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Biomedical subjects

G Strauss

Publications and source records attributed to G Strauss.

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

Serum levels of thrombopoietin, IL-11, and IL-6 in pediatric thrombocytopenias.

We measured serum levels of thrombopoietin (TPO), interleukin (IL)-11, and IL-6 in 90 different samples from 67 pediatric patients with thrombocytopenia (TP). The cytokine levels were determined by enzyme-linked immunosorbent assays (ELISA), and the biological activity of TPO was measured using a cell line transfected with human c-mpl. In patients with impaired megakaryocytopoiesis, as found in diseases such as aplastic anemia, amegakaryocytic TP, or TP with absent radii, we found TPO levels which were highly elevated compared with normal values (mean=261 AU/ml, n=52, vs. 22 AU/ml in healthy controls). In contrast, patients suffering from idiopathic thrombocytopenic purpura (mean=16 AU/ml, n=31) or platelet function defects (mean=23 AU/ml, n=7) demonstrated normal TPO levels. The biological activity tested in the bioassay correlated well with the ELISA data. However, sera of some patients with amegakaryocytic TP demonstrated a remarkably higher biological activity of TPO than expected from the ELISA data. Within the different groups there was no correlation between platelet counts and TPO levels. Only 27% of all samples had elevated levels of IL-11 (mean=450 pg/ml, n=20). Elevated IL-6 serum levels were detected in only 13% of all samples analyzed (mean=42 pg/ml, n=12). We conclude that megakaryocytopoiesis is regulated mainly by TPO, that it is dependent on the platelet and the megakaryocytic mass, and that IL-11 plays an additional role in supporting the platelet production. IL-6 does not appear to be up-regulated in children with thrombocytopenia.

Adolescent↗
PubMed1999

Varese meeting report.

Explore the source record for details and available documents.

Consensus Statements as Topic↗
PubMed1999

High-dose paclitaxel plus G-CSF for malignant mesothelioma: CALGB phase II study 9234.

BACKGROUND: New agents with activity in mesothelioma are sorely needed. The Cancer and Leukemia Group B (CALGB) therefore performed a phase II study of high-dose paclitaxel in patients with malignant mesothelioma who had no prior chemotherapy. PATIENTS AND METHODS: Thirty-five patients accrued to this multi-institutional phase II study of paclitaxel given as a 24-hour infusion at 250 mg/m2 every three weeks plus filgrastim (G-CSF) 300 mcg subcutaneously days 3-18. RESULTS: There were three (9%) regressions of evaluable disease. The median survival was five months (95% confidence interval (95% CI): 1.9-9.6 months), the one-year survival rate was 14% and the two-year survival rate was 6%. Toxicity was tolerable with one death from pneumonia (without neutropenia) on day 18 and a 23% rate of grade 4 granulocytopenia. CONCLUSIONS: The level of activity seen with paclitaxel is similar to that seen in other CALGB trials of the single agents carboplatin, trimetrexate and 5-azacytidine. Future studies of of paclitaxel (at lower doses) in combination with synergistic agents could be considered.

Adult↗
PubMed1999

Without prior stimulation, tumor-associated lymphocytes from malignant effusions lyse autologous tumor cells in the presence of bispecific antibody HEA125xOKT3.

