HDACi have shown promise in some cancers, variable efficacy and off‐target effects have limited their use. To overcome some of the challenges of traditional HDACi, we sought to use a tumor‐specific dendrimer scaffold to deliver HDACi directly to cancer cells. Here we report the design and evaluation of tumor‐specific dendrimer–HDACi conjugates. The HDACi was conjugated to the dendrimer using an ester linkage through its hydroxamic acid group, inactivating the HDACi until it is released from the dendrimer. Using a cancer cell model, we demonstrate the functionality of the tumor‐specific dendrimer–HDACi conjugates. Furthermore, we demonstrate that unlike traditional HDACi, dendrimer–HDACi conjugates do not affect tumor‐associated macrophages, a recently recognized mechanism through which drug resistance emerges. We anticipate that this new class of cell‐specific epigenetic therapeutics will have tremendous potential in the treatment of cancer.Targeting tumors via epigenetics: Histone deacetylase inhibitors (HDACi) alter the epigenetic state of tumors and are promising therapeutics for cancer. Although studies with HDACi have shown promise in some cancers, variable efficacy and off‐target effects have limited their use. Here we report the design and evaluation of a tumor‐specific dendrimer–HDACi.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111996/1/open201402141.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/111996/2/open201402141-sup-0001-misc_information.pd

Length of Anticoagulation in Provoked Venous Thromboembolism: A Multicenter Study of How Real-World Practice Mirrors Guideline Recommendations

Background For more than a decade, guidelines have recommended a limited 3 months of anticoagulation for the treatment of provoked venous thromboembolism (VTE). How closely real-world practice follows guideline recommendations is not well described. Methods and Results In our multicenter, retrospective cohort study, we evaluated trends in anticoagulation duration for patients enrolled in the MAQI(2) (Michigan Anticoagulation Quality Improvement Initiative) registry who were receiving anticoagulation for a provoked VTE. The MAQI(2) registry comprises 6 centers in Michigan that manage patients\u27 long-term anticoagulation. We identified 474 patients on warfarin and 302 patients on direct oral anticoagulants who were receiving anticoagulation for a primary indication of provoked VTE between 2008 and 2020. Using a predefined threshold of 120 days (3 months plus a buffer period), predictors of extended anticoagulant use were identified using multivariable logistic regression. Most patients received \u3e120 days of anticoagulation, regardless of which medication was used. The median (25th-75th percentile) length of treatment for patients taking warfarin was 142 (91-234) days and for direct oral anticoagulants was 180 (101-360) days. Recurrent VTE (odds ratio [OR], 2.75 [95% CI, 1.67-4.53]), history of myocardial infarction (OR, 3.92 [95% CI, 1.32-11.7]), and direct oral anticoagulant rather than warfarin use (OR, 2.22 [95% CI, 1.59-3.08]) were independently associated with prolonged anticoagulation. Conclusions In our cohort of patients with provoked VTE, most patients received anticoagulation for longer than the guideline-recommended 3 months. This demonstrates a potential opportunity to improve care delivery and reduce anticoagulant-associated bleeding risk

p63 Expression Defines a Lethal Subset of Muscle-Invasive Bladder Cancers

<div><h3>Background</h3><p>p63 is a member of the p53 family that has been implicated in maintenance of epithelial stem cell compartments. Previous studies demonstrated that p63 is downregulated in muscle-invasive bladder cancers, but the relationship between p63 expression and survival is not clear.</p> <h3>Methodology/Principal Findings</h3><p>We used real-time PCR to characterize p63 expression and several genes implicated in epithelial-to-mesenchymal transition (EMT) in human bladder cancer cell lines (n = 15) and primary tumors (n = 101). We correlated tumor marker expression with stage, disease-specific (DSS), and overall survival (OS). Expression of E-cadherin and p63 correlated directly with one another and inversely with expression of the mesenchymal markers Zeb-1, Zeb-2, and vimentin. Non-muscle-invasive (Ta and T1) bladder cancers uniformly expressed high levels of E-cadherin and p63 and low levels of the mesenchymal markers. Interestingly, a subset of muscle-invasive (T2–T4) tumors maintained high levels of E-cadherin and p63 expression. As expected, there was a strongly significant correlation between EMT marker expression and muscle invasion (p<0.0001). However, OS was shorter in patients with muscle-invasive tumors that retained p63 (p = 0.007).</p> <h3>Conclusions/Significance</h3><p>Our data confirm that molecular markers of EMT are elevated in muscle-invasive bladder cancers, but interestingly, retention of the “epithelial” marker p63 in muscle-invasive tumors is associated with a worse outcome.</p> </div

Sulforaphane induces cell cycle arrest by protecting RB-E2F-1 complex in epithelial ovarian cancer cells

