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Biomedical subjects

H Schreiber

Publications and source records attributed to H Schreiber.

At least 91 records · Page 5Linked to original sources
PubMed1992

Cachexia and graft-vs.-host-disease-type skin changes in keratin promoter-driven TNF alpha transgenic mice.

Tumor necrosis factor alpha (TNF alpha) orchestrates a wide range of effects that combat severe infections in animals. At lower levels, TNF alpha plays an important protective role in stimulating chemotaxis and antimicrobial activity of neutrophils, macrophages, and eosinophils. During chronic illness, TNF alpha secretion can be elevated markedly, giving rise to cachexia, hemorrhage, necrosis and, ultimately, death. Although TNF alpha may mediate many of its effects through macrophages, 30% of TNF alpha injected into animals concentrates in the skin. In recent years, it has been shown that keratinocytes can be induced to synthesize TNF alpha. To explore the role of TNF alpha synthesis in keratinocytes, we used a keratin-14 (K14) promoter to target human TNF alpha expression in the epidermis and other stratified squamous epithelia of transgenic mice. Most mice expressing the K14-TNF alpha transgene stopped gaining weight within 1 week postbirth, and exhibited retarded hair growth. In the skin, adipose production was profoundly inhibited, whereas signs of fibrosis and immune infiltration were evident in the dermis. Over time, the epidermis exhibited an increased stratum corneum, as signs of necrosis began to appear in the skin. Within 3-5 weeks, the mice displayed features characteristic of cachexia and necrosis. Our results suggest that TNF alpha expression by keratinocytes not only plays a role in inflammatory and graft-versus-host-disease-like responses in the skin, but also in other tissues, apparently by virtue of stratified squamous epithelial-derived TNF alpha entering the bloodstream. Our results have enabled the first evaluation of many of the effects of TNF alpha in transgenic animals.

Animals↗
PubMed1992

Tumor antigens.

This review solidifies a new concept that common and rare types of human cancers harbor a variety of tumor-specific mutant proteins that may be recognized as tumor-specific antigens. These mutant proteins are encoded by oncogenes or suppressor genes that have undergone structural mutations resulting from point mutations, chromosomal translocations, internal deletions and viral insertional mutagenesis; several of these changes result in fusion proteins. While there is no evidence that immunosurveillance against these mutant proteins can prevent the development of primary cancers without prior immunization of the host, such tumor-specific molecules might be important for diagnosis and as targets for specific immunotherapy once the cancer has developed or even as targets for preventive cancer vaccines. Evidence further supports the notion that cytolytic or helper T cells are exquisitely selective in recognizing intracellular mutant proteins, and tumor-specific T cell clones presently available may become useful for identifying previously unrecognized tumor-specific mutations. Many tumor-specific mutant proteins clearly play a causative role in the establishment of malignant behavior, whereas other carcinogen-induced changes have at least immunological relevance. In any case strong evidence in mouse and man indicates that a single malignant cell can express multiple independent antigenic target sites. Such multiplicity may allow a multi-pronged immune attack that substantially decreases the chance of tumor escape. Future work must explore whether immune responses to tumor-specific mutant proteins can lead to immunological tumor rejection and explore the possibility of chemically engineering tumor mutant peptides to be highly immunogenic, even in hosts that have previously failed to respond to the tumor.

Antigens, Neoplasm↗
PubMed1992

Ileocolonic anastomosis: a comparison of the patency of stapled versus hand-sewn techniques.

This study compared strength of hand-sewn sutures to that of staples for end-to-end anastomoses of ileocolostomies in 20 mongrel dogs. In ten dogs, the authors used four applications of staples for the anastomoses. In the other ten, they performed single-layer anastomoses using 4-0 polypropylene sutures. Half the dogs were sacrificed on the third postoperative day; half were sacrificed on the fifth postoperative day. Bursting strengths were obtained by infusing air through a catheter inserted into the colon. Results showed the single-layer hand-sewn anastomosis was significantly stronger than the stapled anastomosis. In addition, a histologic comparison of the two closures showed no difference in inflammatory responses.

Anastomosis, Surgical↗
PubMed1992

Carcinoma of the ampulla of vater after curative treatment for Hodgkin's disease.

