Citations

SUMMARYMurine experimental autoimmune thyroiditis (EAT), characterized by thyroid destruction after immunization with thyroglobulin (Tg), has long been a useful model of organ-specific autoimmune disease. More recently, porcine thyroid peroxidase (pTPO) has also been shown to induce thyroiditis, but these results have not been confirmed. When (C57BL/6 × CBA)F1 mice, recently shown to be susceptible to mouse TPO-induced EAT, were immunized with plasmid DNA to human TPO (hTPO) and cytokines IL-12 or GM-CSF, significant antibody (Ab) titres were generated, but minimal thyroiditis was detected in one mouse only from the TPO + GM-CSF immunized group. However, after TPO DNA immunization of HLA-DR3 transgenic class II-deficient NOD mice, thyroiditis was present in 23% of mice injected with TPO + IL-12 or GM-CSF. We also used another marker for assessing the closeness of the model to human thyroid autoimmunity by examining the epitope profile of the anti-TPO Abs to immunodominant determinants on TPO. Remarkably, the majority of the anti-TPO Abs was directed to immunodominant regions A and B, demonstrating the close replication of the model to human autoimmunity. TPO protein immunizations of HLA-DR3 transgenic mice with recombinant hTPO did not result in thyroiditis, nor did immunization of other mice expressing HLA class II transgenes HLA-DR4 or HLA-DQ8, with differential susceptibility to Tg-induced EAT. Moreover, our efforts to duplicate exactly the experimental procedures used with pTPO also failed to induce thyroiditis. The success of hTPO plasmid DNA immunization of DR3+ mice, similar to our reports on Tg-induced thyroiditis and thyrotropin receptor DNA-induced Graves’ hyperthyroidism, underscores the importance of DR3 genes for all three major thyroid antigens, and provides another humanized model to study autoimmune thyroid disease.

AbstractThese cancer genetic counseling recommendations describe the medical, psychosocial, and ethical ramifications of identifying at‐risk individuals through cancer risk assessment with or without genetic testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors Cancer Genetic Counseling Special Interest Group. The information contained in this document is derived from extensivereview of the current literature on cancer genetic risk assessment and counseling as well as the personal expertise of genetic counselors specializing in cancer genetics. The recommendations are intended to provid information about the process of genetic counseling and risk assessment for hereditary cancer disorders rather than specific information about individual syndromes. Key components include the intake (medical and family histories), psychosocial assessment (assessment of risk perception), cancer risk assessment (determination and communication of risk), molecular testing for hereditary cancer syndromes (regulations, informed consent, and counseling process), and follow‐up considerations. These recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. These recommendations do not displace a health care provider's professional judgment based on the clinical circumstances of a client.

SUMMARYFamilial and twin studies in Caucasians have established that the MHC class II allele HLA-DRB1*0301 (DR3) is a strong susceptibility gene in Graves’ hyperthyroid disease (GD). To determine if a DR3 transgene could help establish an animal model for GD, we expressed DR3 molecules in class II-knockout NOD mice (H2Ag7–). DR3+g7– mice were given cardiotoxin prior to immunization on weeks 0, 3 and 6 with plasmid DNA encoding human thyrotropin receptor (TSHR). Two groups of mice were also coimmunized with plasmid DNA for IL-4 or GM-CSF. Serial bleeds on weeks 8, 11 and 14 showed that approximately 20% of mice produced thyroid-stimulating antibodies (Abs), and approximately 25% had elevated T4 levels. In particular, a subset displayed both signs of hyperthyroidism, resulting in approximately 30% with some aspect of GD syndrome. Additional mice had thyroid-stimulating blocking Abs and/or TSH-binding inhibitory immunoglobulins, while most mice showed strong labelling of TSHR+ cells by flow cytometry. Interestingly, lymphocytic infiltration with thyroid damage and Abs to mouse thyroglobulin were also noted. Vector controls were uniformly negative. Thus, DR3 transgenic mice can serve as a model for GD, similar to our earlier reports that this allele is permissive for the Hashimoto's thyroiditis model induced with human thyroglobulin.

