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Biomedical subjects

L Weiss

Publications and source records attributed to L Weiss.

At least 181 records · Page 10Linked to original sources
PubMed1993

Hepatitis B virus transactivator HBx uses a tumour promoter signalling pathway.

The hepatitis B virus (HBV) transactivator protein HBx is enigmatic in that it stimulates a striking variety of promoters which do not share a common cis-regulatory element. As it does not bind to DNA, it has been speculated that HBx acts indirectly through cellular pathways. Under certain conditions HBx can have an oncogenic potential, which may be relevant for HBV-associated liver carcinogenesis, but until now the mechanism for transactivation and cell transformation by HBx was unclear. We report here that HBx uses a complex signal transduction pathway for transactivation. An increase in the endogenous protein kinase C (PKC) activator sn-1,2-diacylglycerol and the subsequent activation of PKC give rise to activation of the transcription factor AP-1 (Jun-Fos). As a result, HBx transactivates through binding sites for AP-1 and other PKC-dependent transcription factors (AP-2, NF-kappa B), thereby explaining the as-yet incomprehensible variety of HBx-inducible genes. As the PKC signal cascade also mediates cell transformation by tumour-promoting agents, the mechanism presented here might account for the oncogenic potential of HBx.

Animals↗
PubMed1993

Cancer-cell traffic in the liver. II. Arrest, transit and death of B16F10 and M5076 cells in the sinusoids.

Fluorescent probes were used to detect BUdR-labelled B16F10 and M5076 cancer cells delivered to the livers of mice via intrasplenic injection. In liver sections stained for succinic dehydrogenase, which permits the periportal, acinar zone 1 to be distinguished from the pericentral zone 3, counts were made of the zonal distribution of fluorescent, intact cancer cells and, by default, the numbers of "lost" cells. Very few intact cancer cells leave the liver from the single bolus of the intrasplenic injection, and even fewer of these generate pulmonary lesions; therefore, within the time limits of these experiments, the liver is virtually a closed system. A dynamic view of intrahepatic cancer-cell traffic with respect to zones 1 (periportal) and 3 (pericentral) was obtained from static measurements of cell densities at different times after intrasplenic injection, by means of Markov chain probability analysis. This indicated that, during the first hour after arrival in zone 1 of the liver sinusoids, there is a 10% probability of a B16F10 cell remaining intact in zone 1, an 89% probability of cell death in zone 1 and only a 1% probability of the cell passing into zone 3. During the same period, there is a 77% probability of an M5076 cell remaining intact in zone 1, a 21% probability of death, and a 2% probability of relocation to zone 3. In both cell types, very few cells were lost from zone 3. Further proportional death in zone 1 diminished over the next 23 hr, concomitant with an increased proportion of cell death in zone 3. Our results indicate that, although there is considerable variation between the 2 cell types studied here, most (B16) or many (M5076) of these cancer cells entering the liver via the portal vein die within 1 hr in zone 1 of liver lobules. In addition, very few of the cells delivered to zone 1 travel along the sinusoids to zone 3, and few of these reach the lungs in a viable state.

Animals↗
PubMed1993

Characterization of a de novo 48,XX,+r(X),+r(17) by in situ hybridization in a patient with neurofibromatosis (NF1).

We describe a patient with familial neurofibromatosis (NF1), short stature, developmental delay, and a de novo chromosome abnormality. In situ hybridization was done using chromosome specific centromere probes to characterize the karyotype as 46,XX/47, XX,+r(X) (p11q11)/47,XX,+r(17) (p11q11)/48, XX,+r(X) (p11q11),+r(17) (p11q11). The NF1 mutation, as well as each supernumerary ring chromosome, may have played a role in perturbing the normal developmental process of this patient.

Adolescent↗
PubMed1993

Prognostic value of triple phase bone scanning for reflex sympathetic dystrophy in hemiplegia.

