Abstract Disulfiram (DS), an anti-alcoholism drug, shows very strong cytotoxicity in many cancer types. However its clinical application in cancer treatment is limited by the very short half-life in ...the bloodstream. In this study, we developed a poly lactic-co-glycolic acid (PLGA)-encapsulated DS protecting DS from the degradation in the bloodstream. The newly developed DS-PLGA was characterized. The DS-PLGA has very satisfactory encapsulation efficiency, drug-loading content and controlled release rate in vitro . PLGA encapsulation extended the half-life of DS from shorter than 2 minutes to 7 hin serum. In combination with copper, DS-PLGA significantly inhibited the liver cancer stem cell population. CI-isobologram showed a remarkable synergistic cytotoxicity between DS-PLGA and 5-FU or sorafenib. It also demonstrated very promising anticancer efficacy and antimetastatic effect in liver cancer mouse model. Both DS and PLGA are FDA approved products for clinical application. Our study may lead to repositioning of DS into liver cancer treatment.
Bioengineered self-seeding heart valves Jordan, James E., PhD; Williams, J. Koudy, DVM; Lee, Sang-Jin, PhD ...
The Journal of thoracic and cardiovascular surgery,
2012, 2012-Jan, 2012-01-00, 20120101, Volume:
143, Issue:
1
Journal Article
Peer reviewed
Open access
Objective Mechanical and biological prostheses are used to replace damaged heart valves but are associated with significant morbidities. Although there is increased interest in bioengineering ...cell-seeded heart valve scaffolds, it is a time-consuming and technically difficult process. The goal of this project was to engineer self-seeding heart valves that mature quickly in vivo and have a shorter preparation time. Methods Porcine pulmonary valves were decellularized using detergent methods and then either (1) left untreated (unconjugated, n = 6), (2) reseeded with autologous endothelial progenitor cell–derived endothelial cells (cell-seeded, n = 4), or (3) conjugated with CD133 antibodies (conjugated, n = 8). The valve constructs were transplanted into the pulmonary position of sheep using standard surgical techniques. After 1 or 3 months, the implants were removed and assessed for cell and matrix content as well as biomechanical properties. Results Endothelial cells expressing von Willebrand factor lined the entire length of both ventricular and arterial surfaces of conjugated valves by 1 month after implantation. Interstitial cell and structural protein content of conjugated valves increased from 1 month to 3 months with interstitial expression of metalloproteinase-9 and new collagen formation. In contrast, there were few endothelial or interstitial cells associated with unconjugated, or cell-seeded valves at any time point. No calcification or thrombi were noted on any of the valves. Young’s modulus and tensile strength was greater in the conjugated valves versus unconjugated or cell-seeded valves. Conclusions Results indicate that tissue-engineered heart valve replacement constructs can be made quickly and therefore may be a clinically relevant option for patients needing heart valve surgery in a timely fashion.
Background Although child abuse is associated with obesity, it is not known whether early abuse increases risk of type 2 diabetes. Purpose To investigate associations of child and adolescent abuse ...with adult diabetes. Methods Proportional hazards models were used to examine associations of lifetime abuse reported in 2001 with risk of diabetes from 1989 to 2005 among 67,853 women in the Nurses' Health Study II. Data were analyzed in 2009. Results Child or teen physical abuse was reported by 54% and sexual abuse by 34% of participants. Models were adjusted for age, race, body type at age 5 years, and parental education and history of diabetes. Compared to women who reported no physical abuse, the hazards ratio (HR) was 1.03 (95% CI=0.91, 1.17) for mild physical abuse; 1.26 (1.14, 1.40) for moderate physical abuse; and 1.54 (1.34, 1.77) for severe physical abuse. Compared with women reporting no sexual abuse in childhood or adolescence, the HR was 1.16 (95% CI=1.05, 1.29) for unwanted sexual touching; 1.34 (1.13, 1.59) for one episode of forced sexual activity; and 1.69 (1.45, 1.97) for repeated forced sex. Adult BMI accounted for 60% (95% CI=32%, 87%) of the association of child and adolescent physical abuse and 64% (95% CI=38%, 91%) of the association of sexual abuse with diabetes. Conclusions Moderate to severe physical and sexual abuse in childhood and adolescence have dose–response associations with risk of type 2 diabetes among adult women. This excess risk is partially explained by the higher BMI of women with a history of early abuse.
