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1.
Monaldi Arch Chest Dis ; 67(3): 135-41, 2007 Sep.
Article in English | MEDLINE | ID: mdl-18018752

ABSTRACT

BACKGROUND AND AIM: Asthma that begins around the time of menopause is frequently characterised by marked clinical severity and poor response to treatment. We sought to assess the clinical characteristics, bronchial responsiveness, perception of induced bronchoconstriction and airway inflammation in women with menopausal asthma, as compared to women of a similar age with pre-existing asthma. METHODS: Nine women with pre-existing asthma were selected for clinical severity (symptoms, lung function and medication requirements) similar to that in 11 women with menopausal asthma. Anti-asthmatic treatment in all of the study patients included high dose inhaled (with or without oral) corticosteroids. RESULTS: The women with menopausal asthma demonstrated less atopy, more chronic recurrent sinusitis, similar airway responsiveness, and similar perception of induced bronchoconstriction, but a significantly higher sputum eosinophil count (19.5 +/- 10.8 versus 3.3 +/- 4.3%; p < 0.001) and a higher severe exacerbation rate during the 1-year follow-up period (5.09 +/- 4.85 versus 0.78 +/- 0.97; p < 0.05). Sputum eosinophil count and severe asthma exacerbation rate correlated well in both groups considered as a whole (r = 0.65; p < 0.005). CONCLUSION: The eosinophilic airway inflammation present in women with menopausal asthma is poorly responsive to anti-inflammatory treatment with corticosteroids and predisposes to frequent severe exacerbations. Airway inflammation should be monitored in women with menopausal asthma.


Subject(s)
Age of Onset , Anti-Asthmatic Agents/administration & dosage , Asthma/physiopathology , Health Status , Menopause/physiology , Adult , Asthma/etiology , Female , Humans , Middle Aged , Respiratory Function Tests , Severity of Illness Index
2.
G Ital Med Lav Ergon ; 29(3 Suppl): 836-8, 2007.
Article in Italian | MEDLINE | ID: mdl-18409989

ABSTRACT

Obstructive Sleep Apnea Syndrome (OSAS) is a very common disease in work age. Aim of study is to assess the impact of OSAS in a workers population. 138 workers (M 117, F 21), age 35-65 (mean 52.66 +/- 3.042) consecutively referred to Respiratory Hospital Monaldi and to Occupational Health Medicine Department of Second University of Naples performed an anthropometric evaluation of BMI, neck and an overnight polisomnography with Embletta X10 (Flaga Medical Devices; Reykjavik, Iceland). Workers' population was divided into three groups according to the impact of daytime sleepiness on work efficiency. Occupational Health Medicine needs to evaluate the high prevalence of obesity and metabolic syndrome (OSAS, diabetes, insulin-resistance) in work age population.


Subject(s)
Occupational Health , Sleep Apnea, Obstructive , Work , Adult , Aged , Female , Humans , Male , Middle Aged , Sleep Apnea, Obstructive/physiopathology
3.
Oncogene ; 25(38): 5201-9, 2006 Aug 28.
Article in English | MEDLINE | ID: mdl-16936738

ABSTRACT

Rb family proteins (pRb/p105, Rb2/p130 and p107) play a key role in cell cycle control and are worthily involved in transcription repression and tumor suppression. The mechanisms of transcriptional activation and repression by the Rb gene family has been extensively investigated: pRb, pRb2/p130 and p107 interact with different E2F family factors and can inhibit E2F responsive promoters, interfering with progression of cell cycle, gene transcription, initiation of apoptotic process and cell differentiation. Recent studies have indicated that Rb and Rb2/p130 may be involved in cellular response to DNA damage events, by influencing the transcription of factors involved in DNA repair pathways. In particular, evidences suggest that Rb loss and target gene deregulation impacts on the repair of UV-induced pyrimidine pyrimidone photoproducts (6-4 PP) by regulating the expression of several DNA damage factors involved in UV DNA damage repair processes, including proliferating cell nuclear antigen. Ongoing studies are focused on the mechanisms by which Rb family genes drive cell cycle exit following DNA damage induction, and how Rb gene family's interaction with chromatin remodeling factors can influence DNA repair dynamics.


