Biomedical subjects

K Rosen

Publications and source records attributed to K Rosen.

At least 19 recordsLinked to original sources

PubMed2001

Transforming growth factor-alpha prevents detachment-induced inhibition of c-Src kinase activity, Bcl-XL down-regulation, and apoptosis of intestinal epithelial cells.

Detachment of epithelial cells from the extracellular matrix (ECM) results in apoptosis, a phenomenon often referred to as anoikis. Acquisition of anoikis resistance is now thought to be a prerequisite for the progression of carcinomas. Colorectal cancer cells frequently secrete epidermal growth factor receptor (EGFR) ligands, which are known to have anti-apoptotic activity. However, whether these ligands have the ability to inhibit anoikis of intestinal epithelial cells is unclear, since at least in some cell types efficient EGFR signaling requires cell-ECM adhesion. Here we report that transforming growth factor-alpha (TGF-alpha), an EGFR ligand that is frequently secreted by colorectal cancer cells, strongly inhibits anoikis of the non-malignant rat intestinal epithelial cell lines, IEC-18 and RIE-1. TGF-alpha exerts its anti-anoikis effect by preventing detachment-induced inhibition of c-Src kinase activity. We also show that Fas activation, a molecular event known to play a critical role in anoikis, is not suppressed by TGF-alpha. On the other hand, this growth factor strongly inhibits the detachment-induced down-regulation of Bcl-X(L), another change that is involved in the induction of anoikis. We further demonstrate that this inhibition occurs in a c-Src-dependent manner. We conclude that TGF-alpha has the ability to suppress anoikis of intestinal epithelial cells, at least in part, by reverting the loss of c-Src activity and Bcl-X(L) expression induced by detachment from the ECM.

Animals↗

PubMed2001

Induction of anoikis and suppression of human ovarian tumor growth in vivo by down-regulation of Bcl-X(L).

Normal or immortal epithelial cells are sensitive to a form of apoptosis, commonly referred to as anoikis, which is induced by detachment from the extracellular matrix (ECM). In contrast, development of carcinomas is associated with acquisition of cellular resistance to anoikis. However, whether human cancer cells deprived of anoikis resistance necessarily display reduced tumorigenic properties in vivo is unknown. We decided to address this question using human ovarian carcinoma cells as a model. Bcl-X(L), an apoptotic factor considered to play an important role in (resistance to) anoikis, is overexpressed in ovarian cancer, and represents an unfavorable prognostic indicator for this type of human malignancy. We therefore evaluated whether Bcl-X(L) can be used as a tool to manipulate anoikis resistance and tumorigenicity of ovarian cancer cells. We show here that when nonmalignant ovarian epithelial cells are detached from the ECM, down-regulation of Bcl-X(L) and apoptotic cell death are observed, although these events do not occur in ovarian carcinoma cells. Moreover, enforced down-regulation of Bcl-X(L) by transfection with antisense cDNA in the anoikis-resistant and highly tumorigenic HEY ovarian carcinoma cell line had no impact on the viability of these cells under adherent conditions but caused significant apoptosis in response to detachment from the ECM. This change was associated with a strong inhibition of tumorigenicity of the Bcl-X(L)-deficient HEY cells in nude mice, both s.c. and in the peritoneal cavity. These results suggest a critical role for Bcl-X(L) in the maintenance of anoikis resistance in ovarian cancer cells. They also serve to establish a functional linkage between this property and the ability of human cancer cells to grow aggressively in vivo. Consequently, targeting molecular mechanisms responsible for anoikis resistance may serve as a potentially effective therapeutic strategy for the treatment of such human malignancies as ovarian cancer.

Anoikis↗

PubMed2001

Bcl-2 expression in F-MuLV-induced erythroleukemias: a role for the anti-apoptotic action of Bcl-2 during tumor progression.