Twenty-two patients with cerebral vascular accident (CVA), clinically confirmed by head computed tomography, were observed for symptoms of the reflex sympathetic dystrophy syndrome (RSDS). All patients received triple phase bone scans; 16 scans were positive for RSDS. Patients with negative scans had no symptoms of RSDS. Five patients with positive scans had RSDS symptoms at the time of bone scanning. Seven of 11 patients with positive scans but no symptoms of RSDS at the time of bone scan developed symptoms of RSDS within six months. We found a significant relationship between positive bone scans and the subsequent development of RSDS (p < 0.01). Considering only those patients who were asymptomatic for RSDS at the time of bone scanning, we found bone scanning to be a good predictor for the future development of clinical RSDS. We found the correlation between positive bone scans and the subsequent development of clinical RSDS in previously asymptomatic individuals to be statistically significant (p < 0.05). We conclude that bone scans may be a good predictor of patients at risk for developing clinical RSDS after CVA.

Bone and Bones↗
PubMed1993

Minimal residual disease in murine B-cell leukemia (BCL1) detected by PCR.

Small proportions of leukemic cells escaping chemo-radiotherapy and/or dormant leukemic cells present in undetectable amounts in patients post therapy, i.e. minimal residual disease (MRD), are a source for relapse. The study of MRD and its treatment in a murine model for human B-cell leukemia/lymphoma, (BCL1), should lead to an improved understanding of the human disease. The standard assay for MRD in experimental mice is the adoptive transfer of spleen cells from experimental animals into naive secondary syngeneic recipients. We describe here the detection of MRD in BCL1-carrying BALB/c mice using the polymerase chain reaction (PCR). A BCL1 specific sequence from the rearranged VH-region was amplified yielding a 456 bp long fragment. PCR products hybridized to the cloned BCL1 sequence allowed the detection of a single BCL1 cell. This assay, therefore, reveals the presence of very small numbers of leukemic cells without sacrificing experimental animals.

Animals↗
PubMed1993

Complement activation by gp160 glycoprotein of HIV-1.

The ability of the gp160 envelope glycoprotein of HIV-1 to activate human complement and to bind C3 fragments was investigated by incubating mammalian-derived recombinant gp160 with seronegative serum and by quantitating the binding of C3b/iC3b to the protein using a biotinylated monoclonal antibody directed against a neoepitope expressed by cleaved human C3. Recombinant gp160 activated complement in a dose- and time-dependent fashion. Complement activation occurred through the classical pathway, independently of antibodies, and required C1q. Binding of anti-HIV IgG to rgp160 prior to exposure of the envelope glycoprotein to serum resulted in enhanced complement activation. Complexes of rgp120 with anti-HIV IgG also cleaved C3 in serum, resulting in deposition of C3b on gp120. These results provide a basis for C3-mediated facilitation of viral entry into target cells expressing receptors for fragments of human C3.

Antibody Specificity↗
PubMed1993

Renal disease associated with HIV infection: a multicentric study of 60 patients from Paris hospitals.

Sixty HIV-infected patients presenting renal symptoms who underwent percutaneous renal biopsies were analysed. According to the CDC classification, 44 patients were staged in group IV, five in group III, and 11 in group II. Patients were divided in two groups according to their ethnic origin (29 black patients and 31 white patients). Risk factors such as homosexuality, multiple transfusions or intravenous drug abuse (IVDA) were identified in all white patients except two, but in only nine (31%) of the black patients. Three main patterns of renal disease were observed: focal and segmental glomerulosclerosis (FSGS) was found predominantly in black patients (23 black patients versus 3 Caucasians, P < 0.001) and was associated with the nephrotic syndrome; immune-complex-type glomerulonephritis (ICGN) was frequent in black and white patients (21% and 52% respectively) including four cases of IgA nephritis all seen in white patients; and 10 cases of lupus-like nephritis (4 black and 6 white patients). The frequent hypergammaglobulinaemia in those patients suggests a pathogenic role of polyclonal B cell activation in ICGN. Interstitial nephritis was present in 48 and 52% of the black and white patients respectively and did not seem related to drug toxicity or superimposed infectious disease. In addition to interstitial nephritis, the coexistence of multivisceral lymphocytic infiltration involving accessory salivary glands, liver and/or lung, found in six patients possibly suggests a virus-induced immune disorder.