Subject(s)
Cell Cycle/genetics , Eye Neoplasms , Genes, Retinoblastoma , Retinoblastoma , Animals , DNA Damage/radiation effects , DNA Repair/radiation effects , Eye Neoplasms/genetics , Eye Neoplasms/prevention & control , Humans , Multigene Family , Retinoblastoma/genetics , Retinoblastoma/prevention & control , Transcription, Genetic , Ultraviolet Rays
4.
Monaldi Arch Chest Dis ; 63(2): 114-7, 2005 Jun.
Article in English | MEDLINE | ID: mdl-16128228

ABSTRACT

The follow-up of Differentiated Thyroid Cancer conventionally includes serum thyroglobulin and periodic Whole Body Scans. The uptake of 131-I in normal and pathological tissues different from metastatic thyroid cancer sites is a cause of false-positive scans. Among them, mediastinal uptake caused by thymic hyperplasia can be observed. The aim of the present study was to review a series of 573 patients with differentiated thyroid cancer treated with 131-I after surgery between 1992 and 2003 looking above all for those with mediastinal images resembling thymus. This evaluation is presented together with some hypotheses on the relationships between thymus and thyroid. Moreover, some considerations are made on the differential diagnosis between thymus and mediastinal tumour thyroid residues.


Subject(s)
Iodine Radioisotopes/therapeutic use , Mediastinum/diagnostic imaging , Radiopharmaceuticals/therapeutic use , Thymus Gland/diagnostic imaging , Thyroid Neoplasms/radiotherapy , Adenocarcinoma/radiotherapy , Adenocarcinoma/surgery , Adenocarcinoma, Follicular/radiotherapy , Adenocarcinoma, Follicular/surgery , Adolescent , Adult , Aged , Aged, 80 and over , Carcinoma, Papillary/radiotherapy , Carcinoma, Papillary/surgery , False Positive Reactions , Female , Humans , Hyperplasia , Male , Middle Aged , Radionuclide Imaging , Radiotherapy, Adjuvant , Retrospective Studies , Thymus Gland/pathology , Thyroid Neoplasms/surgery , Whole-Body Counting
5.
J Clin Pathol ; 58(7): 734-9, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15976342

ABSTRACT

BACKGROUND: Experimental evidence suggests that lung cancer development and progression can be linked to an increased proliferation rate. AIMS/METHODS: To evaluate the immunohistochemical expression of seven components of the cell cycle machinery in a series of well characterised non-small cell lung cancer (NSCLC) specimens (n = 105). RESULTS: Multivariate analysis revealed that simultaneous loss of expression of three of these factors--cyclin D1, the cyclin dependent kinase inhibitor p16, and the tumour suppressor retinoblastoma protein Rb2/p130--correlated with survival, confirming the hypothesis that the cyclin D1-p16-retinoblastoma tumour suppressor pathway is inactivated in most lung cancer samples. CONCLUSIONS: These results suggest that loss of control of cell cycle checkpoints is a common occurrence in lung cancer and support the idea that functional cooperation between different cell cycle regulatory proteins constitutes another level of regulation in cell growth control and tumour suppression.


Subject(s)
Biomarkers, Tumor/metabolism , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Cycle Proteins/metabolism , Lung Neoplasms/metabolism , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/surgery , Cyclin D1/metabolism , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Female , Humans , Immunoenzyme Techniques , Lung Neoplasms/pathology , Lung Neoplasms/surgery , Male , Middle Aged , Neoplasm Proteins/metabolism , Neoplasm Staging , Prognosis , Proteins/metabolism , Retinoblastoma-Like Protein p130 , Survival Analysis
6.
J Clin Pathol ; 57(9): 993-4, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15333666

ABSTRACT

Hibernomas are rare benign tumours that arise most often in adults from the remnants of fetal brown adipose tissue. They usually affect muscle and subcutaneous tissue and are asymptomatic and slow growing. The distribution of this tumour follows the sites of persistence of brown fat. Out of more then 100 cases described in the word literature only three hybernomas were mediastinal. A recent clinicopathological study of 170 cases from the Armed Forces Institute of Pathology confirmed the exceptionality of the intrathoracic location. This report describes a very rare case of mediastinal hibernoma in a young man.