Erythroleukemias induced by various strains of Friend virus are multistage malignancies that result from the accumulation of genetic mutations, including the activation of proto-oncogenes and the inactivation of tumor suppressor genes. In this study, we demonstrate that Bcl-2 expression is activated in the majority of F-MuLV-induced erythroleukemia cell lines. In contrast, Bcl-2 was not expressed in any of the FV-P-induced erythroleukemia cell lines and protein levels were low or negligible in FV-A-induced erythroleukemia cell lines examined. In vivo, Bcl-2 expression levels gradually increased in F-MuLV-induced erythroleukemic cells prior to adaptation to culture. High expression of Bcl-2 in F-MuLV-induced erythroleukemic cells was shown to proceed the emergence of p53 mutation suggesting that Bcl-2 expression may delay p53 mutation in the leukemic cells. This is further supported by the demonstration that the majority of F-MuLV-induced erythroleukemia cell lines established from primary tumors induced in p53 mutant mice express low to negligible levels of Bcl-2. We have shown that the high levels of Bcl-2 expression in FV-P-induced erythroleukemic cells inhibited apoptosis induced by etoposide, low serum and p53 expression. Similarly, ectopic Bcl-2 expression within these cells also provided protection from apoptosis induced by etoposide and growth in low serum. These results suggest that the anti-apoptotic action of Bcl-2 may confer a selective in vivo and in vitro growth advantage to F-MuLV-induced erythroleukemic cells, which is not shared by FV-P/FV-A-induced erythroleukemic cells. The observed induction of Bcl-2 expression in vivo constitutes a novel but late oncogenic event associated with the progression of F-MuLV-induced erythroleukemias.

Animals↗

PubMed2001

Training of nurse practitioners and physician assistants to perform screening flexible sigmoidoscopy.

PURPOSE: To describe the colorectal cancer-screening program at Harvard Vanguard Medical Associates, a large multispecialty medical group, in which nurse practitioners (NPs) and physician assistants (PAs) perform screening flexible sigmoidoscopies. DATA SOURCES: Scientific literature, consensus statements and guidelines, and the protocol utilized to train NPs and PAs to perform flexible sigmoidoscopy. Data from 9,500 screening procedures are presented. CONCLUSIONS: In comparison with gastroenterologists, trained NP and PA endoscopists perform screening flexible sigmoidoscopy with similar accuracy and safety but at lower cost. IMPLICATIONS FOR PRACTICE: Screening flexible sigmoidoscopy performed by NPs and PAs may increase the availability and lower the cost of flexible sigmoidoscopy for colorectal cancer screening.

Colorectal Neoplasms↗

PubMed2001

Acute care crisis simulation for jury education.

A major impediment to appropriate adjudication in medical malpractice cases is the large difference in knowledge and background of the expert witness compared to judges, other litigants and juries. Such disparities make it plausible for an expert witness to support an issue, even in defiance of common sense. The most basic understanding of the atmosphere and practices surrounding critical events and the routine procedures, techniques and equipment which are employed in critical situations is absent. (McAbee GN: Improper expert medical testimony: existing and proposed mechanisms of oversight. Journal of Legal Medicine 19: 257-272, 1998).

Education↗

PubMed2000

Activated Ras prevents downregulation of Bcl-X(L) triggered by detachment from the extracellular matrix. A mechanism of Ras-induced resistance to anoikis in intestinal epithelial cells.

Detachment of epithelial cells from the extracellular matrix (ECM) results in a form of apoptosis often referred to as anoikis. Transformation of intestinal epithelial cells by oncogenic ras leads to resistance to anoikis, and this resistance is required for the full manifestation of the malignant phenotype. Previously, we demonstrated that ras-induced inhibition of anoikis in intestinal epithelial cells results, in part, from the ras-induced constitutive downregulation of Bak, a pro-apoptotic member of the Bcl-2 family. Since exogenous Bak could only partially restore susceptibility to anoikis in the ras-transformed cells, the existence of at least another component of the apoptotic machinery mediating the effect of activated ras on anoikis was suggested. Indeed, here we show that, in nonmalignant rat and human intestinal epithelial cells, detachment from the ECM or disruption of the cytoskeleton results in a significant downregulation of the antiapoptotic effector Bcl-X(L), and that activated H- or K-ras oncogenes completely abrogate this downregulation. In addition, we found that enforced downregulation of Bcl-X(L) in the ras-transformed cells promotes anoikis and significantly inhibits tumorigenicity, indicating that disruption of the adhesion-dependent regulation of Bcl-X(L) is an essential part of the molecular changes associated with transformation by ras. While the ras-induced downregulation of Bak could be reversed by pharmacological inhibition of phosphatidylinositol 3 kinase (PI 3-kinase), the effect of ras on Bcl-X(L) was PI 3-kinase- and mitogen-activated protein kinase (MAP kinase)-independent. We conclude that ras-induced resistance to anoikis in intestinal epithelial cells is mediated by at least two distinct mechanisms: one that triggers downregulation of Bak and another that stabilizes Bcl-X(L) expression in the absence of the ECM.

