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Biomedical subjects

M Colombi

Publications and source records attributed to M Colombi.

At least 37 records · Page 2Linked to original sources
PubMed1998

Allelic deletion at chromosome 11p13 defines a tumour suppressor region between the catalase gene and D11S935 in human non-small cell lung carcinoma.

A previous study of 48 primary non-small cell lung carcinomas (NSCLC) for allelic loss at five polymorphic chromosome 11p loci indicated regions of allelic deletion for both 11p13 and 11p15. To further delineate the extent of this deletion 28 NSCLCs were examined by high resolution deletion mapping for allelic loss at 11p13.95% (18/28) of the informative cases displayed allelic loss at the catalase gene locus (CAT), 64% (18/28) at D11S935 and D11S941E, respectively, and 23% (6/26) at D11S907. The minimal region of deletion is bordered by CAT and D11S935 and spans about 3 cM. The relationship between allelic loss within this chromosomal region, the presence of a putative predisposition locus and the pathogenetics of NSCLC are discussed.

Adult↗
PubMed1998

Weekly administration of vincristine, cyclophosphamide, mitoxantrone and bleomycin (VEMB) in the treatment of elderly aggressive non Hodgkin's lymphoma. Gruppo Italiano per lo Studio dei Linfomi.

BACKGROUND AND OBJECTIVE: Aim of the study was to assess the efficacy of VEMB, a short-lasting therapeutic regimen (50 days) which alternates two myelotoxic drugs (cyclophosphamide and mitoxantrone) every week with two less hematologically toxic drugs (vincristine and bleomycin) in the treatment of aggressive NHL in the elderly (over 70). DESIGN AND METHODS: Between November 1994 and March 1996, 37 patients aged more than 70 years, with highly or moderately malignant NHL (according to the Working Formulation) have been enrolled into the study. The stage of the disease ranged between II and IV according to Ann Arbor. Mean age was 77 years; 14 patients (38%) had stage IV; 19 patients (51%) had LDH higher than normal; 26 patients (70%) had extranodal and 9 patients (24%) had bulky disease at time of diagnosis. RESULTS: Sixty-two percent of patients achieved a complete and 22% a partial remission. Non-responders amounted to 5%. Four patients (11%) died during the therapy. Nine patients (24%) experienced grade III-IV neutropenia. The most frequently observed event was mild neurotoxicity (43% of cases). The overall survival rate at 30 months was 55%. DFS at 24 months was 66%. INTERPRETATION AND CONCLUSIONS: VEMB is a therapeutic regimen whose efficacy is comparable to that of the other derived MACOP-B therapeutic regimens used in the elderly NHL. It has proved to have a good feasibility, though the number of toxic deaths should not be neglected.

Aged↗
PubMed1997

A pilot study on the use of the ProMACE-CytaBOM regimen as a first-line treatment of advanced follicular non-Hodgkin's lymphoma. Gruppo Italiano per lo Studio dei Linfomi.

BACKGROUND: The role of intensive conventional dose chemotherapy in advanced low grade non-Hodgkin's lymphomas is a matter of debate. The Gruppo Italiano per lo Studio dei Linfomi conducted a study to evaluate the efficacy and toxicity of a third-generation polychemotherapeutic regimen, ProMACE-CytaBOM, as a first-line therapy in a selected group of patients with advanced follicular non-Hodgkin's lymphoma (Fo-NHL) who were younger than 60 years. METHODS: Thirty-nine patients were included in the study (14 males, 25 females; median age, 44 years; age range, 22-60 years). Their WF histotypes were B (9 patients), C (23 patients), and D (7 patients). All of the patients had disease in an advanced clinical stage (Stage III, 15 patients; Stage IV, 24 patients), and 9 patients had B symptoms. According to the age-adjusted International Prognostic Index (IPI), 20 patients exhibited low-intermediate risk, 14 high-intermediate risk, and 5 high risk. Three of the patients were not considered evaluable because they withdrew their consent after three (one patient) and four (two patients) cycles of therapy (one of these patients was in complete remission [CR], and two were in partial remission [PR]). Of the 36 evaluable patients, 4 received IF-RT after the 6 planned cycles of therapy. RESULTS: CR was achieved in 20 patients (55.5%) and PR in 14 (38.8%). One patient (2.7%) experienced disease progression during the treatment program. Eight of the 20 patients with CR (40%) relapsed. Eight patients (22.2%) died: 6 died of disease progression, 1 died of therapy consequences, and 1 died of an unrelated cause. With a median follow-up of 49 months (range, 28-79 months), the disease free survival rate was 60%. The overall survival rate was 80% after a median follow-up of 44 months (range, 3-79 months). The IPI stratification of patients showed a borderline statistical difference in terms of time to treatment failure and overall survival. The main hematologic toxicity was neutropenia (Grade 3 in approximately 10% of patients). One patient died of sepsis. Cotrimoxazole prophylaxis was always given. Cardiac toxicity (Grade 3) was observed in 1 patient at the end of the planned therapy. The average relative dose intensity of the drugs was 89% of the projected dose, without the regular use of growth factors. CONCLUSIONS: This study indicates that ProMACE-CytaBOM could be a suitable regimen for adult patients with advanced Fo-NHL, allowing a good CR rate and very good disease free survival rate. However, the occurrence of severe, albeit limited, adverse effects suggests that this regimen should first be used in controlled therapeutic protocols to verify its efficacy with respect to less intensive approaches.

