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Biomedical subjects

A Gemma

Publications and source records attributed to A Gemma.

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

Allelic deletion analysis of the FHIT gene predicts poor survival in non-small cell lung cancer.

The fragile histidine triad (FHIT) gene at chromosome 3p14.2 is a candidate tumor suppressor gene linked to cancers of the lung, breast, colon, pancreas, and head and neck. Reports of frequent allelic deletion and abnormal transcripts in primary lung tumors plus recent evidence that it is targeted by tobacco smoke carcinogens suggest that it plays an important role in lung carcinogenesis. Non-small cell lung carcinoma still maintains a poor 5-year survival rate with the stage of disease at presentation as a major determinant of prognosis. We examined for allelic deletion at the FHIT locus in a series of 106 non-small cell lung carcinomas for which a full clinical, epidemiological, and 5-year survival profile was available. We found an allelic deletion frequency of 38% at one or two intragenic microsatellites. Allelic deletion of FHIT was related to tumor histology with 4 of 20 adenocarcinomas (20%) displaying loss of heterozygosity (LOH) compared with 12 of 22 (55%) nonadenocarcinomas (P = 0.03). We found that 63% of tumors with LOH of FHIT also had p53 missense mutations whereas only 26% with LOH had wild type p53 negative sequence (P = 0.02). We also found a significant trend toward poorer survival in patients with LOH of at least one locus of the FHIT gene (log rank, P = 0.01). This survival correlation is independent of tumor stage, size, histological subtype, degree of differentiation, and p53 mutation status. Our data support the hypothesis that the loss of the FHIT contributes to the molecular pathogenesis of human lung cancer and is an indicator of poor prognosis.

Acid Anhydride Hydrolases↗
PubMed1998

hSmad5 gene, a human hSmad family member: its full length cDNA, genomic structure, promoter region and mutation analysis in human tumors.

hSmad (mothers against decapentaplegic)-related proteins are important messengers within the Transforming Growth Factor-beta1 (TGF-beta1) superfamily signal transduction pathways. To further characterize a member of this family, we obtained a full length cDNA of the human hSmad5 (hSmad5) gene by rapid amplification of cDNA ends (RACE) and then determined the genomic structure of the gene. There are eight exons and two alternative transcripts; the shorter transcript lacks exon 2. We identified the hSmad5 promoter region from a human genomic YAC clone by obtaining the nucleotide sequence extending 1235 base pairs upstream of the 5' end of the cDNA. We found a CpG island consistent with a promoter region, and we demonstrated promoter activity in a 1232 bp fragment located upstream of the transcription initiation site. To investigate the frequency of somatic hSmad5 mutations in human cancers, we designed intron-based primers to examine coding regions by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. Neither homozygous deletions or point mutations were found in 40 primary gastric tumors and 51 cell lines derived from diverse types of human cancer including 20 cell lines resistant to the growth inhibitory effects of TGF-beta1. These results suggest that the hSmad5 gene is not commonly mutated and that other genetic alterations mediate the loss of TGF-beta1 responsiveness in human cancers.

Alternative Splicing↗
PubMed1998

Changes in nutritional status during the hospital stay: a predictor of long-term survival.

The objectives of this prospective observational study were to assess whether: 1) midarm circumference (MAC), previously shown to predict in-hospital mortality, maintains its prognostic implication after discharge; 2) in-hospital changes in aspecific indicators of the health status are predictors of long-term survival. The study population consisted of 249 patients from the general community [mean age 80 +/- 7 (70-99) years], consecutively discharged from geriatric and medical wards of an acute care hospital. Changes in health status during hospitalization were recorded (dynamic or delta variables) and health-related variables were collected at discharge (discharge variables). The relationship of both sets of variables to survival over a 3-year period was assessed by Cox's proportional hazards regression analysis. The discriminatory efficacy of predictive models was estimated by the Hanley and McNeil method. Survival curves were drawn with the patients alternatively grouped according to the presence or absence of each of the predictive variables. Serum albumin < 3.5 g/dL (hazard rate = 0.57, 95% confidence limits = 0.33-0.96) and dependency in at least one ADL (h.r. = 0.87, c.l. = 0.79-0.98) were found to be associated with increased mortality, and delta MAC (h.r. = 1.03, c.l. = 1.01-1.05), i.e., there was a positive change or no change in MAC from admission to discharge, with increased survival. A slightly weaker predictive model was obtained using only discharge variables. However, Hanley and McNeil's analysis showed that both models were far from achieving the optimal discrimination of high from low risk subjects. Effects on survival of individual variables varied in magnitude and dependency on time. We concluded that measuring in-hospital changes in nutritional status might improve prediction of long-term survival. Attempts should be made to identify variables having the strongest prognostic implications, and to tailor dynamic assessment to the needs of selected categories of patients.

