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Biomedical subjects

M Schultz

Publications and source records attributed to M Schultz.

At least 55 records · Page 3Linked to original sources
PubMed1999

Docetaxel (Taxotere) as monotherapy in the treatment of hormone-refractory prostate cancer: preliminary results.

Previous chemotherapy trials in hormone refractory prostate cancer have resulted in low response rates and minimal survival impact. Clearly, better agents are needed to improve outcomes in such patients. Microtubule inhibitors have been a recent focus of investigation as chemotherapeutic agents in prostate cancer; in tissue culture, docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA) appears to be the most active of these drugs. Patients enrolled in this trial had hormone refractory prostate cancer and were required to have progressive disease despite hormonal therapy and, if previously treated with antiandrogens, have progressive disease despite antiandrogen withdrawal. Patients had not been exposed to any prior chemotherapy. Testosterone suppression was continued during the trial when patients received docetaxel at 75 mg/m2 every 21 days. Thirty-five patients with ages ranging from 49 to 85 years (median age, 70 years) were enrolled in the trial. Three hundred twelve treatments have been given (median, six treatments), with a minimum follow-up of 4 months. The median prostate-specific antigen (PSA) at the time of entry was 96 ng/mL (range, 24 to 2,070 ng/mL). Seven patients (20%) have had a more than 80% decline in PSA and 16 (46%) have had a more than 50% decline. Six additional patients have had a PSA decline of 40% to 50%. Soft tissue disease was seen in 25 of 35 patients. One patient had a complete response; three others had a nearly complete response. Three patients met criteria for a partial response, yielding a 28% response rate with measurable disease. Three additional patients had substantial shrinkage and 12 had prolonged stable disease. Combining both PSA and soft tissue responses, one complete response and five partial responses were seen. Substantial responses, defined as a more than 40% PSA decline and a more than 50% reduction of bidimensional cross-products in patients with measurable disease, were seen in 17 of 35 patients enrolled. Responses were maintained for a median of 9 months (range, 2 to 24 months). The median overall survival was 27 months. Three patients remain under therapy. Toxicity remained tolerable throughout the treatment. Grade 4 toxicities requiring discontinuation of treatment included stomatitis, small bowel obstruction, and a gluteal abscess. There were two deaths during the study: one due to lung toxicity/pneumonia and one due to pulmonary embolus. The patient with lung toxicity had markedly elevated transaminases with marked involvement of the liver with tumor. Six patients stopped voluntarily due to fatigue or edema Other common toxicities were neutropenia, anemia, mild edema and hyperglycemia (due to steroids), anorexia, myalgias, and mild alopecia The responses seen in this population are very encouraging and suggest substantial durable activity for docetaxel as single-agent therapy for hormone refractory prostate cancer.

Aged↗
PubMed1998

Increased expression of DNA-dependent protein kinase confers resistance to adriamycin.

Acquired resistance to adriamycin (ADR) in an HL60 cell line is shown to be accompanied by an increase in DNA-dependent protein kinase catalytic subunit (DNA-PKcs) at both the protein and mRNA levels (15-20-fold) and an overall 3-fold increase in DNA-PK enzyme activity. The other components of the DNA-PK Ku autoantigen complex, Ku70 and Ku80, were 3-fold increased and unchanged, respectively. Time dependent repair of ADR-induced DNA damage was measured by the neutral comet assay and found to be more efficient in the drug resistant cell line (HL60/ADR). Antisense RNA transfection reduced the protein expression of DNA-PKcs to 50% in HL60/ADR and partially reversed drug resistance. A fibroblast cell line from a severe combined immunodeficient (SCID) mouse was deficient in functional DNA-PKcs and showed increased sensitivity to ADR and other DNA damaging agents compared to wild type. These studies demonstrate that alteration in DNA-PK can contribute to chronic stress response leading to acquired drug resistance. The overexpression of DNA-PK is thus shown to be a novel cellular adaptation mechanistically contributing to the resistance of cancer cells to the anthracycline drug adriamycin, and as such, may have implications for its therapeutic use.

Adaptation, Physiological↗
PubMed1998

Bolus thrombolytic infusions during CPR for patients with refractory arrest rhythms: outcome of a case series.

