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Biomedical subjects

E Brambilla

Publications and source records attributed to E Brambilla.

At least 127 records · Page 7Linked to original sources
PubMed1997

[Pulmonary epithelioid hemangioendothelioma (or IVBAT). Report of a case of exclusively myxoid form].

Epithelioid hemangioendothelioma of the lung, therefore labeled as IntraVascular BronchioAlveolar Tumor (IVBAT), is a tumor of endothelial origin; its presentation with multiple pulmonary nodules radiographically suggests metastatic disease. We describe here an epithelioid hemangioendothelioma with an exclusively myxoid pattern. The tumor was composed of nodules extending in a polypoid fashion from the alveolar septa. The cells within the tumor were epithelial-like and contained cytoplasmic lacunae positive for anti-FVIII, CD31 and CD34 antibodies. According to usual criteria, it was considered as a tumor of low grade malignancy, without vascular or bronchiolar extension or cytonuclear atypia and mitosis; the prognosis, difficult to determine, depends on locoregional tumor progression.

Hemangioendothelioma, Epithelioid↗
PubMed1997

The potential role of BAX and BCL-2 expression in diffuse alveolar damage.

Apoptosis of type II pneumocytes has been identified in diffuse alveolar damage (DAD), is associated with p53 and WAF1 expression, and may be of pathogenetic importance. BAX, a homologue of BCL-2, is induced by p53 and is a promoter of apoptosis. The proapoptotic effect of BAX is negatively regulated by its binding with BCL-2. In this study, we sought to investigate that role of BAX and BCL-2 in DAD. We hypothesized that alterations in BAX and BCL-2 expression may be important in determining the susceptibility of type II pneumocytes and interstitial cells to apoptosis. Twenty-eight cases of DAD and 16 control cases (i.e., lung tissues adjacent to resected tumors) were retrieved from the files of the University of Utah and the Armed Forces Institute of Pathology. Immunohistochemical stains were performed with antigen retrieval by microwave using antibodies recognizing BAX and BCL-2. The percentage of positively staining pneumocytes and interstitial cells was estimated in each case to the nearest 10%. BAX expression was markedly increased in pneumocytes and interstitial cells in DAD compared with control lung tissues. In DAD, BAX was identified on an average of 80% of alveolar pneumocytes (range 30 to 100%) and 70% of interstitial cells (range 20 to 90%). In control lungs, BAX was identified on an average of 10% of pneumocytes (range 0 to 20%) but not in interstitial cells. Focal BCL-2 staining was identified in interstitial myofibroblasts in 7 of 25 cases of DAD but was only identified in bronchiolar epithelium of control lungs. These results suggest that the induction of BAX in DAD may enhance the susceptibility of alveolar epithelial cells to apoptosis, whereas BCL-2 expression may contribute to the absence of apoptosis in interstitial myofibroblasts. Expression of BCL-2 in interstitial myofibroblasts may contribute to the development of pulmonary fibrosis in some patients.

Adult↗
PubMed1997

Clear cell tumor of the lung: an immunohistochemical and ultrastructural study supporting a pericytic differentiation.

Clear cell tumor ("sugar tumor") of the lung is a rare benign lesion with unclear histogenesis. It is composed of large cells with a clear cytoplasm rich in glycogen, blended with an abundant network of sinusoid-type vessels. We report two cases of sugar tumor, one of these lacking clearly demonstrable glycogen storage. In both, the tumor cells lacked keratin expression and were positive for vimentin and HMB 45, an antibody recognizing perivascular or myoid cell proliferation such as lymphangioleiomyomatosis and angiomyolipoma. The tumor cells were also immunoreactive for an endothelial cell marker, CD 34, but negative for Factor VIII or smooth muscle actin. Intercellular deposition of basal-like material was immunostained with Type IV collagen. At ultrastructural examination of one of these cases, tumor cells showing features of pericytes or poorly differentiated perivascular leiomyocytes encased in basement material were observed in close association with endothelial cells; their cytoplasm contained numerous membrane-bound glycogen and pinocytic vesicles. We conclude that on the basis of immunohistochemical and ultrastructural phenotype, sugar tumor presents pericytic features and that glycogen storage is not a constant feature of these benign tumors.

