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Biomedical subjects

S Reich

Publications and source records attributed to S Reich.

At least 55 records · Page 3Linked to original sources
PubMed1996

Induction of graft versus leukemia effects by cell-mediated lymphokine-activated immunotherapy after syngeneic bone marrow transplantation in murine B cell leukemia.

The feasibility of inducing graft versus leukemia (GVL) effects with allogeneic T cells in recipients of autologous bone marrow transplantation (BMT) was studied in a murine model (BCL 1) of human B cell leukemia/ lymphoma. Allogeneic cell therapy, induced by infusion with peripheral blood lymphocytes, a mixture of allogeneic spleen and lymph node cells and allogeneic activated cell therapy, induced by in vitro recombinant-interleukin-2(rIL-2)-activated allogeneic bone marrow cells in tumor-bearing mice, prevented disease development in adoptive BALB/c recipients. Concomitant in vivo activation of allogeneic lymphocytes with rIL-2 suppressed even more effectively the development of leukemia in secondary adoptive recipients of spleen cells obtained from treated mice. In contrast, in vivo administration of rIL-2 after syngeneic BMT, with or without equal numbers of syngeneic lymphocytes, led to disease development in secondary recipients. Our data suggest that effective cell therapy can be achieved after SBMT by allogeneic but not syngeneic lymphocytes and that anti-leukemic effects induced by allogeneic lymphocytes can be further enhanced by in vitro or in vivo activation of allogeneic effector cells with rIL-2. Therefore, cell therapy by allogeneic lymphocytes following autologous BMT could become an effective method for inducing GVL-like effects on minimal residual disease provided that graft versus host disease can be prevented or adequately controlled.

Adjuvants, Immunologic↗
PubMed1996

Use of an integrated sideport for diagnosis and management of decreased flow rates in a programmable implanted insulin delivery system. Implantable Insulin Pump Trial Study Group.

The aim of this study was to develop procedures for the diagnosis and nonsurgical management of decreased insulin flow in an implantable programmable pump for long-term intraperitoneal or intravenous insulin delivery featuring a sideport. Patency of the catheter lumen was tested by measuring the time needed for sideport pressure to decrease by 50% after the injection of 0.1 ml of buffer solution. Pumping unit performances were assessed by measuring the volume of pump pulses after diverting the pump flow at the sideport. A catheter flush with buffer solution through the sideport was effective in clearing 79% of intraperitoneal and 84% of intravenous catheter occlusions. Washing the pumping unit with an alkaline solution after diverting pump flow at the sideport was effective in dissolving insulin aggregates inside the pumping unit and in restoring normal pump flow. These procedures were associated with a 1.3% rate of hypoglycemic episodes.

Buffers↗
PubMed1996

Antiviral and resistance studies of AG1343, an orally bioavailable inhibitor of human immunodeficiency virus protease.

AG1343 ([3S-(3R*,4aR*,8aR*,2'S*,3'S*)]-2-[2' hydroxy-3'-phenylthiomethyl-4'-aza-5'-oxo-5'-(2''-methyl-3''-hydro xy-phenyl) pentyl]-decahydroiso-quinoline-3-N-t-butylcarboxamide methanesulfonic acid) is a selective, nonpeptidic inhibitor of human immunodeficiency virus (HIV) protease (Ki = 2 nM) that was discovered by protein structure-based drug design methodologies. AG1343 was effective against the replication of several laboratory and clinical HIV type 1 (HIV-1) or HIV-2 isolates including pyridinone- and zidovudine-resistant strains, with 50% effective concentrations ranging from 9 to 60 nM. In reversibility studies, inhibition of gag (p55) proteolytic processing in HIV-1 particles from cells treated with AG1343 was maintained for up to 36 h after drug removal. The ability of virus to develop resistance to AG1343 was studied by serial passage of HIV-1 NL4.3 in the presence of increasing concentrations of drug. After 28 passages, a variant with a 30-fold reduction in susceptibility to AG1343 was isolated. Molecular analysis of the protease from this variant indicated a double change from a Met to Ile at residue 46 and an Ile to Val or Ala at residue 84 (M46I+I84V, A). Consistent with these findings, reductions in susceptibility were observed for recombinant viruses constructed to contain the single I84V change or the double M46I+I84V substitutions. Resistance, however, was not detected for recombinant viruses containing other key mutations in HIV-1 protease, including a Val to Ile change at residue 32 or a Val to Ala or Phe at residue 82. The potent anti-HIV activity of AG1343 against several isolates suggests that AG1343 should perform well during ongoing human phase II clinical trials.

