Biomedical subjects

G Chiesa

Publications and source records attributed to G Chiesa.

At least 37 records · Page 2Linked to original sources

PubMed1994

Surgery following neoadjuvant MPV chemotherapy (mitomycin, cisplatin, vinblastine) in locally advanced (IIIa and IIIb) non-small cell lung cancer.

From November 1990 to August 1993, 32 patients with non-small cell lung cancer (NSCLC) entered a multimodality treatment study with neoadjuvant Mitomycin, Cisplatin and Vinblastine (MPV), surgery and radiotherapy at the San Raffaele Hospital in Milan, Italy. Neoadjuvant chemotherapy was performed on an outpatient basis. To date 23 patients (11 stage IIIa and 12 stage IIIb) have completed the chemotherapy treatment and are available for evaluation of response, toxicity, surgical eligibility and resection rate. The overall major response to MPV chemotherapy was 87%. The overall resection rate after major response to treatment was 60% (90% in stage IIIa and 17% in stage IIIb). After a median follow-up of 21 months (8-31) 17 patients are still alive (74%). Ten patients (83%) who had a complete resection are alive after a median follow-up of 23 months (21-30) and eight of them (66%) are in complete pathological remission. No treatment-related mortality was observed. The authors conclude that MPV is a highly effective neoadjuvant regimen for NSCLC and is feasible on an outpatient basis. Favorable resection rates can be obtained in stage IIIa patients. Stage IIIb patients can be downstaged and undergo complete resection. A longer follow-up is needed to assess the impact of this multimodality approach on long-term survival and to evaluate the role of adjuvant radiotherapy.

Adult↗

PubMed1994

V delta 1+ gamma/delta T lymphocytes infiltrating human lung cancer express the CD8 alpha/alpha homodimer.

Murine gamma/delta T lymphocytes localize to different epithelial tissues and are phenotypically distinct from peripheral gamma/delta T cell-populations in that they show limited TCR diversity, express the CD8 alpha/alpha homodimer and lack the CD8 beta chain. In humans, a compartmentalization of gamma/delta cells sharing similar phenotypic features has been documented to date only in the case of intestinal epithelium. In the present study we show that about half of V delta 1+ (as well as V delta 1-V delta 2-) gamma/delta lymphocytes, which can be selectively expanded from human lung cancers, coexpress the CD8 alpha/alpha homodimer. The accumulation of intraepithelial CD8+ gamma/delta+ lymphocytes might then be a more general phenomenon, possibly as a result of common mechanisms operating at those sites.

Animals↗

PubMed1994

Self-expanding stents in the treatment of tracheobronchial obstruction.

The self-expandable stainless steel stents (Gianturco, William Cook, Bjaeverskov, Denmark) used extensively in biliary ducts and the vascular system have recently been modified for use in the tracheobronchial tree. Between March 1991 and September 1992, six patients with unresectable tracheobronchial and mediastinal diseases were treated with the placement of one or more self-expanding stents under direct vision with a fiberoptic bronchoscope. All patients had been intubated for severe respiratory insufficiency. In all cases, immediate relief of respiratory symptoms was achieved and all patients were extubated 1 or 2 days after stent placement. Tolerance of the stents was excellent. No patient complained of pain, discomfort, or foreign body sensation. No infection or obstruction of the stents was observed. The chest roentgenogram and the bronchoscopies performed during follow-up have shown no change in the position of the stents. Our results seem promising since these devices provide effective palliation of airway obstructions and are well tolerated.

Adult↗

PubMed1994

A critical assessment of the effects of aminoguanidine and ascorbate on the oxidative modification of LDL: evidence for interference with some assays of lipoprotein oxidation by aminoguanidine.