AIDS-Associated Nephropathy↗
PubMed1993

Analysis of the incidence of intraocular metastasis.

The incidence of metastases to the uvea is compared with that in eight other (extraocular) target sites, in patients with metastatic primary carcinomas of the breast, colorectum, and lungs. The incidence of intraocular metastases from breast cancer is lower than in the eight other target organs surveyed; in the other primary cancers, the incidences were midway between those in the other sites, However, when the incidence of intraocular metastases is viewed in relation to the calculated numbers of cancer cells delivered via the arterial route, the uveal tract is the most highly favoured target site for the development of metastases per unit of delivered cancer cells.

Breast Neoplasms↗
PubMed1993

Effect of recombinant human manganese superoxide dismutase on radiosensitivity of murine B cell leukemia (BCL1) cells.

Recombinant human manganese superoxide dismutase (SOD) protects cells from oxidative damage and is known to ameliorate post-irradiation damage in mice exposed to whole body or localized chest irradiation. The concept behind the present experiments was to investigate whether it is possible to improve the outcome in leukemia following total body irradiation used as part of the conditioning prior to allogeneic bone marrow transplantation. We determined whether SOD protects leukemic cells from the effects of ionizing irradiation both in vitro and in vivo. Murine B cell leukemia (BCL1) cells, derived from tumor-bearing mice, were irradiated in vitro with or without SOD and injected into BALB/c mice. All mice receiving 10(4) unirradiated BLC1 cells developed leukemia and died within 19-39 days. In vitro exposure of BCL1 cells to 800 cGy or 1600 cGy abolished the potential to induce leukemia by inoculation with 10(4) or 10(6) BCL1 cells, respectively. Addition of SOD in vitro during irradiation increased the resistance of BCL1 cells to ionizing irradiation; all mice receiving 10(6) BCL1 cells previously exposed in vitro to 1200 cGy in the presence of SOD died of leukemia, whereas only 40% of mice receiving a similar inoculum of irradiated BCL1 cells died of leukemia. In contrast, when BCL1-bearing mice were irradiated with 600-800 cGy with or without intravenous injection of SOD (100 mg/kg) 30 minutes prior to irradiation, development of leukemia was unaffected. Residual leukemia cells following therapy were assessed by adoptive transfer of 10(5) spleen cells to secondary BALB/c recipients.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Prevention and treatment of relapse by bone marrow transplantation.

High, myeloablative doses of chemoradiotherapy represent the treatment of choice for a large number of malignant hematological diseases that cannot be successfully treated with conventional chemotherapy. Residual tumor cells following high dose chemotherapy represent the most common treatment failure, resulting in frequent relapse following autologous bone marrow transplantation (ABMT) and even allogeneic bone marrow transplantation (BMT). Graft vs leukemia (GVL) effects mediated by immunocompetent donor lymphocytes represent a major therapeutic potential of allogeneic BMT which results in reduced rate of relapse, especially when immune interactions between immunocompetent donor's T lymphocytes and host allogantigens is apparent, a reaction which might result in graft vs host disease (GVHD). Recent experiments in animal models of murine leukemias suggest that post-transplant immunotherapy may be successfully accomplished by lymphokine-mediated immunotherapy (LMI) and cell-mediated immunotherapy (CMI). Following allogeneic BMT, provided GVHD can be prevented by T-cell depletion, CMI may be amplified by repeated administration of immunocompetent donor's lymphocytes in graded increments following successful induction of chimerism and sustained hematopoiesis. GVL effects induced by CMI may be further potentiated by in-vivo administration of a short course of recombinant human interleukin-2 (rhIL2). Taken together, our data suggest that post-transplant immunotherapy by cytokines and adoptive cell therapy may successfully prevent relapse in patients at high-risk and even result in complete elimination of tumor cells following overt relapse. Thus, immunotherapy may represent an optimal approach for prevention and treatment of minimal residual disease.