Subject(s)
Lipoma/diagnosis , Mediastinal Neoplasms/diagnosis , Adult , Humans , Lipoma/pathology , Lipoma/surgery , Male , Mediastinal Neoplasms/pathology , Mediastinal Neoplasms/surgery , Tomography, X-Ray Computed
7.
Int J Obes Relat Metab Disord ; 26(3): 370-5, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11896492

ABSTRACT

OBJECTIVE: To investigate the possible associations between sleep apnea syndrome, hyperinsulinemia/insulin resistance and hyperleptinemia in subjects with different degrees of body mass index. DESIGN: To test for the presence or absence of sleep apnea syndrome in association with hyperinsulinemia/insulin resistance and hyperleptinemia. SUBJECTS: Twenty subjects with different body mass index (mean BMI 30.9+/-4.2). MEASUREMENTS: Insulin action and plasma soluble leptin receptor were measured by euglycemic hyperinsulinemic glucose clamp and by ELISA method, respectively. Occurrence of sleep apnea syndrome was assessed by clinical and nocturnal monitoring using a validated sleep apnea recorder. RESULTS: The apnea/hypopnea index (AHI) was positively correlated with plasma soluble leptin receptor (0.76; P<0.001) and negatively with the degree of insulin-mediated glucose uptake (r=-0.73; P<0.001). In a multivariate analysis AHI was associated with plasma soluble leptin receptor and insulin mediated glucose uptake independently of age, gender, BMI, plasma leptin levels and PaCO(2). CONCLUSION: Sleep apnea syndrome is associated with plasma soluble leptin receptor and insulin resistance independently of BMI.


Subject(s)
Carrier Proteins/blood , Insulin Resistance , Receptors, Cell Surface , Sleep Apnea Syndromes/etiology , Adult , Body Mass Index , Carbon Dioxide/analysis , Enzyme-Linked Immunosorbent Assay , Female , Glucose Clamp Technique , Humans , Insulin/blood , Leptin/blood , Male , Middle Aged , Receptors, Leptin , Solubility , Triglycerides/blood
8.
Monaldi Arch Chest Dis ; 57(3-4): 177-9, 2002.
Article in English | MEDLINE | ID: mdl-12619378

ABSTRACT

Lung cancer is the most frequent cause of death from neoplastic pathology in the western world (28% of total mortality from neoplasia); in 90% of cases it is caused by tobacco smoke. In Italy, a stabilisation trend in males is observed, while female mortality is still increasing. During the first two decades of 2000, a more or less evident pathology decline is expected in males and a decline/stabilisation in females, according to the results of anti-smoking and anti-pollution campaigns. Lung cancer can be considered a pathology of multifactorial etiopathogenesis, where out- and indoor environmental risk factors, together with genetic factors and living habits, combine to explain the differences in increase of neoplasy incidence in exposed populations and categories. Several chemical, physical and biological agents have been identified as promoting or initiating factors of a series of genic modifications inducing "genetic instability" and subsequent alteration of the programmed cell death regulation ("apoptosis") and of the cell cycle responsible for somatic cell alterations ("transformed phenotype") in previously normal tissues. This paper outlines the different risk factors responsible for lung neoplasies, and discusses the molecular-biological mechanisms involved in the pathogenesis of lung cancer.


Subject(s)
Air Pollution/adverse effects , Lung Neoplasms/physiopathology , Apoptosis/physiology , Causality , Cell Cycle/physiology , Humans , Lung Neoplasms/epidemiology , Lung Neoplasms/etiology , Lung Neoplasms/genetics , Risk Factors , Tobacco Smoke Pollution , Urban Population
9.
FEBS Lett ; 508(3): 379-84, 2001 Nov 23.
Article in English | MEDLINE | ID: mdl-11728456

ABSTRACT

We have recently reported that the urokinase-type plasminogen activator (uPA) up-regulates the cell surface expression of its own receptor (uPAR) in several cell types, independently of its enzymatic activity. uPA has no effect on kidney 293 cells which do not express uPAR and then cannot bind uPA. Kidney cells, transfected with the coding region of uPAR cDNA, express very large amounts of uPAR and respond to uPA stimulation by regulating uPAR both at mRNA and protein levels. uPA effect occurs also in the presence of the transcriptional inhibitor dichloro-ribobenzimidazole, whereas it is abolished by the protein synthesis inhibitor cycloheximide. Moreover, uPA-dependent uPAR up-regulation correlates with the increase of a complex between the coding region of uPAR mRNA and an unknown cellular factor. We then propose that uPA regulates uPAR expression at a post-transcriptional level, by promoting the binding of uPAR mRNA to a stabilizing factor.