Several lines of evidence support a role for oxidized low density lipoprotein (LDL) in the genesis of the atherosclerotic lesion. Hence, the effect of compounds with antioxidant properties on LDL oxidation assumes great significance. Ascorbate, a potent water-soluble chain-breaking antioxidant, has been shown to inhibit LDL oxidation. Aminoguanidine (AMG) is a pharmacological inhibitor of advanced non-enzymatic glycosylation. Recently it has been suggested that aminoguanidine might have an inhibitory effect on LDL oxidation, but total lipid peroxidation assayed by conjugated diene formation was not inhibited. Thus, in this study, we compared the effect of aminoguanidine with ascorbate to obtain a better appreciation of the effect of AMG on Cu(2+)-catalyzed LDL oxidation. Oxidative modification of LDL was monitored by assaying intermediates and end products of lipid peroxidation, conjugated dienes (CD), lipid peroxides (LPO), and relative electrophoretic mobility (REM). Apolipoprotein B-100 modification (increased fluorescence, fragmentation on SDS-PAGE, and 125I-labeled LDL degradation by human macrophages) was also measured. Ascorbate (100 microM) inhibited LDL oxidation by > 95%, as evidenced by all of the selected indices. Aminoguanidine (20 mM) substantially decreased thiobarbituric acid-reactive substances (TBARS) activity and lipid peroxide formation, but only partially prevented the increase of REM (-55%), apoB fluorescence (-39%), and degradation by macrophages (-54%). Unlike ascorbate, AMG failed to preserve alpha-tocopherol in LDL, prevent apoB-100 fragmentation, or inhibit conjugated diene formation during LDL oxidation. Furthermore, incubation of AMG with already oxidized LDL resulted in a significant decrease in TBARS activity and LPO, and 26.9% decrease in the REM of LDL.(ABSTRACT TRUNCATED AT 250 WORDS)

Apolipoprotein B-100↗

PubMed1993

Expression of human apolipoprotein B100 in transgenic mice. Editing of human apolipoprotein B100 mRNA.

Apolipoprotein B (apoB) is a large glycoprotein that circulates in plasma as a major constituent of numerous lipoproteins. ApoB exists in two forms: apoB48 and apoB100. ApoB48 is identical in sequence to the N-terminal region of apoB100 and is generated by sequence-specific mRNA editing of the apoB100 transcript. Here, we describe the development of a line of mice expressing a human apoB transgene driven by promoter/enhancer sequences from the transthyretin gene. In these mice, immunodetectable human apoB100 is synthesized by the liver, kidney, and brain. Human apoB100 is found in low concentration (approximately 0.1 mg/dl) in the plasma of the transgenic mice and circulates in the low density lipoprotein fraction. The hepatic human apoB100 transcripts undergo mRNA editing at only slightly lower efficiency than the endogenous mouse apoB100 message. Therefore, there is no absolute species specificity to the apoB100 mRNA editing process.

Animals↗

PubMed1993

Mechanisms of high-density lipoprotein reduction after probucol treatment: changes in plasma cholesterol esterification/transfer and lipase activities.

Probucol treatment results in a significant reduction of plasma high-density lipoprotein (HDL) levels. Since the remodeling of HDL within the plasma compartment is a crucial determinant of HDL levels, the activities of several factors participating in the process, ie, lecithin:cholesterol acyltransferase (LCAT), cholesteryl ester transfer protein (CETP), and lipoprotein and hepatic lipases (LPL, HL), were evaluated in 15 hypercholesterolemic patients treated with probucol (1 g/d) for 8 weeks. Drug treatment was associated with significant reductions of HDL cholesterol ([HDL-C] -32%), HDL2-C (-65%), HDL3-C (-22%), apolipoprotein (apo)A-I (-27%), and apo A-II (-11%) levels and with the accumulation of small HDL in plasma. CETP activity increased by 48%, with minor changes in LCAT (-7%), LPL (+4%), and HL (-7%) activities. By linear regression analysis, CETP activity correlated inversely with HDL-C, HDL2-C, and apo A-I levels (r = -.63, -.52, and -.73, respectively) and with HDL particle size. In multivariate analysis, CETP activity was the strongest predictor of HDL-C levels, apo A-I levels, and HDL particle size. The hypothetical mechanism of probucol is a stimulation of CETP activity, resulting in the formation of triglyceride (TG)-enriched HDL. These are acted on by HL, leading to the accumulation of small HDL in plasma.

Apolipoprotein A-I↗

PubMed1993

Sequence polymorphisms in the apolipoprotein (a) gene. Evidence for dissociation between apolipoprotein(a) size and plasma lipoprotein(a) levels.