Adenocarcinoma, Clear Cell↗
PubMed1997

[Pulmonary inflammatory pseudotumor complicating the course of a community-acquired pneumopathy. A deceptive radio-clinical presentation].

The case of a 46 years old man presenting a chronic history of right upper lobe pneumonia is reported. The clinical presentation associated with nodular pulmonary computed tomographic scan lesions, highly suggested a malignant bronchopulmonary process. A lobectomy was performed. Histological analysis revealed an inflammatory pseudotumor. This inflammatory process may be a particular end stage disease of pulmonary infectious disease.

Biopsy↗
PubMed1997

[Lymphocytic alveolitis, chronic viral hepatitis C, lipoproteinosis and cryoglobulinemia in a patient].

Chronic hepatitis C virus (HCV) infection, lipoproteinosis and cryoglobulinemia may all be associated with lymphocyte alveolitis. The pathogenic mechanisms involved would suggest a compromised immune system. We report the first observation of a patient with lipoproteinosis, cryoglobulinemia and hepatitis C virus infection who developed lymphocyte alveolitis. Taken individually, each of these three disease states could explain cellular modifications observed in the lung, but their association aggravated the clinical course.

Cryoglobulinemia↗
PubMed1997

p53 and lung cancer.

The malignant transformation of pulmonary epithelial cells is the result of multistep accumulation of genetic and molecular alterations highly related to tobacco carcinogens, involving key mechanisms of proliferation and apoptosis. Clonal expansion is the net result of acceleration of cell division and inhibition of active cell death (apoptosis). Oncogene activation in lung cancer (ras, myc, autocrine growth factor loops) results in acceleration of cell division. More importantly, tumor suppressor genes inactivation (p53, Rb, cyclin-dependent-kinase-Inhibitor p16) at genetic, epigenetic, or post-translational level removes important constraints on cell division at G1-check-point increasing cell proliferation. p 53 inactivation, through loss of transcription function may abrogate both G1-arrest control and apoptosis, thus accelerating clonal expansion. It is the most frequent alteration in lung cancer (70% of genetic alterations) with some differentiation dependent differences. p53 missense mutation is highly concordant with p53 stabilization and immunoreactivity. However, 20% of mutations with null phenotype (no p53 protein) provides 20% of false negative using immunohistochemistry for evaluation of p53 mutations in lung cancer. Rare situations are described with wild type p53 stabilization. p53 mutational spectrum in lung cancer reveals some specificities: 3 hot spot codons (codon 157, 248, 273) are the main target of selective adduct formation from a defined chemical carcinogen of cigarette smoke (BP). p53 stabilized mutants proteins are the targets for immune recognition in patients, leading to secretion of p53 auto-antibodies, and can also elicit T-cell specific cytotoxicity in vitro. p53 was not proven to be of prognostical importance once the tumor has developed. However, p53 stabilization is one of the best predictor of progression and irreversitiblity of preneoplastic bronchial lesion overwhelming morphological changes such as severe dysplasia. Restoration of wild type p53 function through p53 gene therapy, immunotherapy or modification of carboxy terminal end enable new therapeutic intervention. Finally, target genes and proteins situated on the downstream pathway of p53 transcription appears to be the most important factors of growth acceleration or even cell dissemination in lung cancer (Rb and its phosphorylation pathway, Bax-Bc12 balance and matrix degrading enzymes UPA and inhibitor PAI). Their constitutive deregulation could by-pass wild type p53 functions. p53 pathway offers several targets for future gene therapy or modulation in the future in lung cancer.

Antigens, Neoplasm↗
PubMed1996

Metabolic effects of successful intraportal islet transplantation in insulin-dependent diabetes mellitus.

