Babette Weksler - Profile on Academia.edu (original) (raw)

Papers by Babette Weksler

Effect of Preoperative Antiplatelet Drugs on Vascular Prostacyclin Synthesis

The Annals of Thoracic Surgery, 1987

Patients undergoing aortocoronary bypass using autogenous saphenous veins were randomly divided i... more Patients undergoing aortocoronary bypass using autogenous saphenous veins were randomly divided into three comparable groups. Group 1 (n = 10) acted as a control, Group 2 (n = 14) received 80 mg of aspirin at midnight before the operation, and Group 3 (n = 12) received 80 mg of aspirin and 75 mg of dipyridamole at midnight and an additional 75-mg dose of dipyridamole at 6 AM. The purpose was to determine which regimen would maximally inhibit platelet function without depressing vascular prostacyclin synthesis. Serum thromboxane A2, saphenous vein wall and aortic wall prostacyclin, platelet aggregation, and bleeding time were measured in all patients. None was restarted on a regimen of aspirin or dipyridamole postoperatively. Aspirin alone and in combination with dipyridamole significantly inhibited thromboxane A2 and platelet aggregation in all treated patients but spared venous prostacyclin synthesis. Aortic prostacyclin synthesis was partially inhibited in both treated groups. Chest tube drainage was comparable in all three groups. These results indicate that the combination of aspirin and dipyridamole offers no measurable advantage over aspirin alone in the perioperative period.

Neurobiology of Disease, Mar 18, 2009

Abstract 8987: Prostacyclin Reduction Upregulates Tissue Factor and Predisposes COX-2 Knockout Mice to Thrombosis

Circulation, Nov 22, 2011

Cancer Research, Jan 15, 2005

Cyclooxygenase-2 (COX-2) is a promising pharmacologic target for preventing aerodigestive maligna... more Cyclooxygenase-2 (COX-2) is a promising pharmacologic target for preventing aerodigestive malignancies. In this study, we investigated the effects of tobacco smoke on the expression of COX-2 in oral mucosa. An~4-fold increase in amount of COX-2 mRNA was observed in the oral mucosa of active smokers versus never smokers. Thus, a series of in vitro studies were carried out to elucidate the mechanism by which tobacco smoke induced COX-2. Treatment of a nontumorigenic oral epithelial cell line (MSK-Leuk1) with a saline extract of tobacco smoke (TS) stimulated COX-2 transcription, resulting in increased amounts of COX-2 mRNA, COX-2 protein, and prostaglandin E 2 (PGE 2 ) synthesis. Exposure of cells to TS also caused an increase in epidermal growth factor receptor (EGFR) tyrosine kinase activity. Both an inhibitor of EGFR tyrosine kinase activity and a neutralizing anti-EGFR antibody blocked TS-mediated induction of COX-2. To define the mechanism by which TS activated EGFR, the release of amphiregulin and transforming growth factor a, two ligands of the EGFR, was measured. Exposure to TS caused a rapid increase in the release of both ligands. TS also markedly induced the expression of mRNAs for amphiregulin and transforming growth factor a. Importantly, increased expression of both ligands was also detected in the oral mucosa of active smokers. Taken together, these results suggest that activation of EGFR signaling contributes to the elevated levels of COX-2 found in the oral mucosa of smokers. Moreover, these findings strengthen the rationale for determining whether inhibitors of COX-2 or EGFR tyrosine kinase activity can reduce the risk of tobacco smoke-related malignancies of the aerodigestive tract. (Cancer Res 2005; 65(2): 664-70) Requests for reprints: Andrew J.

Blood, May 1, 2003

6. Hagelberg C, Allan D. Restricted diffusion of integral membrane proteins and polyphosphoinosit... more 6. Hagelberg C, Allan D. Restricted diffusion of integral membrane proteins and polyphosphoinositides leads to their depletion in microvesicles released from human erythrocytes. Biochem J. 1990;271:831-834. 7. Allan D, Thomas P, Limbrick AR. The isolation and characterization of 60 nm vesicles ('nanovesicles') produced during ionophore A23187-induced budding of human erythrocytes. Biochem J. 1980;188:881-887. Acquired factor VIII (FVIII) inhibitors can cause life-threatening bleeding. Rapid restoration of coagulation is vital. Therapeutic approaches include factor substitution, 1,2 immunosuppression (eg, steroids, cyclophosphamide 3 ), and plasmapheresis. 4 A novel treatment option is rituximab, a chimeric monoclonal antibody targeting the CD20 antigen and blocking proliferation of normal B cells. Recently, Wiestner et al reported on the reduction of acquired FVIII inhibitors in 4 patients by an immunosuppressive regimen including rituximab. 6 Patients presented with FVIII activity (FVIIIc) ranging from less than 1% to 4% (normal range, 70%-200%) and inhibitor titers ranging from 5 to 60 Bethesda units (BU). In 3 patients, FVIIIc normalized after the first of 1 to 4 treatment courses. The inhibitor became undetectable within 3 to 12 weeks. Plasmaphereses were not necessary.