Activities of Daily Living↗
PubMed1998

Predicting cognitive decline in patients with hypoxaemic COPD.

The objective was to identify predictors of cognitive decline in patients with hypoxaemic COPD on continuous oxygen therapy. Eighty-four consecutive ambulatory hypoxaemic COPD patients in stable clinical conditions were prospectively studied over the course of 2 yr. Baseline multidimensional assessment included respiratory function tests, blood gas analysis, Mini Mental Status (MMS) test, Geriatric Depression Scale (GDS), Activities of Daily Living (ADLs) and Charlson's index of comorbidity. Reassessments were made 1 yr and 2 yr thereafter. Sequential changes in MMS, GDS and ADLs were assessed by Friedman's ANOVA by rank test. Forty patients completed the study (group A), while 44 died or were lost to follow-up (group B). Group B was characterized by more severe respiratory function impairment and worse performances on ADLs and GDS. In group A, MMS deteriorated from baseline to the 1 yr and 2 yr reassessments (27 +/- 2.9 vs. 25.8 +/- 4.1 and 25.4 +/- 4, P < 0.005), whereas GDS and ADLs did not change significantly; the 23 patients experiencing a decline of MMS had baseline lower percentage predicted FVC (52.3 +/- 17.1 vs. 66.9 +/- 13.4, P < 0.03) and FEV1 (27.2 +/- 8.6 vs. 44 +/- 26.8, P < 0.02) values and better affective status (GDS score: 11.9 +/- 7.7 vs. 16.5 +/- 5.6, P < 0.04). Two-year changes in MMS and in GDS scores were inversely correlated (Spearman's p = -0.32, P = 0.04). Cognitive decline is faster in the presence of severe bronchial obstruction and parallels the worsening of the affective status in COPD patients on oxygen therapy. The onset of depression rather than baseline depressive symptoms seems to be a risk factor for cognitive decline.

Activities of Daily Living↗
PubMed1997

Mutation analysis of the transforming growth factor-beta type II receptor in human cell lines resistant to growth inhibition by transforming growth factor-beta.

The transforming growth factor-beta (TGF-beta) binds the type II TGF-beta growth factor receptor (RII) to inhibit the growth of most epithelial tissues. Most human colon and gastric cancers with microsatellite instability (MI) have frameshift mutations in polynucleotide repeats within the RII coding region; these mutations truncate the receptor protein and disable the serine/threonine kinase to produce TGF-beta resistance. To further investigate the type, frequency and tissue distribution of RII mutations, we selected 24 human cancer cell lines from various tissues which were previously reported to be resistant to the inhibitory effects of TGF-beta. We developed protocols for non-isotopic SSCP analysis of PCR products from genomic DNA samples, and we tested them for microsatellite instability. PCR-SSCP analysis followed by DNA sequencing identified deletion mutations in the exon 3 poly-adenine tract in three colon tumor cell lines: LS174T and SW48 had a single base deletion and LS411 had a two base deletion. Among the 24 previously unreported cell lines, only these three demonstrated microsatellite instability. These and other recent data indicate that RII mutations are essentially confined to colon and gastric cancers with microsatellite instability. The narrow spectrum of tissues containing RII mutations illustrates the complexity of genetic checkpoints in human carcinogenesis.

Cell Division↗
PubMed1997

FHIT mutations in human primary gastric cancer.