The intraportal injection of human pancreatic islets has been indicated as a possible alternative to the pancreas transplant in insulin-dependent diabetic patients. Aim of the present work was to study the effect of intraportal injection of purified human islets on: (a) the basal hepatic glucose production; (b) the whole body glucose homeostasis and insulin action; and (c) the regulation of insulin secretion in insulin-dependent diabetes mellitus patients bearing a kidney transplant. 15 recipients of purified islets from cadaver donors (intraportal injection) were studied by means of the infusion of labeled glucose to quantify the hepatic glucose production. Islet transplanted patients were subdivided in two groups based on graft function and underwent: (a) a 120-min euglycemic insulin infusion (1 mU/kg/min) to assess insulin action; (b) a 120-min glucose infusion (+75 mg/di) to study the pattern of insulin secretion. Seven patients with chronic uveitis on the same immunosuppressive therapy as grafted patients, twelve healthy volunteers, and seven insulin-dependent diabetic patients with combined pancreas and kidney transplantation were also studied as control groups. Islet transplanted patients have: (a) a higher basal hepatic glucose production (HGP: 5.1 +/- 1.4 mg/kg/ min; P < 0.05 with respect to all other groups) if without graft function, and a normal HGP (2.4 +/- 0.2 mg/kg/min) with a functioning graft; (b) a defective tissue glucose disposal (3.9 +/- 0.5 mg/kg/min in patients without islet function and 5.3 +/- 0.4 mg/kg/min in patients with islet function) with respect to normals (P < 0.01 for both comparisons); (c) a blunted first phase insulin peak and a similar second phase secretion with respect to controls. In conclusion, in spite of the persistence of an abnormal pattern of insulin secretion, successful intraportal islet graft normalizes the basal HGP and improves total tissue glucose disposal in insulin-dependent diabetes mellitus.

Adult↗
PubMed1996

Cellular sociology applied to neuroendocrine tumors of the lung: quantitative model of neoplastic architecture.

This paper reports on cellular sociology, which consists of modeling tissular architecture based on graph theory. Voronoi's diagram was chosen to build the models. This diagram derives from a cell neighborhood concept and generates parameters which objectively represent tissue architecture. Minimal spanning tree (MST) is probably the more frequently used among graphs and successfully discriminates different grades of pathological process. However, Voronoi's diagram is more comprehensive and a more complete representation of architecture with the advantage of stability. The lung neuroendocrine tumor classification is far from being consensual, especially for lesions which don't fall in with typical carcinoid and small cell carcinoma groups. By comparing architectural models of 20 neuroendocrine tumors of the lung, this work supports the morphologic spectrum concept of these tumors and also supports the recently proposed concept of large-cell neuroendocrine tumors of the lung. Finally, architectural parameters separate small-cell-lung carcinomas from neuroendocrine non-small-cell lung carcinomas.

Carcinoid Tumor↗
PubMed1996

Human T-cell lymphotropic virus type-I infection in the severe combined immunodeficiency mouse.

Human T-cell lymphotropic virus type-I (HTLV-I) is the etiologic agent of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia (ATL). HAM/TSP and ATL occur infrequently among HTLV-I-infected individuals, and rarely develop in the same individual. To study host and viral factors involved in the induction, tissue tropism, as well as pathogenesis of HAM/TSP, peripheral blood lymphocytes (PBL) from 14 patients with HAM/TSP and from 9 controls were introduced into severe combined immunodeficiency (SCID) mice by intraperitoneal injection. Mice were followed for up to 26 weeks. Human IgG was produced from 2 to 14 weeks after reconstitution in all animals. Thirty-two of 44 mice (72%) showed circulating human antibody against the major viral protein products of HTLV-I. Analysis of viral sequences by polymerase chain reaction (PCR) demonstrated HTLV-I sequences in 21/38 (55%) brains and in 7/17 (41%) spinal cords from HTLV-I-hu SCID mice. No animal had clinical evidence of neurological impairment or pathological findings similar to those seen in HAM/TSP. Seven mice who received PBL from Epstein Barr virus (EBV)-seropositive patients developed an intraperitoneal lymphoma. In 2 mice an infiltration of brain by a lymphoblastic tumor of B/T cell type was observed. By PCR, all the tumors were EBV-positive; HTLV-I sequences were detected in 5 of them. Our study suggests that the HTLV-I-hu-SCID mouse provides a potentially valuable system for studying the production, kinetics, and pathogenicity of anti-HTLV-I antibody, and may help clarify the interaction of EBV and retroviruses in the development of disease.