Thrombolytic therapy has been accepted in the treatment of acute myocardial infarction. Given historical recommendations that thrombolytic therapy is contraindicated in patients receiving CPR, its potential clinical benefit for facilitating conversion of rhythm in patients in refractory cardiac arrest has not been investigated. We present three case reports in which patients with confirmed acute myocardial infarction had a witnessed cardiac arrest in the ED. Standard Advanced Cardiac Life Support measures failed in all three cases. A bolus infusion of tissue plasminogen activator was administered during CPR in refractory ventricular fibrillation (two cases) and pulseless ventricular tachycardia (one case). Patients were given tissue plasminogen activator and had defibrillation, followed by a spontaneous return of circulation, with resuscitation and subsequent discharge. No postarrest sequelae were observed as a result of thrombolytic use during the resuscitative process. We conclude that bolus thrombolytic infusions during CPR may facilitate spontaneous return of circulation in select patients with confirmed acute myocardial infarction, witnessed cardiac arrest in the ED, and refractory ventricular fibrillation or tachycardia.

Adult↗
PubMed1998

Improved quantitative electron probe X-ray microanalysis of biological cryosections using an EDS germanium detector and a super-atmosphere thin window (SuperATW).

A new Link energy-dispersive GEM detector with SuperATW window was tested for quantitative electron probe microanalysis of low calcium and sodium concentrations ([Ca], [Na]) in intracellular compartments of cardiac myocytes. We compare Ca profiles with high count statistics and similar peak area collected under the same conditions with either a Be-windowed Si and a Ge SuperATW detector. The height of the Ca peak was increased by 7%, the full width at half-maximum height was reduced by 9% with the Ge detector. The counts statistics of the Ca K alpha peak improved by 9% and the partial overlap with the K K beta peak was better deconvoluted. We calculate [Ca] and errors of the single measurement in mitochondria of guinea-pig cardiac myocytes from spectra acquired with a Si or Ge detector. For identical analysis conditions, the [Ca] were identical; however, with the Ge SuperATW detector, the calculated error of the single measurement was only 1/2.7 of that calculated from measurements with the Si detector. We compare the peak area of identical [Na] in spectra collected with the Be-windowed Si detector and Ge SuperATW detector. The peak area was significantly higher with the SuperATW Ge than with the Si detector and Be window, whereas the continuum in the range 4-10 keV was comparable, demonstrating the improved sensitivity for low atomic elements such as Na of the Ge SuperATW detector. [Na] and errors of the single measurement in mitochondria of quiescent guinea-pig cardiac myocytes were calculated from spectra acquired with the Si or the Ge detector. The use of the Ge SuperATW detector improved the detectability limit for sodium by more than 80% and reduced the error of the single measurement by a factor of 7-8.

Animals↗
PubMed1998

Pathological bone changes in the mandibles of wild red deer (Cervus elaphus L.) exposed to high environmental levels of fluoride.

A macroscopic, microscopic and scanning electron microscope study was performed on the pathological bone changes of the mandibles of wild red deer (n = 61) exhibiting severe dental fluorosis. The animals originated from a highly fluoride polluted area in Central Europe (Ore mountains and their southern foreland, Czech-German border region) and constituted 11.2 % of the studied red deer sample (n = 545) from this area. Pathologically increased wear and fracture of fluorosed teeth caused a variety of mandibular bone alterations, including periodontal breakdown, periostitis, osteitis and chronic osteomyelitis. As a further consequence of severe dental attrition, opening of the pulp chamber and formation of periapical abscesses were occasionally observed. In case of severe periodontal breakdown, loss of teeth from the mandibles was found. In addition to the inflammatory bone changes, the occurrence of osteofluorotic alterations was also diagnosed in the specimens with the highest bone fluoride concentrations (> 4000 mg F-/kg dry wt). These changes comprised extended apposition of periosteal bone onto the mandibular cortex as well as deformation of the mandibular body, which was attributed to a fluoride-induced osteomalacia. The present study provided circumstantial evidence that, in addition to fluoride induced dental lesions, the occurrence of marked periodontal disease and tooth loss is an important factor responsible for a reduction of life expectancy in severely fluorotic wild red deer.

Animals↗
PubMed1998

Measurement of oxygen production by in vitro human and animal lenses with an oxygen electrode.