Amino Acid Sequence↗
PubMed1996

Effect of deoxyspergualin on graft-versus-host disease and graft- versus-leukemia in mice.

The effect of 15-deoxyspergualin (DSG) on bone marrow (BM) engraftment and graft-versus-host disease (GVHD) was studied in mice across both major (MHC) and minor (MiHC) histocompatibility barriers. (BALB/c x C57BL/6)F1 mice were inoculated with C57BL/6 cells, CBA mice were given B10.BR cells and BALB/c mice were transplanted with B10.D2 cells. All recipient mice were irradiated lethally or sublethally prior to transplantation. DSG had no effect on engraftment of parental cells in F1 mice at both 2.5 mg/kg and 10 mg/kg given daily for 10 days after treatment. Survival of F1 recipients of C57BL/6 cells increased significantly with 2.5 mg/kg DSG (p < 0.05). Across MiHC, 75% of DSG-treated CBA mice survived transplant for more than 150 days. No effect on GVHD was observed in the B10.D2 --> BALB/c setting. DSG abolished graft-versus-leukemia (GVL) effects in F1 mice transplanted with both BM and spleen cells (20%) of C57BL/6 mice and additionally inoculated with B cell leukemia (BCL1). In summary, in the semi-allogeneic murine models presented here DSG prevented GVHD but at the same time suppressed GVL effects induced by the allograft. For clinical use, DSG might therefore be very useful for prevention of GVHD post-allogeneic bone marrow transplantation for non-malignant diseases or for leukemia.

Animals↗
PubMed1995

Glutathione-S-transferase (GST) theta polymorphism influences background SCE rate.

Polymorphism of glutathione S-transferase theta (GSTT1) modulates the toxicity of halogenated alkanes and epoxides in humans. The enzymatic activity of glutathione S-transferase theta and its corresponding gene is lacking in about 30% of the central European population. It has now been demonstrated that the background rate for sister chromatid exchange (SCE) is affected by this particular polymorphism. Smoking as a known inducer of SCE was taken into account. A group of GSTT1-positive subjects exhibited lower SCE rates than GSTT1-negative individuals (7.55 +/- 0.77 versus 8.74 +/- 1.24 SCE/mitosis, respectively, p < 0.005). Non-smoking GSTT1-positive individuals showed the lowest SCE rate (7.26 +/- 0.71 SCE/mitosis), significantly lower than the rates of smoking GSTT1-positive and non-smoking GSTT1-negative subjects (8.14 +/- 0.55 SCE/mitosis and 8.12 +/- 0.88 SCE/mitosis, respectively, p < 0.025 in both cases). Smoking GSTT1-negative subjects exhibited the highest SCE rates (9.28 +/- 1.3 SCE/mitosis). It is hypothesized that GSTT1 is protective against background genotoxic damage. Since ethylene oxide is a proven substrate of GSTT1, the detoxification of this epoxide arising from endogenous ethylene may modulate SCE background rates.

Adult↗
PubMed1995

The role of antibodies to IL-2 receptor and Asialo GM1 on graft-versus-leukemia effects induced by bone marrow allografts in murine B cell leukemia.

