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Biomedical subjects

M Thomas

Publications and source records attributed to M Thomas.

At least 343 records · Page 19Linked to original sources
PubMed1998

Paclitaxel, carboplatin, and extended-schedule oral etoposide for small-cell lung cancer.

We evaluated the feasibility and efficacy of combination paclitaxel (Taxol) (via 1-hour infusion), carboplatin (Paraplatin), and oral etoposide (VePesid) in the first-line treatment of patients with small-cell lung cancer. Between June 1993 and July 1996, 117 patients with small-cell lung cancer. were treated in two sequential phase II studies. The first 38 patients received a lower-dose regimen: paclitaxel 135 mg/m2, via 1-hour infusion; carboplatin dosed to an area under the concentration-time curve (AUC) of 5.0, and oral etoposide 50 mg alternating with 100 mg on days 1 through 10. Based on a very favorable toxicity profile, the paclitaxel and carboplatin doses were increased in the subsequent cohort of 79 patients (paclitaxel 200 mg/m2 by 1-hour infusion; carboplatin target AUC increased to 6.0). Thoracic radiation therapy (1.8 Gy/day; total dose, 45 Gy) was administered concurrently with courses 3 and 4 of chemotherapy in patients with limited-stage small-cell lung cancer. The combination of paclitaxel 200 mg/m2, carboplatin to an AUC of 6.0, and extended-schedule oral etoposide 50 or 100 mg alternating days 1 through 10 is highly active and well tolerated in patients with small-cell lung cancer. The regimen can be administered concurrently with radiation therapy with no unusual side effects, although a minority of patients develop esophagitis. Median survival rates in patients with both extensive- and limited-stage disease compare favorably with other reported regimens.

Administration, Oral↗
PubMed1998

Effect of aspirin and sodium salicylate on cataract development in diabetic rats.

The role of acetylation in the antiglycating and anticataract effects of aspirin (ASA) is explored by comparing ASA's effects with that of sodium salicylate (SS), a nonacetyl analog of ASA, on cataract development in diabetic rats. Streptozocin diabetic rats were provided with either ASA or SS, orally, for 24 weeks. Appropriate drug controls, normal controls and diabetic controls were run in parallel. Periodic estimations of blood glucose, glycated hemoglobin and assessments of cataract progression were done. After 24 weeks lenses were removed, homogenised and separated into water soluble fraction and urea soluble fraction. The glycated lens proteins in each fraction was quantified. Results were analysed statistically and interpreted in relation to serum salicylate levels. Both ASA and SS did not influence blood glucose levels. In the untreated diabetic groups the onset and progression of cataract was quicker and complete within 16 weeks. Both ASA and SS delayed the onset and progression in diabetic rats, but ASA's effect was more pronounced than that of SS. The levels of glycated Hb and lens proteins in diabetic rats were significantly reduced by ASA and not by SS for the same serum salicylate levels. ASA's anticataract potential far exceeds that of SS and it is ASA, and not SS, that inhibits protein glycation. Thus the results favour the hypothesis that acetylation plays a major role in ASA's anticataract effect via inhibition of glycation.

Animals↗
PubMed1997

Inflammatory mediators in BAL fluid as markers of evolving pneumonia in leukocytopenic patients.

STUDY OBJECTIVES: Pneumonia during chemotherapy-induced leukocytopenia is a major cause of overall treatment failure in patients with hematologic malignancies. To improve outcome in these high-risk patients, early diagnosis of pulmonary infiltrates and institution of adequate antimicrobial treatment are mandatory. To identify patients with evolving pneumonia, we have prospectively studied the prognostic value of cytokine and complement measurements in early BAL samples from febrile leukocytopenic patients. DESIGN: Prospective, comparative study. SETTING: Hematology/oncology section of a university hospital. PATIENTS: Twenty-one patients with leukocytopenia (WBC count < 1.000/microL) following cytoreductive chemotherapy for malignant disorders. INTERVENTION: Early BAL sampling primarily for microbiologic diagnostic purposes. MEASUREMENTS AND RESULTS: Proinflammatory cytokines and activated complement components were measured in the BAL aspirates and the results were related to the prevalence or subsequent evolution of overt pneumonia. Of the 21 patients studied, 10 patients presented with overt pneumonia at BAL sampling (group A), 5 patients developed objective signs of pneumonia 3 to 5 days after BAL (group B), and 6 patients remained free of pneumonia during follow-up (group C). In comparison with group C, patients in groups A and B both had distinctly elevated bronchoalveolar levels of tumor necrosis factor-alpha, interleukin-6, granulocyte colony-stimulating factor, C3a, and C5a. CONCLUSIONS: Cytokine and complement determinations in early BAL samples may aid in the identification of febrile leukocytopenic patients with evolving pneumonia 3 to 5 days prior to the manifestation of diagnostic clinical and radiographic signs.