PURPOSE: This paper describes an advantageous method of measuring the activity of the enzyme catalase, which has an important antioxidative role in the lens. This method allows the measurement of catalase in whole lenses. METHODS: Exposure to UVA (99% UV-A) radiation was used to stress animal and human (Eye Bank) lenses in vitro. The ability of lens catalase to convert H2O2 into O2 was measured directly, using an oxygen electrode and meter. This method is very specific, as catalase is the only enzyme that converts H2O2 to O2. RESULTS: Catalase in the lenses of humans, rabbits, and squirrels catalyzed the production of O2 from H2O2 very efficiently. The anterior equatorial regions of these lenses were the most active O2 producing areas. More than 95% of lens catalase activity was found in the capsule-epithelium layer. Exposure to UVA radiation, up to approximately 100 J/cm2 in 18 h, strongly inhibited O2 production from 0.77 mM H2O2 by the lenses. Catalase activity decreased with increasing age. Mixed cataractous human lenses produced O2 from H2O2 at only 60% of the rate of normal lenses of similar ages. Nuclear cataracts produced O2 at only 75% of the rate of normal lenses. Alpha-tocopherol (10(-5) M) protected lens catalase activity strongly. Alpha-tocopherol is known to accumulate in and protect against cell membrane peroxidation, and against singlet oxygen formation. These oxidative mechanisms appear to contribute to catalase photoinactivation. CONCLUSIONS: The method described indicated that catalase is a crucial antioxidative enzyme in the normal lens. Its inactivation could upset the oxidation-reduction balance in the lens and stimulate lens opacification.

Adult↗
PubMed1998

Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice.

Mice with targeted deletion of the gene for interleukin-10 (IL-10) spontaneously develop enterocolitis when maintained in conventional conditions but develop only colitis when kept in specific-pathogen-free (SPF) environments. This study tested the hypothesis that enteric bacteria are necessary for the development of spontaneous colitis and immune system activation in IL-10-deficient mice. IL-10-deficient mice were maintained in either SPF conditions or germfree conditions or were populated with bacteria known to cause colitis in other rodent models. IL-10-deficient mice kept in SPF conditions developed colitis in all segments of the colon (cecum and proximal and distal colon). These mice exhibited immune system activation as evidenced by increased expression of CD44 on CD4(+) T cells; increased mesenteric lymph node cell numbers; and increased production of immunoglobulin A (IgA), IgG1, and IL-12 p40 from colon fragment cultures. Mice populated with bacterial strains, including Bacteroides vulgatus, known to induce colitis in other rodent models had minimal colitis. Germfree IL-10-deficient mice had no evidence of colitis or immune system activation. We conclude therefore that resident enteric bacteria are necessary for the development of spontaneous colitis and immune system activation in IL-10-deficient mice.

Animals↗
PubMed1997

Interleukin-1-induced nuclear factor kappa B activation is inhibited by overexpression of phospholipid hydroperoxide glutathione peroxidase in a human endothelial cell line.

Oxygen radicals are commonly accepted mediators in the tumour necrosis factor-mediated nuclear factor kappa B (NF kappa B) signalling cascade, but evidence for their role during interleukin-1 (IL-1) signalling is lacking. To test the involvement of hydroperoxides we investigated whether IL-1-induced NF kappa B activation could be influenced by glutathione peroxidases (GPx). These enzymes remove hydroperoxides with various specificities for the hydroperoxide substrate. By overexpressing phospholipid hydroperoxide glutathione peroxidase (PHGPx), which characteristically reacts with lipophilic hydroperoxides, the roles of H2O2 and lipid hydroperoxides were assessed. A human umbilical endothelial cell line, ECV 304, was stably transfected with the genes for both PHGPx and selenophosphate synthetase (selD), which provides selenophosphate for selenoprotein biosynthesis. When grown in selenium-deficient culture medium, the double-transfected clone (ECVPHGPx+SelD+) expressed 5-fold higher (P<0.005) PHGPx activity (measured by phosphatidylcholine hydroperoxide removal) than controls. The rate of H2O2 removal was also significantly (P<0.01) higher in this clone. When grown with high levels of extracellular selenium (up to 100 nM selenite), PHGPx activity and H2O2 removal were enhanced substantially in control cells and transfected cells. Under these conditions, PHGPx activity was 1.7-fold (P<0.005) higher in ECVPHGPx+SelD+, but H2O2 removal was the same as in controls. IL-1-induced NF kappa B activation was inhibited by selenium supplementation in control cells. In ECVPHGPx+SelD+ under conditions of selenium restriction, IL-1 induced NF kappa B activation only to a similar extent as under conditions of selenium supplementation in controls, and activation was abolished with 50 nM sodium selenite. These results show that overexpressed PHGPx is sufficient to inhibit NF kappa B activation, and suggests that NF kappa B activation by IL-1 is mediated by a preferential substrate of PHGPx, such as a fatty acid hydroperoxide, rather than by H2O2, the preferred substrate of the more abundant cytosolic GPx.