The role of various cell subpopulations involved in the graft-versus-leukemia (GVL) effect induced by allogeneic bone marrow transplantation (BMT) was investigated in (BALB/c x C57BL/6)F1 (F1) recipients, inoculated with murine B cell leukemia (BCL1), by using monoclonal murine anti-IL-2 receptor antibodies or rabbit anti-Asialo GM1 antibodies directed predominantly against murine NK cells. F1 mice with BCL1 were irradiated and reconstituted with parental (C57BL/6) bone marrow cells (BMC) or a mixture of BMC and spleen cells and treated in vivo for 10 days with anti-IL-2 receptor antibody or anti-Asialo-GM1 antibody. Both treatments lessened the GVL effects induced by the allograft and resulted in development of leukemia relapse, as documented in vivo by adoptive transfer of 10(5) spleen cells obtained from treated mice into secondary syngeneic adoptive recipients. Our data indicate that IL-2 receptor-positive T cells and possibly IL-2-activated allogeneic NK cells play a key role in inducing GVL following allogeneic BMT.

Animals↗
PubMed1994

Effective graft-versus-leukemia effects independent of graft-versus-host disease after T cell-depleted allogeneic bone marrow transplantation in a murine model of B cell leukemia/lymphoma. Role of cell therapy and recombinant IL-2.

After allogeneic bone marrow transplantation (BMT) for leukemia, beneficial graft-vs-leukemia (GVL) effects are usually accompanied by potentially serious graft-vs-host disease (GVHD). Because T cell depletion is the only effective way to prevent GVHD it seems important to understand whether effective GVL can develop after BMT with T cell depletion in GVHD-free recipients. Well-established C57BL/6-->BALB/c chimeras that were free of GVHD, reconstituted with T cell-depleted allogeneic bone marrow cells, and inoculated 3 mo after BMT with a high inoculation of murine B cell leukemia (BCL1) showed no evidence of disease, whereas all control mice developed leukemia and died within 58 days. Results from adoptive transfer experiments in secondary naive BALB/c recipients indicated that all BCL1 cells were eliminated in the chimeras within 14 days. Hence, complete resistance to BCL1 developed in the chimeras despite complete tolerance to host alloantigens. The GVL effects observed in tolerant chimeras were further amplified by administration of immunocompetent allogeneic C57BL/6 spleen cells, low dose rIL-2, or both for 5 days. Our data suggest that GVL effects can develop even after T cell depletion in the absence of clinically overt GVHD and that GVL can be further amplified by rIL-2, either with or without use of additional immunocompetent donor T cells. Our data may provide the basis for new approaches to induce effective GVL after allogeneic BMT with cell therapy and rIL-2 at the stage of minimal residual disease, while avoiding early GVHD induced by the BMT procedure.

Animals↗
PubMed1994

Successful purging of murine plasmacytoma by mafosfamide (ASTA-Z).

Mafosfamide (ASTA-Z) is a chemotherapeutic agent currently in use for in vitro purging of tumor-bearing human BM cells prior to autologous bone marrow transplantation (ABMT). We tested the efficacy of ASTA-Z against mouse plasmacytoma cells MOPC-315 (MOPC), a model of human multiple myeloma. BALB/c mice were injected intraperitoneally with different doses of MOPC preincubated with ASTA-Z. All control mice receiving > or = 10(4) MOPC intraperitoneally (ip) died within 23 days. All recipients of ASTA-Z pretreated MOPC remained healthy for > 180 days. To simulate the clinical situation, BALB/c mice received lethal doses of 10(3) MOPC ip prior to ABMT. Subsequently, mice were treated with cyclophosphamide 200 mg/kg one day prior to syngeneic BMT with 10(7) BMC containing 10(6) MOPC; 90% of the mice receiving unpurged syngeneic BMC died within 45 days whereas all mice transplanted with ASTA-Z-treated BMC/MOPC mixtures remained disease-free for > 100 days. Our results suggest that a similar approach may be successful in patients with multiple myeloma and residual disease prior to cryopreservation of their BM for ABMT. Bone marrow purging with ASTA-Z is effective and under certain conditions could be critical for prevention of relapse following ABMT, provided that effective elimination of residual disease in the host can be achieved by the conditioning regimen prior to ABMT.