Subject(s)
Receptors, Cell Surface/genetics , Urokinase-Type Plasminogen Activator/pharmacology , 3' Untranslated Regions , Cell Line , Cycloheximide/pharmacology , Humans , Isoflurophate/pharmacology , Promoter Regions, Genetic , Protein Synthesis Inhibitors/pharmacology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Cell Surface/metabolism , Receptors, Urokinase Plasminogen Activator , Reverse Transcriptase Polymerase Chain Reaction , Transcription, Genetic , Transfection , Up-Regulation , Urokinase-Type Plasminogen Activator/metabolism
10.
J Biol Chem ; 276(47): 43850-9, 2001 Nov 23.
Article in English | MEDLINE | ID: mdl-11571276

ABSTRACT

Members of the heterogeneous nuclear ribonucleoprotein (hnRNP) H protein family, H, H', F, and 2H9, are involved in pre-mRNA processing. We analyzed the assembly of these proteins from splicing extracts onto four RNA regulatory elements as follows: a high affinity hnRNP A1-binding site (WA1), a sequence involved in Rev-dependent export (p17gag INS), an exonic splicing silencer from the beta-tropomyosin gene, and an intronic splicing regulator (downstream control sequence (DCS) from the c-src gene. The entire family binds the WA1, instability (INS), and beta-tropomyosin substrates, and the core-binding site for each is a run of three G residues followed by an A. Transfer of small regions containing this sequence to a substrate lacking hnRNP H binding activity is sufficient to promote binding of all family members. The c-src DCS has been shown to assemble hnRNP H, not hnRNP F, from HeLa cell extracts, and we show that hnRNP 2H9 does not bind this element. The DCS contains five G residues followed by a C. Mutation of the C to an A changes the specificity of the DCS from a substrate that binds only hnRNP H/H' to a binding site for all hnRNP H family members. We conclude that the sequence GGGA is recognized by all hnRNP H family proteins.


Subject(s)
Heterogeneous-Nuclear Ribonucleoprotein Group A-B , RNA, Messenger/metabolism , RNA-Binding Proteins/metabolism , Ribonucleoproteins/metabolism , Animals , Base Sequence , Chromatography, Affinity , Exons , Gene Products, gag/chemistry , Gene Products, gag/metabolism , HeLa Cells , Heterogeneous Nuclear Ribonucleoprotein A1 , Heterogeneous-Nuclear Ribonucleoprotein Group F-H , Heterogeneous-Nuclear Ribonucleoproteins , Humans , RNA Splicing , RNA, Messenger/chemistry , RNA-Binding Proteins/isolation & purification , Rats , Ribonucleoproteins/isolation & purification , Tropomyosin/genetics , Tropomyosin/metabolism
11.
Cancer Res ; 61(2): 462-8, 2001 Jan 15.
Article in English | MEDLINE | ID: mdl-11212232

ABSTRACT

Angiogenesis is an essential step in the progression of tumor formation and development. The switch to an angiogenetic phenotype can occur as a distinct step before progression to a neoplastic phenotype and is linked to genetic changes such as mutations in key cell cycle regulatory genes. The pathogenesis of the angiogenetic phenotype may involve the inactivation of tumor suppressor genes such as the "guardian of the genome," p53, and the cyclin-dependent kinase inhibitor p16. Retinoblastoma family member RB2/p130 encodes a cell cycle regulatory protein and has been found mutated in different tumor types. Overexpression of RB2/p130 not only suppresses tumor formation in nude mice but also causes regression of established tumor grafts, suggesting that RB2/p130 may modulate the angiogenetic balance. We found that induction of RB2/p130 expression using a tetracycline-regulated gene expression system as well as retroviral and adenoviral-mediated gene delivery inhibited angiogenesis in vivo. This correlated with pRb2/p130-mediated down-regulation of vascular endothelial growth factor protein expression both in vitro and in vivo.


