Biomedical subjects

H Schreiber

Publications and source records attributed to H Schreiber.

At least 73 records · Page 4Linked to original sources

PubMed1993

Genetically engineered vaccines. Comparison of active versus passive immunotherapy against solid tumors.

Late tumor bearers (LTB), that is, mice that had tumors 3 weeks or longer, can have a selective immune dysfunction and fail to respond to target antigens expressed by the cancer cells. Such mice, however, do respond to nonmalignant cells engineered to express the rejection antigen, and they can be vaccinated with such cells to reject growing tumors. In this study, we compared the efficacy of passive immunization with that of active immunization using the engineered vaccine. An allogeneic MHC class I molecule was used as model tumor antigen. We found that active immunotherapy was only effective for small tumors in early stages of growth. In a later stage of tumor growth, active immunotherapy did not cure any mice, whereas passive immunotherapy was successful in all animals. Reasons for the failure of these LTB to respond to active vaccination with the engineered vaccine may be related to the decreased primary or secondary response we observed in these mice after active immunization. It is suggested that normal antigen-presenting cells expressing the tumor rejection antigen can elicit, in the presence of IL-2, antigen-specific T-cell responses by LTB, and that such T cells may be curative when used in adoptive therapy. We also suggest that the stage of tumor growth and the immune status of LTB more closely simulate the conditions observed in cancer patients.

Animals↗

PubMed1993

Footprinting of individual tumors and their variants by constitutive cytokine expression patterns.

We have examined the cytokine mRNA expression profile of six different human cell lines derived from Ewing sarcomas using polymerase chain reaction and found each to constitutively express a characteristic pattern. Furthermore, each cell line differed in the levels of secreted cytokines. We also analyzed the expression of several cytokines in murine UV-induced sarcomas and their heritably stable progressive variants. Each murine tumor also constitutively expressed a large number of cytokines, and in some cases, the more malignant variants differed from their parental tumors. These results demonstrate that tumors of the same type, and even in the same lineage, can have distinct cytokine expression and/or secretion profiles. Some cytokines may stimulate tumor growth while others may have antitumor effects. Cytokine therapy may be tailored depending upon the cytokine profile of the individual malignancy.

Animals↗

PubMed1993

DNA sequence analysis of T-cell receptor genes reveals an oligoclonal T-cell response to a tumor with multiple target antigens.

Human and murine cancers can express multiple independent antigens as targets for cytolytic T-cells (CTLs). The immune response against one such tumor was studied at the cellular and molecular level by analyzing the T-cell receptor beta chains of CTLs responding in vivo to a murine UV light-induced cancer. A 5-13-fold enhancement of V beta 13+ CTLs above background (naive spleen, 4-5% V beta 13+ among CD8+ T-cells) was demonstrated in the responses of ten individual animals to this tumor. The dominance of V beta 13 usage was exclusively limited to the CD8+ compartment and correlated with recognition of the A but not the B and C antigens on the tumor. In addition, the amino acid sequences of the putative third complementarity determining regions of the T-cell receptor beta chains of CTLs isolated in vivo were remarkably similar to each other suggesting restriction also at the clonal level. Cells responding to four other syngeneic UV-induced tumors, each expressing different unique antigens, or to a variant of the same tumor that had selectively lost the A but retained the independent B and C antigens, induced a 2-fold or less enhancement of V beta 13+ CD8+ cells above background. Thus, the host responds to only one of the several possible target antigens and with relatively few CTL clonotypes.

Amino Acid Sequence↗

PubMed1993

Tumors with reduced expression of a cytotoxic T lymphocyte recognized antigen lack immunogenicity but retain sensitivity to lysis by cytotoxic T lymphocytes.