<p>Abstract</p> <p>Background</p> <p>Sulforaphane (SFN), an isothiocyanate phytochemical present predominantly in cruciferous vegetables such as brussels sprout and broccoli, is considered a promising chemo-preventive agent against cancer. In-vitro exposure to SFN appears to result in the induction of apoptosis and cell-cycle arrest in a variety of tumor types. However, the molecular mechanisms leading to the inhibition of cell cycle progression by SFN are poorly understood in epithelial ovarian cancer cells (EOC). The aim of this study is to understand the signaling mechanisms through which SFN influences the cell growth and proliferation in EOC.</p> <p>Results</p> <p>SFN at concentrations of 5 - 20 μM induced a dose-dependent suppression of growth in cell lines MDAH 2774 and SkOV-3 with an IC50 of ~8 μM after a 3 day exposure. Combination treatment with chemotherapeutic agent, paclitaxel, resulted in additive growth suppression. SFN at ~8 μM decreased growth by 40% and 20% on day 1 in MDAH 2774 and SkOV-3, respectively. Cells treated with cytotoxic concentrations of SFN have reduced cell migration and increased apoptotic cell death via an increase in Bak/Bcl-2 ratio and cleavage of procaspase-9 and poly (ADP-ribose)-polymerase (PARP). Gene expression profile analysis of cell cycle regulated proteins demonstrated increased levels of tumor suppressor retinoblastoma protein (RB) and decreased levels of E2F-1 transcription factor. SFN treatment resulted in G1 cell cycle arrest through down modulation of RB phosphorylation and by protecting the RB-E2F-1 complex.</p> <p>Conclusions</p> <p>SFN induces growth arrest and apoptosis in EOC cells. Inhibition of retinoblastoma (RB) phosphorylation and reduction in levels of free E2F-1 appear to play an important role in EOC growth arrest.</p

The driver landscape of sporadic chordoma.

Chordoma is a malignant, often incurable bone tumour showing notochordal differentiation. Here, we defined the somatic driver landscape of 104 cases of sporadic chordoma. We reveal somatic duplications of the notochordal transcription factor brachyury (T) in up to 27% of cases. These variants recapitulate the rearrangement architecture of the pathogenic germline duplications of T that underlie familial chordoma. In addition, we find potentially clinically actionable PI3K signalling mutations in 16% of cases. Intriguingly, one of the most frequently altered genes, mutated exclusively by inactivating mutation, was LYST (10%), which may represent a novel cancer gene in chordoma.Chordoma is a rare often incurable malignant bone tumour. Here, the authors investigate driver mutations of sporadic chordoma in 104 cases, revealing duplications in notochordal transcription factor brachyury (T), PI3K signalling mutations, and mutations in LYST, a potential novel cancer gene in chordoma

Assessment of an Intervention to Reduce Aspirin Prescribing for Patients Receiving Warfarin for Anticoagulation

Importance: For some patients receiving warfarin, adding aspirin (acetylsalicylic acid) increases bleeding risk with unclear treatment benefit. Reducing excess aspirin use could be associated with improved clinical outcomes. Objective: To assess changes in aspirin use, bleeding, and thrombosis event rates among patients treated with warfarin. Design, Setting, and Participants: This pre-post observational quality improvement study was conducted from January 1, 2010, to December 31, 2019, at a 6-center quality improvement collaborative in Michigan among 6738 adults taking warfarin for atrial fibrillation and/or venous thromboembolism without an apparent indication for concomitant aspirin. Statistical analysis was conducted from November 26, 2020, to June 14, 2021. Intervention: Primary care professionals for patients taking aspirin were asked whether an ongoing combination aspirin and warfarin treatment was indicated. If not, then aspirin was discontinued with the approval of the managing clinician. Main Outcomes and Measures: Outcomes were assessed before and after intervention for the primary analysis and before and after 24 months before the intervention (when rates of aspirin use first began to decrease) for the secondary analysis. Outcomes included the rate of aspirin use, bleeding, and thrombotic outcomes. An interrupted time series analysis assessed cumulative monthly event rates over time. Results: A total of 6738 patients treated with warfarin (3160 men [46.9%]; mean [SD] age, 62.8 [16.2] years) were followed up for a median of 6.7 months (IQR, 3.2-19.3 months). Aspirin use decreased slightly from a baseline mean use of 29.4% (95% CI, 28.9%-29.9%) to 27.1% (95% CI, 26.1%-28.0%) during the 24 months before the intervention (P \u3c .001 for slope before and after 24 months before the intervention) with an accelerated decrease after the intervention (mean aspirin use, 15.7%; 95% CI, 14.8%-16.8%; P = .001 for slope before and after intervention). In the primary analysis, the intervention was associated with a significant decrease in major bleeding events per month (preintervention, 0.31%; 95% CI, 0.27%-0.34%; postintervention, 0.21%; 95% CI, 0.14%-0.28%; P = .03 for difference in slope before and after intervention). No change was observed in mean percentage of patients having a thrombotic event from before to after the intervention (0.21% vs 0.24%; P = .34 for difference in slope). In the secondary analysis, reducing aspirin use (starting 24 months before the intervention) was associated with decreases in mean percentage of patients having any bleeding event (2.3% vs 1.5%; P = .02 for change in slope before and after 24 months before the intervention), mean percentage of patients having a major bleeding event (0.31% vs 0.25%; P = .001 for change in slope before and after 24 months before the intervention), and mean percentage of patients with an emergency department visit for bleeding (0.99% vs 0.67%; P = .04 for change in slope before and after 24 months before the intervention), with no change in mean percentage of patients with a thrombotic event (0.20% vs 0.23%; P = .36 for change in slope before and after 24 months before the intervention). Conclusions and Relevance: This quality improvement intervention was associated with an acceleration of a preexisting decrease in aspirin use among patients taking warfarin for atrial fibrillation and/or venous thromboembolism without a clear indication for aspirin therapy. Reductions in aspirin use were associated with reduced bleeding. This study suggests that an anticoagulation clinic-based aspirin deimplementation intervention can improve guideline-concordant aspirin use