Apolipoprotein(a) [apo(a)], an apolipoprotein unique to lipoprotein(a) [Lp(a)], is highly polymorphic in size. Previous studies have indicated that the size of the apo(a) gene tends to be inversely correlated with the plasma level of Lp(a). However, several exceptions to this general trend have been identified. Individuals with apo(a) alleles of identical size do not always have similar plasma concentrations of Lp(a). To determine if these differences in plasma Lp(a) concentrations were due to sequence variations in the apo(a) gene, we examined the sequences of apo(a) alleles in 23 individuals homozygous for same-sized apo(a) alleles. We identified four single-strand DNA conformation polymorphisms (SSCPs) in the apo(a) gene. Of the 23 homozygotes, 21 (91%) were heterozygous for at least one of the SSCPs. Analysis of a family in which a parent was homozygous for the same-sized apo(a) allele revealed that each allele, though identical size, segregated with different plasma concentrations of Lp(a). These studies indicate that the apo(a) gene is even more polymorphic in sequence than was previously appreciated, and that sequence variations at the apo(a) locus, other than the number of kringle 4 repeats, contribute to the plasma concentration of Lp(a).

Alleles↗

PubMed1993

Transgenic mice expressing high plasma concentrations of human apolipoprotein B100 and lipoprotein(a).

The B apolipoproteins, apo-B48 and apo-B100, are key structural proteins in those classes of lipoproteins considered to be atherogenic [e.g., chylomicron remnants, beta-VLDL, LDL, oxidized LDL, and Lp(a)]. Here we describe the development of transgenic mice expressing high levels of human apo-B48 and apo-B100. A 79.5-kb human genomic DNA fragment containing the entire human apo-B gene was isolated from a P1 bacteriophage library and microinjected into fertilized mouse eggs. 16 transgenic founders expressing human apo-B were generated, and the animals with the highest expression had plasma apo-B100 levels nearly as high as those of normolipidemic humans (approximately 50 mg/dl). The human apo-B100 in transgenic mouse plasma was present largely in lipoproteins of the LDL class as shown by agarose gel electrophoresis, chromatography on a Superose 6 column, and density gradient ultracentrifugation. When the human apo-B transgenic founders were crossed with transgenic mice expressing human apo(a), the offspring that expressed both transgenes had high plasma levels of human Lp(a). Both the human apo-B and Lp(a) transgenic mice will be valuable resources for studying apo-B metabolism and the role of apo-B and Lp(a) in atherosclerosis.

Animals↗

PubMed1993

Adjuvant treatment of stage I lung cancer with high-dose vitamin A.

PURPOSE: Vitamin A and retinoids are strong inhibitors of epithelial cancer promotion and progression in experimental carcinogenesis. This study examined whether they may prevent the occurrence of upper aerodigestive cancer in subjects heavily exposed to tobacco smoking, such as patients already cured of an early-stage lung cancer. PATIENTS AND METHODS: The adjuvant effect of high-dose vitamin A was tested on 307 patients with stage I non-small-cell lung cancer. After curative surgery, patients were randomly assigned to either a group prescribed retinol palmitate administration (orally 300,000 IU daily for 12 months) or a control group prescribed no treatment. RESULTS: After a median follow-up of 46 months, the number of patients with either recurrence or new primary tumors was 56 (37%) in the treated arm and 75 (48%) in the control arm. Eighteen patients in the treated group developed a second primary tumor, and 29 patients in the control group developed 33 second primary tumors. A statistically significant difference in favor of treatment was observed concerning time to new primary tumors in the field of prevention (P = .045, log-rank test). The treatment difference in terms of disease-free interval was close to statistical significance (P = .054, log-rank test) and just significant when adjusted for primary tumor classification (P = .038, Cox regression model). CONCLUSION: Daily oral administration of high-dose vitamin A is effective in reducing the number of new primary tumors related to tobacco consumption and may improve the disease-free interval in patients curatively resected for stage I lung cancer. The impact of such a treatment on survival needs to be further explored.

Adolescent↗

PubMed1993

Three-step tumor pre-targeting in lung cancer immunoscintigraphy.