A murine solid tumor was transfected to express various levels of an allogeneic major histocompatibility complex class I gene (K216), in order to test the effect of the level of antigen expression on immunogenicity and sensitivity to lysis by cytotoxic T lymphocytes (CTL). The growth rates of clones of tumor cells expressing different levels of the transfected gene were similar in vitro and in nude mice. Although all tumor cells, including cells freshly isolated from growing tumors, were equally sensitive to lysis by specific CTL, only tumor cells expressing the highest level of the K216 antigen stimulated CTL and were rejected by normal mice. In contrast, tumor cells expressing lower levels of antigen failed to immunize for CTL and grew progressively in normal mice, despite retaining expression of the transfected gene and remaining fully sensitive to CTL-mediated lysis; thus, the threshold of antigen needed to stimulate CTL responses was considerably higher than that needed to lyse tumor cells. Reduction of K216 antigen expression from 100-fold to 40-fold above background, impaired significantly the ability of the tumor cells to induce a K216-specific immune response, while tumor cells expressing K216 at levels 2-fold above background were as susceptible to CTL-mediated lysis as tumor cells expressing 50-fold more antigen. The important implication of these findings is that some tumors occurring in nature may not be immunogenic but nevertheless express antigens which are potential targets for immune therapy.

Animals↗

PubMed1993

Prevention of runting and cachexia by a chimeric TNF receptor-Fc protein.

Tumor necrosis factor alpha (TNF) is an important mediator of septic shock and cachexia. A soluble form of the human type 2 TNF receptor, constructed by joining the Fc region of human IgG1 to the TNF receptor, prevents weight loss in nude mice bearing a TNF-secreting tumor. This soluble receptor was also used to treat TNF transgenic mice which were runting and died before reaching reproductive age. After continuous treatment with soluble TNF receptor, the TNF transgenic mice grew to normal size and reproduced. Thus, soluble TNF may be useful in counteracting the detrimental systemic effects of TNF in a clinical setting.

Animals↗

PubMed1993

Acute and long-term effects of adrenocorticotropin and dexamethasone on the auditory brainstem response in multiple sclerosis patients.

Auditory brain-stem responses (ABRs) were compared in two groups of multiple sclerosis (MS) patients receiving standard treatment with adrenocorticotropin (ACTH) and with dexamethasone (DEX). ABRs were recorded prior to treatment, on the 1st and 8th day of therapy, and 21 days after the hormonal treatment had been discontinued. ABRs in MS patients were within the normal range of variability. Latencies of ABR components increased with increasing rate of presentation, and with decreasing intensity of the click stimuli. Changes in ABRs displayed a consistent pattern in patients treated with ACTH, but showed less coherence after DEX. In ACTH treated patients' latencies of the late ABR waves V and Vn were prolonged after clicks of high intensity, and reduced following clicks of low intensity resulting in a decreased slope of the latency-intensity function of these ABR waves. This pattern became most prominent in the recordings after the treatment had been discontinued, and could reflect an improved transmission across both afferent excitatory and recurrent inhibitory synapses in the auditory pathways. The findings indicate that--besides a common anti-inflammatory action--therapies with ACTH and DEX differ with regard to their influence on central nervous functioning.

Adolescent↗

PubMed1993

Radiographic characteristics of isolated invaginated Meckel's diverticulum.

A 3-year-old boy with a radiographic finding of an isolated invaginated Meckel's diverticulum is presented. The abnormality simulates a polypoid filling defect in the distal small bowel on barium examination. This particular manifestation of Meckel's diverticulum is very rare and has been reported only once previously. This article re-emphasizes the need to think about this possibility when a polypoid filling defect is seen in the distal small bowel. At the time laparotomy was performed, the abnormality had progressed into a triple intussusception, a rare surgical finding.

Child, Preschool↗

PubMed1993

Cytogenetics of Askin's tumour. Case report and review of the literature.

The eleventh cytogenetically analyzed Askin's tumour, diagnosed in a two-year-old girl, is reported. Chromosomal analysis revealed a pseudodiploid karyotype of tumour cells with translocations of t(11;22)(q24;q12) and der(4)t(2;4)(q24;q35). The observed t(11;22)(q24;q12) is not only a unique characteristic of all cytogenetically analyzed Askin's tumours but it also occurs in 92-100% of peripheral neuroepithelioma and of Ewing's sarcoma, irrespective of its osseous or extraosseous localization. This genetical similarity further supports a nosological concept according to which Askin's tumour, Ewing's sarcoma and peripheral neuroepithelioma represent phenotypic variations of the same tumour, namely the peripheral primitive neuroectodermal tumour.