Animals↗

PubMed1998

Downregulation of the pro-apoptotic protein Bak is required for the ras-induced transformation of intestinal epithelial cells.

Anoikis is a form of programmed cell death induced in normal epithelial cells by detachment from the extracellular matrix [1] [2] [3]. In epithelial cells of the intestine and other organs, activated rasinduces resistance to anoikis [3] [4], but the actual molecular effectors directly involved in the apoptotic machinery that execute or block anoikis have not yet been identified. Bak, a pro-apoptotic member of the Bcl-2 family, is downregulated in a high proportion of colorectal tumours [5]. In addition, Bak is an important regulator of apoptosis in normal intestinal epithelial cells [6] [7]. Here, we show that activated rasinduces the downregulation of Bak in rat and human intestinal epithelial cells. This ras-induced downregulation of Bak expression could be suppressed by an inhibitor of phosphatidylinositol (PI) 3-kinase, an enzyme already implicated in ras-induced resistance to anoikis [8]. Ectopic expression of Bak in ras-transformed rat intestinal epithelial IEC-18 cells inhibited ras-induced resistance to anoikis and significantly reduced their tumorigenicity. We conclude, therefore, that the ability of rasto downregulate Bak, and the consequent resistance to anoikis, are essential components of the transforming capacity of this oncogene in intestinal epithelial cells.

Animals↗

PubMed1998

Double-blind placebo-controlled study of long-term low-dose cyclosporin in the treatment of palmoplantar pustulosis.

We previously showed in a double-blind, placebo-controlled study that cyclosporin at a dose of 2.5 mg/kg per day is an effective treatment for palmoplantar pustulosis (PPP). In the present randomized, double-blind, placebo-controlled multicentre study we treated 58 PPP patients with placebo or cyclosporin at an initial dose of 1 mg/kg per day. Disease activity was calculated from the number of fresh pustules. Treatment success was defined as the number of fresh pustules not exceeding 50% of the patients' own baseline pustule number. In cases of treatment success the dose of the test medication was not increased and the treatment was kept blinded for a maximum of 12 months. Blinding was broken only on treatment failure of the initial test medication dose. The mean blinded treatment time was 5.1 months for the patients receiving cyclosporin and 2.1 months for placebo (P < 0.01). Treatment was kept blinded for 12 months for seven patients in the cyclosporin and two in the placebo group (P < 0.05). Patients whose treatment code was broken continued in an open dose-finding part of the study with dose adjustments of cyclosporin every second month. In cases of treatment failure the dose of cyclosporin was increased in steps of 1 mg/kg per day; in cases of treatment success the cyclosporin dose was decreased by 1 mg/kg per day. The minimum and maximum doses were 1 and 4 mg/kg per day, respectively. The mean effective dose during the dose-finding part was between 1.2 and 1.7 mg/kg per day. Two patients did not respond to the highest dose of 4 mg/kg per day. In two patients serum creatinine levels increased by > 30% of their own baseline. The other main adverse events were hypertension (seven patients) and hypertrichosis (six patients). After stopping cyclosporin treatment the mean number of fresh pustules showed a maximum after 2 weeks with a continuous decline after that. Twelve months after completing the treatment the mean number of pustules was reduced to 20.0 compared with 63.6 at baseline (P < 0.001); 11 patients were free from pustules and two of these were totally cleared. We conclude that cyclosporin at 1-2 mg/kg per day is an effective and well tolerated treatment for PPP in most patients.