Adult↗
PubMed1996

Interferon-gamma activated calcium influx in peripheral blood lymphocytes from patients with primary and secondary progressive multiple sclerosis.

Interferon-gamma (IFN-gamma) contributes to the early events leading to T cell activation in relapsing-remitting (RR) multiple sclerosis (MS) by activating a transplasmalemma calcium influx, the detection of which is closely associated with clinical and MRI evidence of disease activity. The appearance of this influx represents one of the earliest peripheral events in the pathogenesis of RRMS. It is still questioned whether the same immune mediated mechanisms also operate in primary progressive (PP)MS. Fluorimetric evidence of the IFN-gamma activated calcium influx was sought in 16 patients with PPMS and 39 patients with secondary progressive (SP)MS. To compare peripheral versus CNS evidence of immune activation 11 of the patients with PPMS and 27 of the patients with SPMS underwent gadolinium enhanced brain MRI. The IFN-gamma activated influx was detected in peripheral blood lymphocytes from eight of 16 (50%) patients with PPMS, and 20 of 39 (51%) patients with SPMS, a frequency similar to that previously reported in patients with RRMS during phases of disease stability. Gadolinium enhancing brain MRI lesions were found in only one of 11 (9%) patients with PPMS and 12 of 27 (41%) with SPMS. Our study shows that peripheral blood lymphocytes from patients with PPMS and patients with SPMS express with the same frequency as patients with RRMS, an IFN-gamma dependent intracellular process leading to T cell activation able to trigger disease activity.

Adult↗
PubMed1996

Comparison of 35S and chemiluminescence for HPV in situ hybridization in carcinoma cell lines and on human cervical intraepithelial neoplasia.

For in situ hybridization (ISH), development of sensitive, nontoxic alternatives to the use of radioactivity is a constant concern. In this trend, and close to chromogenes and fluorophores, chemiluminescence appears an attractive method. A first positive experience in immunocytochemistry and in ISH, by using the enhanced luminol as luminogene substrate for horseradish peroxidase (HRP) led us to compare the sensitivity of 35S autoradiography and chemiluminescence. For this purpose, we used three human carcinoma cell lines, CaSki [400-600 copies of human papilloma virus (HPV) 16], HeLa (10-50 copies of HPV 18), and SiHa (1-5 copies of HPV 16), and 40 biopsy specimens of human cervical preneoplastic and neoplastic lesions. We performed ISH by using HPV cDNA biotin-labeled probes, detected by a two-step immunocytochemical reaction, the secondary antibodies being either 35S-labeled for autoradiography or HRP-labeled for chemiluminescence. An intensified CCD camera allowed acquisition of the luminescent signal. After only 10 min of photon accumulation, on cell line smears as well as on serial tissue sections, chemiluminescence gave comparable results to those obtained by a 3-week exposure for 35S autoradiography. A quantitative approach on cervical biopsy specimens confirmed this similar level of sensitivity by measuring the area of 35S- or chemiluminescence-stained nuclei. Our results indicate that chemiluminescence is a credible and perfectible alternative to radioisotopes for in situ detection of nucleic acids by hybridization.

Biopsy↗
PubMed1996

In situ apoptotic cell labeling by the TUNEL method: improvement and evaluation on cell preparations.

TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling) is a method of choice for rapid identification and quantification of the apoptotic cell fraction in cultured cell preparations. However, TUNEL application has been restricted to a narrow spectrum of sample conditions, and only detergents have been proposed as labeling enhancers. This study was aimed at extending TUNEL to variously fixed cells and improving TUNEL sensitivity by optimized pretreatments, the specificity being assessed by reference to the apoptotic morphology. Comparative TUNEL was performed with three protocols on CEM-C7 cells, a model of glucocorticoid-induced apoptosis. Samples were submitted to six modalities of fixation and TUNEL was performed after each of the following conditions: no pretreatment; detergent permeabilization; proteolytic digestion; microwave irradiation; and a recently published combination of the latter two. The proportion of TUNEL-stained elements within the cell fraction, with and without apoptotic morphology, was quantified. Our results showed that: (a) with an adequate pretreatment, reliable TUNEL can be obtained after each fixative tested; (b) detergent was inefficient in improving sensitivity; (c) whatever the fixation, microwave pretreatment provided the best TUNEL sensitivity without notable loss of specificity; (d) under adaptive technical conditions, TUNEL can be associated with detection of various proteins by double labeling; and (e) the existence of a limited population of intensely TUNEL-positive cells that lacked apoptotic morphology contributes to the current debate about a preapoptotic state.

Apoptosis↗
PubMed1996

Clinical and radiologic correlates of a novel T lymphocyte gamma-interferon-activated Ca2+ influx in patients with relapsing-remitting multiple sclerosis.

T lymphocytes are the main cellular mediators in MS pathogenesis, and their activity is modulated by a complex cytokine network in which gamma-interferon (gamma-IFN) is considered essential. We have recently identified a new transplasmalemma Ca2+ influx activated by gamma-IFN in T lymphocytes (mainly CD4+) from patients with MS that makes T cells more susceptible to proliferation. To define the possible role of this Ca2+ influx as a marker of disease activity, we correlated its appearance with clinical and MRI findings in a cross-sectional study of 67 patients with relapsing-remitting MS (RR-MS). We also conducted a short-term longitudinal evaluation (every 15 days over a 5- to 7-month period) in three of the RR-MS patients. Sixty-five percent of all clinically active RR-MS patients showed the gamma-IFN-activated Ca2+ influx. However, positivity was higher in the first week (78%) after the onset of a clinical exacerbation than the second (57%) and third (44%) weeks. The influx was also detected in 45% of clinically stable RR-MS patients, 30% of RR-MS patients with a "benign" course of the disease, 14% of the other active autoimmune or neurologic disease patients, and 9% of healthy subjects (RR-MS versus control subjects, p < 0.001). Brain-MRI gadolinium-enhancing lesions were more frequently found in influx-positive (72%) than in influx-negative (47%) patients (p < 0.005). In the longitudinal study, we recorded five intracellular Ca2+ ([Ca2+]i) elevations and three clinical attacks (one per patient). A peak increase of [Ca2+]i due to the gamma-IFN-activated Ca2+ influx always preceded the clinical attacks from 4 to 45 days and coincided to MRI evidence of inflammation. [Ca2+]i had returned to baseline levels by the time of the onset of two clinical attacks. This finding may account for the lack of detection of the gamma-IFN-activated Ca2+ influx in some RR-MS patients during the first week after clinical onset. The strong association between the influx and clinical and MRI evidence of disease activity supports its role in the early phases of cellular immune activation leading to demyelination in MS. The detection of [Ca2+]i elevations due to the gamma-IFN-activated Ca2+ influx may represent a valuable prognostic marker of disease activity and may be useful to monitor immunologic studies of MS patients in future clinical trials.

Adolescent↗
PubMed1996

Overexpression of nucleoside diphosphate/kinase A/nm23-H1 protein in human lung tumors: association with tumor progression in squamous carcinoma.

Levels of nm23-H1/nucleoside diphosphate/kinase A expression have been reported to correlate inversely with metastatic potential in some tumors but not in others. To clarify the role of nm23 in lung carcinoma, the genetic abnormalities of nucleoside diphosphate/kinase A/nm23-H1 were investigated at the DNA and protein levels. A series of 104 human lung tumors (42 neuroendocrine (NE) and 62 non-NE tumors) was analyzed for nm23-H1 protein expression by immunohistochemistry using one polyclonal and two monoclonal Ab and for genomic alterations using Southern blotting and single-strand conformation polymorphism. Overexpression of the nm23-H1 protein relative to the normal lung epithelia (pneumocyte and bronchial epithelial cells) was observed in 83% (35/42) of NE carcinomas and in 89% (55/62) of non-NE carcinomas. Eight of nine carcinoids exhibited an increased expression of nm23-H1 protein, suggesting that this overexpression of the nm23 protein is necessary for proliferation in any tumors. No significant correlation was found between nm23 staining and any clinicopathologic parameters in NE carcinoma or in adenocarcinoma. In squamous carcinoma, high levels of nm23-H1 protein expression were associated with tumor stage (p = 0.0036). Allelic deletion or genetic amplification was never found. No altered mobility was detected using single-strand conformation polymorphism analysis. These data show that nm23-H1 protein is overexpressed in a large number of lung tumors of all histologic types, in association with advanced tumor stage in squamous carcinoma. They also suggest that nm23-H1 might play a role in the progression of lung tumors rather than in antimetastatic function.