Statement of problem Initial implant stability has been used as an indicator for future osseointegration and whether an immediate/early loading protocol should be applied. However, differences in ...initial stability in relation to anatomical regions of jawbone have not been studied extensively because of the risks involved with stability measurements. Purpose The purpose of this study was to determine whether initial implant stability varies with anatomical regions of the jawbone. Material and methods Four pairs of edentulous maxillae and mandibles were retrieved from fresh human cadavers. Six implants (Biomet 3i) per pair were placed in different anatomical regions (maxillary anterior, right and left maxillary posterior, mandibular anterior, right and left mandibular posterior). Immediately after implant placement, initial implant stability was measured with a custom-made resonance frequency analyzer, a commercial resonance frequency analysis device (Osstell), and a mechanical tapping device (Periotest). All implant surgeries and initial stability measurements were performed within 72 hours of death to simulate a clinical setting. Repeated measures ANOVA (α=.05) and univariate correlation analyses were used to analyze the data. Results Mandibular implants had significantly higher initial stability than maxillary implants. Posterior maxillary implants were least stable. Stability was less buccolingually than mesiodistally. The measurements from 3 stability measuring devices were strongly associated with each other. Conclusions Initial implant stability varied among anatomical regions of jawbone. Rank of Periotest value and implant stability quotient (Osstell) had the highest correlation (r=-0.852). (J Prosthet Dent 2008;99:425-434)
Abstract Background: Patients with hypertension may require combination therapy to attain the blood pressure targets recommended by US and European treatment guidelines. Combination therapy with a ...calcium channel blocker and an angiotensin II-receptor blocker would be expected to provide enhanced efficacy. Objectives: Two studies were conducted to compare the efficacy of various combinations of amlodipine and valsartan administered once daily with their individual components and placebo in patients with mild to moderate essential hypertension (mean sitting diastolic blood pressure MSDBP ≥95 and < 110 mm Hg). A secondary objective was to evaluate safety and tolerability. Methods: The 2 studies were multinational, multicenter, 8-week, randomized, double-blind, placebo-controlled, parallel-group trials. In study 1, patients were randomized to receive amlodipine 2.5 or 5 mg once daily, valsartan 40 to 320 mg once daily, the combination of amlodipine 2.5 or 5 mg with valsartan 40 to 320 mg once daily, or placebo. In study 2, patients were randomized to receive amlodipine 10 mg once daily, valsartan 160 or 320 mg once daily, the combination of amlodipine 10 mg with valsartan 160 or 320 mg once daily, or placebo. The primary efficacy variable in both studies was change from baseline in MSDBP at the end of the study. Secondary variables included the change in mean sitting systolic blood pressure (MSSBP), response rate (the proportion of patients achieving an MSDBP <90 mm Hg or a ≥ 10-mm Hg decrease from baseline), and control rate (the proportion of patients achieving an MSDBP <90 mm Hg). Safety was assessed in terms of adverse events (spontaneously reported or elicited by questioning), vital signs, and laboratory values. Results: A total of 1911 patients were randomized to treatment in study 1 (1022 amlodipine + valsartan; 507 valsartan; 254 amlodipine; 128 placebo); 1250 were randomized to treatment in study 2 (419, 415, 207, and 209, respectively). In all