Adult↗
PubMed1997

Selective targeting and inhibition of yeast RNA polymerase II by RNA aptamers.

To probe the complex nucleic acid binding domains of yeast RNA polymerase II (Pol II), we have isolated in the presence of heparin RNA molecules that selectively bind to yeast Pol II. A class of RNA molecules was found to bind and strongly interfere with enzyme-DNA interaction but not with RNA chain elongation. Remarkably, one selected RNA ligand was a specific inhibitor of Saccharomyces cerevisiae Pol II. S. cerevisiae Pol I and Pol III and Pol II from Schizosaccharomyces pombe or wheat germ cells were not affected. Photocross-linking experiments showed that the RNA ligand preferentially interacted with B220, the largest subunit of Pol II and, to a lesser extent, with B150, the second largest subunit. The selected RNA was expressed in yeast cells under the control of a Pol III promoter. Yeast cells that expressed the anti-Pol II aptamer grew normally. However, a cell growth defect was observed when expressing the RNA aptamer in cells having an artificially reduced level of Pol II.

Base Sequence↗
PubMed1997

[Neoadjuvant combined therapy in stage IIIA if non-small-cell bronchial cancer].

BACKGROUND AND OBJECTIVE: The overall prognosis of patients with stage IIIA non-small-cell lung cancer is unfavourable (median survival time 12 months). Tolerance to and efficacity of a multimodal neoadjuvant treatment was assessed in a prospective study. PATIENTS AND METHODS: 25 patients (median age 59 [37-69] years), with histologically confirmed mediastinal lymph node metastases, underwent chemotherapy. Immediately after two cycles with carboplatin/Ifosfamid (dimethoate)/etoposide they received hyperfractionated accelerated radiotherapy (45 Gy; 2 x 1.5 Gy daily) with simultaneous administration of carboplatin and vindesine. This was followed by tumour resection. RESULTS: After conclusion of the neoadjuvant treatment 19 of 25 patients (76%) had a remission. Of the 20 operated patients complete resection (R0) was possible in 17 (85%) and 14 of the 20 patients with resection (70%) had histologically demonstrated marked tumour regression. Critical toxicity consisted of pneumonitis and bronchial stump problems. Median survival time of all patients was 24.8 months and for patients with R0 resection 35.9 months. CONCLUSION: Neoadjuvant multimodal treatment of stage IIIA non-small-cell lung cancer can achieve prolongation in survival time. The place of radiotherapy or radiotherapy with chemotherapy in such a treatment concept will need to be defined in a randomized study.

Adult↗
PubMed1997

CD45 regulates Src family member kinase activity associated with macrophage integrin-mediated adhesion.

BACKGROUND: Adhesion of leukocytes to the extracellular matrix and to other cells is mediated by members of the integrin family of adhesion molecules. Src family kinases are activated upon integrin-mediated adhesion. In lymphocytes, CD45 is a leukocyte-specific transmembrane protein tyrosine phosphatase that activates Src family kinases associated with B-cell and T-cell antigen receptor signaling by constitutive dephosphorylation of the inhibitory carboxy-terminal tyrosine phosphorylation site. Here, we show that CD45 is also important in downregulating the kinase activity of Src family members during integrin-mediated adhesion in macrophages. RESULTS: We found that CD45 colocalized with beta2 integrin and the Src family kinase p53/56(lyn) to adhesion sites in bone marrow-derived macrophages. Macrophages from CD45(-/-) mice were unable to maintain integrin-mediated adhesion. In adherent macrophages, absence of CD45 led to the hyperphosphorylation and hyperactivation of p56/59(hck) and p53/56(lyn), but not of p58(c-fgr). CD45 directly inactivated p59(hck) but not p56(lck) in transient transfection assays. Furthermore, coexpression of CD45 with p59(hck) or p56(lyn) containing a tyrosine to phenylalanine mutation at the carboxy-terminal negative regulatory site resulted in decreased tyrosine phosphorylation of the Src family member kinases due to dephosphorylation of the potentiating tyrosine phosphorylation site within the kinase domain. CONCLUSIONS: Using primary bone marrow macrophages, these studies demonstrate that CD45 regulates Src family kinases and is required to maintain macrophage adhesion. CD45 decreases Src family kinase activity by dephosphorylating the tyrosine residue located within the kinase domain.

Animals↗
PubMed1997

Limb defects in homozygous alpha-thalassemia: report of three cases.