Base Sequence↗
PubMed1996

Changes in the expression of matrix proteases and of the transcription factor c-Ets-1 during progression of precancerous bronchial lesions.

Matrix proteases and the transcription factor c-Ets-1, which regulates in vitro stromelysin 1, collagenase 1, and urokinase type plasminogen activator gene promoters, are frequently expressed in invasive carcinomas. Using in situ hybridization and immunohistochemistry, we analyzed collagenase 1, stromelysins 1 and 3, matrilysin, urokinase type plasminogen activator, and c-Ets-1 gene expression on serial frozen sections of 39 intraepithelial bronchial lesions, including areas of hyperplasia, metaplasia, dysplasia, carcinoma in situ, and corresponding lung carcinomas in 13 patients. In intraepithelial lesions, expression of all matrix proteases was detected in epithelial cells. Conversely, in microinvasive or invasive lesions, a fibroblastic expression was observed. Collagenase 1 and matrilysin were expressed seldomly in intraepithelial lesions and frequently in carcinomas (p = 0.0016 and p < 0.0001, respectively). Stromelysin 1 was expressed inconsistently in 31% of intraepithelial lesions of all grades and in 50% of carcinomas. Stromelysin 3 and urokinase type plasminogen activator were expressed only, but frequently, in preinvasive lesions (dysplasia, carcinoma in situ) and in carcinomas. The expression of stromelysin 3 in fibroblasts started with dysplasia and carcinoma in situ, but was more frequent in invasive than preinvasive lesions (p = 0.0012). c-Ets-1 was more often expressed in carcinomas than in intraepithelial lesions (p < 0.0001) and was always expressed in fibroblasts. Comparing preinvasive lesions adjacent to or at a distance from squamous lung carcinoma, stromelysin 3 epithelial expression was more frequent in preinvasive lesions adjacent to invasive foci than in others (p = 0.036). We conclude that (a) both epithelial expression of matrix proteases in intraepithelial bronchial lesions and their stromal expression in microinvasive and invasive lesions suggest their role in lung tumor development; (b) c-Ets-1 does not act as a transcriptional activator for matrix proteases genes in preinvasion, although it might regulate collagenase 1 gene during lung tumor progression; and (c) matrix proteases might offer new therapeutic targets for chemoprevention of lung cancer.

Bronchial Neoplasms↗
PubMed1996

Interest of targeting AgNORs measurement in cycling cells: in vivo cell kinetic evaluation of non-small cell lung cancer.

This study investigated the actual growth rate of 30 low stage operable non-small cell lung carcinomas, including disease-free surviving and deceased patients. The actual growth rate was defined as the cell production rate and was calculated from the growth fraction and the cell cycle time of each tumor at the time of surgical resection. The growth fraction was assessed by the Ki67 index while the cell cycle time was assumed to be reflected by the AgNORs content in the cells positive for Ki67. AgNORs content was evaluated by means of image analysis of double-stained AgNOR-Ki67 tissue section. The actual growth rate did not discriminate between the disease-free surviving and deceased patients but the AgNORs content in Ki67 cells correlated with the survival time of those patients who died of the tumor. Patients expressing a small AgNORs content, which might indicate a long cell cycle, may die but later; patients with a high AgNORs content, which might indicate a short cell cycle, die early or will survive. A twilight curve was derived from this data and might provide new prognostic indicators.

Aged↗