362 N Broadway Fl 2
Sleepy Hollow NY 10591
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Long-Term Recovery of Reduced Left Ventricular Ejection Fraction after Aortic Valve Replacement in Patients with Bicuspid Aortic Valve Disease. - The Thoracic and cardiovascular surgeon
Backgroundâ€ƒLong-term prognosis of patients with bicuspid aortic valve (BAV) disease and poor left ventricular ejection fraction (LVEF) who underwent aortic valve replacement (AVR) is unknown. We aimed to analyze the recovery of LVEF and incidence of adverse events after AVR in patients with BAV and poor LVEF. Materials and Methodsâ€ƒA total of 90 consecutive BAV patients (mean age 57â€‰Â±â€‰10 years, 89% male) with baseline LVEF â‰¤40% underwent an isolated AVR between January 1, 1995, and June 30, 2008, and served as our study population. Follow-up data (800 patient-years) were obtained for all 90 hospital survivors. A subgroup of patients who underwent AVR for BAV stenosis (Group aortic stenosis [AS], nâ€‰=â€‰70) was compared with those who underwent AVR for BAV regurgitation (Group aortic regurgitation [AR], nâ€‰=â€‰20). Primary end point was the recovery of LVEF in AS Group versus AR Group. Secondary end points were survival and freedom from adverse cardiac events (i.e., cardiac-related death and need for reinterventions due to persisting heart failure). Resultsâ€ƒThere was a significant increase in LVEF (mean follow-up 9.0â€‰Â±â€‰5 years) in AS versus AR Group (i.e., 32â€‰Â±â€‰7% [baseline] and 53â€‰Â±â€‰9% [follow-up], pâ€‰<â€‰0.001 in AS Group vs. 33â€‰Â±â€‰7% [baseline] and 38â€‰Â±â€‰13% [follow-up], pâ€‰=â€‰0.07 in AR Group). Recovery rate of LVEF was significantly higher in AS Group versus AR Group (i.e., 2.8 percentage points (pp)/year vs. 0.7 pp/year, respectively). In Group AS, 86% of patients were responders, whereas in Group AR, only 30% (pâ€‰<â€‰0.001). The subjects in Group AR did not show a difference between baseline and follow-up left ventricular end-diastolic diameter (LVEDD) (baseline 61â€‰Â±â€‰12 vs. follow-up 58â€‰Â±â€‰8, pâ€‰=â€‰0.813), whereas in Group AS, there was a significant difference of LVEDD (baseline 56â€‰Â±â€‰7 vs. follow-up 54â€‰Â±â€‰6â€‰mm, pâ€‰=â€‰0.019). Ten-year survival was 76â€‰Â±â€‰6.5% in AS Group versus 78â€‰Â±â€‰11% in AR Group (pâ€‰=â€‰0.3). Prevalence of late adverse cardiac events was 7% in AS Group versus 40% in AR Group (pâ€‰=â€‰0.03). Conclusionâ€ƒThe recovery of reduced LVEF after AVR surgery is significantly impaired in patients with BAV regurgitation as compared with BAV stenosis.Georg Thieme Verlag KG Stuttgart Â· New York.
Aortic events after isolated aortic valve replacement for bicuspid aortic valve root phenotype: echocardiographic follow-up studyâ€ . - European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery
Various forms of bicuspid aortic valve (BAV) aortopathy exist, and the optimal treatment for the different subgroups is insufficiently defined. We aimed to analyse the risk of adverse aortic events after aortic valve replacement (AVR) for BAV insufficiency and concomitant mild-to-moderate dilatation of the aortic root (i.e. BAV root phenotype).A total of 56 consecutive patients (mean age 47 Â± 11 years, 95% men) with BAV insufficiency and a root diameter of 40-50 mm underwent AVR surgery from 1995 to 2008. All patients, as identified from our institutional BAV database, had a dilated aortic annulus (i.e. defined as valve prosthesis size â‰¥27 mm) without aortic stenosis (i.e. mean gradient â‰¤20 mmHg). Patients who underwent concomitant aortic surgery were excluded. Follow-up (622 patient-years) including echocardiography data was available for all patients. Aortic events were defined as the need for proximal aortic surgery, the occurrence of aortic dissection/rupture, echocardiographic evidence of increasing aortic root diameter/occurrence of late paravalvular leakage or sudden death during follow-up.Actuarial survival was 90% at 10 years and 78% at 15 years. Adverse aortic events occurred in 19 (34%) study patients. Redo aortic surgery was performed in 6 patients (11%), 2 of which were for aortic dissection. Four patients (7%) suffered sudden cardiac death. Moreover, follow-up echocardiography revealed a significant, progressive enlargement of the aortic root diameter in 7 (13%) patients and occurrence of late de novo paravalvular leakage in 2 (3%) patients. The resultant freedom from aortic events was 81% at 10 years and 51% at 15 years.Patients with a BAV root phenotype are at significant risk of aortic events after isolated AVR. Simultaneous root/ascending aortic surgery should be strongly considered in such patients.Â© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
