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Biomedical subjects

E Fridman

Publications and source records attributed to E Fridman.

16 recordsLinked to original sources
PubMed2006

The tumor suppressor neurofibromin confers sensitivity to apoptosis by Ras-dependent and Ras-independent pathways.

Neurofibromatosis type 1 (NF1) is characterized by a high incidence of benign and malignant tumors attributed to loss of function of Nf1, which encodes neurofibromin, a tumor suppressor with Ras-GAP activity. Neurofibromin deficiency typically causes chronic activation of Ras, considered the major contributor to manifestation of NF1. Resistance to radio- and chemotherapy are typical of NF1-associated tumors, but the underlying mechanism is unknown. Here, we investigated interrelationships between neurofibromin expression, Ras activity, and sensitivity to apoptosis. Neurofibromin-deficient mouse embryonic fibroblasts (MEFs) and human NF1 tumor cells were more resistant than neurofibromin-expressing cells to apoptosis. Moreover, Nf1(-/-), Nf1(+/-), and Nf1(+/+) MEFs exhibited gene-dosage-related resistance to apoptosis. Resistance of the Nf1-deficient cells was mediated by two survival pathways: a Ras-dependent pathway, and a Ras-independent pathway promoted by the lack of an NF1-GRD-independent proapoptotic action of neurofibromin. Therefore, besides its Ras-dependent growth inhibition, neurofibromin can exert tumor suppression via a proapoptotic effect.

Animals↗
PubMed2006

Expression of cyclooxygenase-2 in Wilms tumor: immunohistochemical study using tissue microarray methodology.

PURPOSE: Cyclooxygenase-2, a key enzyme in prostaglandin biosynthesis, has been shown to be involved in the modulation of cell growth, inflammation and apoptosis. Its involvement in the development of several human neoplasms has also been documented as well as the significant antitumor effects of its inhibitors. To our knowledge cyclooxygenase-2 expression in Wilms tumor has not been studied. MATERIALS AND METHODS: A tissue microarray multitissue block was prepared from 14 samples of Wilms tumor, each from a different patient, from xenografts derived thereof, and from normal human lung, liver, renal cortex and medulla tissues as controls. Each sample was represented in the block by 3 or 4 cores 0.6 mm in diameter. After serial slicing to 4 mum the histological slides were stained with hematoxylin and eosin, and immunostained with anti-cyclooxygenase-2 antibodies. Immunostaining was graded semiquantitatively according to the percent of stained cells with the cytoplasmic pattern of staining and according to staining intensity. RESULTS: All authentic human pathological samples except 1 anaplastic Wilms tumor as well as Wilms tumor xenografts expressed cyclooxygenase-2 in all Wilms tumor cellular components except the stroma. Expression was also observed in Wilms tumor lung metastasis and in tumors that overgrew chemotherapy. In comparison, cyclooxygenase-2 expression in normal kidneys was less prominent than in Wilms tumor samples and it was confined to the tubular epithelium in the cortex and medulla. CONCLUSIONS: Cyclooxygenase-2 expression is characteristic of all nonanaplastic Wilms tumors at all stages. It is similar to the previously observed pan-expression of ErbB2 receptors in these tumors. The potential therapeutic role of cyclooxygenase-2 inhibitors should be evaluated for Wilms tumor.

Animals↗
PubMed2004

ErbB2 is a tumor associated antigen and a suitable therapeutic target in Wilms tumor.