Allelic deletion of multiple regions on the short arm of chromosome 3 (3p) implies the presence of multiple important tumor suppressor genes in human carcinogenesis. The FHIT gene, identified recently in chromosome 3p14.2, shows frequent allelic deletion and aberrant transcripts in gastrointestinal tumors. After determining the intron sequences flanking each of the coding exons of the FHIT gene and designing intron primers to facilitate mutation analysis of genomic DNA samples, we analyzed the complete coding sequences in matched cancer and normal tissues from 40 cases with primary gastric cancer using intron primers, PCR-single-strand conformation polymorphism analysis, and direct sequencing. A somatic missense mutation in exon 6, codon 61, ACG (threonine) --> ATG (methionine) was found in a signet ring cell adenocarcinoma. We also evaluated allelic deletion in these tumors by PCR-based microsatellite analysis; allelic deletion occurred in 42.1% (16 of 38) of evaluable cases. This is the first report of a somatic missense mutation of the FHIT gene in a primary tumor. Presence of a point mutation and frequent allelic deletions are consistent with the hypothesis that FHIT gene alterations are involved in the development of primary gastric cancers.

Acid Anhydride Hydrolases↗
PubMed1997

The interaction between age and comorbidity contributes to predicting the mortality of geriatric patients in the acute-care hospital.

OBJECTIVE: To test the predictive power of comorbidity and of the interaction between age and comorbidity in geriatric patients with acute medical illness. DESIGN: Prospective observational study. SETTING: Medical and geriatric wards of an acute-care hospital. SUBJECTS: Three hundred and seventy patients over 70 years of age consecutively admitted in an 18-month period. MAIN OUTCOME MEASURE: In-hospital mortality. METHOD: On admission a multidimensional assessment was performed, and a comorbidity index and an age-comorbidity index developed on a comparable training population were calculated. The comorbidity index is based upon a scoring system that quantifies the prognostic weight of individual diseases, while the age-comorbidity index corrects the former for the age-related increase of the risk of death. The predictive power of variables univariately correlated with the outcome was tested by logistic regression. RESULTS: Death was independently predicted by clinical diagnosis of malnutrition (odds ratio = 1.87, confidence limits CL = 1.20-2.86), age-comorbidity index > 7 (odds ratio = 1.77, CL = 1.15-2.72), preadmission impairment in activities of daily living (odds ratio = 1.74, CL = 1.13-2.69), lymphocytopenia (odds ratio = 1.74, CL = 1.15-2.61). A weaker predictive model was obtained by substituting the comorbidity index for the index of age-comorbidity. Excluding comorbidity from the logistic regression greatly weakened the predictive model.

Acute Disease↗
PubMed1997

Neuropsychologic effects of carotid endarterectomy.

This study assessed neuropsychologic changes after internal carotid endarterectomy using a design that limited the confounding effects of surgical and anesthesiological stress. Twenty-eight patients (mean age = 65.9 years, SD = 8.4, range 45-79), underwent extensive neuropsychological assessment before and on the seventh day after carotid endarterectomy for symptomatic carotid stenosis greater than 75%. A similarly assessed control group of 30 patients underwent elective orthopaedic surgery. A third cognitive assessment was performed 4 months postoperatively on a subgroup of the study patients. No significant cognitive change occurred in the control group. The study patients showed significant improvement in verbal memory, constructive abilities, verbal attainment, and visual attention; a trend towards further improvement of verbal functions was evident at the late postoperative assessment. No side-specific cognitive change was observed. In conclusion, carotid endarterectomy performed for currently accepted indications significantly improves several cognitive functions.

Aged↗
PubMed1997

Absence of mutations in the transforming growth factor-beta type II receptor in sporadic lung cancers with microsatellite instability and rare H-ras1 alleles.

The transforming growth factor-beta type II receptor (RII) is commonly mutated in colon and gastric cancers with microsatellite instability (MI). We utilized our series of lung cancers with MI and rare alleles of the H-ras1 gene to determine the association between MI and RII mutations and searched the entire RII coding region in 33 lung cancers with MI by polymerase chain reaction-single-strand conformation polymorphism analysis. We found no mutations, and these data support other recent evidence that RII mutations rarely occur except in colon and gastric tumors with MI.

Alleles↗
PubMed1997

Verbal memory impairment in COPD: its mechanisms and clinical relevance.