Aortopathy in patients with bicuspid aortic valve stenosis: role of aortic root functional parametersâ€ . - European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery
We prospectively examined functional characteristics of the aortic root and transvalvular haemodynamic flow in order to define factors associated with the severity of aortopathy in patients undergoing surgery for bicuspid aortic valve (BAV) stenosis.A total of 103 consecutive patients with BAV stenosis (mean age 61 Â± 9 years, 66% male) underwent aortic valve replacement Â± concomitant aortic surgery from January 2012 through March 2014. All patients underwent preoperative cardiac magnetic resonance imaging (MRI) in order to evaluate the systolic transvalvular flow and the following functional parameters: (i) angulation between the left ventricular outflow axis and the aortic root, (ii) geometrical orientation of residual aortic valve orifice and (iii) BAV cusp fusion pattern. MRI data were used to guide sampling of the ascending aorta during surgery [i.e. jet-sample from the area where the flow-jet impacts on the aortic wall and control sample from the opposite aortic wall (obtained from the aortotomy site)]. Aortopathy was quantified by means of a histological sum-score (0 to 21+) in each sample.A significant correlation was found between histological sum-score in the jet-sample and the angle between the LV outflow axis and the aortic root (r = 0.6, P = 0.007). Moreover, there was a linear correlation between proximal aortic diameter and the angle between systolic flow-jet and ascending aortic wall (r = 0.5, P = 0.006). Logistic regression identified the angle between the LV outflow axis and the aortic root (OR 1.1, P = 0.04) and the angle between the flow-jet and the aortic wall (OR 1.2, P = 0.001) as independent predictors of an indexed proximal aortic diameter â‰¥22 mm/m(2).Functional parameters of the aortic root may be used to predict the severity of aortopathy in patients with BAV stenosis, and may be useful in predicting future risk of aortic disease in such patients.Â© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
Nanobiopolymer for direct targeting and inhibition of EGFR expression in triple negative breast cancer. - PloS one
Treatment options for triple negative breast cancer (TNBC) are generally limited to cytotoxic chemotherapy. Recently, anti-epidermal growth factor receptor (EGFR) therapy has been introduced for TNBC patients. We engineered a novel nanobioconjugate based on a poly(Î²-L-malic acid) (PMLA) nanoplatform for TNBC treatment. The nanobioconjugate carries anti-tumor nucleosome-specific monoclonal antibody (mAb) 2C5 to target breast cancer cells, anti-mouse transferrin receptor (TfR) antibody for drug delivery through the host endothelial system, and Morpholino antisense oligonucleotide (AON) to inhibit EGFR synthesis. The nanobioconjugates variants were: (1) P (BioPolymer) with AON, 2C5 and anti-TfR for tumor endothelial and cancer cell targeting, and EGFR suppression (P/AON/2C5/TfR), and (2) P with AON and 2C5 (P/AON/2C5). Controls included (3) P with 2C5 but without AON (P/2C5), (4) PBS, and (5) P with PEG and leucine ester (LOEt) for endosomal escape (P/mPEG/LOEt). Drugs were injected intravenously to MDA-MB-468 TNBC bearing mice. Tissue accumulation of injected nanobioconjugates labeled with Alexa Fluor 680 was examined by Xenogen IVIS 200 (live imaging) and confocal microscopy of tissue sections. Levels of EGFR, phosphorylated and total Akt in tumor samples were detected by western blotting. In vitro western blot showed that the leading nanobioconjugate P/AON/2C5/TfR inhibited EGFR synthesis significantly better than naked AON. In vivo imaging revealed that 2C5 increased drug-tumor accumulation. Significant tumor growth inhibition was observed in mice treated with the lead nanobioconjugate (1) [Pâ€Š=â€Š0.03 vs. controls; P<0.05 vs. nanobioconjugate variant (2)]. Lead nanobioconjugate (1) also showed stronger inhibition of EGFR expression and Akt phosphorylation than other treatments. Treatment of TNBC with the new nanobioconjugate results in tumor growth arrest by inhibiting EGFR and its downstream signaling intermediate, phosphorylated Akt. The nanobioconjugate represents a new generation of nanodrugs for treatment of TNBC.