Adult↗
PubMed1997

Poor prognosis in non-villous splenic marginal zone cell lymphoma is associated with p53 mutations.

We have recently reported a series of 15 non-villous splenic marginal zone lymphoma patients, six of whom showed p53 mutations (40%). This molecular alteration did not correlate with any particular clinico-pathologic feature at diagnosis. After a median follow-up of 56 months, four cases evolved into aggressive fatal non-Hodgkin's lymphoma (NHL) and two had refractory progressive disease; interestingly, p53 mutations were demonstrated in five of these patients at diagnosis. As the patients with wild-type p53 presented responsive or indolent disease, this genetic alteration may be an early marker of aggressive transformation or refractoriness. p53 evaluation at diagnosis could be advisable in this particular subset of NHL.

Adolescent↗
PubMed1996

Role of different hematologic variables in defining the risk of malignant transformation in monoclonal gammopathy.

The presenting clinico-hematologic features of 386 patients with nonmyelomatous monoclonal gammopathy (MG) were correlated with the frequency of malignant transformation to evaluate the most important variables conditioning its evolution into multiple myeloma (MM) or Waldenström macroglobulinemia (WM). Most of the patients (335) had monoclonal gammopathy of undetermined significance (MGUS: 39 IgA, 242 IgG, 54 IgM): the remaining 51 patients (12 IgA, 39 IgG) fulfilled all of the MGUS diagnostic criteria (according to Durie) except that bone marrow plasma cell (BMPC) content was 10% to 30%, and so they were defined as having monoclonal gammopathy of borderline significance (MGBS). There were no significant differences between the MGUS and MGBS groups in terms of age, sex, or median follow-up. After a median follow-up of 70 and 53 months, respectively, 23 of 335 MGUS and 19 of 51 MGBS patients had undergone a malignant evolution. Univariate analysis of the IgA and IgG patients showed that the cumulative probability of the disease evolving into MM correlated with diagnostic definition (MGBS v MGUS), BMPC content (> or = 10% v < 5% and < or = 5% v > 5%) and reduced serum polyclonal Ig. In the IgG cases, there was also a significant correlation with detectable Bence Jones proteinuria, serum monoclonal component (MC) levels and age at diagnosis (> 70 v < = or 55 years). In the IgG cases as a whole, the same variables remained in the Cox model where the BMPC percentage was considered after natural logarithmic transformation and the monoclonal component as g/dL value. The relative risks of developing MM are the following: 2.4 for each 1 g/dL increase of IgG, serum MC, 3.5 for detectable light chain proteinuria, 4.4 for the increase of 1 unit in log. BMPC percentage, 6.1 for age > 70, 3.6 and 13.1 for a reduction in one or two polyclonal Ig. In conclusion, our study allows the identification of a particular subset of MGUS patients (MC < = or 1.5 g/dL, BMPC < 5%, no reduction in polyclonal Ig and no detectable light chain proteinuria) at very low-risk of evolution, who can be considered as having benign monoclonal gammopathies. We also describe a previously undefined group of MG patients (with monoclonal gammopathy of borderline significance) who are at high-risk of malignant evolution. These findings could have a considerable impact on the cost/benefit ratio of monitoring programs in these patients.