Child, Preschool↗

PubMed1993

[Early functional conservative therapy of fresh fibular capsular ligament rupture from the socioeconomic viewpoint].

The expected direct and indirect costs following a fresh fibular rupture of the capsular ligament, and hence the socioeconomic burden on the patient, was investigated by a prospective randomised study comprising 120 males and females between 18 and 45 years of age. A comparison of three different conservative treatment methods A (immobilisation in a plaster cast for three weeks, followed by mobilisation with the aircast splint), B (mobilisation with the aircast splint) and C (Unna's paste dressing for two weeks with subsequent tape dressings and in each case immediate mobilisation) showed a significantly better stability after 6 months in the groups B (2.6 +/- 2.3) and C (3.6 +/- 3.8) than in A (4.8 +/- 3.5). The direct subsequent costs were also significantly lower in the groups B (DM 175.-) and C (DM 206.-) than in A (DM 340,-). Taking an average daily hospital care fee of DM 319.- (1991 in West Germany) as basis, the direct costs sequential to early functional treatment are the lowest also in comparison with surgical treatment in a hospital. The indirect sequential costs due to loss of working hours are mainly dependent on professionally conditioned physical stress but increase with the period of immobilisation after a fresh fibular rupture of the capsular ligament.

Adolescent↗

PubMed1993

Antiretroviral therapy in sporadic adult amyotrophic lateral sclerosis.

Clinical and experimental findings in idiopathic amyothrophic lateral sclerosis (ALS) would be compatible with a retroviral involvement. In 35 adult patients with non-familial ALS we observed elevated circulating immune complexes, a decrease in IgG3 isotype and enzyme-linked sorbent assay (ELISA) serum antibodies against human spuma retrovirus (HSRV), confirmed by specific human foamy virus immunoblots. All 35 were negative for IgM or relevant IgG anti-ganglioside antibodies. We treated 12 HIV-negative, immune-complex-positive ALS patients with 500 mg d-1 zidovudine p.o. over 2-10 months and found reductions of serum creatine kinase and circulating immune complexes from two days to two weeks after the beginning of medication.

Adult↗

PubMed1993

CD4-positive and B lymphocytes in transplantation immunity. I. Promotion of tumor allograft rejection through elimination of CD4-positive lymphocytes.

The elimination of CD4+ cells by anti-CD4 antibody caused regression of a malignant solid tumor allograft that does not lose a cytotoxic T lymphocyte-defined target antigen during tumor progression and requires specific CD8+ CTL for tumor rejection. Treatment with anti-CD4 antibody was effective when started 1-2 weeks after tumor challenge and was at least as effective as treating with anti-CD3 antibody or specific immunization with the antigen expressed on malignant or nonmalignant cells. None of these treatments caused rejection of tumors that were larger than 1 cm3 or had been growing for 3 weeks or longer in the host. Mice bearing large and long-established tumors treated with anti-CD4 antibody rejected a new tumor challenge but failed to reject the long-established tumor. Similarly, mice with established tumors mounted effective CTL responses to reject skin grafts but failed to reject tumors which expressed the same antigen. Treatment with anti-CD4 antibody eliminated primary T lymphocyte dependent antibody responses but failed to suppress ongoing antibody responses to continuous antigenic stimulation. Possibly, the effectiveness of early treatment and the failure of later treatment with anti-CD4 antibody results indirectly from the effect treatment has on B lymphocytes.

Animals↗

PubMed1993

CD4+ and B lymphocytes in transplantation immunity. II. Augmented rejection of tumor allografts by mice lacking B cells.

