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Biomedical subjects

P A Cohen

Publications and source records attributed to P A Cohen.

At least 19 recordsLinked to original sources
PubMed1995

Helper T cells infiltrating human renal cell carcinomas have the phenotype of activated memory-like T lymphocytes.

Human renal cell carcinomas are characterized by an inflammatory infiltrate containing many T lymphocytes. Attempts to grow T cells from such tumors by culture in interleukin (IL)-2 have yielded heterogeneous populations of cells with functional characteristics typical of lymphokine-activated killer cells obtained by similar culture of cells from peripheral blood mononuclear cells. We examined a panel of surface markers expressed on T lymphocytes to determine if the CD4+ T cells infiltrating human renal cell carcinomas are different from those in peripheral blood mononuclear cells. By flow cytometry analysis the CD4+ T cells in a panel of freshly digested human renal cell carcinoma primary and metastatic tumors expressed the activation markers CD69 and HLA-DR and manifested an increase in CD45RO and a reciprocal decrease in CD45RA expression as compared with peripheral blood CD4+ T cells. This suggests that CD4+ T cells infiltrating renal cell carcinomas are activated and have encountered antigen. However, the expression of the IL-2R alpha chain (CD25) was not different in tumor-infiltrating CD4+ T cells and peripheral blood CD4+ T cells, suggesting that T cells infiltrating human renal cell carcinomas may have a block in proliferative capacity. The general failure of cultured tumor-infiltrating lymphocyte (TIL) from renal cell carcinoma to demonstrate tumor-specific reactivity may be due to the failure of such cells to grow in IL-2.

CD4-Positive T-Lymphocytes↗
PubMed1995

Defective major histocompatibility complex class I expression in a sarcomatoid renal cell carcinoma cell line.

We studied major histocompatibility complex (MHC) class I expression in 12 tumor cell culture lines established from patients with metastatic renal cell carcinoma (RCC). In one of these cell culture lines, UOK 123, we found no surface expression of beta 2-microglobulin (beta 2m) and MHC class I by flow cytometry. Immunofluorescence staining using three different monoclonal antibodies to beta 2m revealed no detectable beta 2m in the endoplasmic reticulum (ER), Golgi apparatus, cytoplasm, or on the cell surface. There was no evidence of folded class I molecules inside or on the surface of the cells; however, the ER stained intensively for unfolded class I molecules. Transient expression of beta 2m by UOK 123 after infection with a recombinant vaccinia virus containing the gene for beta 2m resulted in normal expression of both beta 2m and class I (HLA-A, B, C) determinants assessed by flow cytometry analysis. No expression of class I or beta 2m was seen with the recombinant vaccinia vector carrying a control gene. The inability of class I molecules to reach the cell surface is due to the requirement of beta 2m for proper folding and presentation of the class I MHC complex. The failure to assemble and express MHC class I complex on the cell surface renders these cells incapable of antigen presentation to cytotoxic T cells and provides a mechanism for escape from immune recognition by the tumor.

Carcinoma, Renal Cell↗
PubMed1994

Treatment of established lung metastases with tumor-infiltrating lymphocytes derived from a poorly immunogenic tumor engineered to secrete human TNF-alpha.

The growth of a poorly immunogenic methylcholanthrene (MCA)-induced murine (m) sarcoma genetically engineered to secrete human (h) TNF-alpha (MCA-102-hTNF) was studied. MCA-102-hTNF tumor cells were implanted in animals bearing three- or 7-day pulmonary metastases established with the parental line MCA-102-WT (wild type). This model approximates the clinical situation in which patients with metastatic cancer would be vaccinated with autologous tumor genetically modified to stimulate the host immune response. Reduction in the number of pulmonary metastases was occasionally seen but was not consistently reproducible. Other cytokine-producing tumors had either no effect on distant pulmonary metastases (mIL-4, IFN-gamma) or a mild, inconclusive effect similar to hTNF-alpha (mTNF-alpha). Significant growth inhibition of MCA-102-hTNF was noted in animals bearing pulmonary metastases. This inhibition was: 1) tumor specific (regression occurred only in animals bearing pulmonary metastases from the same parental line), 2) TNF specific (it was inhibited by in vivo administration of anti hTNF mAbs), 3) dependent on cellular immunity (immune-depletion with anti-CD4 or CD8 mAbs permitted growth). Tumor-infiltrating lymphocytes (TIL) could not be grown from MCA-102-WT or MCA-102-hTNF tumors nor from MCA-102-WT subcutaneous implants in mice bearing MCA-102-WT pulmonary metastases. However, TIL could be grown from hTNF-secreting tumors implanted in mice bearing MCA-102-WT metastases. These TIL were therapeutic against established lung metastases from the parental tumor in adoptive immunotherapy models. These studies suggest a strategy for using gene modified tumors for the therapy of established cancer.