A 43-yr-old woman developed carcinoma of the ampulla of Vater 20 yr after being successfully treated for Hodgkin's disease with radiotherapy and chemotherapy. Conditions related to the chronic effect of radiation, such as narrowing and fibrosis of abdominal tissue, hampered her diagnosis and treatment. After a total pancreatectomy to remove the carcinoma, the patient recovered. However, 15 months later, she developed severe digestive disturbances, adrenal insufficiency, pulmonary emboli, and vasculitis. She died the next month of sepsis and adult respiratory distress syndrome. Although her complications probably were related to residual effects from therapy and surgery, she had no clinical evidence of tumor recurrence.

Adenocarcinoma, Papillary↗
PubMed1992

Primary midgut volvulus in the adult: two case reports.

Primary midgut volvulus is associated with a high mortality rate. The presentation and management of two patients with primary midgut volvulus are reviewed. Both presented with severe abdominal pain inconsistent with clinical findings. Diagnosis was made intraoperatively in one case and at autopsy in the other. Surgeons need to suspect primary midgut volvulus when they encounter patients with atypical presentation of small bowel obstructions, i.e., when the severity of symptoms is inconsistent with physical findings. Primary midgut volvulus should be considered in the differential diagnosis in these patients, and, if suspected, emergent abdominal exploration is indicated.

Abdominal Pain↗
PubMed1991

Endogenous event-related brain potentials and psychometric performance in children at risk for schizophrenia.

Two independent groups of high-risk children for schizophrenia and their matched control children were submitted to the following experiments: an auditory oddball paradigm registrating late event-related potentials (ERPs) and a psychometric test battery including the assessment of Wechsler Intelligence Scales, reaction times (after regular and irregular preparatory intervals), and the d2-attention test. The study was intended to clarify whether long-latency ERPs and the selected psychometric tests would contribute to reliably differentiating between these groups. The results showed significantly prolonged latencies of the P3 component of the ERPs to rare, task-relevant target stimuli in both high-risk groups compared with the controls. Similarly, the N2 latencies were delayed in both groups. By contrast, ERP patterns to frequent, nontask-relevant stimuli were very similar, with no significant differences between high-risks and normals; nor did any ERP amplitudes show significant differences. The data are interpreted as a reflection of a subtle deficit in maintaining attention and a subsequent impairment of stimulus discrimination in high-risk children. This is consistent with the psychometric findings of higher error scores in target counts and d2-test, and significantly prolonged reaction times after regular preparatory intervals (PIs) in the high-risks. The findings may hint at a vulnerability for schizophrenia in high-risk children. Given the high prevalence of the attentional dysfunctions in both high-risk groups, however, it is hypothesized their presence does not necessarily imply an unequivocal manifestation of schizophrenia.

Adolescent↗
PubMed1991

Long-term inhibition of tumor growth by tumor necrosis factor in the absence of cachexia or T-cell immunity.

The relationship between detrimental (cachectic) and beneficial (antitumor) effects of tumor necrosis factor (TNF) was studied in mice bearing murine tumors transfected to secrete human TNF. In vitro, the TNF-producing transfectants were resistant to the secreted TNF and grew at rates similar to those of untransfected cells or transfected cells that did not secrete TNF. However, tumors formed by the TNF-secreting cells in vivo remained much smaller than the nonsecreting (transfected and untransfected) tumors. This inhibition of tumor growth required only relatively low serum levels of TNF, persisted for many weeks, and was independent of T cells since it occurred in nude mice. Growth of the TNF-secreting tumors increased dramatically after treatment with anti-human TNF antibody, indicating that extracellular TNF secreted by the tumor cells was necessary for the tumor inhibition. Severe weight loss characteristic of cachexia only occurred in animals with very high serum TNF levels (250 pg/ml) and could be prevented or reversed by anti-TNF antibody treatment. These data are consistent with the existence of a therapeutic window in which persistent exposure to human TNF can lead to prolonged inhibition of tumor growth in the absence of T-cell immunity or severe weight loss and without development of resistant tumor variants.

Animals↗
PubMed1991

Cytokines and cancer: experimental systems.

The transfer of certain cytokine genes into cancer cells can provide very powerful suppression of tumor growth in the absence of any toxic side effects. Some of these cytokines, such as interleukin-4, granulocyte colony-stimulating factor and tumor necrosis factor, can mediate powerful immune suppression even in T-cell-deficient animals and appear to be effective for poorly or non-antigenic tumors. However, approaches must be found to induce or deliver cytokines locally at the tumor site.