Adolescent↗

PubMed1998

Use of dialectical behavior therapy in a partial hospital program for women with borderline personality disorder.

Dialectical behavior therapy, an outpatient psychosocial treatment for chronically suicidal women with borderline personality disorder, has been adapted for use in a partial hospital program for women. Patients attend the program for a minimum of five days of individual and group therapy, and full census is 12 women. About 65 percent of participants meet at least three criteria for borderline personality disorder, and most have suicidal and self-injurious behavior. Their comorbid diagnoses include trauma-related diagnoses and anxiety disorders, severe eating disorders, substance abuse, and depression. The partial hospital program is linked to an aftercare program offering six months of outpatient skills training based on dialectical behavior therapy. Both programs focus on teaching patients four skills: mindfulness (attention to one's experience), interpersonal effectiveness, emotional regulation, and distress tolerance. Two years of operation of the women's partial hospital program provides promising anecdotal evidence that dialectical behavioral therapy, an outpatient approach, can be effectively modified for partial hospital settings and a more diverse population.

Adult↗

PubMed1997

Mood disorders and menopause.

Studies of depressive symptoms in menopausal women indicate that menopause is not associated with increased rates of depression, although mild mood and anxiety symptoms may occur in the few years prior to menopause. Women with previous affective disorders that are cyclic or that are associated with reproductive events may be at increased risk for depression at menopause. Because women presenting to menopause clinics are more likely to have affective disorders, the efficacy of estrogen for enhancing mood is an important question. Although some researchers suggest that estrogens have proven mood-elevating and antidepressant properties, others caution that the psychologic benefits of HRT deserve more systematic study before conclusions can be made. It has been suggested that minor psychologic symptoms at menopause or psychologic symptoms accompanied by vasomotor symptoms warrant a trial of HRT before considering psychotropic medication. If the psychologic symptoms do not respond to HRT, are not accompanied by vasomotor symptoms, or are clinically severe, antidepressant medication should be considered first or in addition to HRT. The psychologic effects of progesterone and androgens are less extensively studied than those of estrogen, and further research is needed.

Androgens↗

PubMed1997

An affect-management group for women with posttraumatic stress disorder and histories of childhood sexual abuse.

Systematic research on effective treatment for survivors of childhood sexual abuse with posttraumatic stress disorder (PTSD) is virtually non-existent. The aim of the present study was to compare the effectiveness of an affect-management treatment (AM) group to a wait list control condition for female survivors of childhood sexual abuse with PTSD. Forty-eight female survivors of childhood sexual abuse with PTSD were randomly assigned to either a 15-week affect-management treatment group or to a wait list control condition. All subjects received individual psychotherapy and pharmacotherapy for the duration of the study, and for at least 1-month prior to the study. Controlling for pretreatment scores, subjects who completed the affect-management treatment group (n = 17) reported significantly fewer posttreatment symptoms of PTSD and dissociation than subjects in the wait list control condition (n = 16). Our findings suggest that an affect-management group treatment is beneficial as an adjunct to individual psychotherapy and pharmacotherapy for survivors of childhood sexual abuse with PTSD.

Affect↗

PubMed1996

Transfer of radiocaesium in sensitive agricultural environments after the Chernobyl fallout in Sweden. I. County of Gavleborg.

In 1986, 15 farms in the Chernobyl-affected area of the county of Gavleborg were investigated for radiocaesium transfer to grass and cereal grain. The soil surface layer (0-5 cm) in 1986 and the crop products in 1986-1994 were analysed. The aim was to study the impact of site and soil characteristics on sensitivity of 137Cs transfer in a long-term perspective. The transfer was much higher to grass than to cereal grain. For both crop products, however, there was a considerable annual reduction. For grass, and especially in the fallout year 1986, the transfer depended on interception capacity of the stubble and grass sward, on soil fertility and K-fertilization as well as on dilution by crop growth. In the following years, the annual reduction in transfer to grass was reduced by a factor of 2 to 100. Both ploughing through the surface layer and the mixing of radiocaesium with soil contributed to a decreased transfer of radiocaesium to crops. Thick stubble and grass sward on the grassland sites was the main reason for a lag period of high persistent transfer. The annual reduction was less on organic than on mineral soils. Measures to decrease the transfer to crops are discussed in relation to a new concept to evaluate the long-term behaviour of 137Cs in agricultural environments.