Cell Line↗
PubMed1997

Inhibitors of glutathione S-transferases as therapeutic agents.

Glutathione S-transferases (GST) are a family of phase II detoxification enzymes with broad substrate specificities. They catalyze the conjugation of glutathione with many different types of xenobiotics, rendering the compound more water soluble and thus more easily eliminated. Resistance to cancer chemotherapeutic drugs, such as the alkylating agents, has been directly correlated with the overexpression of GSTs. Subsequently, a rationale has been established to utilize agents that inhibit GST in combination with alkylating agents to circumvent this resistance. Two such agents, ethacrynic acid (EA) and Terrapin 199 (TER 199), have been examined for this purpose. EA, an inhibitor of all classes of GST isozymes, has been used clinically in combination with thiotepa. More recently, TER 199, a glutathione analog-based GST inhibitor, has been modeled specifically to inhibit GST pi, an enzyme which is commonly found at high levels in human tumor biopsies. Furthermore, a therapeutic strategy has been designed to take advantage of GST pi activation of a prodrug, TER 286. Recent studies have investigated the molecular mechanisms involved in the cellular response to GST inhibitors and have employed techniques such as differential display to examine altered gene expression as well as to identify novel genes induced by these agents. Overall, this strategy may provide further insight into the action of these agents in the cell as well as prove useful in endeavors to modulate anticancer drug resistance.

Journal Article↗
PubMed1997

Significance of p53 overexpression in urinary bladder transitional cell carcinoma in situ before and after bacillus Calmette-Guérin treatment.

OBJECTIVES: Overexpression of p53, normally secondary to gene mutation, in invasive uroepithelial neoplasms (transitional cell carcinoma) and a high percentage of transitional cell carcinoma in situ (CIS) has been described; however, the role of p53 before and after bacillus Calmette-Guérin (BCG) treatment of CIS needs to be defined. METHODS: Immunohistochemical reaction for p53 overexpression was performed on 12 patients with CIS before and after BCG treatment. Thirty cystectomy specimens with invasive TCC were also evaluated for the presence of CIS, hyperplasia, and dysplasia. RESULTS: Twenty-three cases of CIS were identified. Approximately 90% of CIS cases (21 of 23) were positive for p53 overexpression, whereas transitional cell hyperplasia was uniformly negative. Less than 5% of the cells in morphologically dysplastic lesions were positively stained. Ten of 12 CIS patients displayed p53 overexpression before BCG treatment. After BCG treatment, 4 patients displayed residual CIS with p53 overexpression, and 8 patients showed no residual CIS or p53 overexpression. Three of the 4 patients with residual CIS and overexpression rapidly developed invasive transitional cell carcinoma requiring cystectomy. The 1 remaining patient was treated with a second course of BCG; further biopsies displayed the development of grade 1 papillary transitional cell carcinoma without invasion, and the patient is currently being followed CONCLUSIONS: Our data suggest that follow-up biopsy procedures are essential in all patients with CIS treated with BCG. The biopsy specimens should be evaluated for p53 overexpression, because our data indicate that persistent p53 overexpression in uroepithelial lesions after BCG treatment is an ominous finding for probable tumor progression.

Adjuvants, Immunologic↗
PubMed1997

A sequencing strategy for the localization of O-glycosylation sites of MUC1 tandem repeats by PSD-MALDI mass spectrometry.