Subject(s)
Endothelial Growth Factors/genetics , Lymphokines/genetics , Neovascularization, Pathologic/genetics , Phosphoproteins/genetics , Proteins , Animals , Blotting, Northern , Cell Line , Down-Regulation , Endothelial Growth Factors/analysis , Female , Gene Expression Regulation , Genetic Therapy , Humans , Immunochemistry , Lymphokines/analysis , Mice , Mice, Nude , Neoplasm Transplantation , Neoplasms, Experimental/blood supply , Neoplasms, Experimental/genetics , Neoplasms, Experimental/therapy , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/therapy , Phosphoproteins/analysis , Platelet Endothelial Cell Adhesion Molecule-1/analysis , RNA/genetics , RNA/metabolism , Retinoblastoma-Like Protein p130 , Transplantation, Heterologous , Tumor Cells, Cultured , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors
12.
Anticancer Res ; 20(5A): 3301-5, 2000.
Article in English | MEDLINE | ID: mdl-11062757

ABSTRACT

The first cyclin dependent kinase inhibitor to be discovered was the p21 cdk interacting protein (a.k.a., WAF1, Cip1, CAP20, Sdi1, mda6). p21 expression may or may not be dependent on p53. This pathway also inhibits DNA replication by merit of p21's interaction with PCNA, but it has also been shown that this same inhibitory interaction with p21 does not affect PCNA DNA repair abilities. We assessed the immunohistochemical expression of p21 protein in 60 curative surgical resected non small cell lung cancers relating it to the expression of PCNA to clarify the contribution of the p21/PCNA pathway to the development of NSCLC. We did not find any relationship between PCNA and p21 expression. This last result may indicate that the mechanism by which PCNA controls the DNA repair is the most important activity of this protein during lung cancer progression and development, compared to its contribution to cell proliferation. In fact, this last event is strongly counteracted by p21 expression, which in this last case works as an inhibitor of PCNA expression. In conclusion this study highlighted the important role of the p21/PCNA pathway in lung carcinogenesis, pointing out the contribution of PCNA to the response to lung aggression and not only it's role as a proliferation index. Therefore, these results offer a background to further study to evaluate potential novel therapeutic approaches to lung cancer treatment.


Subject(s)
Carcinoma, Non-Small-Cell Lung/metabolism , Cyclins/biosynthesis , Enzyme Inhibitors , Lung Neoplasms/metabolism , Proliferating Cell Nuclear Antigen/biosynthesis , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Cyclin-Dependent Kinase Inhibitor p21 , Humans , Lung Neoplasms/pathology
13.
Cancer Res ; 60(10): 2737-44, 2000 May 15.
Article in English | MEDLINE | ID: mdl-10825149

ABSTRACT

The retinoblastoma family of proteins, pRb/p105, p107, and pRb2/ p130, cooperate to regulate cell cycle progression through the G1 phase of the cell cycle. Each of the family members realize their common goal of G1-S checkpoint regulation through overlapping and unique growth regulatory pathways. We took advantage of a tetracycline-regulated gene expression system to control the expression of RB2/p130 in JC virus-induced hamster brain tumor cells to study in vivo the molecular mechanisms used by pRb2/p130 to elicit its growth-suppressive function. We have previously used this system to demonstrate that induction of pRb/ p130 expression suppresses tumor growth in vivo by overcoming neoplastic transformation mediated by the large T-antigen oncoprotein of JCV (JCV TAg). Here we found that induction of pRb2/p130 in vivo specifically inhibits cyclin A- and cyclin E-associated kinase activity and by doing so induces p27Kip1 levels presumably by inhibiting p27Kip1-targeted proteolysis by cyclin E-Cdk2 phosphorylation of p27Kip1. RB2/p130 induction also decreased cyclin A and the transcription factor E2F-1 while increasing cyclin E at both the transcriptional and protein levels of expression. The growth inhibitory activity of pRb2/p130 also correlated with its E2F-binding capacity. Furthermore, p27Kip1 and pRb2/p130 were found to be targets of the JCV TAg oncoprotein and to interact in vivo with each other independently from the presence of TAg. Interestingly, pRb2/p130 expression negatively modulated the binding of p27Kip1 to JCV TAg. These data suggest that pRb2/p130 and p27Kip1 may cooperate in regulating cellular proliferation, and both may be involved in a negative feedback regulatory loop with cyclin E.