PURPOSE: The modern multimodality therapeutic approach to Wilms tumor (WT), combining surgery with radiotherapy and chemotherapy results in high cure rates even for high stage disease. However, the combination of radiotherapy and chemotherapy is associated with severe early and late complications such as neutropenic sepsis, growth retardation and secondary malignancies. Therefore, novel therapeutic strategies, which would decrease the treatment burden, are required. We studied the expression of erbB2 growth factor receptor in WT cells as well as its role as a tumor therapeutic target in an in vivo xenograft model of Wilms tumor. MATERIALS AND METHODS: Paraffin embedded pathological samples from 14 different WT cases as well as xenografts derived thereof were immunostained with anti-erbB2 monoclonal antibody. The immunostaining was graded in comparison to a known positive control (breast cancer) and was scored by the intensity of staining (0 to +3) multiplied by the percentage of cells expressing the antigen. The expression of erbB2 in the human WT xenograft was verified also by fluorescence activated cell sorter analysis. In addition, nude mice bearing established subcutaneous human WT xenografts were treated with either 3 intraperitoneal injections of N29 anti-erbB2 monoclonal antibody or irrelevant antibody. RESULTS: All of the authentic human pathological samples, except 1 anaplastic WT as well the WT xenografts (at different stages), expressed erbB2. Expression was also observed in WT metastasis and in tumors which out grew chemotherapy. Systemic administration of anti-erbB2 monoclonal antibody inhibited and even prevented the growth of WT xenograft in vivo. CONCLUSIONS: ErbB2 is a tumor associated antigen in WT. Being expressed in almost all tumor stages, our in vivo model suggests that erbB2 may serve as a WT therapeutic target. Further work is needed to establish the role of erbB2 in the disease and its potential use in decreasing current treatment burden.

Adolescent↗
PubMed2004

The loss of calretinin expression indicates aganglionosis in Hirschsprung's disease.

BACKGROUND: Hirschsprung's disease (HD) is a congenital disorder characterised by the absence of ganglion cells in the large bowel, leading to functional obstruction and colonic dilatation proximal to the affected segment. A subclass of nerve cell bodies in both submucosa and myenteric ganglia of the human gastrointestinal tract were found to show immunopositivity for calretinin, a calcium binding protein, which plays an important role in the organisation and functioning of the central nervous system. AIM: To investigate calretinin immunostaining in ganglionic and aganglionic HD colon specimens, and compare it with staining for S100, neurone specific enolase, and c-kit. METHODS: Ten large bowel, full thickness specimens from patients with classic rectosigmoid HD were selected from the pathology repository. In total, 54 paraffin wax blocks-24 from the ganglionic zone, 17 from the aganglionic zone, and 13 from the transitional zone-were processed. RESULTS: Calretinin was not expressed in aganglionic segments of HD and associated nerve fibres, whereas in ganglionic HD segments and in normal colon both ganglion cells and nerve fibres were immunopositive. In addition, c-kit showed an altered distribution in the interstitial cells of Cajal. The transitional zone showed a broad spectrum of histomorphological and immunohistochemical patterns of both calretinin and c-kit expression. CONCLUSION: The absence of calretinin expression may serve as a diagnostic aid in identifying aganglionic segments in HD.

Adult↗
PubMed2002

Pilomatrixoma of the retroauricular area and arm.

Pilomatrixoma is a benign tumor of hair follicles that usually occurs as a single tumor and appears in the head and neck region, extremities, and trunk. The authors present a case of pilomatrixoma with multifocal localization. Simple excision of lesions is the recommended procedure, and recurrence usually is rare.

Arm↗
PubMed2001

Two tightly linked QTLs modify tomato sugar content via different physiological pathways.

Congenic lines that differ in a single defined chromosome segment are useful for the study of complex phenotypes, as they allow isolation of the effect of a particular quantitative trait locus (QTL) from those of the entire genome. We conducted high-resolution QTL mapping of a 9-cM introgression, originating from the wild tomato species Lycopersicon pennellii, in two extremely different genetic and physiological backgrounds. In the "indeterminate" glasshouse background we identified only a single QTL ( Brix9-2-5) that affects the total soluble solids of the fruit [mainly sugars, measured in Brix units (B)]. This QTL was previously delimited within the gene for an apoplastic invertase, Lin5, that modulates sugar partitioning to the fruit. Analysis of the effects of the same chromosome segment in "determinate", open-field tomatoes, revealed two QTLs, 0.3 cM apart: the fruit-specific Brix9-2-5 that affects B only, and the shoot-specific PW9-2-5, which accounts for an altered growth habit resulting in increases in plant weight, yield, and B. This study highlights the power of the congenic approach for dissecting developmental pathways leading to complex phenotypes.