It is demonstrated with glycopeptides of the polymorphic epithelial mucin (MUC1) that post-source decay matrix-assisted laser desorption ionization (PSD-MALDI) is a fast, highly sensitive, and reproducible method for the localization of O-glycosylation sites by reflectron time-of-flight (TOF) mass spectrometry. We have analyzed GalNAc-carrying peptides of up to 25 amino acids, and could distinguish even neighboring glycosylation sites. This method was also able to localize and characterize disaccharides (e.g., the Thomsen-Friedenreich disaccharide) on MUC1 derived peptides. PSD-MALDI-MS fragment ion patterns were recorded in the positive ion mode from the synthetic peptide TAP25 [(T1aAPPAHGVT9S10APDT14RPAPGS20) T1bAPPA], an overlapping sequence of MUC1 tandem repeats, which was glycosylated with GaINAc in vitro. The glycosylation sites found were either Thr9 or Thr1b in the monoglycosylated, Thr9 and Thr1b in the diglycosylated, and Thr9, Thr1b, and Ser20 in the triglycosylated peptide. A single PSD-MALDI-MS spectrum of the underivatized and uncleaved di- or triglycosylated TAP25 peptide was sufficient to identify the glycosylation sites, thereby distinguishing six potential, partly adjacent, glycosylation sites. The monoglycosylated fraction was found to consist of a mixture of two glycosylated species with the same molecular weight. This was shown by the analysis of proteolytic digests. PSD-MALDI-MS of the resulting peptides right out of the digestion probe was sufficient to identify the Gal-NAc-glycosylation sites as either Thr9 or Thr1b, respectively. Beyond the methodical aspects the results revealed that in vitro glycosylation of the TAP25 peptide with a transferase system from human milk differs from that obtained with a breast cancer cell transferase system.

Amino Acid Sequence↗
PubMed1997

Accuracy of invasive and noninvasive tests to diagnose Helicobacter pylori infection after antibiotic treatment.

OBJECTIVES: To compare the diagnostic accuracy of the most widely available tests for diagnosis of Helicobacter pylori infection after antibiotic treatment. METHODS: A total of 59 H. pylori-positive, duodenal ulcer patients (mean age, 40.7 +/- 11.7 yr; 40 male and 19 female) were treated for 2 wk with either amoxicillin-metronidazole (n = 36) or omeprazole-amoxicillin-tinidazole (n = 23), and after 4 wk, were tested for H. pylori infection by [14C]urea breath test (UBT), serum IgG antibody level, and multiple antral biopsies for rapid urease testing, histology, Warthin-Starry stain, and polymerase chain reaction to detect H. pylori DNA. Infection status was established by a concordance of test results. RESULTS: H. pylori was eradicated in 47 patients (80%). UBT and rapid urease testing had the best sensitivity and specificity, although not statistically different to Warthin-Starry stain and polymerase chain reaction. Serology and histology had little diagnostic value in this setting due to high proportion of false-positive results. CONCLUSIONS: Noninvasive UBT is as accurate in predicting H. pylori status after antibiotic treatment as rapid urease testing and Warthin-Starry stain. Especially for duodenal ulcer patients, UBT could be considered the gold standard to confirm eradication of H. pylori.

Adolescent↗
PubMed1996

Tumors of the respiratory tract observed at the German Primate Center, 1978-1994.

Eight spontaneous pulmonary tumors (four bronchiolar tubular adenomas, two bronchiolar adenocarcinomas, two squamous-cell carcinomas) occurred in a total of 54 adult tree shrews (Tupaia belangeri) of the GPC colonies between 1978 and 1994. The adenomas and adenocarcinomas consisted of tubularly or trabecularly arranged cuboidal to cylindrical cells interspersed with some PAS-positive goblet cells, thus resembling the epithelial lining of respiratory bronchioles of tree shrews. The two squamous-cell carcinomas probably originated from the pulmonary alveoles. Three more pulmonary tumors (one small-cell carcinoma, one bronchial adenoma, one squamous-cell carcinoma) developed in 409 adult callitrichids of the GPC colonies during the same period, and one more bronchial adenoma was observed in a common marmoset (Callithrix jacchus) of another colony located in Göttingen. With regard to the adenomas and squamous-cell carcinomas, a similar cellular origin with the three shrews is assumed. The small-cell carcinoma possibly developed from the bronchial epithelium, provided a pathogenesis parallel to that of human small-cell carcinoma is suggested. Four of the tree shrew pulmonary adenomas/adenocarcinomas and the small-cell Ca were macroscopically visible as yellowish-grey nodules of 1 mm x 1 mm to 15 mm x 15 mm diameter, predominantly involving the main lobes (2 x right main lobes, 2 x left main lobes, 1 x all lobes). The pulmonary tumors of the other animals were below macroscopical detectability.

Adenocarcinoma↗