Subject(s)
CDC2-CDC28 Kinases , Carrier Proteins , Cyclin E/physiology , Microtubule-Associated Proteins/physiology , Phosphoproteins/physiology , Proteins , Retinoblastoma Protein/biosynthesis , Retinoblastoma Protein/physiology , Tumor Suppressor Proteins , Animals , COS Cells , Cell Cycle Proteins/metabolism , Chlorocebus aethiops , Cricetinae , Cyclin A/metabolism , Cyclin-Dependent Kinase 2 , Cyclin-Dependent Kinase Inhibitor p27 , Cyclin-Dependent Kinases/metabolism , DNA-Binding Proteins/metabolism , Down-Regulation , E2F Transcription Factors , E2F1 Transcription Factor , Genes, Tumor Suppressor , Humans , Models, Biological , Phosphoproteins/genetics , Protein Serine-Threonine Kinases/metabolism , Retinoblastoma-Binding Protein 1 , Retinoblastoma-Like Protein p130 , Transcription Factor DP1 , Transcription Factors/metabolism , Tumor Cells, Cultured
14.
Clin Cancer Res ; 6(3): 754-64, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10741694

ABSTRACT

Lung cancer is the second cause of death after cardiovascular diseases and is the major cause of cancer deaths in the Western world. Large scale screening trials conducted 15-20 years ago using chest X-rays and sputum cytology were able to detect stage I cancers but failed to impact on survival. This is because of the early metastatic potential of small primary tumors. It is important then to detect lung cancer at an earlier stage, studying and identifying genetic lesions that could indicate a new target(s) for gene therapy. The retinoblastoma-related gene pRb2/p130, a new tumor suppressor gene cloned in 1993, is emerging as one of the candidate markers and targets for gene therapeutic approach. Effective genetic therapy requires both a genetic material to be used therapeutically and a means to deliver it. A scope for this review is to examine some of the gene delivery systems mostly used, discussing their weaknesses and strengths, and to discuss the role of pRb2/p130 in lung cancer.


Subject(s)
Genetic Therapy , Lung Neoplasms/therapy , Phosphoproteins/genetics , Proteins , Gene Transfer Techniques , Genetic Vectors , Humans , Lung Neoplasms/genetics , Retinoblastoma-Like Protein p130
15.
Cancer Res ; 60(2): 372-82, 2000 Jan 15.
Article in English | MEDLINE | ID: mdl-10667590

ABSTRACT

The retinoblastoma (Rb) family consists of the tumor suppressor pRb/p105 and related proteins p107 and pRb2/p130. Recent immunohistochemical studies of the retinoblastoma family of proteins in 235 specimens of lung cancer show the tightest inverse association between the histological grading in the most aggressive tumor types and pRb2/p130. This led us to study a panel of human lung cancers for mutations in the RB2/p130 gene. Mutations in the Rb-related gene RB2/p130 were detected in 11 of 14 (78.5%) primary lung tumors by single-strand conformation polymorphism and sequence analysis. A Moloney leukemia virus-based retroviral system was set up, and a comparable viral concentration of 1 x 10(7) infectious units/ml was obtained. Retrovirus-mediated delivery of wild-type RB2/p130 to the lung tumor cell line H23 potently inhibited tumorigenesis in vitro and in vivo, as shown by the dramatic growth arrest observed in a colony assay and the suppression of anchorage-independent growth potential and tumor formation in nude mice. The tumors transduced with the RB2/p130 retrovirus diminished in size after a single injection, and a 12-fold reduction in tumor growth after RB2/p130 transduction compared with the Pac-transduced tumors (92% reduction, P = 0.003) and lacZ-transduced tumors (93% reduction, P < 0.001) was found to be statistically significant. These findings provide the missing confirmation that RB2/p130 is a "bona fide" tumor suppressor gene and strengthen the hypothesis that it may be a candidate for cancer gene therapy for lung cancer.


