Biomedical subjects
Publications and source records attributed to K Krauss.
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Developing primary systemic chemotherapy (PST) regimens that induce higher pathological complete response (pCR) rates remains a challenge in operable breast cancer. We recruited 77 eligible patients into a multicentre phase I/II study to evaluate the maximum tolerated dose (MTD), toxicity and efficacy of preoperative gemcitabine day 1 and 8 (800 mg/m(2) fixed dose), epirubicin and docetaxel on day 1 (doses escalated from 60 mg/m(2)) (GEDoc), repeated 3-weekly for 6 cycles with filgrastim support. MTD for epirubicin was 90 mg/m(2) and for docetaxel 75 mg/m(2). Dose-limiting toxicities (DLTs) included febrile neutropenia and grade 3 diarrhoea. Clinical response rate was 92%, pCR rate was 26%. 79% of patients had breast-conserving surgery. Grade 3/4 leucopenia was the main toxicity, occurring in 55 (87%) of 63 patients treated at the MTD. Non-haematological toxicity caused no serious clinical problems. In conclusion, GEDoc is highly active as PST. Efficacy and toxicity compare favourably with other effective combinations.
The ectodomain of certain transmembrane molecules can be released by proteolysis, and the solubilized antigens often exert important biological functions. We demonstrated before that the L1 adhesion molecule is shed from the cell surface. Here we show that L1 release in AR breast carcinoma cells is mediated by a member of the disintegrin metalloproteinase (ADAM) family of proteinases. Up-regulation of L1 shedding by phorbol ester or pervanadate involved distinct mechanisms. Pervanadate induced shedding and rounding-up of cells from the substrate, which was blocked by the Src kinase inhibitor PP2. Tyr phosphorylation of the L1 cytoplasmic tail and the Src kinase Fyn was observed following pervanadate treatment. Up-regulation of L1 release and activation of Fyn occurred also when cells were detached by EDTA suggesting that the regulation of L1 shedding by this pathway was linked to cell morphology and adhesion. The phorbol 12-myristate 13-acetate-induced shedding was inhibited by the protein kinase C inhibitor bisindolylmaleimide I and by PD98059, a specific inhibitor of the mitogen-activated protein kinase pathway. Soluble L1 binds to the proteoglycan neurocan and in bound form could support integrin-mediated cell adhesion and migration. We propose that the release of cell-associated adhesion molecules such as L1 may be relevant to promote cell migration.
The leukocyte function-associated antigen-1 (LFA-1) integrin (CD11a/CD18) is an important adhesion molecule for lymphocyte migration and the initiation of an immune response. At the cell surface, LFA-1 activity can be regulated by divalent cations that enhance receptor affinity but also by membrane clustering induced by treatment of cells with substances such as phorbol esters. Membrane clustering leads to increased LFA-1 avidity. We report here that LFA-1-mediated binding of mouse thymocytes or activated T lymphocytes to intercellular adhesion molecule 1 can be rapidly induced by clustering of membrane rafts using antibodies to the glycosylphophatidylinositol-anchored molecule CD24 or cholera toxin (CTx). CD24 and CD18 were found to co-localize in rafts and cross-linking with CTx lead to enhanced LFA-1 clustering. We observed that disruption of raft integrity by lowering the membrane cholesterol content abolished the CTx and the phorbol 12-myristate 13-acetate-induced LFA-1 binding but left the ability to activate LFA-1 with Mg(2+)/EGTA unimpaired. In contrast to activation with Mg(2+)/EGTA, activation via raft clustering was dependent on PI3-kinase, required cytoskeletal mobility, and was accompanied by Tyr phosphorylation of a 18-kDa protein. Our results support the notion that rafts as preformed adhesion platforms could be important for the rapid regulation of lymphocyte adhesion.
Academic medical centers (i.e., medical schools and their principal hospitals) are following very similar strategies in attempts to secure their futures. It is likely that these undifferentiated strategies will fail, since most of them have been copied from the lower-cost, geographically better-positioned hospitals and health systems. Despite a wealth of innovative, entrepreneurial talent and the potential to reshape the world that AMCs live in, most AMCs are in reactive modes. Future directions and strategies are almost always shaped, forced, and justified by external pressures. The major problem with the strategic plans of most AMCs is that they are based on conventional industry wisdom. Strategic plans tend not to be analytically driven. The insight and understanding of those factors that drive the demand for AMCs' services and determine the performances of AMCs are lacking. The authors note some questions that are critical to the formulation of strategies for AMCs. For example, how can the research mission be changed from a cost-based to a value-based endeavor? Most AMCs cannot answer these questions, and if they do address them in the planning process, they do so superficially. Several examples of the factors that need to be understood are also given, such as patients' purposes and needs in seeking specialty care. Alternative strategies are listed, such as maintaining and exploiting the economic irrationality of the market rather than acting as if it were economically rational or forcing it to become so. Last, the authors outline the scope of the changes that are required and urge AMCs to reject conventional wisdom, determine their own unique situations, and work from there.
