PubMed Health⌕ Search

Biomedical subjects

Scott T Hollenbeck

Publications and source records attributed to Scott T Hollenbeck.

9 recordsLinked to original sources
PubMed2004

Type I collagen synergistically enhances PDGF-induced smooth muscle cell proliferation through pp60src-dependent crosstalk between the alpha2beta1 integrin and PDGFbeta receptor.

Smooth muscle cells (SMCs) are exposed to both platelet-derived growth factor (PDGF) and type I collagen (CNI) at the time of arterial injury. In these studies we explore the individual and combined effects of these agonists on human saphenous vein SMC proliferation. PDGF-BB produced a 5.5-fold increase in SMC DNA synthesis whereas CNI stimulated DNA synthesis to a much lesser extent (1.6-fold increase). Alternatively, we observed an 8.3-fold increase in DNA synthesis when SMCs were co-incubated with CNI and PDGF-BB. Furthermore, stimulation of SMCs with PDGF-BB produced a significant increase in ERK-2 activity whereas CNI alone had no effect. Co-incubation of SMCs with PDGF-BB and CNI resulted in ERK-2 activity that was markedly greater than that produced by PDGF-BB alone. In a similar fashion, PDGF-BB induced phosphorylation of the PDGF receptor beta (PDGFRbeta) and CNI did not, whereas concurrent agonist stimulation produced a synergistic increase in receptor activity. Blocking antibodies to the alpha2 and beta1 subunits eliminated this synergistic interaction, implicating the alpha2beta1 integrin as the mediator of this effect. Immunoprecipitation of the alpha2beta1 integrin in unstimulated SMCs followed by immunoblotting for the PDGFRbeta as well as Src family members, pp60(src), Fyn, Lyn, and Yes demonstrated coassociation of alpha2beta1 and the PDGFRbeta as well as pp60(src). Incubation of cells with CNI and/or PDGF-BB did not change the degree of association. Finally, inhibition of Src activity with SU6656 eliminated the synergistic effect of CNI on PDGF-induced PDGFRbeta phosphorylation suggesting an important role for pp60(src) in the observed receptor crosstalk. Together, these data demonstrate that CNI synergistically enhances PDGF-induced SMC proliferation through Src-dependent crosstalk between the alpha2beta1 integrin and the PDGFRbeta.

Animals↗
PubMed2004

Two-year follow-up of areola-sparing mastectomy with immediate reconstruction.

OBJECTIVE: Areola-sparing mastectomy (ASM) is defined as resecting the nipple and any existing surgical biopsy scar, removing all breast parenchyma, and leaving a natural envelope of skin (including the areola), which improves the aesthetic result of immediate reconstruction. We previously demonstrated a <1% incidence of malignant involvement of the areola in a retrospective mastectomy series. Subsequently, we performed ASM on selected patients undergoing mastectomy. We report here our results from an ongoing study of ASM at our institution. METHODS: During a 20-month period, 17 ASMs with immediate reconstruction were performed on 12 patients. Patients were followed-up prospectively by the surgical oncologist for complications and recurrence. RESULTS: ASM was performed for breast cancer prophylaxis (n = 10), ductal carcinoma in situ (DCIS) (n = 4), and <2-cm peripheral infiltrating carcinoma (n = 3). The mean patient age was 47.7 years (range 37 to 61). Thirteen patients were reconstructed with tissue expanders and 4 with pedicle transverse rectus abdominus myocutaneous flaps. Ten patients underwent sentinel lymph node biopsy. None of the ten patients showed sentinel lymph node metastasis. Two patients with DCIS and microinvasion underwent subareolar touch-prep cytology, both of which were negative for malignancy. All mastectomy specimens had negative histologic margins. No patient received chemotherapy or radiation therapy. One postoperative consisted of a localized wound infection that resolved with oral antibiotics. At a median follow-up of 24 months (range 11 to 28), there were no instances of local or distant recurrence. CONCLUSIONS: Overall, we found that ASM with immediate reconstruction provides excellent aesthetic results with infrequent complications. Furthermore, in this small series we showed no recurrence at 2 years. We continue to offer ASM for selected patients including those desiring surgical breast cancer prophylaxis as well as those with DCIS or small peripheral infiltrating ductal carcinoma.

Adult↗
PubMed2004

Stem cell factor and c-kit are expressed by and may affect vascular SMCs through an autocrine pathway.