Subject(s)
Genetic Therapy , Lung Neoplasms/genetics , Lung Neoplasms/therapy , Moloney murine leukemia virus , Mutation , Phosphoproteins/genetics , Proteins , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Adenocarcinoma/therapy , Amino Acid Substitution , Animals , Cell Line , Codon, Terminator , Gene Transfer Techniques , Genetic Vectors , Heterozygote , Homozygote , Humans , Lung Neoplasms/pathology , Mice , Mice, Nude , Mutagenesis, Site-Directed , Point Mutation , Polymorphism, Single-Stranded Conformational , Retinoblastoma Protein/genetics , Retinoblastoma-Like Protein p130 , Transfection , Transplantation, Heterologous , Tumor Cells, Cultured
16.
Cancer Res ; 60(1): 8-12, 2000 Jan 01.
Article in English | MEDLINE | ID: mdl-10646842

ABSTRACT

Nasopharyngeal carcinoma (NPC) is an endemic cancer in southern China and northern Africa, and its pathogenesis is not yet well defined at the molecular level. Although the involvement of p53 and of the retinoblastoma gene (RB/p105) in NPC has been well studied, there is paucity of mutational data regarding the retinoblastoma-related gene RB2/p130 in primary tumors and particularly in NPC. We have shown previously that RB2/p130 could be rearranged in a nasopharyngeal cell line. In the present study, we screened by single-strand conformation polymorphism and sequence analysis the retinoblastoma-related gene RB2/p130 for mutations within exons 19-22. Mutations in the RB2/p130 gene were detected in 3 of 10 primary human NPCs from Northern Africa (30%). These findings, along with previous data showing that genetic replacement of RB2/p130 restores a normal growth pathway in the nasopharyngeal cell line Hone-1, strengthen the hypothesis that genetic changes of RB2/p130 may be involved in the development and/or progression of nasopharyngeal cancer and suggest that RB2/p130 could be considered a tumor suppressor gene and may be a candidate for novel gene therapeutic approaches for NPC.


Subject(s)
Frameshift Mutation , Genes, Retinoblastoma/genetics , Nasopharyngeal Neoplasms/genetics , Retinoblastoma Protein/genetics , DNA Mutational Analysis , DNA, Neoplasm/genetics , Humans , Polymerase Chain Reaction , Polymorphism, Single-Stranded Conformational
17.
Anticancer Res ; 20(5C): 3919-22, 2000.
Article in English | MEDLINE | ID: mdl-11268477

ABSTRACT

A case of benign, cystic intrapulmonary teratoma occurring in the right lobe of a 22-year old female is described with grossly and microscopically findings. The connection between the tumor and the segmental bronchus, together with the absence of germ cell neoplasms in other locations, clearly established the true intrapulmonary nature of the lesion. The unusual finding of thymic tissue within the wall supports the possible origin from the third pharyngeal pouch.


Subject(s)
Lung Neoplasms/pathology , Teratoma/pathology , Thymus Gland/pathology , Actins/analysis , Adult , Antigens, CD/analysis , Autopsy , Collagen/analysis , Female , Humans , Keratins/analysis
18.
J Thorac Cardiovasc Surg ; 118(3): 529-35, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10469971

ABSTRACT

OBJECTIVES: The cyclin-dependent kinase p16 (also known as Ink4A, Mts1, Cdkn2, and Cdkn4i) has been proposed as a tumor suppressor gene mapped on chromosome segment 9p21. This study evaluated p16 protein expression in 135 lung cancer specimens and investigated potential genetic alterations occurring in this gene. RESULTS: We found altered p16 immunohistochemical expression to be a frequent event in lung cancer and to be independent of either the histologic type or any other clinical-pathologic feature. Western blot analyses performed on about one third of the specimens correlated highly with these results. In addition, we found p16 immunohistochemical expression to be a favorable prognostic factor in lung cancer in that its reduction or loss correlated with a worse outcome for the patients. Polymerase chain reaction amplification and direct sequencing of p16 exons 1 and 2 revealed no mutations, indicating that p16-altered expression in lung cancer is not necessarily linked to mutational events of these genes. CONCLUSIONS: We conclude that p16-altered expression is both an independent and frequent event in lung cancer and may have an important role in tumorigenesis and in malignant progression of a significant proportion of these cancers. However, the actual incidence and relevance of p16 mutations in this neoplasm continues to be debated, and its analysis seems inconclusive. Our results suggest a prognostic role for the immunodetection of this protein on formalin-fixed and paraffin-embedded specimens. They further suggest its routine use in the evaluation of the frequently unpredictable behavior of lung cancer.