Abstract Multiple myeloma (MM) is a progressive disease that is thought to result from multiple genetic insults to the precursor plasma cell that ultimately affords the tumor cell with proliferative potential despite its differentiated phenotype and resistance to undergoing apoptosis. Altered expression of antiapoptotic factors as well as growth factors have been described in a significant number of patients. However, the key regulatory elements that control myeloma development and progression remain largely undefined. Because of the knowledge that B-lymphocyte stimulator (BLyS), a tumor necrosis factor (TNF) family member shown to be critical for maintenance of normal B-cell development and homeostasis, promotes the survival of malignant B cells, we began a coordinated study of BLyS and its receptors in MM. All MM cells studied expressed one or more of 3 known receptors (B-cell maturation antigen [BCMA], transmembrane activator and CAML interactor [TACI], and B-cell activating factor receptor [BAFF-R]) for BLyS; however, the pattern of expression was variable. Additionally, we provide evidence that BLyS can modulate the proliferative capacity and survival of MM cells. Finally, we provide evidence that BLyS is expressed by MM cells and is present in the bone marrow of patients with MM. Expression of BCMA, TACI, and BAFF-R by MM taken together with the ability of BLyS to support MM cell growth and survival has exciting implications because they may be potential therapeutic targets.

Purpose: To evaluate the antitumor activity, safety, immune response, and replication of CI-1042 (ONYX-015), an E1B 55-kd gene-deleted replication-selective adenovirus, administered intravenously to patients with metastatic colorectal cancer Patients and Methods: Eighteen patients with metastatic colorectal cancer for whom prior chemotherapy failed were enrolled onto an open-label, multicenter, phase II study. CI-1042 was administered intravenously at a dose of 2 × 1012 viral particles every 2 weeks. Patients were evaluated for tumor response and toxicity; in addition, blood samples were taken for adenovirus DNA and neutralizing antibody analysis. Results: Common toxicities included flu-like symptoms, nausea, and emesis. All 18 patients eventually were removed from study because of progressive disease. Seven patients were assessed as having stable disease after 2 months of treatment, whereas two patients were considered to have stable disease after 4 months. Detectable circulating CI-1042 DNA was identified in 36% of patients 72 hours after last infusion, which is suggestive of ongoing viral replication. Conclusion: In this phase II study, intravenous CI-1042 was administered safely to patients with advanced colorectal cancer. Toxicity was manageable, consisting primarily of flu-like symptoms. Stable disease was experienced by seven patients for 11 to 18 weeks.

Abstract Background Digitalis has a long history in the treatment of heart failure but its effects on cardiac hemodynamics and neurohormonal modulation are not well characterized. Aims The purpose of this study was to evaluate the relationship between atrial natriuretic peptide (ANP) and the hemodynamic responses to acute digitalis administration in patients with normal and impaired left ventricular function (LVD). Methods and Results Thirty patients were enrolled in the study, 20 with LVD (LVEF-22±8%) and 10 control subjects (LVEF-77±10%). Hemodynamics and plasma ANP concentrations were measured supine and with leg elevation before and after digitalis. In patients with normal ventricular function, the hemodynamic stress of leg elevation in the pre-digitalis state resulted in significant (P<0.05) increases in PAWP and MPAP. Digitalis administration in the supine position produced reductions in heart rate, PAWP, MPAP and CI; SVR was increased. In LVD patients leg elevation further increased PAWP, RAP and MPAP. Digitalis in the supine position, however, reduced RAP, MPAP and PAWP and increased CI. These improved hemodynamics were preserved during the stress of leg elevation. Leg elevation following digitalis resulted in increased ANP concentrations despite decreased cardiac filling pressures. Conclusions Acute digitalis administration results in hemodynamic improvement in LVD patients which may in part result from digitalis stimulated release of myocardial ANP under conditions of hemodynamic stress.