Agriculture↗

PubMed1996

Transfer of radiocaesium in sensitive agricultural environments after the Chernobyl fallout in Sweden. II. Marginal and semi-natural areas in the county of Jamtland.

In 1986, two Chernobyl-affected areas in the county of Jamtland, a mountain area and a river valley area, were investigated as to radiocaesium behaviour and transfer to grass. The soil surface layer (0-10 cm) in 1986 and 1989 and grass samples in 1986-1994 were analysed on 9 temporary grassland sites and 8 permanent pasture sites, described individually. The aim of this investigation was to study the sensitivity of different soil types and the influence of normal farming practices, ploughing and K-fertilization on the caesium transfer, in short- and long-term perspectives after the Chernobyl fallout. As expected, the transfer of 137Cs to grass was usually higher on permanent pasture than on temporary grassland. For both types of grassland, however, there was a considerable but different change of transfer with years. The transfer to grass in the year of the fallout, 1986, depended to a large extent on the thickness and interception capacity of the grass sward. In the following years, it also depended on the caesium-fixing capacity to clay minerals, on K-fertilization and the reverse process of K removal by plant uptake. Ploughing down the contaminated surface layer and the mixing of caesium with mineral soil were effective in reducing the transfer. During the period 1986-1994, the transfer was reduced considerably, showing a range of (0.1-177.3 m2/kg d.w.) x 10(-3). The calculated annual reduction halftime, Tar, increased with years after fallout. It is clearly shown that both countermeasures, ploughing and K-fertilization, are of potential value to decrease grass contamination. Where both measures were employed a reduction in the range of 78%-95% was recorded in the year after ploughing.

Agriculture↗

PubMed1996

Investigation into the relationship between personality traits and OCD: a replication employing a clinical population.

The relationship between obsessional personality traits and Obsessive Compulsive Disorder (OCD) has long been the subject of debate. Although clinicians have asserted for nearly a hundred years that such a relationship exists, empirical investigations have failed to provide consistent support; however, none of these empirical investigations have undertaken analyses that control for the effect of mood variables. Employing a non-clinical sample, Rosen and Tallis (1995) [Behaviour, Research and Therapy, 4, 445-450] found that when mood variables are taken into account, a unique relationship between obsessional traits and obsessional symptoms emerges. A replication was undertaken on a large group of individuals with OCD. After the effects of depression and anxiety were removed from a correlational analysis, obsessional symptoms were found to be significantly associated with obsessional and passive aggressive traits. Obsessive Compulsive Disorder was not associated with any other grouping of traits as specified in the DSM-III-R (Axis II) classification system.

Adolescent↗

PubMed1996

Rhythm and blues: the theory and treatment of seasonal affective disorder.

Seasonal affective disorder (SAD) is a depressive disorder which occurs during the winter and remits in the spring and summer. It differs from non-seasonal depression in its seasonal variation and in the presence of neurovegetative symptoms such as increased appetite and hypersomnia. This review is aimed at clinical practitioners and presents a detailed description of the syndrome before discussing the assessment of SAD and the current treatment of choice of phototherapy. Particular attention is paid to the impotant issue of differential diagnosis during assessment and the practicalities involved in the administration of light therapy during treatment.

Adult↗

PubMed1993

Localization of abnormal parathyroid glands of the mediastinum with MR imaging.

PURPOSE: To determine the sensitivity of magnetic resonance (MR) imaging for preoperative localization of abnormal parathyroid glands in the mediastinum and to compare the sensitivity of MR imaging with those of scintigraphy and ultrasonography (US). MATERIALS AND METHODS: The prospective sensitivity of MR imaging was compared with those of thallium-technetium scintigraphy and US in 25 patients in whom the abnormal gland was located in the mediastinum at surgery. RESULTS: MR imaging had a much higher sensitivity (22 of 25 cases [88%]) than did scintigraphy (11 of 19 cases [58%]) or US (three of 24 cases [12%]). The most common locations for the mediastinal gland were intrathymic (eight of 25 cases) and paraesophageal (six of 25 cases) sites. CONCLUSION: MR imaging should be considered the modality of choice for preoperative localization in this group of patients.