N-Acetyl-leukotriene E4 has been identified as an endogenous, biologically less active cysteinyl leukotriene metabolite in rodents and humans. To evaluate the ratio of hepatobiliary to renal elimination of leukotrienes noninvasively by positron emission tomography (PET), we synthesized N-[11C]acetyl-leukotriene E4 by chemical N-acetylation of leukotriene E4. After the intravenous injection of N-[11C]acetyl-leukotriene E4 in normal rats and monkey, uptake by the liver and subsequent excretion into bile were largely responsible for its rapid elimination from blood. In the Cynomolgus monkey, renal excretion of the leukotriene into urine was of additional quantitative importance. Kinetic modeling indicated a mean transit time through the liver of 17 minutes and 34 minutes in rat and monkey, respectively; the corresponding hepatic excretion half-times amounted to 8.5 minutes and 16 minutes. In a mutant rat strain deficient in the hepatobiliary excretion of cysteinyl leukotrienes across the canalicular membrane, the apparent mean liver transit time was 54 minutes, and the hepatic excretion half-time was 29 minutes, indicating prolonged organ storage and metabolism. After transport from the liver back into the circulating blood of omega-oxidized and beta-oxidized metabolites of N-[11C]acetyl-leukotriene E4, renal excretion compensated for the impairment of hepatobiliary elimination in the transport mutant. Metabolite analyses in urine after intravenous injection of N-[3H]acetyl-leukotriene E4 indicated the extensive inactivation of N-acetyl-leukotriene E4 by beta-oxidation from the omega-end in the mutants. A similar shift from hepatobiliary to renal cysteinyl leukotriene elimination was monitored in rats with cholestasis due to bile duct obstruction.(ABSTRACT TRUNCATED AT 250 WORDS)
Transport processes control not only synthesis and release of LTC4 but also the elimination and excretion of LTC4 and its metabolites. (i) A primary-active ATP-dependent export carrier mediates the release of LTC4 from a leukotriene-generating cell, as exemplified by mastocytoma cells, and as measured in mastocytoma plasma membrane vesicles (2). (ii) Release of cysteinyl leukotrienes into the blood circulation is followed by a rapid elimination with an initial half-life of 38 sec in rats and 4.0 min in man, as measured with the labeled, representative LTC4 catabolite, N-acetyl-LTE4. (iii) 11C-labeled N-acetyl-LTE4 can serve for non-invasive studies on cysteinyl leukotriene elimination and excretion by the liver and kidney in the intact organism using positron emission tomography. An impairment of leukotriene transport from the liver across the canalicular membrane into bile, studied in mutant rats and in extrahepatic cholestasis, leads to a compensatory diversion of cysteinyl leukotriene elimination to the kidney. N-Acetyl-LTE4 labeled with a short-lived positron-emitting isotope provides quantitative insight into the pathways of cysteinyl leukotriene elimination in vivo. (iv) Cysteinyl leukotriene export from the liver into bile is mediated by an ATP-dependent primary-active export carrier. This decisive step in cysteinyl leukotriene elimination has been characterized in hepatocyte canalicular membrane vesicles (3). The leukotriene exporter is deficient in transport mutant rats. The leukotriene carrier is distinct from other ATP-dependent export carriers identified in this membrane domain, such as the ATP-dependent bile salt export carrier (25) and the multidrug export carrier (27).
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Between 1982 and 1984, 181 operations of the carotid artery were performed--180 of these in primary awake patients--36 in stage I (19.9%), 72 in stage II (39.8%), 72 in stage IV (39.8%) and only one in stage III (0.6%). 144 patients (79.6%) tolerated clamping of the carotid artery very well. In 37 patients (20.4%) clamping was not tolerated (two patients, in whom the control of cerebral function was not possible, were submitted to the latter group). In three of 181 patients clamping-intolerance started at the end of operation, more than 30 minutes after clamping. Clamping intolerance in these cases was found to be confined to pulmonary and cardiac factors, no shunt was used, but operation was brought to an end as quickly as possible. Complications were present in 15 patients (8.3%), three of them resulting in death (hospital mortality rate 1.7%), 2 of them in permanent loss of function (morbidity rate 1.1%). Only in 2 patients (asystolism with consecutive successful reanimation in one case, and thoracotomy due to enlargement of surgical procedure in the other case) a primary general anaesthesia would have facilitated surgery. Surgery of the carotid artery under local anaesthesia is considered to be a guarantee for a secure intraoperative surveillance followed by a low postoperative complication rate. In a few cases more difficult surgical procedures have to be accepted in account of that.
The effects of hypertonic glucose infusion on the anginal threshold determined by atrial pacing was studied in 14 patients with significant coronary artery disease. After glucose, angina occurred at a significantly lower heart rate and double product (systolic arterial pressure x heart rate), suggesting a decreased tolerance to ischemic stress. No stoichiometric relationship was noted between glucose uptake and lactate production, and there was no evidence that hypertonic glucose infusion resulted in enhanced anaerobic glycolysis in the ischemic myocardium. Acute elevation of plasma glucose levels may not be beneficial to patients with coronary artery disease.