Animals↗
PubMed1993

Neoplastic disorders after pediatric heart transplantation.

BACKGROUND: Because of their life-long requirement for immunosuppressive therapy, neoplastic disorders could represent a significant threat to long-term survival in infants and children after heart transplantation. This study determined the incidence and clinical spectrum of neoplastic disorders in 80 pediatric patients who underwent heart transplantation between 1974 and 1992. METHODS AND RESULTS: Follow-up ranged from 6 to 189 months (mean, 50.0 months). Tumors occurred in 10 patients (12.5%). Time to detection ranged from 3.3 to 139.2 months (mean, 52.7 months). Tumor incidence was greatest in 9 patients transplanted before the cyclosporine era (44%) compared with the subsequent 71 patients (8.5%, P < .05). There was no increase in risk related to sex, age, underlying disease, or blood type; however, patients with tumors received higher initial doses of cyclosporine and prednisone and had more rejection episodes in the first 3 months (P < .05). There was an increased risk associated with anti-thymocyte globulin (33%, P < .05) but not with OKT3 (6%, P = NS). There were eight lymphoproliferative disorders (four B-cell, one T-cell, three not determined) and one hepatocellular and one squamous cell carcinomas. Six cases of lymphoproliferative disorder had in situ evidence of Epstein-Barr virus. Patients were treated by reducing immunosuppression (7), radiotherapy (2), and chemotherapy (1). There were five deaths: two tumor related and the others due to rejection, renal failure, and infection. Of 5 survivors, 1 had tumor recurrence 4 years after diagnosis, and 4 are disease free. CONCLUSIONS: Tumors represent a small but serious long-term risk to pediatric heart transplant recipients. The incidence in children transplanted in the cyclosporine era is similar to that in adults, and the majority of tumors are lymphoproliferative disorders that often regress by reducing immunosuppression.

Actuarial Analysis↗
PubMed1993

The differential resistance of B16 wild-type and F10 cells to mechanical trauma in vitro.

Following intravenous injection of B16 melanoma cells into mice, more than 99.9% of the cells are killed by a combination of rapid and slow processes: however, the F10 line of B16 mouse melanoma cells produces approximately 10 times as many pulmonary colonies as wild-type cells. We have attempted to determine the role of one rapid cancer cell-killing process, namely deformation-driven, loss of surface membrane integrity of the type occurring in capillaries, by the use of an in vitro model in which cells are filtered through 8-microns pores in polycarbonate membranes. In accord with in vivo observations, more wild-type than F10 cells were killed by filtration in vitro. The hypothesis that resistance to mechanical trauma of this type is enhanced by a small cell diameter and a high degree of surface rugosity is supported by measurements of these parameters on viable cells and electron micrographs. Differential resistance in these cells is associated to a major extent with a high degree of utilizable surface membrane excess, and to a minor extent with the smaller mean diameter of the F10 cells. Calculations, which are in accord with previous in vivo observations, indicate that most of the cells delivered to the capillary beds of target organs during hematogenous metastasis can be destroyed by rapid mechanical trauma, which is therefore implicated as one of a number of major contributors to metastatic inefficiency.

Filtration↗
PubMed1993

Low-dose heparin inhibits acute graft versus host disease in mice.

We have studied the effect of low-dose heparin on GVHD, marrow engraftment and graft-versus-leukemia (GVL) effects in an experimental murine model. Recipient (C57BL/6 x BALB/c) F1 mice were transplanted with C57BL/6 marrow and/or spleen cells and treated with daily sc injection of 5 micrograms heparin for 30 days. We have shown that heparin in low doses attenuates the severity of acute GVHD and reduces the mortality rate from 69 to 37.5% without abrogating the GVL effect induced by the allograft and without impairing marrow engraftment.

Acute Disease↗