Women suffering from advanced stage ovarian or mammary carcinoma frequently develop malignant ascites or pleural effusions consisting of tumor cells and tumor-associated lymphocytes (TALs). Locoregional immunotherapy with bispecific antibodies (bsAbs), which retarget T cells to tumor cells and induce their lysis, has been applied as an adjuvant treatment in the late stage of the disease. Until now, most of these therapies use peripheral blood mononuclear cells (PBMCs) as effector cells that have been stimulated and expanded ex vivo and loaded with bsAb before reinjection. Here we investigated whether TALs derived from malignant ascites or pleural effusions can be used as bsAb-guided effector cells without prior in vitro stimulation. For this we established a bsAb, HEA125xOKT3, which recognizes the epithelial antigen Egp34 on carcinoma cells and the CD3 molecule on T cells. BsAb HEA125xOKT3 induced lysis of various Egp34-expressing carcinoma lines by stimulated PBMCs. Optimal cytotoxicity was achieved at a bsAb concentration of 1 microg/ml. In three ovarian and two mammary carcinoma patients, we demonstrated efficient lytic activity of lymphocytes, isolated from malignant ascites or pleural effusion. Without prior stimulation, they lysed autologous tumor cells in the presence of bsAb HEA125xOKT3, indicating that they are already activated. Along this line, a subset of CD4+ and CD8+ unstimulated TALs expressed the early activation marker CD69. They are, however, negative for CD95, and only a small subpopulation of CD4+ TALs expresses CD25. OKT3/interleukin 2 stimulation of TALs increased the expression of activation markers on the CD4+ and CD8+ T-cell compartment. The activation markers CD69, CD25, CD95, and DR molecules are up-regulated on both T-cell types. However, lysis of autologous tumor cells by stimulated TALs is not significantly enhanced compared with unstimulated TALs. Our results may offer a novel and promising concept of adjuvant immunotherapy for ovarian and mammary carcinoma patients. Preactivation and expansion of PBMCs can be circumvented by exploring the cytotoxic capacity of unstimulated TALs in the presence of bsAbs in a locoregional therapeutic approach.

Animals↗
PubMed1998

Bispecific CD3 x CD19 diabody for T cell-mediated lysis of malignant human B cells.

For the treatment of minimal residual disease in patients with leukemias and malignant lymphomas, we constructed a heterodimeric diabody specific for human CD19 on B cells and CD3epsilon chain of the T cell receptor complex. The bispecific diabody was expressed in Escherichia coli using a vector containing a dicistronic operon for co-secretion of V(H)3-V(L)19 and V(H)19-V(L)3 single-chain Fv fragments (scFv). It was purified in one step by immobilized metal affinity chromatography (IMAC) from the periplasmic extract and culture medium. Flow cytometry experiments revealed specific interactions of the diabody with both CD3 and CD19 positive cells, to which it bound with affinities close to those of the parental scFvs. It was less stable than anti-CD3 scFv but more stable than anti-CD19 scFv when incubated in human serum at 37 degrees C. In cytotoxicity tests, the diabody proved to be a potent agent for retargeting peripheral blood lymphocytes to lyse tumor cells expressing the CD19 antigen. The efficiency of cell lysis compared favorably with that obtained with a bispecific antibody (BsAb) of the same dual specificity that was prepared by the quadroma technique.

Amino Acid Sequence↗
PubMed1998

Biosynthesis of the diterpene verrucosan-2beta-ol in the phototrophic eubacterium Chloroflexus aurantiacus. A retrobiosynthetic NMR study.

The biosynthesis of verrucosan-2beta-ol in the green phototrophic eubacterium Chloroflexus aurantiacus was investigated by in vivo incorporation of singly or doubly 13C-labeled acetate. The 13C labeling of the isolated diterpene was analyzed by one- and two-dimensional NMR spectroscopy. The 13C-labeling patterns of verrucosan-2beta-ol were compared with the labeling patterns of intermediary metabolites (acetyl-CoA, pyruvate, and glyceraldehyde 3-phosphate) which were deduced from amino acids and nucleosides by retrobiosynthetic analysis. The results show that verrucosan-2beta-ol is synthesized via mevalonate and not via the deoxyxylulose pathway, which was discovered recently in some eubacteria, algae, and plants. A scheme for the formation of the unusual tetracyclic ring system is offered. The cyclization process is initiated by the solvolysis of pyrophosphate from geranyllinaloyl pyrophosphate and the mechanism involves a Wagner-Meerwein rearrangement, a 1,5-hydride shift, and a cyclopropylcarbinyl to cyclopropylcarbinyl rearrangement.

Acetyl Coenzyme A↗
PubMed1998

Expression of the human histocompatibility leukocyte antigen DR3 transgene reduces the severity of demyelination in a murine model of multiple sclerosis.