Blood, Jul 1, 1994

To examine potential mechanisms by which hematopoiesis may be regulated by endothelial cells with... more To examine potential mechanisms by which hematopoiesis may be regulated by endothelial cells within the bone marrow (BM) microenvironment, we have devised a technique for the in vitro study of the interaction of human BM microvascular endothelial cells (BMEC) with hematopoietic cells. Microvessels isolated by collagenase digestion of spicules obtained from filtered B M aspirate were plated on gelatincoated plastic dishes, and colonies of endothelial cells grown from microvessel explants were further purified by Ulex europaeus lectin affinity separation. BMEC monolayers isolated by this technique grew in typical cobblestone fashion, stained positively with antibody to factor Vllllvon Willebrand factor, and incorporated acetylated LDL. Immunohistochemical studies showed that B M microvessels and BMEC monolayers express 0 3 4 , PECAM, and thrombospondin. In-HE BONE MARROW (BM) microenvironment is a complex, three-dimensional structure where hematopoietic elements proliferate, differentiate, mature, and ultimately migrate into the circulation. Stromal cells, which form the backbone of the BM microenvironment, consist of fibroblasts, endothelial cells, adipocytes, osteoclasts, and monocytes. They secrete cytokines, produce extracellular matrix, and mediate direct cellular contact that regulates hematopoiesis. The fibroblasts of the BM adventitia are composed of adventitial reticular cells,' perisinusoidal adventitial cell, periarterial adventitial cells, and intersinusoidal reticular cells.' Most studies on stromal regulation of hematopoiesis derive from investigations of BM fibroblasts. However, little is known about the role of BM-derived microvascular endothelial cells (BMEC) in the regulation of hematopoiesis. The anatomic location of BM microvascular endothelium suggests that it may serve as a gatekeeper regulating the passage of cells between the marrow and the cir~ulation,"~ but its role in regulating the trafficking and development of T ACKNOWLEDGMENT We are grateful to D r Jim Young and Janice Godwin, MT, for providing samples and support of this project.

Aging favors arteriosclerosis through dysregulation of growth factors for smooth muscle cell prolife

Potentially Reduced Exposure Cigarettes Accelerate Atherosclerosis: Evidence for the Role of Nicotine

Cardiovasc Toxicol, 2007

The tobacco industry markets potentially reduced exposure products (PREPs) as less harmful or add... more The tobacco industry markets potentially reduced exposure products (PREPs) as less harmful or addictive alternatives to conventional cigarettes. This study compared the effects of mainstream smoke from Quest, Eclipse, and 2R4F reference cigarettes on the development of atherosclerosis in apolipoprotein E-deficient (apoE -/-) mice. Mice were exposed to smoke from four cigarette types for 12 weeks beginning at age of 12 weeks, and in a separate study for 8 weeks, beginning at age of 8 weeks. In both studies, mice exposed to smoke from high-nicotine, high-tar Quest 1, and 2R4F cigarettes developed greater areas of lipid-rich aortic lesions than did non-smoking controls. Exposure to smoke from the lower-nicotine products, Eclipse, and Quest 3, was associated with smaller lesion areas, but animals exposed to smoke from all of the tested types of cigarette had larger lesions than did control animals not exposed to smoke. Urinary levels of isoprostane F2 alpha VI, increased proportionally to cigarette nicotine yield, whereas induction of pulmonary cytochrome P4501A1 was proportional to tar yield. Lesion area was associated with both nicotine and tar yields, although in multiple regression analysis only nicotine was a significant predictor of lesion area. Smoke exposure did not alter systolic blood pressure (SBP), heart rate (HR), blood cholesterol, or leukocyte count. Taken together, these observations suggest that smoking may accelerate atherosclerosis by increasing oxidative stress mediated at least in part via the actions of nicotine.