Base Sequence↗
PubMed2001

Leptin induces angiopoietin-2 expression in adipose tissues.

Adipose tissues consisting of adipocytes, microvasculature, and stroma are completely ablated upon over-expression of leptin in rats. This tissue regression is mediated by enhanced lipid beta-oxidation, adipocyte dedifferentiation, and apoptosis. To further characterize this phenomenon, we studied the possible effect of leptin on the adipose microvasculature. Tissue microvasculature is maintained by the interplay between positive and negative signals mediated by factors including vascular endothelial growth factor (VEGF), basic fibroblast growth factor, angiopoietin-1 (Ang-1), and Ang-2. Expression of the negative signal Ang-2 was reported in fetal tissues and in the adult ovary, which undergoes vascular remodeling or regression. We demonstrate that leptin induces the expression of Ang-2 in adipose tissue without a concomitant increase in VEGF. Induction of Ang-2 occurred in an autocrine manner, as demonstrated in cultured adipocytes but not in several other cell types. This tissue-specific induction of Ang-2 coincided with initiation of apoptosis in adipose endothelial cells. We propose that induction of Ang-2 by leptin in adipose cells is one of the events leading to adipose tissue regression.

3T3 Cells↗
PubMed2001

Carbon dioxide laser and silver halide infrared transmitting fibers for tympanoplasty: an experimental animal model.

OBJECTIVE: This study evaluates the effectiveness and safety of fiberoptic carbon dioxide (CO2) laser welding for graft closure of tympanic membrane perforations in an animal model. STUDY DESIGN AND SETTING: Tympanic membrane perforation was surgically induced in 11 eardrums of 7 given pigs. A lumbar facial graft was placed over the wound, and albumin drops served as a biologic solder. CO2 laser energy, transmitted through silver halide infrared transmitting fibers, was used for "spot-welding" along the circumference of the graft. The welded sites were evaluated by using a surgical microscope as well as by evaluating the sites histologically. RESULTS: Healing started 3 to 4 days after surgery and was completed within 3 weeks with the formation of a neotympanum. Some inflammation with granulation tissue was noted in 5 eardrums. CONCLUSIONS AND SIGNIFICANCE: These preliminary results indicate that CO2 laser tympanoplasty with a fiberoptic delivery system may be a promising new technique for the clinical setting.

Animals↗
PubMed2001

Insulin-like growth factor I and II preserve myocardial structure in postinfarct swine.

BACKGROUND: Insulin-like growth factors (IGF) I and II improve myocardial function after coronary occlusion in different animal models. OBJECTIVES: To investigate the mechanism of improved myocardial function after administration of IGF-I or IGF-II in acute myocardial infarction. METHODS: Female pigs (mean (SD) weight 25 (5) kg) were subjected to acute myocardial infarction by microembolisation with 75-150 micrometer affigel blue beads. The beads contained and slowly released 150 microgram/pig of IGF-I (n = 6), IGF-II (n = 6), or pig albumin (n = 6). Echocardiography, perfusion imaging, and haemodynamic measurements were performed before infarction and during four weeks after infarction. Regional wall motion of different left ventricular segments was scored semiquantitatively on the basis of a three point scoring system, from normal = 0 to dyskinesia = 3. Serum cardiac troponin I concentration was measured before, immediately after, and three hours after the infarct. Excised hearts were analysed for actin, desmin, blood vessel density, and DNA laddering within the infarct, border, and normal myocardial areas. RESULTS: Myocardial function of the infarct related area improved significantly during the four weeks of follow up in both the IGF groups (p = 0.01). Myocardial perfusion, heart rate, and blood pressure were similar in all the animals during the study. Treated animals had lower serum cardiac troponin I concentration (p = 0.001), more actin in the border area (p = 0.01) and infarct area (p = 0.0001), and reduced DNA laddering in the infarct area compared with the controls (p < 0.05). IGF groups had more blood vessels in the border area (p = 0.04) and the infarct area (p = 0.003). CONCLUSIONS: Both types of IGF improved myocardial function and the improvement was associated with preservation of myocardial structure. IGF-I was more effective than IGF-II.