treatment groups in both studies, the majority of patients were white (79.5% study 1, 79.4% study 2) and male (53.5% and 50.3%, respectively). The overall mean age was 54.4 years in study 1 and 56.9 years in study 2. The mean weight of patients in study 1 was higher than that in study 2 (88.8 vs 79.7 kg). The overall baseline mean sitting BP was 152.8/99.3 mm Hg in study 1 and 156.7/99.1 mm Hg in study 2. With the exception of a few combinations that included amlodipine 2.5 mg, the combination regimens in both studies were associated with significantly greater reductions in MSDBP and MSSBP compared with their individual components and placebo ( P < 0.05). A positive dose response was observed for all combinations. The highest response rate in study 1 was associated with the highest dose of combination therapy (amlodipine 5 mg + valsartan 320 mg: 91.3%). Amlodipine 5 mg, valsartan 320 mg, and placebo were associated with response rates of 71.9%, 73.4%, and 40.9%, respectively. In study 2, the 2 doses of combination therapy were associated with similar response rates (amlodipine 10 mg + valsartan 160 mg: 88.5%; amlodipine 10 mg + valsartan 320 mg: 87.5%). Amlodipine 10 mg was associated with a response rate of 86.9%; valsartan 160 and 20 mg were associated with response rates of 74.9% and 72.0%, respectively; and placebo was associated with a response rate of 49.3%. Control rates followed a similar pattern. The incidence of peripheral edema with combination therapy was significantly lower compared with amlodipine monotherapy (5.4% vs 8.7%, respectively; P = 0.014), was significantly higher compared with valsartan monotherapy (2.1%; P < 0.001), and did not differ significantly from placebo (3.0%). Conclusions: In these adult patients with mild to moderate hypertension, the combination of amlodipine + valsartan was associated with significantly greater blood pressure reductions from baseline compared with amlodipine or valsartan monotherapy or placebo. The incidence of peripheral edema was significantly lower with combination therapy than with amlodipine monotherapy.
Abstract In the ENSURE-AF study (NCT 02072434), edoxaban was compared to enoxaparin–warfarin in 2199 patients undergoing electrical cardioversion of non-valvular atrial fibrillation (AF). In this ...multicenter PROBE trial, we analyzed patients randomized to enoxaparin–warfarin. We determined time to achieve therapeutic range (TtTR), time in therapeutic range (TiTR), their clinical determinants, relation to SAMe-TT2 R2 score, and impact on primary endpoints (composite of stroke, systemic embolic event SEE, myocardial infarction MI, and cardiovascular death CVD and composite of major + clinically relevant non-major CRNM bleeding). Among 1104 patients randomized to enoxaparin––warfarin, 27% were oral anticoagulant naïve. Mean age was 64.2±11 years and mean CHA2 DS2 -VASc score was 2.6. Mean TtTR was 7.7 days (median 7 days) and mean TiTR after reaching INR 2.0–3.0 was 71%. In 695 patients with INR <2.0 prior to first dose and who reached ≥2.0, 436 had a SAMe-TT2 R2 score ≤2 and 259 a score of >2. On multivariate regression, an independent predictor of extended TtTR was creatinine clearance (CrCl) P =0.02. TtTR was marginally related to stroke/SEE/MI/CVD ( P =0.06; OR=0.23, 95% CI 0.02–1.17) but not to any bleeding. Independent predictors of TiTR were prior VKA experience ( P <0.01) and low HAS-BLED score ( P =0.02). TiTR was related to any bleeding ( P =0.02; OR=0.39, 95% CI 0.16–0.88), but not stroke/SE/MI/CVD. In this cohort of warfarin users with a high TiTR no difference was seen between TtTR and TiTR in relation to SAMe-TT2 R2 score. In conclusion, even in this short-term study, TiTR was significantly related to bleeding events.