Animals↗
PubMed1994

CD4+ T-cells from mice immunized to syngeneic sarcomas recognize distinct, non-shared tumor antigens.

We have utilized a newly developed culture system to study the properties of antitumor CD4+ T-cells relevant to the rejection of syngeneic methylcholanthrene sarcomas. Fresh syngeneic dendritic cells prepared from spleen, then pulsed with crude lysates of methylcholanthrene sarcomas, evoke antigen-specific proliferation by CD4+ but not by CD8+ T-cells from tumor-immune mice. Unfractionated splenocytes display similar antigen presenting capacity if they are not irradiated before the pulse with tumor lysate. CD4+ T-cells from mice immunized to individual methylcholanthrene sarcomas proliferate cross-reactively to dendritic cells pulsed with fresh tumor digests, but not to dendritic cells pulsed with cultured tumor cells. This apparent shared recognition of sarcoma lysates was demonstrated to be a result of sensitization to bacterial collagenase during the immunization procedure. Therefore, the murine CD4+ T-cell response to tumor immunization is similar to the CD8+ response in that sensitization occurs predominantly to tumor specific transplantation antigens rather than to shared tumor antigens. Strategies to avoid artefactual tumor cross-recognition by CD4+ T-cells are discussed.

Animals↗
PubMed1994

Cells of Th2 cytokine phenotype prevent LPS-induced lethality during murine graft-versus-host reaction. Regulation of cytokines and CD8+ lymphoid engraftment.

A murine parent-into-F1 graft-vs-host reaction (GVHR) model that utilizes LPS to induce lethality was used to evaluate the in vivo regulatory role of donor cells of Th2 cytokine phenotype. Transfer of B6 spleen cells into B6C3F1 hosts was lethal when LPS endotoxin (15 micrograms) was administered on day 7 after cell transfer. Parental cells of Th2 cytokine phenotype were generated by treating B6 mice in vivo with a combination of IL-2 and IL-4 or with high dose IL-2. The CD4-enriched population from these cytokine-treated mice expressed and secreted increased levels of IL-4 and IL-10, with concomitantly decreased IL-2 and IFN-gamma. Cell mixing experiments (parental spleen cells+parental CD4-enriched. Th2-type cells) demonstrated that the Th2-type cells protected F1 hosts from LPS-induced lethality. These mice were analyzed to study possible mechanisms by which this protection was mediated. Compared with mice undergoing LPS-induced lethality during GVHR, Th2-protected mice had: 1) lower levels of donor CD8+ lymphoid engraftment, 2) in vivo suppression of IFN-gamma mRNA, 3) in vivo augmentation of IL-4 mRNA, and 4) a reduction in serum TNF-alpha. We thus conclude that donor cells of Th2 cytokine phenotype prevent LPS-induced, TNF-alpha-mediated lethality during GVHR, and that this protection is associated with regulation of both cellular- and cytokine-mediated events. As a result, we propose that cells of Th2 cytokine phenotype may represent a novel approach for establishing allogeneic lymphoid engraftment without lethal graft-vs-host disease.

Animals↗
PubMed1994

Propagation of mouse and human T cells with defined antigen specificity and function.