Aged↗
PubMed1996

Multilobated B cell lymphoma (Pinkus variant) with isolated muscular localization in a patient with systemic sclerosis: a case report.

The association of systemic sclerosis (SSc) and non-Hodgkin's lymphoma (NHL) is a rare event whose pathogenesis remains to be clarified. We describe a case of NHL in a patient with SSc, in whom the NHL was particular in terms of clinical presentation (primitive muscle and bone involvement) and histologic type (large multilobated B-cell variant). The lymphoma was clinically aggressive but responded well to therapy. Surveillance for the development of "atypical" NHL is suggested in SSc cases.

Aged↗
PubMed1996

Frequent TP53 gene alterations (mutation, allelic loss, nuclear accumulation) in primary non-small cell lung cancer.

Mutations of the TP53 tumour suppressor gene have been reported for many human cancers. A variety of TP53 mutations have also been reported for both primary non-small cell lung cancer (NSCLC) and associated metastases. To assess the pathogenetic significance of TP53 gene alterations in NSCLC, 24 paired samples of primary NSCLC and the corresponding normal lung tissue were analysed for mutations of the TP53 gene (exons 5-8) using exon-specific PCR, single-strand conformation polymorphism PCR (SSCP-PCR) and direct DNA sequencing; for p53 protein accumulation by immunohistochemistry and for 17p allelic loss using restriction fragment length polymorphism (RFLP) probes on Southern blots and amplified fragment length polymorphism-PCR. TP53 point mutations were observed in 9/24 (38%) tumours encompassing a total of 14 mutations. Two tumours displayed the same double mutation while a third harboured four different mutations. Seventeen of 24 NSCLCs (71%) overexpressed p53 protein and all 17 immunopositive tumours (100%) showed a mutation and/or allelic loss at the D17S30 locus. Of the 17 NSCLCs informative at the DS17S30 locus, 10 (59%) showed allelic loss, of which five (50%) were also mutated on the remaining TP53 allele. These results suggest that TP53 gene alterations are involved in the pathogenesis of primary NSCLC and that such alterations may serve a selective role in the development of NSCLC by diminishing the apoptotic potential of bronchial epithelial cells heterozygous for a TP53 point mutation. This may also explain the accumulation of multiple TP53 point mutations in 3/24 of our NSCLC samples.

Alleles↗
PubMed1996

Identification of two splicing mutations in the collagen type VII gene (COL7A1) of a patient affected by the localisata variant of recessive dystrophic epidermolysis bullosa.

Collagen type VII gene (COL7A1) has been demonstrated to be altered in several variants of dystrophic epidermolysis bullosa (DEB), with either recessive or dominant mode of inheritance. We have identified two mutations in a patient affected by a localisata variant of recessive DEB (L-RDEB), which is characterized by the less severe phenotype of the syndrome. These mutations are the first splicing mutations so far described for COL7A1 in DEB. One mutation is a paternally inherited A-->G transition at position -2 of the donor splicing site of intron 3, which results in three aberrant mRNAs, depending on the skipping of exon 3, the usage of a cryptic donor site inside exon 3, or the maintenance of intron 3. The second mutation is a maternally inherited G-->A transition at position -1 of the donor splicing site of intron 95, which induces the activation of a cryptic donor site 7 nt upstream the normal site and gives rise to a deleted mRNA, in addition to the normal one. All aberrant mRNAs show a shift of the reading frame, thus generating premature termination codons of translation. Allele-specific analysis of the transcripts has shown that the maternal mutation does not completely abolish the correct splicing of COLVII pre-mRNA, thus allowing, in the patient, the synthesis of a certain level of a functional protein. This result is compatible with the mild clinical L-RDEB phenotype observed in our patient.

Adolescent↗
PubMed1995

Genomic organisation and chromosomal localisation of the gene encoding human beta adducin.