Homozygosity for the South-Asian alpha-thalassemia (--SEA/) deletion is a serious hematological condition that results, in most cases, in intrauterine or postnatal death due to anemia and severe hypoxia of prenatal onset. A relationship between congenital abnormalities and intra-uterine hypoxia has been postulated. However, since homozygosity for the (--SEA/) deletion is most common in underdeveloped countries where detailed autopsies are lacking, the incidence of congenital abnormalities among these babies has not been well delineated. We report on three newborn infants, homozygous for the (--SEA/) deletion, who were born with limb defects. We postulate that this combination is the result of prenatal hypoxia which may affect other fetal body organs. This should be taken into consideration when prenatal treatment of affected fetuses, with intrauterine blood transfusion, is suggested.

Adult↗
PubMed1997

Retroperitoneal and intraperitoneal CO2 insufflation have markedly different cardiovascular effects.

Both retroperitoneoscopic and laparoscopic surgical approaches to kidney and adrenal gland have been reported but their cardiopulmonary pathophysiology has been incompletely characterized. To test the hypothesis that these approaches have markedly different impact on the circulatory and respiratory systems, we assessed at similar insufflation pressures alterations in cardiovascular and respiratory variables during retroperitoneal and intraperitoneal CO2 insufflation. Eighteen healthy, anesthetized (propofol, alfentanil, vecuronium), mechanically ventilated pigs were randomly instrumented for either retroperitoneoscopic (n = 9) or laparoscopic (n = 9) surgery. After CO2 insufflation cardiovascular and respiratory variables were measured at four cavity pressures (baseline, 10, 15, and 20 mmHg), while end-expiratory CO2 tension was maintained by adjusting tidal volume. Data were analyzed for both insufflation-pressure-dependent and group effects by one-way and two-way ANOVA for repeated measurements, respectively, followed by Newman-Keuls post hoc test (P < 0.05). Cardiac output, mean arterial, pulmonary artery, central venous, and femoral venous pressures increased significantly in both groups in an insufflation-pressure-dependent fashion. However, changes in cardiac output (P < 0.001), pulmonary artery (P < 0.007), central venous (P < 0.001), and iliac venous pressures (P < 0.001) for the same insufflation pressure were markedly and significantly greater with intraperitoneal than retroperitoneal CO2 insufflation. Most important, intraperitoneal unlike retroperitoneal insufflation induced a marked inferior vena caval pressure gradient (8.9 +/- 1.1 mmHg vs 1.0 +/- 0.5 mmHg, P < 0.00001). While both retroperitoneal and intraperitoneal CO2 insufflation required increased tidal volumes to adjust endtidal CO2 tension to baseline, intraperitoneal CO2 insufflation resulted in a significantly greater increase of mixed venous and arterial carbon dioxide tensions (P < 0.007) even at similar insufflation pressures. Furthermore, significantly greater peak airway pressures (P = 0.018) were required with intraperitoneal than with retroperitoneal insufflation to administer the same tidal volume, indicating a greater decrease in quasi-static compliance with intraperitoneal insufflation (P = 0.0436). Thus, (i) cardiovascular and respiratory changes are much less during retroperitoneal than intraperitoneal CO2 insufflation, even at the same insufflation pressures, and (ii) retroperitoneal CO2 insufflation unlike intraabdominal CO2 insufflation does not induce an inferior vena caval pressure gradient and hence does not appear to impair systemic lower body venous return up to insufflation pressures of 20 mmHg.

Animals↗
PubMed1997

Tumour regression in non-small-cell lung cancer following neoadjuvant therapy. Histological assessment.

In the scope of a prospective multi-centre study after neoadjuvant combined chemotherapy (carboplatin, ifosfamide, etoposide, vindesine) and radiotherapy (45 Gy) 40 resection specimens of locally advanced non-small-cell lung cancer were analysed in order to establish reproducible pathological/anatomical results of tumour regression. Resection specimens of 28 squamous cell carcinomas and 12 adenocarcinomas were investigated using serial sections of the primary lesion. The mean age of the patients was 57 years. The results were compared to spontaneous regressive changes in a control group of 50 untreated non-small-cell lung cancers. Marked scarry fibrosis in the region of the former primary tumour, concentric foci of fresh tumour necroses and surrounding foam cell clusters with transition into vascular granulation tissue could be established as characteristic features of therapy-induced tumour regression, whereas untreated carcinomas revealed necroses with adjoining vital tumour tissue. Using a three-step regression system, 3 tumours could be classified as grade I (no or only slight tumour regression), 10 tumours as grade IIA (marked but incomplete tumour regression, more than 10% vital tumour tissue), 20 tumours as grade IIB (less than 10% vital tumour tissue) and 7 tumours as grade III (complete tumour regression without vital tumour tissue). After a median follow-up period of 32.3 months in patients with grade IIB or III tumour regression ("responders") the median survival time of 27.9 months was found to be significantly longer than in patients with grade I or IIA tumour regression ("non-responders") with a median survival period of 13.7 months (log-rank test, P = 0.020). The resection specimens analysed, which were obtained 7 weeks (on average) after the end of radiochemotherapy, did not show specific changes due to preoperative therapy, but quite characteristic histological alterations in the former tumour area were registered, which had been induced by combined neoadjuvant radiation and chemotherapy. The grade of therapy-induced tumour regression could be shown to be a significant prognostic factor in non-small-cell lung cancer.