The role of various MHC genes in determining the progression of multiple sclerosis (MS) remains controversial. The HLA-DR3 gene has been associated with benign relapsing MS in some genetic epidemiologic studies, but with disease progression in others. We induced demyelination in highly susceptible B10.M and B10.Q mice expressing the DR3 (HLA-DRB1*0301) transgene to determine directly the effects of a human transgene by infecting them with Theiler's murine encephalomyelitis virus (TMEV). DR3+ mice experienced a dramatic reduction in the extent and severity of demyelination compared with DR3- littermate controls, whereas anti-TMEV antibody titers, delayed-type hypersensitivity responses, and levels of infectious virus, virus antigen, and virus RNA were similar in both groups. To address a possible mechanism of how the human transgene is reducing virus-induced demyelination, we analyzed cytokine expression in the lesions and also determined whether B10.M mice can respond to peptides derived from the DR3 molecule. Intense staining for IFN-gamma and IL-4, T helper (TH) 1 and TH2 cytokines, respectively, was found in the lesions of TMEV-infected DR3- mice but not in the DR3+ transgenic mice at day 21 after infection. DR3 peptides elicited strong proliferative responses in B10.M mice but not in B10.M (DR3+) mice. These experiments are the first to demonstrate that a human class II DR gene can alter the severity of demyelination in an animal model of MS without influencing viral load. These experiments are consistent with a mechanism by which DR3 reduces demyelination by altering the cytokine expression in the lesions, possibly by deleting T cells involved in virus-induced pathology.

Animals↗
PubMed1998

Defective c-Mpl signaling in the syndrome of thrombocytopenia with absent radii.

Thrombocytopenia with absent radii (TAR) syndrome is a rare congenital defect with severe hypomegakaryocytic thrombocytopenia and bilateral radial aplasia. To elucidate a possible relationship between thrombocytopenia in TAR and defects in the thrombopoietin (TPO)/c-Mpl system, we examined TPO activity in sera from six patients and in vitro reactivity of the patients' platelets to recombinant human TPO. We found elevated TPO serum levels in all patients, excluding a TPO production defect as a pathomechanism for the thrombocytopenia. In contrast to healthy controls, however, platelets of TAR patients failed to respond to recombinant TPO as measured by testing TPO synergism to suboptimal concentration of platelet activators. Most interestingly, TPO-induced tyrosine phosphorylation of platelet proteins was completely absent (four out of five) or markedly decreased (one out of five). More detailed investigations of the signal cascades of c-Mpl demonstrated the absence of Jak2 phosphorylation after TPO stimulation in a TAR patient's platelets. A defect in the early events of c-Mpl signal transduction might be the reason for impaired megakaryocytopoiesis in TAR syndrome.

Blood Platelets↗
PubMed1998

Hyperventilation restores cerebral blood flow autoregulation in patients with acute liver failure.

BACKGROUND/AIMS: In patients with acute liver failure loss of cerebral blood flow autoregulation may result from cerebral vasodilatation. Since arterial hypocapnia induces cerebral vasoconstriction, we investigated whether cerebral blood flow autoregulation could be reestablished by mechanical hyperventilation. METHODS: Seven consecutive patients (median age 45, range 30-50 years) with acute liver failure and hepatic encephalopathy stage IV entered the study. They were all maintained on mechanical ventilation. Cerebral blood flow autoregulation was evaluated by using transcranial Doppler sonography to assess mean flow velocity (Vmean) in the middle cerebral artery, during a rise in mean arterial pressure by norepinephrine infusion (0.5-10 microg/h). The patients were subsequently hyperventilated for 15 min before cerebral blood flow autoregulation was re-evaluated in the same mean arterial pressure range. RESULTS: At baseline PaCO2 (4.0 (3.5-4.9)kPa), all patients had impaired cerebral blood flow autoregulation as Vmean increased from 47 (30-78) to 68 (49-107) cm x s(-1) (p<0.05), as MAP was raised from 82 (60-88) to 106 (89-123) mmHg. During hyperventilation, five of seven patients restored cerebral autoregulation as Vmean remained unchanged at 51 (45-70) cm x s(-1) during a rise in MAP from 84 (65-94) to 110 (89-130) mmHg. Cerebral blood flow autoregulation was not restored in two patients, but hyperventilation reduced the slope of the mean arterial pressure-Vmean correlation. These two patients had renal failure and were treated with intermittent hemodialysis. CONCLUSIONS: Cerebral blood flow autoregulation was restored by hyperventilation in five of seven patients with acute liver failure, indicating that cerebral vasodilatation is of pathophysiological importance in dysregulation of cerebral circulation in acute liver failure.