Adducin (ADD) is a heterodimeric protein of the membrane skeleton with subunits of 103 (alpha) and 97 kDa (beta). It promotes the assembly of the spectrin-actin network. We have previously shown that one point mutation in each of the alpha and beta rat ADD-encoding genes is associated with blood pressure variation in an animal model for hypertension, the Milan hypertensive strain of rats, probably due to a change in the phosphorylation pattern. In fact, the rat mutations, Y to F for alpha and R to Q for beta, are located, respectively, in a tyrosine kinase and a protein kinase A phosphorylation site. We have now determined, for the human beta-ADD-encoding gene, its chromosomal localisation, exon-intron organisation and alternative splicing patterns. We report here that human beta-ADD is localised on chromosome 2 and we also show a characteristic 3' end alternative splicing of the beta-ADD RNA that generates two distinct beta-ADD families, namely ADD 63 and 97; both of them in turn present a very complex differential splicing pattern in the internal exons.

Alternative Splicing↗
PubMed1995

Plasminogen activators in nude mice xenotransplanted with human tumorigenic cells.

Nude mice have been subcutaneously inoculated with human tumorigenic fibrosarcoma cells (HT-1080) producing urokinase-type plasminogen activator (u-PA) or with human tumorigenic melanoma cells (G-361) producing tissue-type plasminogen activator (t-PA). Human u-PA (hu-PA) and t-PA (ht-PA) were found in the plasma and in the tumors of mice injected with HT-1080 or G-361 cells, respectively. Metastases containing ht-PA were observed in different organs of mice transplanted with G-361 cells, while mice injected with HT-1080 cells did not develop metastases. These data would suggest a relationship between the metastatic potential of G-361 cells and t-PA. The parallel increase of the levels of endogenous murine PAs (m-PA) activities might play a crucial role in the early stages of tumor growth and metastasis, since the biological effects of the PAs produced by the transplanted tumor cells can not be dissociated from those of the PAs induced in the host.

Animals↗
PubMed1995

Angiokeratoma corporis diffusum and arteriovenous fistulas with dominant transmission in the absence of metabolic disorders.

BACKGROUND: A three-generation family with members affected by angiokeratoma corporis diffusum (ACD) and arteriovenous fistulas of the legs is described. Our purpose was to investigate possible lysosomal storage defects previously described in association with ACD. OBJECTIVE: Results of physical examination of both affected and unaffected family members were otherwise normal as was the life span. The inheritance pattern of both ACD and arteriovenous fistula traits was autosomal dominant, with variable expressivity and incomplete penetrance. Microscopic examination of ACD lesions showed dilated capillaries without vacuolation of cells. Ultrastructural studies failed to reveal lysosomal abnormalities. Normal levels of alpha-galactosidase, beta-galactosidase, alpha-fucosidase, and alpha-sialidase were detected in peripheral blood leukocytes and skin fibroblasts. CONCLUSIONS: The association of autosomal dominant ACD and arteriovenous fistulas might represent a novel syndrome. However, pathogenesis of these lesions remains unknown.

Adolescent↗
PubMed1994

Identification of genes differentially expressed in normal lung and non-small cell lung carcinoma tissue.

Using a magnet-assisted subtraction technique, 17 complementary DNA (cDNA) clones were isolated that were expressed in the normal lung but were decreased or lost in the corresponding tumor tissue of a nonsmall cell lung carcinoma patient. The lack of expression of six magnet-assisted subtraction technique cDNA clones in three additional non-small cell lung carcinoma cases indicates their possible relevance for non-small cell lung carcinoma. Two cDNA clones revealed homology to genes specifically expressed in lung, i.e., pulmonary surfactant-associated protein B and the receptor for advanced glycosylation end products of proteins. Three cDNA clones showed identity to cDNA sequences encoding calmodulin-like protein, glutamine synthetase, and cytoskeletal beta-actin. One cDNA clone is identical to a recently described human expressed sequence tag whose gene is still unknown.

Base Sequence↗
PubMed1994

RT-PCR detection of fibronectin EDA+ and EDB+ mRNA isoforms: molecular markers for hepatocellular carcinoma.