STUDY OBJECTIVES: Identification of mechanisms accounting for verbal memory impairment in patients with severe COPD; assessing the relationship between verbal memory and the overall cognitive performance; verifying if verbal memory impairment affects medication adherence. DESIGN: Case-comparison study. SETTING: Outpatient Departments of Pneumology and Neurology, Day Hospital of General Surgery. PATIENTS: Forty-two COPD ambulatory patients, age 70+/-9.7 years, with hypoxemia and hypercarbia (group A); 27 normal subjects of comparable age and educational level (group B); 31 patients with Alzheimer's disease (group C); and 26 older normal subjects (group D). MEASUREMENTS AND RESULTS: The overall cognitive function and verbal memory were evaluated by the Mental Deterioration Battery and 14 indexes of verbal memory. Defective retrieval and recognition mechanisms distinguished group A from group B. According to discriminant analysis, verbal memory profile of COPD patients was group specific in 38.1% of cases and conformed to that of group B, C, and D in 19%, 16.7%, and 26.2% of cases, respectively. In COPD patients, both immediate and delayed recall, the strongest determinants of the discriminant function, were significantly correlated with the overall cognitive performance (rho=0.64, p=0.001; rho=0.61, p=0.001, respectively). Poor adherence to medication regimen was significantly associated with abnormal delayed recall score (82.3% vs 36% in subjects with normal delayed recall, p<0.008). CONCLUSIONS: Decline of verbal memory parallels that of the overall cognitive function in COPD patients and is due to the impairment of both active recall and passive recognition of learned material. It could be an important determinant of the level of medication adherence.

Aged↗
PubMed1996

Molecular analysis of the cyclin-dependent kinase inhibitor genes p15INK4b/MTS2, p16INK4/MTS1, p18 and p19 in human cancer cell lines.

Cyclin-dependent kinase-4 inhibitor genes (INK4) regulate the cell cycle and are candidate tumor-suppressor genes. To determine if alterations in the coding regions of the p18 and p19 genes, which are novel members of the INK4 family and if they correlate with the development of human cancer, 100 human cancer cell lines were analyzed. Two other INK4 gene family members, p15INK4b/MTS2 and p16INK4/MTS1 genes were also analyzed. Homozygous deletions of the p15INK4b/MTS2 gene were detected in 29 cancer cell lines. Thirty-five homozygous deletions and 7 intragenic mutations of the pl6INK4/MTS1 gene were also detected in these cell lines. Neither homozygous deletions nor intragenic mutations of the p18 and p19 genes were found except in an ovarian cancer cell line, SKOV3, harboring a single base pair deletion in exon 1 of p19. In p16INK4/MTS1 expression analysis, 5 cell lines with both authentic and alternative spliced p16INK4/MTS1 mRNA had no detectable p16INK4/MTS1 protein. These results suggest the hypotheses that either post-translational modification or enhanced degradation may be responsible for the lack of detection of the p16INK4/MTS1 protein. Using Western blot analysis, subsets of 26 human cancer cell lines were examined for p18 expression and 39 cell lines for p19 expression. All of these cell lines expressed the p18 or p19 protein, with the exception of SKOV3, which did not express p19. Therefore, the INK4 gene family may be divided into 2 groups. One group includes p15INK4b/MTS2 and p16INK4/MTS1, in which genetic and epigenetic alterations might contribute to the development of human cancers. The other group includes p18 and p19, in which somatic mutations are uncommon in many types of human cancer, and their role in human carcinogenesis and cancer progression is uncertain.

Carrier Proteins↗
PubMed1996

The genomic structure of the gene encoding the human transforming growth factor beta type II receptor (TGF-beta RII).

The genomic structure of the human transforming growth factor-beta type II receptor gene (TGF-beta RII) was determined by two PCR-based methods, the "long distance sequencer" method and the "promoter finder" method. Genomic fragments containing exons and adjacent introns were amplified by PCR, and the nucleotide sequences were determined by direct sequencing and subcloning sequencing. The TGF-beta RII protein is encoded by 567 codons in 7 exons. This is the first report about the genomic structure of a gene that belongs to the serine/threonine kinase type II receptor subfamily. Knowledge of the genomic structure of the TGF-beta RII gene will facilitate investigation of the TGF-beta signaling pathway in normal human cells and of the aberrations occurring during carcinogenesis.

Amino Acid Sequence↗