INTRODUCTION: Stem cell factor (SCF) is a membrane-bound and soluble growth factor that activates the c-kit tyrosine kinase receptor. Given the similarities between c-kit and platelet-derived growth factor (PDGF) receptors, we hypothesized that similar to PDGF, SCF/c-kit signaling may play a role in smooth muscle cell (SMC) function and thus the development of intimal hyperplasia. MATERIALS AND METHODS: Human saphenous vein SMCs were harvested from veins procured at the time of bypass grafting. Carotid arteries from rats that were balloon injured (n = 12) at variable time points were compared to sham-operated controls (n = 3). Expression of SCF and c-kit was measured by immunohistochemistry (IHC) and Western blotting. RESULTS: Western blotting revealed that human SMCs express membrane-bound SCF. In separate experiments, we found that this growth factor undergoes proteolytic cleavage to its soluble form following exposure to matrix metalloproteinase-9 (MMP-9), a ubiquitous MMP released at the time of arterial injury. We next evaluated in human SMCs, expression of the SCF receptor, c-kit. Western blotting of human SMC lysates revealed minor but consistent expression of c-kit. IHC demonstrated c-kit expression to be localized to the media. To determine if c-kit is up-regulated during the development of intimal hyperplasia, we evaluated expression of this receptor in a rat carotid balloon injury model. Quantification of IHC staining on injured vessels revealed that c-kit expression within the media was significantly increased at 3, 7, 14, and 28 days following injury (28.1, 30.8, 16, and 10.4% increase over sham controls, respectively, P < 0.05). Furthermore, c-kit expression was prominent within the neointima and maximal at 7 days (53.4 +/- 7.8% of area c-kit positive). CONCLUSION: Human vascular SMCs express the growth factor SCF and its receptor, c-kit. SCF is released from its membrane-bound form via MMP-9. This finding and the dramatic increase in c-kit expression observed in the rat carotid artery after balloon injury suggests SCF/c-kit signaling may affect SMC function via an autocrine pathway.

Animals↗
PubMed2004

Intracellular calcium transients are necessary for platelet-derived growth factor but not extracellular matrix protein-induced vascular smooth muscle cell migration.

PURPOSE: Vascular smooth muscle cell (SMC) migration is a critical component of the hyperplastic response that leads to recurrent stenosis after interventions to treat arterial occlusive disease. We investigated the relationship between intracellular calcium ([Ca(2+)](i)) and migration of vascular SMCs in response to platelet-derived growth factor (PDGF) and extracellular matrix (ECM) proteins. METHODS: Human saphenous vein SMCs were used for all experiments. SMC migration in response to agonists was measured with a microchemotaxis assay. A standard fluorimetric assay was used to assess changes in [Ca(2+)](i) in response to the various combinations of growth factors and ECM proteins. RESULTS: The calcium ionophore A23187 produced a rapid rise in [Ca(2+)](i) and a corresponding 60% increase in SMC migration, whereas chelation of [Ca(2+)](i) with BAPTA (1,2-bis [aminophenoxy] ethane-N,N,N',N'-tetraacetic acid) produced a fivefold decrease in PDGF-induced chemotaxis, suggesting that [Ca(2+)](i) is both sufficient and necessary for SMC migration. Stimulation of SMCs with PDGF produced an early peak followed by a late plateau in [Ca(2+)](i). To establish a relationship between temporal fluctuations in [Ca(2+)](i) and SMC migration, SMCs were pretreated with caffeine and ryanadine, which eliminated the initial peak but not the late plateau in [Ca(2+)](i), and had no effect on chemotaxis in response to PDGF. Incubation of SMCs with nickel chloride eliminated the late plateau, but had no effect on the initial peak in [Ca(2+)](i), and reduced PDGF-stimulated migration by fivefold. We then evaluated the role of calcium in SMC migration induced by ECM proteins such as laminin, fibronectin, and collagen types I and IV. All four matrix proteins stimulated SMC migration, but none produced an elevation in [Ca(2+)](i). Moreover, preincubation of SMCs with caffeine and ryanadine or nickel chloride had no effect on ECM protein-induced chemotaxis. CONCLUSION: [Ca(2+)](i) transients are necessary for PDGF but not ECM protein-induced SMC chemotaxis. Moreover, the ability of PDGF to stimulate vascular SMC migration appears dependent on influx of extracellular calcium through membrane channels. CLINICAL RELEVANCE: Recurrent stenosis after angioplasty or surgical bypass remains a significant challenge in treating vascular occlusive disease. In addition to growth factors, extracellular matrix (ECM) proteins may be potent agonists of this process. In this study we show that the influx of extracellular calcium is an important mechanism for platelet-derived growth factor-induced smooth muscle cell migration but not ECM-induced migration. Of note, in clinical trials calcium channel blockers failed to inhibit recurrent stenosis. Our data provide mechanistic insight to help explain this negative outcome in that therapies designed to inhibit restenosis depend on the effects of both growth factors and ECM proteins.