Subject(s)
Adenocarcinoma/genetics , Carcinoma, Small Cell/genetics , Carcinoma, Squamous Cell/genetics , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Gene Expression , Genes, p16/genetics , Lung Neoplasms/genetics , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Blotting, Western , Carcinoma, Small Cell/metabolism , Carcinoma, Small Cell/pathology , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , DNA, Neoplasm/analysis , Exons , Female , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Polymerase Chain Reaction , Prognosis
19.
EMBO J ; 18(14): 4060-7, 1999 Jul 15.
Article in English | MEDLINE | ID: mdl-10406810

ABSTRACT

Splicing of the human immunodeficiency virus type 1 (HIV-1) pre-mRNA must be inefficient to provide a pool of unspliced messages which encode viral proteins and serve as genomes for new virions. Negative cis-regulatory elements (exonic splicing silencers or ESSs) are necessary for HIV-1 splicing inhibition. We demonstrate that heterogeneous nuclear ribonucleoproteins (hnRNPs) of the A and B group are trans-acting factors required for the function of the tat exon 2 ESS. Depletion of hnRNP A/B proteins from HeLa cell nuclear extract activates splicing of tat exon 2 pre-mRNA substrate. Splicing inhibition is restored by addition of recombinant hnRNP A/B proteins to the depleted extract. A high-affinity hnRNP A1-binding sequence can substitute functionally for the ESS in tat exon 2. These results demonstrate that hnRNP A/B proteins are required for repression of HIV-1 splicing.


Subject(s)
Gene Products, tat/genetics , HIV-1/genetics , Heterogeneous-Nuclear Ribonucleoprotein Group A-B , RNA Splicing , RNA, Messenger/metabolism , RNA, Viral/metabolism , Ribonucleoproteins/metabolism , Base Sequence , Binding Sites , Cell Nucleus/genetics , Exons/genetics , Gene Expression Regulation, Viral , HeLa Cells , Heterogeneous Nuclear Ribonucleoprotein A1 , Heterogeneous-Nuclear Ribonucleoproteins , Humans , Mutation , Nuclear Proteins/chemistry , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , RNA, Messenger/analysis , RNA, Messenger/genetics , RNA, Viral/analysis , RNA, Viral/genetics , RNA-Binding Proteins/chemistry , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Regulatory Sequences, Nucleic Acid/genetics , Ribonucleoproteins/chemistry , Ribonucleoproteins/genetics , tat Gene Products, Human Immunodeficiency Virus
20.
Anticancer Res ; 19(1B): 825-7, 1999.
Article in English | MEDLINE | ID: mdl-10216500

ABSTRACT

Bax, bcl-2 and their homologues regulate a distal step in an evolutionary very well conserved pathway of apoptotic cell death. It plays a crucial role in the balance between proliferation rate and cell viability. Thus in the last years the attention of the scientific community towards these proteins has remarkably increased, in particular in the oncologic field. We developed an immunohistochemical assay allowing us to evaluate the bax expression in formalin fixed and paraffin embedded lung cancer tissues to investigate bax expression in a cohort of 55 patients affected by non-small cell lung cancer. We detected high expression of bax in 72.7% of our patients. When we statistically analyzed our data we did not find any correlation between bax expression and any clinicopathologic parameters (sex, age, TNM status, tumor grade, histological type). In conclusion, our study shows the frequent overexpression of bax, and this highlights the "apoptotic tendency" of cells during the neoplastic proliferation. But, the role of bax in non-small cell lung cancer pathogenesis still remains unclear and further studies of large numbers of patients, including different stage groups, are needed to better define the involvement of this protein in the complex mechanism of lung carcinogenesis.


Subject(s)
Apoptosis , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Proto-Oncogene Proteins , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Cytoplasm/metabolism , Female , Gene Expression , Humans , Immunohistochemistry , Male , Middle Aged , Proto-Oncogene Proteins/biosynthesis , Proto-Oncogene Proteins c-bcl-2/biosynthesis , bcl-2-Associated X Protein
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