Radiolabelled MoAbs have been used in both the diagnosis and the treatment of a variety of tumors. Recently, a three-step tumor pre-targeting strategy has been proposed to overcome one of the major limiting factors in radioimmunodetection: the low tumor-to-background ratio. We evaluated this pre-targeting protocol in 10 patients diagnosed as having pulmonary carcinoma. One milligram of biotinylated anti-CEA MoAb (FO23C5) was administered i.v. (1st step); 24 hours later 5 mg of avidin was injected i.v. (2nd step) followed by 100-500 ng of 111In-biotin (5 mCi) the day after (3rd step). Imaging was performed using single photon emission tomography (SPET). No toxicity and no adverse reactions were observed. Tumor was detected in 8 out of 10 patients. Mediastinal metastases were also localised in 2 out of 3 patients, and adrenal gland recurrency in 1 out of 2 patients. The tumor/background (normal lung), heart, liver and spine ratios were respectively 2.0, 1.0, 1.3 and 4.1 at 90 minutes post-injection. These preliminary data show that the three-step pretargeting method is safe and allows SPECT tumor localization soon after the injection of the radiolabel. In the future, the use of MoAbs with higher specificity could result in improved tumor-targeting, and in the possibility of lung cancer radioimmunotherapy.

Aged↗

PubMed1992

Atherogenesis in transgenic mice expressing human apolipoprotein(a)

Elevated plasma levels of the lipoprotein Lp(a) are associated with increased risk for atherosclerosis and its manifestations, myocardial infarction, stroke and restenosis (for reviews, see refs 1-3). Lp(a) differs from low-density lipoprotein by the addition of the glycoprotein apolipoprotein(a), a homologue of plasminogen that contains many tandemly repeated units which resemble the fourth kringle domain of plasminogen, and single homologues of its kringle-5 and protease domain. As plasma Lp(a) concentration is strongly influenced by heritable factors and is refractory to most drug and dietary manipulation, the effects of modulating it are difficult to mimic experimentally. In addition, the absence of apolipoprotein(a) from virtually all species other than primates precludes the use of convenient animal models. Here we show that transgenic mice expressing human apolipoprotein(a) are more susceptible than control mice to the development of lipid-staining lesions in the aorta, and that apolipoprotein(a) co-localizes with lipid deposition in the artery walls.

Animals↗

PubMed1992

Reconstitution of lipoprotein(a) by infusion of human low density lipoprotein into transgenic mice expressing human apolipoprotein(a).

Lipoprotein(a) (Lp(a)) is an atherosclerosis-causing lipoprotein that circulates in human plasma as a complex of low density lipoprotein (LDL) and apolipoprotein(a) (apo(a)). It is not known whether apo(a) attaches to LDL within hepatocytes prior to secretion or in plasma subsequent to secretion. Here we describe the development of a line of mice expressing the human apo(a) transgene under the control of the murine transferrin promoter. The apo(a) was secreted into the plasma, but circulated free of lipoproteins. When human (h)-LDL was injected intravenously, the circulating apo(a) rapidly associated with the lipoproteins, as determined by nondenaturing gel electrophoresis. Human HDL and mouse LDL had no such effect. When h-VLDL was injected, there was a delayed association of apo(a) with the lipoprotein fraction which suggests that apo(a) preferentially associated with a metabolic product of VLDL. The complex of apo(a) with LDL formed both in vivo and in vitro was resistant to boiling in the presence of detergents and denaturants, but was resolved upon disulfide reduction. These studies suggest that apo(a) fails to associate with mouse lipoproteins due to structural differences between human and mouse LDL, and that Lp(a) formation can occur in plasma through the association of apo(a) with circulating LDL.

Aminocaproates↗

PubMed1992

Activity profile of gemfibrozil on the major plasma lipoprotein parameters.