Actins↗
PubMed2000

A recombination hotspot delimits a wild-species quantitative trait locus for tomato sugar content to 484 bp within an invertase gene.

In nature, genetic variation usually takes the form of a continuous phenotypic range rather than discrete classes. The genetic variation underlying quantitative traits results from the segregation of numerous interacting quantitative trait loci (QTLs), whose expression is modified by the environment. To uncover the molecular basis of this variation, we characterized a QTL (Brix9-2-5) derived from the green-fruited tomato species Lycopersicon pennellii. The wild-species allele increased glucose and fructose contents in cultivated tomato fruits in various genetic backgrounds and environments. Using nearly isogenic lines for the QTL, high-resolution mapping analysis delimited Brix9-2-5 to a single nucleotide polymorphism-defined recombination hotspot of 484 bp spanning an exon and intron of a fruit-specific apoplastic invertase. We suggest that the differences between the Brix9-2-5 alleles of the two species are associated with a polymorphic intronic element that modulates sink strength of tomato fruits. Our results demonstrate a link between naturally occurring DNA variation and a Mendelian determinant of a complex phenotype for a yield-associated trait.

Alleles↗
PubMedDate not supplied

Importance of accurate preoperative diagnosis in the management of aggressive angiomyxoma: report of three cases and review of the literature.

BACKGROUND: Aggressive angiomyxoma is a benign but locally aggressive tumor that occurs mostly in young women. Because excision is often incomplete, the risk of local recurrence is high. This report describes differences in presentation and the importance of accurate preoperative diagnosis of this rare neoplasm. METHODS AND RESULTS: We describe three cases with different presentations. Two were initially misdiagnosed, and local recurrence necessitated reoperation. Accurate diagnosis in the third case was followed by complete excision, with no recurrence. CONCLUSION: Aggressive angiomyxoma should be considered in the differential diagnosis of young women who present with a well-defined mass in the pelvic tissue. Accurate preoperative diagnosis should alert the surgeon to the need for wide excision, which is essential for prevention of local recurrence.

Adult↗
PubMedDate not supplied

Transvaginal ultrasound and diagnostic hysteroscopy as a predictor of endometrial polyps: risk factors for premalignancy and malignancy.

The aim of this study is to assess accuracy of transvaginal ultrasound (TVUS) and diagnostic hysteroscopy in diagnosing endometrial polyps and to determine premalignancy and malignancy rates in asymptomatic women. The study was designed to retrospectively analyze 438 women who underwent operative hysteroscopy in a day-care unit when endometrial polyp was suspected after TVUS and diagnostic hysteroscopy. Multivariate logistic regression modeling showed effects of age, previous breast cancer with tamoxifen treatment, and menopause with or without bleeding on pathologic results. The results indicate that positive predictive value of TVUS with diagnostic hysteroscopy was 79.9%. Premalignancy or malignancy occurred in 3.2% and was significantly related to menopause with abnormal bleeding (P < 0.001), which carried a 20-fold higher risk of pathology than any other group. Age was also a risk factor. It was concluded that TVUS with diagnostic hysteroscopy reliably evaluates endometrial polyps. The low incidence of endometrial tumors in asymptomatic (especially premenopausal) women suggests that their operative evaluation may not be cost effective. Larger studies are needed to support this tentative conclusion.

Adult↗