Animals↗
PubMed1991

Using a Full-depth Wound Drainage System to Decrease Wound Infection Rates in the Morbidly Obese.

The morbidly obese surgical patient is at increased risk for wound complications due to mechanical stresses from a deep and heavy subcutaneous tissue layer that create dead spaces in which hematomas and seromas can form. To drain the full depth of this layer, we revised an existing wound drainage system using cut segments of a Davol drain and added a Velcro binder to minimize lateral stress on the wound. We used the full-depth drain for all 384 morbidly obese patients who underwent vertical banded gastroplasty during a 10-year period. No patient developed a wound infection in the hospital; however, three patients had wound abscesses one month postoperatively, an infection rate of 0.78%. We believe that the drain system was an important factor in producing the low infection rate.

Journal Article↗
PubMed1991

[Expression of ABH and Lewis antigens in endometrium--relation to hormonal stimulation].

From 138 gynaecological abrasiones appropriate histological preparations were chosen. Case history and pathological diagnosis were known. ABH and Lewis antigens were marked immunohistologically. According to our findings, in the endometrial glands the ABH antigen expression is highest in the proliferation phase and decreases within the secretion phase. The same hormonal dependency could be demonstrated for the Lea antigens present in the superficial epithelium of the endometrium. Exogen application of estrogens enhances ABH antigen marking, application of gestagens does not.

ABO Blood-Group System↗
PubMed1991

MHC class I restricted T cells and immune surveillance against transplanted ultraviolet light-induced tumors.

Studies involving tumor escape from host immune surveillance have focused heavily on loss of major histocompatibility class I antigens as well as loss of tumour-associated antigens as possible mechanisms by which tumors escape recognition and lysis by cytolytic T cells. Examples of both phenomena are found in murine tumors induced by viruses, chemical mutagens, a spontaneous tumor mutagenized in vitro and some u.v.-induced tumors. However, evidence also exists for the escape of tumors from immune destruction without loss of major histocompatibility class I molecules or tumor antigens and additional mechanisms undoubtedly are involved in the complex phenomena of tumor progression.

Animals↗
PubMed1991

The rationale for incidental cholecystectomy during major abdominal vascular surgery.

The finding of gallstones during major abdominal vascular surgery warrants a critical decision regarding incidental cholecystectomy. The potential risk for vascular graft infection must be weighed against the risks of severe postoperative cholecystitis requiring surgery, a situation associated with significant morbidity and mortality. This report supports the safety of an incidental cholecystectomy, as long as the vascular graft is covered before the gallbladder is removed. The data also emphasize the hazards of not performing an incidental cholecystectomy for gallstones during major abdominal vascular surgery.

Abdomen↗
PubMed1990

[Myositis ossificans circumscripta following unusual brain injury].

The case reported here demonstrates the need to consider myositis ossificans after acute injury to the CNS, irrespective of the nature of the trauma. This latter by no means needs to be direct trauma--as the present case shows. When the condition does occur, the time needed for rehabilitation may be significantly lengthened.

Adult↗
PubMed1990

Major histocompatibility complex class I and unique antigen expression by murine tumors that escaped from CD8+ T-cell-dependent surveillance.

The rejection of murine UV-induced skin cancers by normal mice is a striking example of powerful immune surveillance of the normal host against malignant cells. In this study, we show that UV-induced regressor tumors regularly grew progressively and killed mice that were depleted of CD8+ T-cells. Depletion of CD4+ T-cells had no effect, suggesting that CD8+ but not CD4+ T-cells were required for this immune surveillance. To determine whether change in major histocompatibility complex (MHC) class I expression was a frequent event that caused low immunogenicity of tumors or facilitated escape from immune destruction, recently isolated murine tumors of varying degrees of immunogenicity, including highly immunogenic UV-induced regressor, less immunogenic UV-induced progressor, and poorly immunogenic spontaneous progressor tumors, were compared. There was no correlation between the ability of a tumor to grow progressively in a normal immunocompetent host and the level of constitutive class I expression or the level of expression induced in vitro by gamma interferon. (Only 1 of more than 20 progressor tumors analyzed showed complete loss of a MHC class I molecule.) Some progressor variants showed loss of a unique tumor-specific cytotoxic T-lymphocyte-defined antigen, consistent with earlier evidence of antigen loss providing a mechanism for tumor escape. However, most of the host-selected progressor variants retained both MHC class I antigens and the unique tumor antigens that we could detect with cytotoxic T-lymphocyte clones, suggesting that mechanisms other than loss of MHC class I or of the unique target antigen may be involved in escape of some tumors from a highly effective CD8-dependent host surveillance.