Outcomes of Direct Oral Anticoagulants with Aspirin Versus Warfarin with Aspirin for Atrial Fibrillation and/or Venous Thromboembolic Disease

Introduction: The direct oral anticoagulants (DOACs) including apixaban, dabigatran, edoxaban, and rivaroxaban are increasingly utilized for the management of venous thromboembolic disease (VTE) and/or non-valvular atrial fibrillation (NVAF). Adding aspirin (ASA) to warfarin or DOAC therapy increases bleeding risk. Patients on combination therapy with ASA and an anticoagulant were not well represented in clinical trials comparing DOACs to warfarin. We sought to compare bleeding and thrombotic outcomes with DOACs and ASA compared to warfarin and ASA in a non-trial setting. Methods: We conducted a retrospective registry-based cohort study of adults on DOAC or warfarin therapy for VTE and/or NVAF. Warfarin treated patients were followed by six anticoagulation clinics. Four out of the six clinics contributed data on their patients that were on DOACs in the Michigan Anticoagulation Quality Improvement Initiative (MAQI 2) from January 2009 to June 2021. Patients were excluded if they had a history of heart valve replacement, recent myocardial infarction, or less than 3 months of follow-up. Two propensity matched cohorts (warfarin+ASA vs DOAC+ASA) of patients were analyzed based on ASA use at the time of study enrollment. The primary outcome was any new bleeding event. Secondary outcomes included new episodes of arterial or venous thrombosis, bleeding event type (major, fatal, life threatening, central nervous system, and non-major bleeding), emergency room visits, hospitalizations, transfusions, and death. Random chart audits were done to confirm the accuracy of the abstracted data. Event rates were compared using Poisson regression. Results: We identified a total of 1,139 patients on DOACs plus ASA and 4,422 patients on warfarin plus ASA. After propensity matching, we compared two groups of 1,114 matched patients. DOAC treated patients were predominately on apixaban (62.3%) and rivaroxaban (30.4%), most often at therapeutic doses (Table 1). Patients were largely (90.5%) on low dose ASA (≤ 100 mg). Patient demographics, co-morbidities, indication for anticoagulation, history of bleeding or clotting, medications, and duration of follow-up were well-balanced after matching. Patients were followed for a median of 11.7 months (interquartile range 4.4 and 34 months). Patients treated with DOAC+ASA had 2.4 thrombotic events per 100 patient years compared to 2.2 thrombotic events per 100 patient years with warfarin+ASA (P=0.78). There were no significant differences observed between groups by thrombotic subtype (stroke, transient ischemic attack, pulmonary embolism, deep vein thrombosis, table 1). Bleeding was also similar with 30.1 bleeding events per 100 patient years with DOAC+ASA compared to 27.8 bleeds per 100 patient years with warfarin+ASA (P=0.24). There were no significant differences by bleeding subtype (table 1). Hospitalizations for clotting occurred less frequently with DOAC+ASA (0.9 hospitalizations per 100 patient years) compared to warfarin+ASA (1.7 hospitalizations per 100 patient years, P=0.03). Mortality, transfusions, and healthcare utilization were otherwise similar between the two groups. Conclusions: For patients on a DOAC versus warfarin with ASA for atrial fibrillation and/or venous thromboembolic disease without a recent myocardial infarction or heart valve replacement, bleeding and thrombotic outcomes were similar

Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial

IMPORTANCE: Secretory phospholipase A2(sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE: To determine the effects of sPLA2inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS: Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES: The primary efficacy measurewas a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS: At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95%CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95%CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE: In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130246. Copyright 2014 American Medical Association. All rights reserved