Adenocarcinoma↗
PubMed1997

[Regression grading of neoadjuvant non-small-cell lung carcinoma treatment].

In the scope of a multi-center-study 35 resection specimens from patients with locally advanced non-small cell lung cancer after neoadjuvant chemotherapy and radiation were processed histologically and graded according to the following regression grading system: grade I: no or only slight, in general spontaneous tumor regression, grade IIa: incomplete tumor regression with more than 10% and grade IIb less than 10% vital tumor tissue as well as grade III: complete tumor regression. In 15 patients with grade II a to III tumor regression roughly concentric foci of various size with a sequence of central tumor necrosis, narrow foam cell rim, vascular granulation tissue and peripheral scar formation were demonstrated as characteristic feature of response to neoadjuvant therapy. In patients with grade IIb to III tumor regression ("responders") median survival time of 27.9 months was significantly longer than in patients with grade I to II a tumor regression ("non-responders") with a median survival time of 12.7 months.

Adult↗
PubMed1997

A simple two-step method for the conversion of [3H]cortisol to [3H]-11-ketotestosterone.

Despite the existence of several protocols, problems appear to persist in the small scale chemical synthesis of radiolabeled 11-ketotestosterone from cortisol. We investigated the possibilities of using the mild oxidant pyridinium dichromate for the oxidative cleavage of the dihydroxyacetone side chain of cortisol and 17 beta-hydroxysteroid dehydrogenase for the subsequent reduction of the resulting 17-keto group. Our protocol has resulted in consistently high yields of both the intermediate, adrenosterone (70-80%), and the product, 11-ketotestosterone (up to 60%). This, taken together with the convenience and relatively low cost of our method, recommends the protocol for its use for the synthesis of [3H]-11-ketotestosterone for endocrine studies.

Androstenes↗
PubMed1997

HIV integrase: a target for AIDS therapeutics.

HIV integrase catalyses the incorporation of virally derived DNA into the human genome. This unique step in the virus life cycle provides a variety of points for intervention and hence is an attractive target for the development of new therapeutics for the treatment of AIDS. In this review we summarize current knowledge of the function of this enzyme and discuss some of the obstacles to the development of appropriate drugs.

Acquired Immunodeficiency Syndrome↗
PubMed1997

[Protein phosphatases and protein kinases in higher plants].

The recent gain in knowledge concerning enzymes involved in signal transduction pathways is a direct consequence of the considerable advances made in molecular biology. Protein kinases and protein phosphatases, the two major enzymes implicated in post-translational modifications, have been studied in particular. The number of characterized plant genes and/or cDNAs encoding these enzymes is increasing everyday. Since 1991, 26 genes and cDNAs coding for plant protein phosphatases have been isolated and characterized. The huge number of protein kinases (estimated at several thousands) makes it impossible to give an exhaustive list of the genes already identified, but a classification of these enzymes, based on phylogenetic criteria, allows us to appreciate the range of functions this protein family may play in plants.

Molecular Biology↗
PubMed1997

Restoration of thymocyte development and function in zap-70-/- mice by the Syk protein tyrosine kinase.

The Syk family of protein tyrosine kinases, consisting of ZAP-70 and Syk, associate with the pre- and alphabeta T cell antigen receptors (TCRs) and undergo tyrosine phosphorylation and activation following receptor engagement. Thymocyte development in zap-70-/- mice is blocked at the CD4+CD8+ TCR(lo) stage. The presence of Syk in the thymus has raised the possibility that Syk may be able to mediate TCR function. To determine if Syk can play a role in thymocyte development, we generated zap-70-/- mice expressing a human syk cDNA. Syk expression restored both thymocyte development and function. In addition, Syk function required the CD45 transmembrane protein tyrosine phosphatase. Hence, ZAP-70 and Syk can play overlapping functions and exhibit similar regulatory mechanisms in mediating alphabeta T cell development.

Animals↗