Animals↗
PubMed1993

Inhibition of metastatic cell colonization in murine lungs and tumor-induced morbidity by non-peptidic Arg-Gly-Asp mimetics.

The spreading and colonization of tumor cells require their migration to metastatic sites via blood vessels. To penetrate blood-vessel walls, cells, including malignant ones, must recognize and associate with the sub-endothelium extracellular matrix (ECM) and its glycoproteins. Recognition of ECM-glycoproteins, such as fibronectin (FN) and vitronectin (VN), is mediated by integrin receptors expressed on various cell types, including platelets, leukocytes and tumor cells. The Arg-Gly-Asp (RGD)-containing peptide, a major adhesive ligand of ECM, is present in various plasma and matrix glycoproteins, such as FN and VN. Non-peptidic mimetics of RGD, consisting of carboxylate and guanidinium groups of Asp and Arg divided by a linear atom spacer, express a high affinity for the alpha IIb-beta 3 integrin and inhibit platelet aggregation. Herein, the ability of RGD mimetics to inhibit adhesive interactions between tumor cells and RGD, and tumor progression in vivo, was examined. RGD-containing peptides and the RGD mimetic, compound SF-6,5, but not the Arg-Gly-Glu (RGE) peptide or the corresponding mimetic, specifically inhibited B16-F10 melanoma cell adhesion to immobilized VN and FN. Daily administration in vivo of SF-6,5 to mice inhibited the formation of B16-F10 colonies in experimental and spontaneous models of metastases. Moreover, SF-6,5 could prevent mouse death caused by massive colonization of tumor cells in the lungs. The therapeutic effect of RGD-containing peptides on tumor metastasis formation was marginal, probably due to the small amounts used, and its susceptibility to proteolysis in situ. Thus, non-peptidic mimetics of small adhesive epitopes may provide a novel therapeutic tool to prevent an adverse pathological event involving integrin-dependent cell-cell and cell-ECM interactions.

Animals↗
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

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↗
PubMed1992

Abnormalities of predictive saccades in hemi-Parkinson's disease.

We studied reflexive and predictive saccades by direct current electro-oculography in nine patients with mild hemi-Parkinson's disease (hemi-PD) and in 16 age-matched controls. In five patients, the neurological syndrome was predominant on the right side of the body (RPD) and in four patients, on the left side (LPD). Reflexive saccades were elicited in response to the random appearance (timing and location) of a light-emitting diode (LED). Predictive saccades were elicited by alternatively illuminating LEDs at 10 degrees right and left, at various fixed frequencies (0.25-1 Hz). In the reflexive task, latency and amplitude of the saccades were normal in both PD groups. In the predictive task, mean saccade latency was not significantly different between patients and normals but there were two significant abnormalities in timing: first, but only in LPD, a directional asymmetry in latency (left greater than right, e.g. at 0.25 Hz, mean difference of 90 ms); secondly, especially in RPD, an abnormal tracking pattern, reflected by more variability of the mean value (for each group of patients) of saccade latency at each point in time, throughout a period of tracking at a given frequency. Predictive saccades were also strongly hypometric in both PD groups but especially in LPD (e.g. for rightwards saccades: controls = 19 degrees, SD = 1.6; LPD = 14 degrees, SD = 2.7; RPD = 15.7 degrees, SD = 2.3). These defects in saccadic timing and amplitude during predictive tracking were most salient at low frequencies. While these defects were largely bilateral, our findings suggest slightly different contributions of the right and left cerebral hemispheres to the spatial and timing components, respectively, that comprise optimal predictive saccadic behaviour.

Adult↗
PubMed1992

Investigations into the fat pads of the sole of the foot: anatomy and histology.