Gemfibrozil (G) is a widely used and highly effective fibric acid derivative. It acts both on lipoprotein disorders characterized by hypertriglyceridemia, as well as in hyperchlolesterolemia. The results of two separate studies are summarized, in order to elucidate the differential activity profile of the drug on the major plasma lipoprotein parameters. In a group of hypertriglyceridemic patients (Study I) the major activity of G was on the VLDL cholesterol (C) and triglyceride levels (respectively -40.4 and -35.7%), associated with a marked increase of the HDL-C levels, in particular in the HDL3 subfraction. In addition, apolipoprotein B levels were significantly reduced (-12%) in all treated patients. In Study II, treatment with G in severe hypercholesterolemia was compared to that with pravastatin, a major hydroxymethylglutaryl coenzyme A reductase inhibitor. G, in these patients, markedly reduced both total (-21.6%) and LDL-cholesterol (-24.4%) levels. The increase of HDL-C was less marked than in type IV patients but G, similarly to pravastatin, induced a significant reduction of apolipoprotein B, together with an increase (+19.2%) of apolipoprotein AII levels. These findings indicate that the activity profile of G is wider than expected and that it may include a reduction of LDL levels in severely hypercholesterolemic patients. The mechanism of this latter change is difficult to establish, although it may also be related to an improved delipidation of LDL, resulting in a more efficient interaction with peripheral high affinity receptors.

Adult↗

PubMed1992

The social and vocational outcome of spinal cord injury patients.

Functional status, perception of adjustment, occupational outcome and social functioning were investigated in a group of spinal cord injury (SCI) patients (mean age 34, range 10-74 years) seen at a specialised spinal unit over the period January 1984-December 1988. Functional status was assessed using a standardised scale measuring patients' performance of specific tasks, and other measures of outcome were investigated by a structured interview. Almost two thirds (68%) of the patients were independent according to the standardised scale (33% quadriplegic and 84% paraplegic). Patients' autonomy appeared to be threatened by architectural barriers in and about the house: approximately one third (34%) of those classified as 'independent' on the standardised rehabilitation scale used needed some help in their everyday life. A negative occupational outcome emerged: compared to the pre-morbid situation, 43 patients (44%) were worse off; 48 (49%) did not experience substantial changes--though it must be noted that 68% of these (33/48) were virtually unemployed (ie student, home maker, retired, unemployed) before the injury; and for 6 (7%) some improvement took place. With a multivariate analysis age was the only statistically significant predictor of poor occupational outcome, with older patients being worse off irrespective of the extent of disease and functional autonomy. The paper discusses these results and stresses the need for integrating results based on the use of standardised rehabilitation scales with the analysis of potential barriers influencing a patient's ability to exploit his/her autonomy.

Activities of Daily Living↗

PubMed1992

Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations.

Plasma lipoprotein(a) [Lp(a)], a low density lipoprotein particle with an attached apolipoprotein(a) [apo(a)], varies widely in concentration between individuals. These concentration differences are heritable and inversely related to the number of kringle 4 repeats in the apo(a) gene. To define the genetic determinants of plasma Lp(a) levels, plasma Lp(a) concentrations and apo(a) genotypes were examined in 48 nuclear Caucasian families. Apo(a) genotypes were determined using a newly developed pulsed-field gel electrophoresis method which distinguished 19 different genotypes at the apo(a) locus. The apo(a) gene itself was found to account for virtually all the genetic variability in plasma Lp(a) levels. This conclusion was reached by analyzing plasma Lp(a) levels in siblings who shared zero, one, or two apo(a) genes that were identical by descent (ibd). Siblings with both apo(a) alleles ibd (n = 72) have strikingly similar plasma Lp(a) levels (r = 0.95), whereas those who shared no apo(a) alleles (n = 52), had dissimilar concentrations (r = -0.23). The apo(a) gene was estimated to be responsible for 91% of the variance of plasma Lp(a) concentration. The number of kringle 4 repeats in the apo(a) gene accounted for 69% of the variation, and yet to be defined cis-acting sequences at the apo(a) locus accounted for the remaining 22% of the inter-individual variation in plasma Lp(a) levels. During the course of these studies we observed the de novo generation of a new apo(a) allele, an event that occurred once in 376 meioses.

Alleles↗

PubMed1991

Laboratory evaluation during high-dose vitamin A administration: a randomized study on lung cancer patients after surgical resection.