Alternative splicing of fibronectin pre-mRNA has been shown to be independently regulated at the EDA and EDB regions in a tissue and developmental stage-specific manner. In this study, RT-PCR approaches were developed for the detection of EDA and EDB FN mRNA isoforms in hepatocarcinoma cells (SK-Hep-I) grown in vitro and in human liver biopsies. While EDA+ and EDB+ isoforms were not present in control adult liver, they were detectable in the hepatocarcinoma cells and in fetal liver. The RT-PCR analysis, extended to biopsies of malignant and non-malignant hepatic tissues, showed that FN mRNAs containing the EDA and EDB sequences were present in the 14 hepatocellular carcinomas (HCCs) tested but absent in the non-tumorous liver tissues (i.e., normal parenchyma, non-specific reactive and chronic hepatitis, steatosis). The EDB+ FN mRNA isoforms were also detected in 3 cases of benign neoplasm (hepatocellular adenoma, HCA, I; nodular focal hyperplasia, NFH, 2), while the EDA+ was only detectable in I of the 2 cases of NFH. In addition, both EDA+ and EDB+ isoforms were expressed in 5 out of 9 cirrhotic livers surrounding the tumors. This molecular analysis, which can also be performed on small liver biopsies (2 mg), may therefore be a useful additional tool in the diagnosis of HCC.

Alternative Splicing↗
PubMed1994

Correction of the defective extracellular matrix of Ehlers-Danlos syndrome skin fibroblasts by dexamethasone.

Skin fibroblasts derived from Ehlers-Danlos syndrome (EDS) patients lack an organized extracellular matrix (ECM) of fibronectin (FN) and often show an accumulation of cytoplasmic FN. The treatment of EDS cells of different types (I to VIII) with 10(-7) M dexamethasone (dex), as well as cocultivation with control fibroblasts, induced in most cases the assembly of a FN-like ECM. The study of FN mRNA expression by dot-blot hybridization and of FN released into the culture media of EDS cells showed that the correction of the defective FN-ECM of EDS cells by dex treatment is associated in most cases with an increase of FN mRNA synthesis and of secreted FN.

Cells, Cultured↗
PubMed1994

Uncommon clinical presentation of a lymphocytic lymphoma of intermediate differentiation in a patient with systemic sclerosis.

The association of systemic sclerosis (SSc) and non-Hodgkin lymphoma is a rare event and its pathogenetic mechanism remains to be clarified. We describe a previously unreported association of SSc with a lymphocytic lymphoma of intermediate differentiation (IDL), involving the gastrointestinal tract, gallbladder and one salivary gland. Whereas the morphological, immunological and cytogenetic features were typical of IDL, the extensive extranodal involvement and the association with an autoimmune disorder were suggestive of two other lymphomas of mantle lineage: mucosa-associated lymphoid tissue (MALT) lymphoma and monocytoid B-cell lymphoma (MBCL).

Female↗
PubMed1993

The type III-9 repeat of human fibronectin is encoded by a single exon which is not alternatively spliced.

Type III homologies of human fibronectin are generally encoded by two exons, with the exception of the ED-A and ED-B repeats which are encoded by a single exon undergoing alternative splicing. We report that also the type III-9 homology is encoded by a single exon. Further more, RT-PCR analysis, performed on mRNA purified from fetal and adult tissues and from normal and tumor-derived cell types, showed that the III-9 region is not undergoing alternative splicing in all samples tested.

Adult↗
PubMed1993

Loss of heterozygosity on chromosome 11p13 in primary bladder carcinoma.

Although the occurrence of bladder cancer is common, the molecular events underlying the pathogenesis of this cancer remain ill-defined. A loss of heterozygosity (LOH) at specific chromosomal loci may predispose individuals to the development of bladder cancer but this has not been examined in detail. Furthermore, the role that deletion or inactivation of putative tumour suppressor genes might play in the genesis of bladder cancer has not been established. In this study, allelic deletion analysis on the short arm of chromosome 17 of patients with primary bladder tumours failed to show deletion at 17p13 (0/7), a region known to contain the p53 tumour suppressor gene. Chromosome 11p15 showed allelic deletion at the IGF2 locus (2/7: 29%) and the PTH locus (1/11: 9%). However, no deletion was observed at the CALCA locus (0/6). LOH at 11p13, a region containing the Wilm's tumour suppressor gene (WT1), was also studied. Analysis of LOH at 11p13 showed deletion at the CAT locus (13/18: 72%), the delta J/D11S414 locus (5/15: 33%), the WT1 locus (7/14: 50%) and the FSHB locus (6/16: 38%). The significance of these findings is discussed.

Alleles↗