Annually, 10% of patients with atrial fibrillation (AF) or venous thromboembolism (VTE) treated with non-vitamin K oral anticoagulants undergo diagnostic or therapeutic procedures. This subanalysis ...of the multicenter, prospective, observational Edoxaban Management in Diagnostic and Therapeutic Procedures real-world registry included patients in Europe and Asia with AF or VTE who underwent transcatheter cardiovascular (CV) procedures. Edoxaban interruption and clinical outcomes were assessed for all arterial or venous access procedures and stratified by bleeding risk. Overall, 2695 procedures were reported; 755 (28.0%) were transcatheter CV procedures, of which 373 (49.4%) were arterial access and 382 (50.6%) were venous access procedures. Patients with arterial versus venous access procedures had significantly higher bleeding and stroke and thromboembolism risk scores ( P < 0.0001 for both) ands having a underwent procedures that were more frequently classified a higher European Heart Rhythm Association bleeding risk. Edoxaban was interrupted in 59.5% (222) arterial versus 42.4% (162) venous access procedures, mostly either only preprocedurally or both pre- and postprocedurally. The combined incidence of clinically relevant ischemic or bleeding event rates and deaths was low (0.8 events/100 procedures). This subanalysis showed that while edoxaban was interrupted in approximately half of all interventions, ischemic events and major bleeding were low, suggesting transcatheter CV procedures can be performed safely in high-risk patients with AF or VTE. Patient and procedural factors should be considered to personalize the decision of edoxaban management around the time of a transcatheter CV procedure. Clinical trial registration number: NCT02950168, NCT02951039
Patients treated with edoxaban may require diagnostic and therapeutic procedures that involve edoxaban interruption. Although heparin bridging strategies are not recommended, heparin is frequently ...used in clinical practice. However, whether heparin use decreases thromboembolic risk remains unclear, and the potential for increased periprocedural bleeding remains a concern. Here, we report factors predicting edoxaban interruption and the use of heparin bridging strategies and associated clinical events from Global EMIT-AF/VTE, a multicenter, prospective, noninterventional study (Clinicaltrials.gov NCT02950168). Eligible patients are adults with atrial fibrillation or venous thromboembolism treated with edoxaban who underwent a diagnostic or therapeutic procedure. Edoxaban interruption, heparin bridging strategies, and clinical event data were collected from 5 days before procedure through 29 days afterwards. Edoxaban was interrupted in 1222/2089 procedures (58.5%); a heparin bridging strategy was used during 178 (14.6%) of these interruptions. Patients who received periprocedural heparin had higher baseline HAS-BLED (2.4±1.0 vs 1.9±1.1, P <0.0001) scores and similar CHA2DS2-VASc (3.6±1.6 vs 3.4±1.6, P = 0.09) scores versus patients who did not. HAS-BLED score >3 and high EHRA procedural risk predicted both edoxaban interruption and the use of a heparin bridging strategy, whereas CHA2DS2-VASc scores did not predict either. Bleeding and ischemic event rates were low; the all-bleeding rate was higher with the use of a heparin bridging strategy versus without (6.2% vs 3.1%, P = 0.04). Periprocedural heparin use was associated with higher bleeding rates, but not with lower thromboembolic risk. Individual patient and procedural bleeding risks appear to contribute more than stroke risk to clinicians’ consideration of a heparin bridging strategy.
Statement of problem There is confusion in the literature about how physical properties of bone vary between maxillary and mandibular regions and which physical properties affect initial implant ...stability. Purpose The purpose of this study was to determine correlations between physical properties of bone and initial implant stability, and to determine how physical properties and initial stability vary among regions of jawbone. Material and Methods Four pairs of edentulous maxillae and mandibles were retrieved from fresh human cadavers. Six implants per pair were placed in different anatomical regions (maxillary anterior, right and left maxillary posterior, mandibular anterior, right and left mandibular posterior). Immediately after surgery, initial implant stability was measured with a resonance frequency device and a tapping device. Implant surgeries and initial stability measurements were performed within 72 hours of death. Elastic modulus (EM) and hardness were measured using nano-indentation. Composite apparent density (cAD) was measured using Archimedes' principle. Bone-implant contact percentage and cortical bone thickness were recorded histomorphometrically. Mixed linear models and univariate-correlation analyses were used (α=.05). Results Generally, mandibular bone had higher initial implant stability and physical properties than maxillary bone. Initial implant stability was higher in the anterior region than in the posterior. EM was higher in the posterior region than in the anterior; the reverse was true for cAD. Conclusions Of the properties evaluated, cAD had the highest correlation with initial implant stability (r=0.82). Both physical properties of bone and initial implant stability differed between regions of jawbone. (J Prosthet Dent 2009;101:306–318)
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