Adult↗
PubMed1998

Faecal progesterone metabolite analysis for non-invasive monitoring of reproductive function in the white rhinoceros (Ceratotherium simum).

The two subspecies of white rhinoceros, southern (Ceratotherium simum simum) and northern (Ceratotherium simum cottoni), breed poorly in captivity, and estimates of oestrous cycle length vary considerably (range, 25-90 days). To characterise reproductive patterns, faecal samples were collected 2-3 times/week for up to 56 months from non-pregnant animals (n=21) of both subspecies. Immununoreactive pregnanes containing a 20-oxo-group (20-oxo-P) were analysed in a group-specific enzyme immunoassay using an antibody against 5alpha-pregnane-3beta-ol-20-one 3HS:BSA. Reproductive patterns were highly variable among and within individual animals. However, rhinoceroses could be classified into four major categories on the basis of oestrous cycle length and luteal phase 20-oxo-P concentrations: (1) regular oestrous cycles of 10 weeks duration and > 800 ng/g (n=2 animals); (2) oestrous cycles between 4-10 weeks and 250-750 ng/g (n=6); (3) no apparent cycle regularity, but luteal activity indicated by 20-oxo-P concentrations of 100-200 ng/g (n=6); (4) no apparent luteal activity as indicated by 20-oxo-P of < 100 ng/g (n=7). In two attempts to induce ovarian activity, chlormadinone acetate was fed daily to one animal for 35 and 45 days, respectively. Each treatment was followed by a subsequent hCG injection which resulted in luteal phases of 17 and 18 days, respectively, beginning about 10 days after hCG. Concentration of faecal 20-oxo-P in one pregnant animal during the 4th and 5th month of gestation were markedly higher than those observed during the luteal phase of the cycle. In conclusion, two thirds of white rhinoceroses in this study had erratic or missing luteal activity, whereas variable cycles of 4-10 weeks in length were evident in six females, and regular oestrous cycles of 10 weeks in length were found in two animals.

Animals↗
PubMed1998

[Cryptosporidiosis in adders (Pituiophis melanoleucus sayi)].

Infection of snakes with cryptosporidia is known to occur as hypertrophic gastritis associated with postprandial regurgitation. This is a report of a severe and fatal intestinal cryptosporidiosis in a group of snakes (Pituophis melanoleucus sayi) kept at a zoological garden. The clinical and pathological findings are described and discussed in this paper. Pathohistologically fibrinous, diphtheroid and necrotizing enteritides were diagnosed. Histological examination was completed by electron microscopy. Transmission electron microscopic examination revealed numerous cryptosporidia in close contact to the luminal surface of the intestinal epithelial cells. Different cryptosporidial stages developing in parasitophorous vacuoles occurred. By scanning electron microscopy the superficial localisation of the cryptosporidia in the damaged brush border of the intestinal epithelial cells was demonstrated. In addition, the ultrastructural examination of the small intestine of three animals revealed adenovirus-like particles.

Animals↗
PubMed1998

Bispecific antibodies increase T-cell stimulatory capacity in vitro of human autologous virus-modified tumor vaccine.

The production and functional testing of two new bispecific (bs) hybrid antibodies [Abs; bs Ab hemagglutinin-neuraminidase (HN) x CD3 and bs Ab HN x CD28] designed for cancer vaccine modification are described. They allow distinct modifications of the human tumor cell vaccine ATV-NDV, an autologous tumor cell vaccine already modified by infection with Newcastle disease virus. The bs Abs use the viral HN molecule as a common foreign anchoring molecule for attachment to the tumor cells and allow the introduction of anti-CD3 or anti-CD28 T-cell-stimulatory molecules. The bs Abs attached to tumor target cells were able to cross-link CTL effector cells and up-regulate T-cell activation markers on autologous cancer patient-derived CD4 and CD8 T lymphocytes. This strategy of combining a cellular vaccine with a bs Ab is highly specific, quick, and economical and has broad-range applications. Five ng or less of target cell-bound bs Ab HN x CD28 were effective at augmenting T-cell-mediated antitumor cytotoxicity.