Calcimycin↗
PubMed2003

Surgical treatment and outcomes of patients with primary inferior vena cava leiomyosarcoma.

BACKGROUND: The inferior vena cava (IVC) is a rare site for primary soft tissue sarcoma. There are limited data in the literature regarding surgical management of the IVC and longterm survival of these patients. STUDY DESIGN: From 1982 to 2002, a total of 25 patients with primary IVC leiomyosarcoma was treated as inpatients and followed in a prospective database at Memorial Sloan-Kettering. Presenting symptoms, tumor characteristics, operative management, postoperative morbidity, and disease-specific survival were assessed for each patient. RESULTS: The 25 patients with primary IVC leiomyosarcoma accounted for 0.5% of all adult patients with soft tissue sarcoma treated during this time. The median patient age was 56 years (range 41 to 79 years). The three most common presenting symptoms were abdominal pain (52%), distention (20%), and deep venous thrombosis (12%). Of the patients, 21 (84%) underwent complete resection of the tumor. The IVC was managed in one of three ways: ligation (n = 11), primary/patch repair (n = 8), and expanded polytetrafluoroethylene tube grafting (n = 2). Among patients undergoing IVC ligation and primary/patch repair (n = 19), 11% had severe postoperative edema and none had worsening renal function. Local recurrence occurred in 33% of patients and distant recurrence occurred in 48% of patients. Patients undergoing complete resection had 3-year and 5-year disease-specific survival rates of 76% and 33%, respectively. There were no 3-year survivors among patients with incomplete resections. CONCLUSIONS: Complete resection of primary IVC leiomyosarcomas is feasible and associated with improved survival. The IVC can be managed by primary repair or ligation with a low risk of severe postoperative edema.

Female↗
PubMed2003

Areola-sparing mastectomy with immediate breast reconstruction.

Skin-sparing mastectomy with immediate breast reconstruction is a proved option for patients with early-stage breast cancer requiring mastectomy. Based on the authors' recent pathologic analysis of mastectomy specimens showing less than 1% malignant involvement of the areola, they have begun to perform areola-sparing mastectomies (ASMs) on a select group of patients. They report their results from an ongoing study of ASM at their institution. During a 20-month period, 17 ASMs with immediate reconstruction were performed on 12 patients. Mastectomy was performed for breast cancer prophylaxis (n = 10), ductal carcinoma in situ (n = 4), and less than 2 cm of peripheral infiltrating carcinoma (n = 3). The most frequent incision performed was intraareola (n = 13). Thirteen patients were reconstructed with tissue expanders and 4 with pedicled transverse rectus abdominis musculocutaneous flaps. There was 1 postoperative complication, which consisted of a localized wound infection. Overall the authors found that ASM with immediate reconstruction provides excellent aesthetic results with infrequent complications.

Adult↗
PubMed2002

Sentinel lymph node biopsy results in less postoperative morbidity compared with axillary lymph node dissection for breast cancer.

BACKGROUND: This study was designed to compare the postoperative morbidity and socioeconomic impact of sentinel lymph node biopsy (SLNB) with axillary lymph node dissection (ALND) in patients with early stage breast cancer. METHODS: A prospective, nonrandomized, controlled study was designed to include patients who underwent breast conservation surgery and SLNB +/- ALND. Group A consisted of patients who had a negative SLNB and did not go on to completion ALND. Group B consisted of patients who underwent a SLNB followed by a completion ALND because either (1) their sentinel node contained cancer or (2) they were within the validation phase of our institution's sentinel lymph node protocol. Patients were evaluated with a questionnaire and underwent a standardized physical examination to determine arm circumference. RESULTS: Data were obtained from 96 patients with a mean follow-up period of 15 months (range 8 to 29). Significant differences were seen in subjective measurements of arm complaints and arm numbness (P <0.001), with fewer complaints reported in group A. The difference in mid-bicep and antecubital fossa circumferences was significant when comparing the ratio of the procedure arm with the nonprocedure arm and when subtracting the nonprocedure arm from the procedure arm (P <0.003 and P <0.016, respectively) in favor of group A. Axillary surgery was performed as an outpatient procedure in 88% of group A patients, compared with 15% in group B (P <0.001). Furthermore, 71% of group A patients returned to "normal activity" in less than 4 days, in comparison with 7% of group B (P <0.001). CONCLUSIONS: SLNB results in less postoperative morbidity in terms of subjective arm complaints and mid-arm swelling. Expeditious return to work or normal activity after SLNB has potentially significant socioeconomic consequences.

Aged↗