A rapid fluorometric DNA assay for the measurement of cell density and proliferation in vitro

In Vitro Cellular Developmental Biology Plant, Feb 29, 1988

Many research efforts require the accurate determination of cell density in vitro. However, physi... more Many research efforts require the accurate determination of cell density in vitro. However, physical cell counting is inaccurate, time-intensive and requires removal of the cells from their growth environment, thereby introducing a host of potential artifacts. The current studies document a very simple method of determining cell density in microtiter wells via DNA-enhanced fluorescence. Fixed cells are stained with the A-T intercalating DNA stains DAPI or Hoechst 33342 and then fluorescence is quantified in a plate fluorometer. Fluorescence is shown to be linearly related to cell density as determined by two physical counting methods. The validity of the method is established in determining serum-stimulated growth of smooth muscle cells and in mitogen-induced growth of endothelial cells. The fixed cells can be stored for prolonged periods, thus allowing time-course proliferation assays without interassay variations. The fixed cells are also suitable for determinations of antigens of interest by ELISA. This method is potentially valuable in many in vitro systems where the quantification of cell density and proliferation is necessary.

Effects of Transforming Growth Factor-β1 on Human Vocal Fold Fibroblasts

The Annals of Otology Rhinology Laryngology, 2009

Objectives: We studied the effect of transforming growth factor (TGF)-β on immortalized human voc... more Objectives: We studied the effect of transforming growth factor (TGF)-β on immortalized human vocal fold fibroblasts. Methods: Normal human vocal fold fibroblasts were subjected to sequential lentiviral transduction with genes for human telomerase (hTERT) and SV40 large T ...

Oral Oncology Supplement, 2005

A total of 41 paraffin-embedded tissue samples with histological diagnoses of normal oral mucosa ... more A total of 41 paraffin-embedded tissue samples with histological diagnoses of normal oral mucosa (n=5), epithelial hyperplasia (n=5), mild epithelial dysplasia (n=9), moderate and severe epithelial dysplasia (n=8) and oral squamous cell carcinoma (OSCC, n=14) were analysed for hTERT protein using IHC. TRAP assays were performed on cultured cells namely fibroblasts (lmmortahsed w:th hTERT) and keratinocytes (O8C-20, O8CC cell line, HSRRB, Japan) as pos:hve controls. The hTERT-labellmg index was determined following previously pubhshed criteria. Results: All the tissues showed Grades 3 & 4 staining (>10% posahve staining nuclei) m basal and parabasal cell layers which are the normal proliferative progemtor compartments where hTERT expression as considered normal, hTERT expression in the superficial layers of the epitheha was elevated in moderate and severe dysplasla (75%) with Grades 3 & 4 staining, reduced m mild dysplasla (33.3%) and with no expression m ep:thehal hyperplas:a and normal oral nmcosa, hTERT protein expression correlated with pos:t:ve telomerase activity m the cultured cells. Conclusion: There seems to be an up-regulation of hTERT expression with the progression of oral cancer and therefore indicates the feas:blhty of IHC detection of hTERT protein as a potentml prognoshc marker m oral carcinogenesis.

Cancer Research, Jan 10, 1996

Cancers form more prostaglandins than the normal tissues from which they arise. Cyclooxygenase-2 ... more Cancers form more prostaglandins than the normal tissues from which they arise. Cyclooxygenase-2 (prostaglandin H synthase-2, PGHS-2, EC 1.14.99.1), an enzyme that catalyzes the formation of prostaglandins from arachidonic acid, is inducible in epithelial cells. We investigated whether transformation of mammary cells was associated with up-regulation of Cox-2 as a basis for increased production of prostaglandin !'._, (PGE2) by these cells. This hypothesis was tested in two pairs of mammary cell lines between which the mode of transformation (viral versus oncogene) dif fered. Virali) transformed Rlll/Prl cells, which are highly tumorigenic in mice, produced markedly increased amounts of PGE, compared to virally initiated Kill/Ml, cells, a weakly tumorigenic strain. Cox-2 mRNA and protein were increased concomitantly in RHI/Prl cells. Similarly, Rasinduced transformation of C57/MG cells resulted in increased levels of Cox-2 mRNA and protein and increased production of PGE2. Nuclear imi-oil's revealed increased rates of Cox-2 transcription in the virally transformed and oncogene-transformed cell lines. Transient transfection experiments demonstrated that the oncogenes src and ras up-regulated Cox-2 promoter activity. Src-mediated up-regulation of Cox-2 promoter activity was suppressed by dominant negative ras. Our data indicate that cellular transformation is associated with enhanced transcription of Cox-2 and increased production of PGE2.