Antibodies, Bispecific↗
PubMed1997

Thrombopoietin in patients with congenital thrombocytopenia and absent radii: elevated serum levels, normal receptor expression, but defective reactivity to thrombopoietin.

The pathophysiology of thrombocytopenia in the syndrome of thrombocytopenia with absent radii (TAR) is not yet understood. We examined thrombopoietin (TPO) serum levels and the in vitro reactivity of platelets to TPO in five patients affected with TAR syndrome. We found elevated TPO serum levels in all patients tested, excluding a TPO production defect as cause for thrombocytopenia in TAR syndrome. In addition, we found similar expression of the TPO receptor c-Mpl on the surface of platelets from TAR patients (5 of 5) and a similar molecular weight of the receptor as compared with healthy controls (4 of 4). Platelet response to adenosine diphosphate or thrombin receptor agonist peptide SFLLRN (TRAP) was normal in TAR patients. However, in contrast to results with healthy controls we could show absence of in vitro reactivity of platelets from TAR patients to recombinant TPO as measured by testing TPO synergism to adenine diphosphate and TRAP in platelet activation. TPO induced tyrosine phosphorylation of platelet proteins was completely absent (3 of 4) or markedly decreased (1 of 4). Our results indicate that defective megakaryocytopoiesis/thrombocytopoiesis in TAR syndrome is not caused by a defect in TPO production but a lack of response to TPO in the signal transduction pathway of c-Mpl.

Blood Platelets↗
PubMed1997

Liver function, cerebral blood flow autoregulation, and hepatic encephalopathy in fulminant hepatic failure.

In acute liver failure, massive hepatic necrosis may result in impaired regulation of cerebral blood flow (CBF), development of encephalopathy, and cerebral edema. In 10 consecutive patients with fulminant hepatic failure (FHF), CBF autoregulation was found to be absent, as transcranial Doppler mean flow velocity (Vmean) in the middle cerebral artery increased from 49 (27-59) to 69 (49-92) cm/s (P < .05) during a 30- (28-34) mm Hg rise in mean arterial pressure (MAP). In 7 patients, restoration of CBF autoregulation was shown within 48 (24-120) hours after spontaneous hepatic recovery or liver transplantation, before complete alleviation of hepatic encephalopathy (HE). The extraordinarily rapid restoration of CBF autoregulation in patients with FHF following re-establishment of liver function is unique compared with other conditions affecting the CBF autoregulation, indicating a close connection between liver function and regulation of cerebral circulation. Because CBF autoregulation was restored after initial alleviation of HE, it does not appear to be of major pathophysiological importance in the mediation of HE.

Adult↗
PubMed1997

Phase II trial of high-dose cisplatin plus ifosfamide as first-line followed by carboplatin as second-line treatment in epithelial ovarian carcinoma.

BACKGROUND: In a previous study of combined platinum and ifosfamide we found a pathologic complete response rate of 42%. The present study was to test whether the high response rate could be reproduced or even improved by combining high-dose cis-platinum and increased dose of ifosfamide. METHODS: Forty-two previously untreated ovarian cancer patients were included in the study. Cisplatin 50 mg/m2 and ifosfamide 2000 mg/m2 together with mesna 1200 mg/m2 were given daily, Day 1-3 every 4 weeks for six cycles, followed by second-look laparotomy. In the event of residual disease carboplatin was given every 4 weeks for a further six cycles. RESULTS: The pathologic complete response rate was 20% (8 of 41). Five of 26 patients achieved a further response on carboplatin. Hematologic and nonhematologic toxicity caused dose reduction in more than 90 and 50% of the patients, respectively. CONCLUSION: The results of this high-dose regimen equals those obtained with conventional, far less toxic, regimens. Only patients with potentially platinum-sensitive tumors achieved further response when crossed over to the analogue, which may indicate that prolonged treatment is better than increased dose. A randomized trial is still needed to assess the importance of dose intensity in ovarian cancer.

Adult↗
PubMed1997

Neoadjuvant therapy for surgically staged IIIA N2 non-small cell lung cancer (NSCLC).