High fetal plasma adenosine concentration: a role for the fetus in preeclampsia? - American journal of obstetrics and gynecology
Clinical observations suggest a role for the fetus in the maternal manifestations of preeclampsia, but the possible signaling mechanisms remain unclear. This study compares the fetal plasma concentrations of adenosine from normal pregnancies with those from preeclampsia.This secondary data analysis included normal pregnancies (n = 27) and patients with preeclampsia (n = 39). Patients with preeclampsia were subclassified into patients with (n = 25) and without (n = 14) abnormal uterine artery Doppler velocimetry (UADV).Fetal plasma concentrations of adenosine were significantly higher in patients with preeclampsia (1.35 Â± 0.09 Î¼mol/L) than in normal pregnancies (0.52 Â± 0.06 Î¼mol/L; P < .0001). Fetal plasma concentrations of adenosine in patients with preeclampsia with abnormal UADV (1.78 Â± 0.15 Î¼mol/L), but not with normal UADV (0.58 Â± 0.14 Î¼mol/L), were significantly higher than in normal pregnancies (P < .0001).Patients with preeclampsia with sonographic evidence of chronic uteroplacental ischemia have high fetal plasma concentrations of adenosine.Copyright Ã‚Â© 2011 Mosby, Inc. All rights reserved.
Polymalic acid-based nanobiopolymer provides efficient systemic breast cancer treatment by inhibiting both HER2/neu receptor synthesis and activity. - Cancer research
Biodegradable nanopolymers are believed to offer great potential in cancer therapy. Here, we report the characterization of a novel, targeted, nanobiopolymeric conjugate based on biodegradable, nontoxic, and nonimmunogenic PMLA [poly(Î²-l-malic acid)]. The PMLA nanoplatform was synthesized for repetitive systemic treatments of HER2/neu-positive human breast tumors in a xenogeneic mouse model. Various moieties were covalently attached to PMLA, including a combination of morpholino antisense oligonucleotides (AON) directed against HER2/neu mRNA, to block new HER2/neu receptor synthesis; anti-HER2/neu antibody trastuzumab (Herceptin), to target breast cancer cells and inhibit receptor activity simultaneously; and transferrin receptor antibody, to target the tumor vasculature and mediate delivery of the nanobiopolymer through the host endothelial system. The results of the study showed that the lead drug tested significantly inhibited the growth of HER2/neu-positive breast cancer cells in vitro and in vivo by enhanced apoptosis and inhibition of HER2/neu receptor signaling with suppression of Akt phosphorylation. In vivo imaging analysis and confocal microscopy demonstrated selective accumulation of the nanodrug in tumor cells via an active delivery mechanism. Systemic treatment of human breast tumor-bearing nude mice resulted in more than 90% inhibition of tumor growth and tumor regression, as compared with partial (50%) tumor growth inhibition in mice treated with trastuzumab or AON, either free or attached to PMLA. Our findings offer a preclinical proof of concept for use of the PMLA nanoplatform for combination cancer therapy.Â©2011 AACR.
Phosphodiesterase type 5 inhibitors increase Herceptin transport and treatment efficacy in mouse metastatic brain tumor models. - PloS one
Chemotherapeutic drugs and newly developed therapeutic monoclonal antibodies are adequately delivered to most solid and systemic tumors. However, drug delivery into primary brain tumors and metastases is impeded by the blood-brain tumor barrier (BTB), significantly limiting drug use in brain cancer treatment.We examined the effect of phosphodiesterase 5 (PDE5) inhibitors in nude mice on drug delivery to intracranially implanted human lung and breast tumors as the most common primary tumors forming brain metastases, and studied underlying mechanisms of drug transport. In vitro assays demonstrated that PDE5 inhibitors enhanced the uptake of [(14)C]dextran and trastuzumab (Herceptin, a humanized monoclonal antibody against HER2/neu) by cultured mouse brain endothelial cells (MBEC). The mechanism of drug delivery was examined using inhibitors for caveolae-mediated endocytosis, macropinocytosis and coated pit/clathrin endocytosis. Inhibitor analysis strongly implicated caveolae and macropinocytosis endocytic pathways involvement in the PDE5 inhibitor-enhanced Herceptin uptake by MBEC. Oral administration of PDE5 inhibitor, vardenafil, to mice with HER2-positive intracranial lung tumors led to an increased tumor permeability to high molecular weight [(14)C]dextran (2.6-fold increase) and to Herceptin (2-fold increase). Survival time of intracranial lung cancer-bearing mice treated with Herceptin in combination with vardenafil was significantly increased as compared to the untreated, vardenafil- or Herceptin-treated mice (p<0.01). Log-rank survival analysis of mice bearing HER2-positive intracranial breast tumor also showed a significant survival increase (p<0.02) in the group treated with Herceptin plus vardenafil as compared to other groups. However, vardenafil did not exert any beneficial effect on survival of mice bearing intracranial breast tumor with low HER2 expression and co-treated with Herceptin (p>0.05).These findings suggest that PDE5 inhibitors may effectively modulate BTB permeability, and enhance delivery and therapeutic efficacy of monoclonal antibodies in hard-to-treat brain metastases from different primary tumors that had metastasized to the brain.