To test the importance of B lymphocytes in immunity to major histocompatibility complex class I alloantigens, B cell-deficient mice were generated by reconstituting severe combined immunodeficiency mice, which lack functional B and T lymphocytes, with T cells or with both T and B cells. The reconstituted mice were challenged with a cancer that expresses an MHC class I alloantigen at a low level and is susceptible to killing by CD8+ cytotoxic T lymphocytes. Tumors grew more slowly in and were rejected more frequently by the mice lacking B cells. Understanding the mechanism by which B cells suppress tumor allograft rejection may lead to new approaches for suppressing immune attack on transplanted tissues.

Animals↗

PubMed1993

Cytomegaloviral acalculous cholecystitis in acquired immunodeficiency syndrome patients.

Abdominal pain and fever in patients with the acquired immunodeficiency syndrome (AIDS) may indicate cytomegaloviral (CMV) acalculous cholecystitis. We reviewed clinical, laboratory, and outcome data from 12 patients with CMV cholecystitis. Ten of 12 patients were homosexual males. Six patients had markedly low CD4: CD8 lymphocyte count ratios. Total leukocyte counts were normal or decreased, serum liver function tests normal or cholestatic, and only one patient had hyperbilirubinemia. Sonographic transmural gallbladder edema is typically more severe than expected for the presenting illness. Five of six patients investigated with HIDA scintigraphy had a nonvisualizing gallbladder. Open cholecystectomy had a 9.1 per cent operative morbidity and a 0 per cent mortality. Cholecystectomy is a safe and curative intervention, regardless of the immunocompromised condition of the host. Intraoperative cholangiography will identify papillary stenosis or sclerotic bile ducts as a potential cause of recurrent symptoms following surgery. A search for other sites of tissue invasion by CMV should follow cholecystectomy.

Acquired Immunodeficiency Syndrome↗

PubMed1992

Taming cut-off induced artifacts in molecular dynamics studies of solvated polypeptides. The reaction field method.

In this paper we present a model system of a solvated polypeptide, which is a suitable reference platform for the systematic exploration of methods for taming artifacts introduced by an incorrect treatment of long-range Coulomb forces. The essential feature of the system composed of an alpha-helical peptide and 1021 water molecules is the strict neutrality of all charge groups. The dynamical properties of the peptide, i.e. unfolding or maintenance of the helix, already give first hints on the influence of boundary effects. A rigorous and deeper insight is gained, however, if analyzing the system by means of the generalized Kirkwood g-factor, which projects the net dipole moment of concentric spheres onto the respective dipole moment of the reference charge group. The g-factor is a global measure for, and a sensitive probe of, the orientational structure, which in its turn reflects even the smallest inconsistencies in the treatment of long-range forces. While the cut-off scheme failed the g-factor test, the "reaction field" method, the simplest cut-off correction scheme, enables a consistent description. In other words, with the aid of the reaction field, the correct orientational structure is restored. As a consequence, the helix stability is regained and we were able to calculate the dielectric constant epsilon approximately 55 to 60 for our system, which is slightly below the corresponding value epsilon SPC = 66 of the pure solvent.

Amino Acid Sequence↗

PubMed1992

Event-related potential correlates of impaired selective attention in children at high risk for schizophrenia.

Auditory event-related potentials (ERPs) associated with selective attention were recorded in 21 children at high-risk for schizophrenia and in 21 matched controls. The subjects performed a selective listening task. For behavioral evaluation, target counts on the selective listening task and on cognitive performance were assessed. Group-specific differences of ERP components could be demonstrated, as reflected by significant amplitude reductions of the frontally located negative difference wave (Nd) and of the P3 component, following selectively attended stimuli, in the high-risk children. P3 latencies tended to be prolonged in the high-risk group. Reduced Nd was found in 14 and reduced P3 in 16 high-risk children among the 21 matched pairs. Significant correlations between the ERP reductions and psychometric deficit (counting accuracy) were observed. Mismatch negativity (MMN), an ERP component associated with automatic processing of physically deviant stimuli, did not differentiate significantly between groups, but was distinctly reduced in the high-risk group. The Nd and P3 reductions suggest deficits of selective attention in a considerable number of the subjects genetically at risk for schizophrenia. The present findings are discussed with respect to their relevance as indicators of a predisposition to schizophrenia.