Anatomical, histological, and histochemical studies were performed on normal and abnormal fat pads of the sole of cadaver feet. The fat pads were found to contain a significant nerve and blood supply separate from that to the surrounding musculature and skin. Pacinian corpuscles and free nerve endings within the fat were identified. Histological analysis indicated a meshwork of fibroelastic septae arranged in a closed-cell configuration. The mechanical consequences of this organization are discussed in the context of the weightbearing role of the fat pads of the feet. Alterations seen in dysvascular or senescent feet are consistent with the hypothesis that the septal anatomy of the fat pads is central to their cushioning function.

Adipose Tissue↗
PubMed1992

Use of recombinant human interleukin-2 in conjunction with bone marrow transplantation as a model for control of minimal residual disease in malignant hematological disorders: I. Treatment of murine leukemia in conjunction with allogeneic bone marrow transplantation and IL-2-activated cell-mediated immunotherapy.

Immunotherapy with recombinant human interleukin-2 (IL-2) and allogeneic spleen cells has led to significant antitumor effects in B-cell leukemia- (BCL1) bearing mice following transplantation with T-lymphocyte-depleted allogeneic bone marrow cells. Graft versus leukemia (GVL) effects were studied in a model mimicking minimal residual disease following bone marrow transplantation (BMT). Lethally irradiated (BALB/c x C57BL/6)F1 recipients were reconstituted with 20 x 10(6) T-lymphocyte-depleted C57BL/6 bone marrow cells mixed with 10(4) to 10(6) BCL1 cells followed by administration of sequential increments of allogeneic C57BL/6 spleen cells; 10(6) cells on Day +1, 10(7) cells on Day +5, and 5 x 10(7) cells on Day +9, with or without concomitant IL-2 treatment (intraperitoneal injections of 20,000 U twice daily for 3 days) together with each spleen cell administration. All mice receiving 10(4)-10(6) BCL1 cells developed marked splenomegaly by Day +21 and all adoptive recipients of 10(5) spleen cells obtained from these mice developed leukemia within 21-36 days. Treatment of mice which received 10(4) BCL1 cells by either three courses of low dose IL-2 or three increments of allogeneic spleen cells alone and certainly by a combination of both resulted in normalization of splenomegaly on Day +21, but only adoptive recipients of 10(5) spleen cells obtained from mice treated by both allogeneic spleen cells and IL-2 (10/10) or allogeneic spleen cells alone (8/10) were disease free (greater than 100 days). Mice inoculated with 10(5) BCL1 cells developed mild splenomegaly on Day +21 after IL2 treatment alone, but showed no clinical evidence of disease following administration of allogeneic spleen cells or both allogeneic spleen cells and IL-2. Following adoptive transfer of 10(5) spleen cells obtained from each treated group no leukemia (greater than 100 days) was evident in recipients of spleen cells obtained from mice treated with both allogeneic spleen cells and IL-2 (10/10) whereas a partial effect was observed in mice treated by allogeneic spleen cells only (4/10). Mice inoculated with a high dose of BCL1 cells (10(6] showed some delay in onset of splenomegaly, but no curative antileukemic effects could be observed even following a synergistic combination of IL-2 and allogeneic spleen cells. Our data suggest that immunocompetent allogeneic lymphocytes may play an important role against leukemic relapse and thus cell therapy may be used therapeutically to treat minimal residual disease after BMT even following initial reconstitution with T-cell-depleted bone marrow cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Memory and attention in patients with senile dementia of the Alzheimer type and in normal elderly subjects.

Previous studies have shown that cholinergic blockade in normal subjects induces impairment of vigilance as well as memory deficits. In the present investigation we have examined the validity of this pharmacological model of dementia by administering a battery of cognitive tasks to patients with mild and moderate senile dementia of the Alzheimer type and to age-matched controls. In contrast to volunteers receiving scopolamine all the mildly demented patients, and half of those moderately affected, performed normally on tests of vigilance whilst exhibiting the expected memory deficits. These data suggest that the mechanism of memory loss in Alzheimer's disease may differ from that found in scopolamine-induced amnesia.

Aged↗