Adenoma↗

PubMed1992

Free fatty acids activate the hypothalamic-pituitary-adrenocortical axis in rats.

Intravenous administration of Intralipid 10% increases blood levels of essential free fatty acids. In rats and man, this is associated with an inhibition of GH secretion from the anterior pituitary. Because GH is lipolytic, the inhibition of its secretion may represent a negative feedback action of the fats on pituitary sensitivity to GH-releasing hormone. Since corticosterone, the final secretory product of the rat hypothalamic-pituitary-adrenocortical (HPA) axis, is also lipolytic, we tested the hypothesis that FFA would inhibit the HPA axis. Rats were cannulated via the jugular vein and infused with different doses of heparin-Intralipid 10% or heparin-saline; sequential blood samples were obtained and analyzed for ACTH, corticosterone, FFA, and glucose. Intralipid at 2.85 ml/kg increased plasma FFA to over 3 meq/liter by 15 min, with a return to baseline by 60-90 min. There was no effect of the infusion on plasma osmolarity or pH. At 60 min, plasma ACTH levels were significantly elevated to over 1500 pg/ml in Intralipid-infused rats, but were unchanged in saline controls. This dose of Intralipid increased corticosterone levels by nearly 20-fold at 120 min. At 180 min, corticosterone levels were still significantly greater than those in saline controls. Lower doses of Intralipid also significantly elevated both FFA and corticosterone levels, but by 180 min, levels of both were similar to those in controls. The effects of Intralipid on corticosterone secretion could not be attributed to the presence of glycerol in the suspension, since glycerol infusions had no significant effect on steroid levels compared to those in saline controls. In dexamethasone-pretreated rats, there was no significant rise in plasma corticosterone after either of two Intralipid doses, suggesting that the action of Intralipid was at a site within the HPA axis above the adrenal gland. This finding also suggested that the high steroid levels after Intralipid treatment were not due to interference with the corticosterone RIA. This was verified by the finding that there was no increase in plasma immunoreactive corticosterone after Intralipid infusion into adrenalectomized rats. Intralipid also caused an increase in plasma glucose levels that was first significant at 60 min and declined to baseline by 180 min, possibly reflecting increased autonomic activity or peripheral insensitivity to insulin. The results suggest that high circulating FFA levels activate, rather than inhibit, the HPA axis in rats. Since stress activates glucocorticoid production and increases FFA levels due to lipolysis, it is possible that FFA and the HPA axis constitute a previously unrecognized positive feedback loop.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenocorticotropic Hormone↗

PubMed1989

Interleukin 6 gene expression in normal and neoplastic B cells.

In the present report we demonstrate that the IL-6 gene is expressed in anti-Ig-activated and neoplastic B cells. After activation with anti-Ig, splenic B cells rapidly expressed IL-6 mRNA with peak expression occurring at 4 h and declining rapidly thereafter. In an attempt to exclude that the IL-6 mRNA expression was in non-B cells, T cells and monocytes were extensively depleted. In this highly purified B cell population, IL-6 mRNA was retained, whereas the expression of the T cell- and monocyte-restricted CD2 and CD14 genes was nearly undetectable. These results are consistent with the conclusion that activated B cells express IL-6 mRNA. Because we found IL-6 mRNA expression in normal activated B lymphocytes, we examined the expression of IL-6 mRNA in B cell neoplasms. 11 of 25 non-Hodgkins B cell lymphomas and 4 of 4 myelomas and plasma cell leukemias expressed IL-6 mRNA, whereas only 1 of 19 B cell leukemias was positive. To exclude that IL-6 mRNA expression in neoplastic B cells was the result of contaminating non-B cells, T cells and monocytes were extensively depleted from the tumor specimens. In the three IL-6-positive tumor samples depleted of T cells and monocytes, IL-6 mRNA expression was retained in all cases. These observations provide support for the idea that the IL-6 gene is expressed in normal activated and neoplastic B cells.

Adult↗