Animals↗
PubMed1990

Animals bearing malignant grafts reject normal grafts that express through gene transfer the same antigen.

Breaking the state of immunological unresponsiveness of tumor-bearing individuals to cancer is a prerequisite for active or passive tumor-specific immunotherapy. To study this problem the immunogenic MHC class I antigen, K216 was transfected into a progressor tumor. The transfected tumors were regularly rejected by normal mice but grew progressively in mice bearing nontransfected tumors. In addition, transgenic mice were derived to obtain normal cells and tissues expressing the same K216 gene product. Normal mice rejected K216-positive normal or malignant tissue grafts and generated K216-specific CTL in vitro and in vivo in response to these challenges. In contrast, mice bearing nontransfected tumors, though rejecting K216-positive nonmalignant tissue grafts, did not reject K216-positive tumors nor generate K216-specific CTL in response to K216-positive tumor cells. Mice bearing K216-positive tumors also rejected the nonmalignant K216-positive tissue grafts, but this in vivo response failed to lead to rejection of the simultaneously present tumor graft expressing the same antigen; in fact, immunity had no measurable effect whatsoever on tumor size or incidence and caused no selection for antigen loss variants. Taken together, the present findings suggest that transfer of expression of a target antigen into nonmalignant cells provides a way for obtaining effective stimulation of antigen-specific CTL in tumor-bearing mice, but that additional manipulations will be required to cause immunological rejection of established tumors.

Animals↗
PubMed1990

Mechanism of tumor rejection in anti-CD3 monoclonal antibody-treated mice.

The present study was undertaken to determine the mechanism of tumor rejection in mice treated with low dose anti-CD3 mAb. It was found that treated mice developed nonrestricted antitumor cytolytic spleen cells of the Thy-1+, asialo GM-1+, CD4-, CD8- phenotype. Although these cells might play a role in immunopotentiating some immune responses, in vivo depletion studies using anti-asialo GM-1 mAb demonstrated that these cells were not involved in the rejection of the progressor tumor, 1591-PRO4L, by anti-CD3 mAb-treated mice. Mice treated with anti-CD3 did develop lasting tumor specific immunity as demonstrated by their ability to reject PRO4L on tumor rechallenge while being unable to reject an unrelated UV-induced tumor. The specificity of this memory implicated T cells in the response to PRO4L in anti-CD3-treated mice. Using in vivo T cell subset depletion of anti-CD3-treated animals, it was shown that both CD4+ and CD8+ T cells are required for anti-CD3-induced tumor rejection. The CD4+ cells provide helper function and are only required in the early rejection period, whereas CD8+ cells are required throughout the immune response. In fact, examination of rejecting tumors from treated animals revealed the presence of tumor-specific CD8+ cytolytic T cells capable of cytolysis immediately after removal from the rejecting PRO4L tumor. Thus, in vivo treatment with anti-CD3 mAb likely results in the pan-stimulation of the entire T cell population, which enhances the generation of specific CD8+ T cells, which then eliminate the tumor.

Animals↗
PubMed1990

A highly immunogenic tumor transfected with a murine transforming growth factor type beta 1 cDNA escapes immune surveillance.

A highly immunogenic C3H-derived UV-induced tumor was cotransfected with a murine transforming growth factor type beta 1 (TGF-beta 1) cDNA and a neomycin-resistance gene. Stable clones were isolated and used in vitro and in vivo to determine the effects of endogenously produced TGF-beta on cytolytic T-lymphocyte (CTL) responses. Tumor cells producing TGF-beta, though retaining expression for class I major histocompatibility complex molecules and the tumor-specific antigen, did not stimulate primary CTL responses in vitro and were not effective in vivo for directly stimulating primary CTL or in priming for CTL responses. Furthermore, TGF-beta-producing tumors grew progressively in transiently immunosuppressed mice without losing the tumor antigen; thus, TGF-beta produced by tumors may promote escape from immune surveillance.

Animals↗