INTRODUCTION: Neoadjuvant therapy in patients with Stage IIIA NSCLC is associated with a 50-70% resection rate and a 3-5 year survival of 20-32%, but few trials have required meticulous staging of the mediastinum to ensure homogeneity of the study population. Continuous infusion cisplatin 25 mg/m2/day 1-5, 5-fluorouracil 800 mg/m2/day 2-5, and high-dose leukovorin 500 mg/m2/day 1-5 (PFL) given every 4 weeks achieved a 41% response rate in metastatic NSCLC (Lynch TJ, Kalish LA, Kass F, Strauss G, Elias A, Skarin A, Shulman L, Sugarbaker D, Frei E. Continuous infusion cisplatin, 5-fluorouracil, and leukovorin for advanced non-small cell lung cancer. Cancer 1994; 73: 1171-1176). The regimen was therefore evaluated in 34 patients with pathologic Stage IIIA N2 disease between 3/91 and 10/92. METHODS: Staging consisted of chest, liver, brain computerized tomography and bone scan, bronchoscopy and surgical mediastinal node mapping. Patients received PFL for 3 cycles, followed by thoracotomy and thoracic radiotherapy (TRT) to 54-60 Gy. RESULTS: Median age was 57 (42-68) years. Demographic factors included: male 56%; adenocarcinoma 59%, squamous cell carcinoma 24%; Stage T3N2 26%, T2N2 56%, and T1N2 18%. No treatment related deaths occurred. Radiographically defined response to PFL was 65% (6% complete). Thoracotomy was performed in 28 patients (82%) (6 had no attempt due to disease progression). Complete resection was achieved in 21 (75%) and seven were unresectable. Pathologic complete response was observed in five patients (15%) and an additional unresectable patient had fibrosis-only documented at thoracotomy for an overall clinicopathologic response rate of 76% (18% pathologic CR). Another ten patients had residual primary with or without hilar disease with resolution of previously documented mediastinal involvement. Six (18%) patients remain alive and disease-free with a median follow-up of 46 (33-50) months, four of whom had achieved pathologic complete response at time of surgery. CONCLUSIONS: Long-term event-free survival was associated with complete surgical resection which in turn was associated with clinical response to chemotherapy. There was a possible trend associating pathologic downstaging (absent residual disease in mediastinal nodes), particularly pathologic complete response observed in patients with non-bulky mediastinal disease, with improved event-free survival. Pathologic downstaging might therefore be a useful surrogate endpoint in trials evaluating the preoperative activity of new chemotherapy regimens. While radiographic response generally correlated with findings at surgery, response as determined by histologic examination of resected tissue was generally more extensive and may more accurately reflect the systemic impact of the chemotherapy regimen.

Adult↗
PubMed1997

The role of second-look laparotomy in the long-term survival in ovarian cancer.

BACKGROUND: To elucidate the role of second-look laparotomy in the management of ovarian cancer patients, were retrospectively reviewed our experience with this procedure in epithelial ovarian cancer patients. PATIENTS AND METHODS: The hospital records of 617 patients with advanced ovarian cancer were reviewed. The 308 patients who underwent second-look laparotomy were followed from four to 18 years with a median follow-up of 12 years after start of primary chemotherapy. RESULTS: Patients who achieved pathological complete response (PCR), microscopic partial response (PPR mic.), macroscopic partial response (PPR mac.), stable disease (PSD), and progressive disease (PPD) at second-look laparotomy had a median survival time of 149, 39.5, 24, 14, and eight months, respectively. Secondary surgical cytoreduction could be performed only in 101 patients with macroscopic persistent disease. The group of all patients with secondary tumor debulking had no survival advantage compared with the group of patients with PPR mac., PSD, and PPD, unable to have secondary cytoreduction. Patients left with no tumor after second-look laparotomy did not survive as long as patients who achieved PCR and PPR mic. at second-look laparotomy. Factors prolonging survival after second-look laparotomy included younger age, good pre-treatment performance status, smaller primary residual tumor size, longer interval between start of chemotherapy and second-look laparotomy, and the pathologically proven CR or PR mic. CONCLUSION: Second-look laparotomy appears to have a minor role in the routine management of ovarian cancer patients, especially in the context of the limited effectiveness of second-line therapy. This procedure should be limited to clinical treatment protocols to determine effectiveness of new agents.

Adult↗