Adolescent↗

PubMed1992

Cutoff size does strongly influence molecular dynamics results on solvated polypeptides.

The behavior of a 17-residue model peptide is analyzed by means of molecular dynamics simulations including explicitly more than a thousand water molecules. On the basis of the charge-group concept, Coulomb interactions are truncated for three values of the cutoff radius: 0.6, 1.0, and 1.4 nm. It is found that the stability of an alpha-helix, which acts as a common starting configuration, is a function of the cutoff size. While the overall stability of the helix is conserved in a simulation using a cutoff of 1.0 nm, it is lost within a very short period of 100 ps when the cutoff is increased to 1.4 nm. This demonstrates that the commonly used cutoff size of 1.0 nm is inappropriate because it does not ensure the convergence of Coulomb interactions. In order to permit an independent judgment, we have performed a 225-ps simulation using the Ewald summation technique, which is more elaborate but circumvents the problem to find an appropriate cutoff value. In contrast to the 1.4-nm cutoff trajectory, the Ewald technique simulation conserves the helical character of the peptide conformation. This demonstrates that even 1.4 nm is too short a cutoff. Due to the fundamental uncertainty introduced by the use of a simple cutoff, this truncation scheme seems questionable for molecular dynamics simulations of solvated biomolecules.

Amino Acid Sequence↗

PubMed1992

Stroma is critical for preventing or permitting immunological destruction of antigenic cancer cells.

Inoculated immunogenic cancer cells after initial growth are potentially rejected by specific host immunity; however, the outcome of the interaction between host and inoculated cancer cells is a function of multiple factors including the route of inoculation, the number of cells, the density of antigens on the injected cancer cells, and the state of the immune system of the host. In the present study, we have examined a different kind of variable: the stroma that inoculated tumor cells initially reside in. The impetus to examine this factor arises from observations that cancer cells from several lines inoculated as fragments of solid tumors often grow progressively, whereas the same number or more than 10-fold larger numbers of identical type cells injected as a suspension are rejected, even though fragments or suspended cells are both tumorigenic at the same doses in nude mice. In the present studies, we found that: (a) indeed, cancer cells inoculated as fragments were more tumorigenic than cancer cells in suspension; (b) the tumorigenicity of suspended cancer cells was increased by injection of the cells into polyurethane sponge implants; (c) cancer cells were more tumorigenic embedded in syngeneic stroma than in transgenic antigenic stroma expressing the K216 major histocompatibility complex class I antigen; and (d) antigenic, bone marrow-derived, stromal components (presumably passenger leukocytes) were sufficient to cause rejection of immunogenic but antigenically unrelated cancer.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Attention, cognition, and motor perseveration in adolescents at genetic risk for schizophrenia and control subjects.

Twenty-three offspring of schizophrenic parents (mean age = 12.1 years, SD = 3.2) and 61 adolescent control subjects (mean age = 12.3 years, SD = 3.3) were compared in their performance of the following psychometric tests: simple reaction times (RTs), warned RTs in a monomodal and cross-modal design, d2 concentration test, a motor perseveration test, and a cognitive performance measure (Wechsler Intelligence Scale). The results were validated in a second analysis in which a subgroup of the control subjects were matched to the high-risk subjects for the following characteristics: age, gender, education, and environmental background. Significant deficits were found in the high-risk group in tests that required sustained attention and information processing under high perceptual load (RT measures and d2 concentration test). Deficits were particularly prominent for the processing of visual stimuli; sensory incongruence might also have been a contributor to this deficit. The attentional dysfunction of high-risk subjects might explain their tendency to show less structured behavior and distractibility as reflected by their higher entropy scores in a motor perseveration test. Cognitive evaluation showed a significant deficit in the high-risk group, primarily as reflected in the verbal IQ score.

Adolescent↗