Journal of Biological Chemistry, Oct 25, 1978

Collagen and glomerular membrane effects on platelets

Transactions - American Society for Artificial Internal Organs

Antiplatelet agents in stroke prevention: Combination therapy: Present and future

Cerebrovascular Diseases

Platelets contribute to arterial thrombosis by multiple mechanisms that promote blood clotting, f... more Platelets contribute to arterial thrombosis by multiple mechanisms that promote blood clotting, favor vasoconstriction, activate the procoagulant capacity of endothelium, and stimulate inflammation. These activities are augmented by turbulent blood flow. Classic antiplatelet therapy with aspirin to prevent occlusive stroke offers significant clinical benefit (20-25% risk reduction), yet is less effective than in prevention of coronary artery occlusion (up to 50% risk reduction of myocardial infarction in unstable angina). Since aspirin's antiplatelet effects are limited to blocking a single metabolic pathway - namely inhibition of thromboxane A(2) formation -, and aspirin fails to alter platelet adhesion, other antiplatelet agents that target ADP receptors, platelet surface glycoproteins (such as the GPIIb/IIIa complex), or platelet-dependent thrombin generation offer additional clinical benefits by blocking additional separate pathways or the final common pathway of platelet activation. Combinations of antiplatelet agents, such as aspirin/dipyridamole, aspirin/clopidogrel, or aspirin/GPIIb/IIIa inhibitors, have recently been tested for improved efficacy in clinical trials. Soluble recombinant CD39, an ecto-ADPase, protects against stroke in animal models by metabolizing released ADP/ATP to antiplatelet derivatives. In general, combinations of antiplatelet agents promise greater efficacy than single drugs in preventing stroke, since interactions among different antiplatelet mechanisms can be synergistic. However, such combinations may also increase the risk of bleeding, so that precise understanding of risk/benefit ratios that address the possibility of intracranial as well as gastrointestinal bleeding will require careful monitoring in large clinical trials of patients at risk of stroke, with particular attention to the elderly.

2 Macroglobulin/Transforming Growth Factor?1 Interactions.: Modulation by Heparin-like Molecules and Effects on Vascular Smooth Muscle Cells a

Alpha 2-macroglobulin/transforming growth factor-beta 1 interactions. Modulation by heparin-like molecules and effects on vascular smooth muscle cells

Annals of the New York Academy of Sciences

FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Jan 11, 2015

Cigarette smoke (CS) increases the incidence of atherothrombosis, the release of prostaglandin (P... more Cigarette smoke (CS) increases the incidence of atherothrombosis, the release of prostaglandin (PG) E2, and the amount of tissue factor (TF). The link between PGE2 and TF, and the impact of this interaction on CS-induced thrombosis, is unknown. Plasma from active smokers (AS) showed higher concentration of PGE2, TF total antigen and microparticle-associated TF (MP-TF) activity compared with never smokers (NS). Similar results were obtained in mice and in endothelial cells (MCEC) after treatment with aqueous CS extracts (CSEs) plus IL-1β [CSE (6.4 puffs/L)/IL-1β (2 μg/L)]. A significant correlation between PGE2 and TF total antigen or MP-TF activity were observed in both human and mouse plasma or tissue. Inhibition of PGE synthase (PGES) reduced TF in vivo and in vitro and prevented the arterial thrombosis induced by CSE/IL-1β. Only PG E receptor (EP) 1 receptor antagonists (SC51089:IC50 ∼ 1 μM, AH6809:IC50 ∼ 7.5 μM) restored the normal TF and sirtuin 1 (SIRT1) levels in MCEC before ...

Regulatory Mechanisms in Prostacyclin-Blood Vessel Interactions

Prostaglandins, Leukotrienes, and Lipoxins, 1985

Synthesis of Prostacyclin by Cultured Endothelial Cells

Pathobiology of the Endothelial Cell, 1982