The laboratory findings in patients receiving high-dose vitamin A as adjuvant treatment for stage I lung cancer are here reported. A group of 283 patients were randomized to either treatment with retinyl palmitate (300,000 IU daily for 12 months) or standard follow-up, and are now evaluable after a median observation period of 28 months. At regular intervals, all the patients underwent a physical examination, chest roentgenogram, blood chemistries, haematological assays, hepatic and renal function tests and determinations of serum triglycerides and cholesterol. Serum transaminase abnormalities were of similar magnitude in cases and controls, while gamma-glutamyltransferase levels were abnormally elevated in 69% of the treated patients compared to 39% of controls (mean values 149 vs 57 IU/l at 24 months, P less than 0.05). Serum triglyceride concentrations over 150 mg/dl were seen in 74% of treated patients compared to 43% of controls at 12 months, the average concentration was 283 mg/dl compared to 179 mg/dl (P less than 0.05). Cholesterol levels showed a modest, non-significant rise with time in both groups, and there was no other laboratory evidence of toxicity attributable to vitamin A. Serum retinol and retinol-binding protein, assessed on a limited sample of patients, were higher in the treatment arm (P less than 0.05) at 12 months. In our experience 300,000 IU/day of retinyl palmitate can be administered as a possible chemopreventive agent with reasonable safety for up to 2 years.

Aspartate Aminotransferases↗

PubMed1991

Probucol increases cholesteryl ester transfer protein activity in hypercholesterolaemic patients.

Probucol, a widely used lipid lowering drug, reduces both low- and high-density (LDL and HDL) lipoprotein levels and can induce a regression of tissue lipid deposits in both animals and man. The suggested mechanism(s) involve the prevention of LDL oxidative modifications and, possibly, an improvement in the reverse cholesteryl ester transport system. Probucol administration to 10 hypercholesterolaemic patients increased the activity of the cholesteryl ester transfer protein (CETP) by 50%. The rise of CETP activity was significantly related with the plasma steady-state drug levels (r = 0.51, P less than 0.005), thus suggesting that probucol may directly stimulate CEPT synthesis and/or release. Furthermore, CETP activity was inversely related with HDL-cholesterol levels, both in the whole series of 10 patients (r = -0.56, P less than 0.001) and, more so, in the single individuals (r between -0.77 and -0.97), thus suggesting that the reduction of plasma HDL-cholesterol levels is a direct consequence of CETP stimulation. These findings support the hypothesis that an improvement in the reverse cholesteryl ester transport is a major mechanism of probucol and that this may explain the drug induced plasma lipoprotein changes.

Arteriosclerosis↗

PubMed1991

Predictability of low-density lipoprotein levels during apheretic treatment of hypercholesterolaemia.

The efficiency and efficacy of low-density lipoprotein (LDL) apheresis performed with a dextran sulphate cellulose (DSC) regenerating unit were tested in five familial hypercholesterolaemic patients. LDL apheresis was repeated four times at both bi-weekly and weekly intervals, processing one plasma volume each time. The efficiency of the procedure (i.e., the extent of lipoprotein removal) was nearly identical with both schedules. Efficacy parameters, i.e., decreases of plasma total and LDL cholesterol (TC and LDL-C) and apo B, were highly correlated (r greater than 0.96) with preapheresis levels, allowing an accurate prediction of the absolute lipid removal in the single individual. Plasma triglycerides, high-density lipoprotein cholesterol, apo A-I and apo A-II recovered rather rapidly, reaching 91-96% of the pre-apheresis values in 48 hours; the recovery of TC, LDL-C and apo B was much slower, with a relatively rapid early phase (80% recovery after about 7 days) followed by a successive slower rise. This pattern was highly reproducible in the single patient, allowing the definition of a simple mathematical model for an accurate (error less than 20%) prediction of the individual process. Based on this model one can design the treatment schedule necessary to maintain lipid levels within the desired range in the single individual. The hypolipidaemic efficacy of DSC apheresis appears, otherwise, not to be dependent upon the procedure per se, but on other individual factors, e.g. the amount of removable lipoproteins and the rate of lipid recovery; both can be predicted with sufficient accuracy.

Apolipoproteins↗