Angiogenic imbalances: the obstetric perspective. - American journal of obstetrics and gynecology
Clinical and experimental evidence indicates that angiogenic imbalances may participate in the mechanisms of disease of several pregnancy complications, some of which may be life threatening. This article reviews current evidence in support of this view and the possibility that the fetus may play a central role in these imbalances; it also reviews recent experimental observations that modulation of angiogenic imbalances during pregnancy may have prophylactic and/or therapeutic value.Copyright (c) 2010 Mosby, Inc. All rights reserved.
Different effects of KCa and KATP agonists on brain tumor permeability between syngeneic and allogeneic rat models. - Brain research
The blood-brain tumor barrier (BTB) significantly limits delivery of effective concentrations of chemotherapeutic drugs to brain tumors. Previous studies suggest that BTB permeability may be modulated via alteration in the activity of potassium channels. In this study, we studied the relationship of BTB permeability increase mediated by potassium channel agonists to channel expression in two rat brain tumor models. Intravenous infusion of KCO912 (K(ATP) agonist), minoxidil sulfate (K(ATP) agonist) or NS1619 (K(Ca) agonist) increased tumor permeability more in the 9L allogeneic brain tumor model than in the syngeneic brain tumor model. Consistently, expression of both K(ATP) and K(Ca) channels in 9L tumors was increased to a significantly greater extent in Wistar rats (allogeneic) as compared to Fischer rats (syngeneic). Furthermore, as a preliminary effort to understand clinical implication of potassium channels in brain tumor treatment, we determined the expression of K(ATP) in surgical specimens. K(ATP) mRNA was detected in glioblastoma multiforme (GBM) from nineteen patients examined, with a wide range of expression levels. Interestingly, in paired GBM tissues from seven patients before and after vaccination therapy, increased levels of K(ATP) were detected in five patients after vaccination that had positive response to chemotherapy after vaccination. The present study indicates that the effects of potassium channel agonists on BTB permeability are different between syngeneic and allogeneic models which have different expression levels of potassium channels. The expression of potassium channels in brain tumors is variable, which may be associated with different tumor permeability to therapeutic agents among patients.
Increase in brain tumor permeability in glioma-bearing rats with nitric oxide donors. - Clinical cancer research : an official journal of the American Association for Cancer Research
The blood-brain tumor barrier (BTB) significantly limits the delivery of chemotherapeutics to brain tumors. Nitric oxide (NO) is involved in the regulation of cerebral vascular permeability. We investigated the effects of NO donors, L-arginine and hydroxyurea, on BTB permeability in 9L gliosarcoma-bearing Fischer rats.The rats implanted with 9L gliosarcoma were dosed orally with hydroxyurea and L-arginine. BTB permeability, defined by the unidirectional transport constant, Ki, for [14C]sucrose was measured. The expression of neural and endothelial NO synthase (NOS) in tumors and normal brain tissue was examined. Further, the levels of NO, L-citrulline, and cGMP in the tumor and normal brain tissue were measured.Oral administration of l-arginine or hydroxyurea significantly increased BTB permeability when compared with the nontreated control. The selective effects were abolished by iberiotoxin, an antagonist of calcium-dependent potassium (KCa) channel that is a cGMP pathway effector. The expression of endothelial NOS, but not neural NOS, was higher in tumor vessels than in those of normal brain. Moreover, the levels of NO, L-citrulline, a byproduct of NO formation from L-arginine, and cGMP were enhanced in the tumor tissue by oral administration of L-arginine and/or hydroxyurea.Oral administration of L-arginine or hydroxyurea selectively increased tumor permeability, which is likely mediated by alteration in cGMP levels. The findings suggest that use of oral NO donors may be a strategy to enhance the delivery of chemotherapeutics to malignant brain tumors.
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