Difficulties maintaining fully functional CD4+ T cells in culture have historically limited the study of their role in tumour rejection as well as other clinical applications. As the therapeutic value of current antitumour CD8+ T cell adoptive therapy becomes better defined, a strong impetus exists to determine optimal conditions for culturing antitumour CD4+ T cells. Our goal is to promote broadly polyclonal, antigen-specific CD4+ T cell responses of either Th1 or Th2 character for use in antitumour therapy or allograft facilitation, respectively. Similar obstacles exist in murine and human cultures: (1) during even brief periods of culture CD4+ T cells develop high 'background' reactivity to class II-positive antigen-presenting cells; (2) maintenance of antigen specificity as evidenced by cytokine secretion and short-term proliferation assays is insufficient to ensure bulk numerical expansion; (3) Th1-type CD4+ T cells often lose their potential for antigen-specific secretion of interleukin 2 on re-stimulation (though remain inducible by 12-O-tetradecanoylphorbol 13-acetate/ionomycin); (4) during prolonged culture selection pressure favours CD4+ subpopulations that recognize artifactual antigens such as culture medium proteins; (5) even with optimal culture conditions, cultured CD4+ T cells may function differently in vivo to uncultured CD4+ T cells. We have devised various strategies to surmount these obstacles by use of selected cytokines, antigen-presenting cells and timely culture manoeuvres.

Animals↗
PubMed1994

Murine epidermal Langerhans cells and splenic dendritic cells present tumor-associated antigens to primed T cells.

We examined the ability of epidermal Langerhans cells and splenic dendritic cells to present tumor-associated antigens (Ag) to immune T cells. Methylcholanthrene (MCA)-induced subcutaneous fibrosarcomas derived from C57BL/6 mice were used as tumor models. Our data demonstrate that both murine Langerhans cells and splenic dendritic cells have the capacity to present tumor-associated Ag to primed T cells. We found that variously treated tumor preparations (irradiated viable tumor cells, irradiated frozen-stored tumor cells, mitomycin C-treated viable tumor cells, and snap freeze-thawed tumor cell lysates) can be utilized for tumor Ag-pulsing. Primed CD4+ T cells demonstrated in vitro specificity towards their respective tumors and did not cross-react to other syngeneic MCA-induced or non-MCA-induced tumors. The T cell proliferative response critically depended on the presence of immune CD4+ T cells. We discuss the implications of these findings for the adoptive immunotherapy of cancer using immune CD4+ T cells.

Animals↗
PubMed1994

False aneurysm following intracranial surgery.

A false aneurysm of the pericallosal artery formed following resection of a colloid cyst. The aneurysm presumably resulted from arterial damage during surgery and its enlargement may have been facilitated by the surgical defect in the corpus callosum. A spherical hyperdense lesion on postoperative CT may indicate a false aneurysm.

Adult↗
PubMed1994

Recognizing and managing the difficult patient.

Expectations, history, attitudes, biases and experiences are part of the dentist-patient relationship. How dentists manage these within themselves and within the delicate, complex dentist-patient relationship is the difference between a stressful day at the office and a satisfying dental experience for everyone involved.

Dental Care↗
PubMed1993

Use of interleukin-7, interleukin-2, and interferon-gamma to propagate CD4+ T cells in culture with maintained antigen specificity.

In contrast to CD8+ T cells, it has been difficult to establish consistently satisfactory conditions for the bulk culture of antitumor CD4+ T cells in either mice or humans. This difficulty is not limited to tumor antigen, since similar problems are encountered growing CD4+ T cells that recognize alloantigen, tetanus, or candida. Four basic findings are reviewed in this article, stemming from work with identical results in both human and mouse. (a) Although CD4+ T cells initially proliferate after exposure to appropriate antigen-presenting cells (APCs), such proliferation is not sustained; however, expansion of CD4+ T cells can be achieved with the addition of recombinant interleukin-2 (rIL2) or rIL-7. (b) Specific CD4+ responses to antigens are often better sustained with exogenous IL-7 than with exogenous IL-2. (c) Adding rIL-7 or rIL-2 permits sustained CD4+ T-cell proliferation, but subsequent culture restimulation is complicated by high background reactivity to APCs whether APCs are antigen pulsed or not; this problem can be overcome by addition of exogenous interferon-gamma (IFN-gamma) to the CD4+ cultures. (d) In certain instances proliferation is paradoxically impaired by reexposure to specific antigen, possibly reflecting apoptosis; this problem is also overcome by addition of rIFN-gamma to culture. We conclude that combinations of exogenous IL-7, IL-2, and IFN-gamma with APC restimulation can be used to sustain antigen-specific CD4+ T cells in culture. Using these techniques, antitumor CD4+ T cells were propagated from the peripheral blood of two tumor-bearing patients.

Animals↗
PubMed1992

Gatekeeping.

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Interprofessional Relations↗
PubMed1992

Oral contraceptive use and cardiovascular disease: is the relationship real or due to study bias?

BACKGROUND: Epidemiologic studies link oral contraceptive use with several cardiovascular events, but the literature is difficult to summarize, and potential biases remain poorly addressed. This study uses meta-analysis to summarize study results and to analyze the influence of study characteristics, including susceptibility to bias, on study outcome. METHODS: Forty-seven case-control and cohort studies of oral contraceptives and four cardiovascular events were coded for relative risk (RR) and study characteristics, including adherence to 14 bias-control standards. Key RRs were pooled to summarize findings for each disease type. Univariate determinants of the magnitude of the relative risks were identified, and partial correlation analysis was performed for each disease type. RESULTS: Relative risks were significantly greater than 1.0 for venous thromboembolism (RR = 2.8, CI = 2.4 to 3.2), stroke (RR = 1.8, CI = 1.6 to 2.0), and myocardial infarction (RR = 1.6, CI = 1.4 to 1.8), but not for death due to any cardiovascular cause (RR = 1.0, CI = 0.8 to 1.3). Study characteristics were diverse, and potential biases were frequently uncontrolled. For three of ten study characteristics identified as independently influencing relative risk, methodologically stronger studies of venous thromboembolism tended to have higher RRs. The RRs for stroke and myocardial infarction were lower in studies that were methodologically stronger with regard to variables identified as important. In studies of cardiovascular death, bias-control standards identified as important were generally well addressed by the studies. CONCLUSIONS: Oral contraceptive use does not appear to increase overall cardiovascular mortality. The associations noted with stroke and myocardial infarction may be due to methodologic flaws in the studies, while the association with venous thromboembolism is more likely to be valid.

Bias↗
PubMed1992

A meta-analysis of individualized instruction in dental education.

Although several dozen studies on individualized instruction in dental education have been conducted over the past 30 years, little has been done to summarize quantitatively these studies. The present investigation used Glass' techniques of meta-analysis to integrate statistically findings from 34 comparative studies on individualized instruction. A majority of these studies favored individualized over conventional instruction. The overall magnitude of effect, however, was small to moderate. One study characteristic variable--pacing of instruction--related significantly to effect size, with instructor-paced versions of individualized instruction producing larger achievement gains than student-paced versions. On average, individualized courses required only three-quarters of the time needed for conventional teaching. The results suggest that more research is needed in this area, particularly concerning applications of computer-based instruction, to assess adequately the potential of individualized modes of instruction for dental education.

Computer-Assisted Instruction↗
PubMed1992

A survey of instructional technology in dental education.

Little is known about current use of hardware and non-hardware instructional technologies in dental education. To address this area, the investigators designed a questionnaire to assess support for the development of instructional technology and determine the extent to which different instructional technologies are used in North American dental schools. Responses were received from 59 of 65 dental schools (91 percent). Respondents at most schools judged the administration at their school to be supportive of the development of instructional technology, but in general, did not feel faculty were enthusiastic about or rewarded for developing innovative methods. The most common computer-based application involves testing and record keeping, which is used extensively in about half the dental schools. Individualized instruction and paper and pencil simulations are used in at least some courses at a majority of dental schools. Schools with available support services apply certain technologies to a significantly greater extent than schools without available support services.

Canada↗
PubMed1991

Effectiveness of student ratings feedback and consultation for improving instruction in dental school.

The effects of student ratings feedback and consultation on instructional improvement over a four-year time interval were examined. Of the 40 course directors who led the same course over a four-year period, nine sought consultation services after receiving results from their initial student course evaluation. A sample of nine course directors who received student ratings feedback but did not seek consultation were matched to this consultation group, and student ratings comparisons were made over the subsequent three-year period. The consultation group received significantly higher ratings than the ratings only group for six of the nine course rating items. The magnitude of these effect sizes were substantial. When viewed in light of previously reported controlled studies on feedback, the results suggest that consultation is an important adjunct to ratings feedback for improving subsequent instruction in dental education. In response to an attitudinal survey, course directors indicated that students were qualified to rate aspects of instruction and that ratings provided useful feedback for making course improvements. Recommendations for using student ratings feedback are provided.

Analysis of Variance↗