Susceptibility rather than resistance to hyperthyroidism is dominant in a thyrotropin receptor adenovirus-induced animal model of Graves' disease as revealed by BALB/c-C57BL/6 hybrid mice.

We investigated why TSH receptor (TSHR) adenovirus immunization induces hyperthyroidism more commonly in BALB/c than in C57BL/6 mice. Recent modifications of the adenovirus model suggested that using adenovirus expressing the TSHR A subunit (A-subunit-Ad), rather than the full-length TSHR, and injecting fewer viral particles would increase the frequency of hyperthyroidism in C57BL/6 mice. This hypothesis was not fulfilled; 65% of BALB/c but only 5% of C57BL/6 mice developed hyperthyroidism.

Schistosoma mansoni and alpha-galactosylceramide: prophylactic effect of Th1 Immune suppression in a mouse model of Graves' hyperthyroidism.

Graves' hyperthyroidism, an organ-specific autoimmune disease mediated by stimulatory thyrotropin receptor (TSHR) autoantibodies, has been considered a Th2-dominant disease. However, recent data with mouse Graves' models are conflicting. For example, we recently demonstrated that injection of BALB/c mice with adenovirus coding the TSHR induced Graves' hyperthyroidism characterized by mixed Th1 and Th2 immune responses against the TSHR, and that transient coexpression of the Th2 cytokine IL-4 by adenovirus skewed Ag-specific immune response toward Th2 and suppressed disease induction.

Phase I/II study of first-line irinotecan combined with 5-fluorouracil and folinic acid Mayo Clinic schedule in patients with advanced colorectal cancer.

Background: This multicentre phase I/II study was designed to determine the maximum tolerated dose of irinotecan when combined with 5-fluorouracil and folinic acid according to the Mayo Clinic schedule and to evaluate the activity of this combination as first-line therapy in patients with advanced colorectal cancer.

Methods: Sixty-three patients received irinotecan (250 or 300 mg/m2, 30- to 90-minute intravenous infusion on day 1), immediately followed by folinic acid (20 mg/m2/day) and 5-fluorouracil (425 mg/m2, 15-minute bolus infusion) days 1 to 5, every four weeks.

Results: Diarrhoea was dose limiting at 300 mg/m2 irinotecan in combination with 5-fluorouracil and folinic acid, and this was determined to be the maximum tolerated dose.

Febrile neutropenia: a prospective study to validate the Multinational Association of Supportive Care of Cancer (MASCC) risk-index score.

Objective: The objective of this study was to prospectively validate the Multinational Association of Supportive Care of Cancer (MASCC) risk-index score in an attempt to accurately predict on presentation with febrile neutropenia those cancer patients who are at low- or high-risk for development of serious medical complications during the episode.

Patients And Methods: Patients who presented with febrile neutropenia during November 2000 and July 2002 were prospectively enrolled in the protocol. All patients were hospitalized until recovery or outcome of the event and were treated with broad-spectrum, empiric, intravenous antibiotic therapy.

First line therapy with paclitaxel (Taxol) and pegylated liposomal doxorubicin (Caelyx) in patients with metastatic breast cancer: a multicentre phase II study.

The aim of this multicentric phase II study was to investigate the efficacy and toxicity of a combination of chemotherapy containing paclitaxel (Taxol) and a novel compound, a liposomal encapsulated doxorubicin (Caelyx), as first line therapy for patients with metastatic breast cancer. Thirty-four patients with advanced breast cancer were treated with a combination of paclitaxel 175 mg/m2 and liposomal doxorubicin 30 mg/m2, every 3 weeks. The combination chemotherapy was effective in 73% of the patients (ITT) (95% CI 55-86%) (7 complete and 18 partial responses).

Directed mutagenesis in region 713-720 of human thyroperoxidase assigns 713KFPED717 residues as being involved in the B domain of the discontinuous immunodominant region recognized by human autoantibodies.

Autoantibodies (aAbs) to thyroid peroxidase (TPO), the hallmark of autoimmune thyroid disease (AITD), recognize conformational epitopes restricted to an immunodominant region (IDR), divided into two overlapping domains A and B. Despite numerous efforts aimed at localizing the IDR and identifying aAb-interacting residues on TPO, only two critical amino acids, Lys(713) and Tyr(772), have been characterized. Precise and complete delineation of the other residues involved in the IDR remains to be defined.

Naked deoxyribonucleic acid vaccination induces recognition of diverse thyroid peroxidase T cell epitopes.

Recently, we observed that vaccination of BALB/c mice with thyroid peroxidase (TPO)-DNA in a plasmid is highly effective at inducing antibodies that interact with the immunodominant region recognized by human autoantibodies. We have now analyzed the TPO epitopes recognized by memory T cells in these animals. Splenocytes from TPO-DNA (not control DNA)-vaccinated mice responded to TPO protein antigen, as measured by interferon-gamma production.

Thyroid stimulation does not require antibodies with identical epitopes but does involve recognition of a critical conformation at the N terminus of the thyrotropin receptor A-subunit.

Whether monoclonal antibodies with thyroid-stimulating activity [thyroid-stimulating antibody/antibodies (TSAb)] from immunized animals are identical to human autoantibodies in Graves' disease is unknown. Here, we compared properties of a monoclonal hamster TSAb (MS-1) with human autoantibodies. The epitopes of neither MS-1 nor human autoantibodies can be determined by peptide scanning, indicating their conformational nature.

Evidence that factors other than particular thyrotropin receptor T cell epitopes contribute to the development of hyperthyroidism in murine Graves' disease.

Immunization with thyrotropin receptor (TSHR)-adenovirus is an effective approach for inducing thyroid stimulating antibodies and Graves' hyperthyroidism in BALB/c mice. In contrast, mice of the same strain vaccinated with TSHR-DNA have low or absent TSHR antibodies and their T cells recognize restricted epitopes on the TSHR. In the present study, we tested the hypothesis that immunization with TSHR-adenovirus induces a wider, or different, spectrum of TSHR T cell epitopes in BALB/c mice.

The oral NK(1) antagonist, aprepitant, given with standard antiemetics provides protection against nausea and vomiting over multiple cycles of cisplatin-based chemotherapy: a combined analysis of two randomised, placebo-controlled phase III clinical trials.

In early clinical trials, the NK(1) receptor antagonist, aprepitant (EMEND(R)) was shown to improve the protection provided by the best available therapy (hereafter referred to as 'standard therapy': a 5-HT(3) receptor antagonist and dexamethasone) against chemotherapy-induced nausea and vomiting over multiple cycles of cisplatin-based chemotherapy. To further study the sustainment of antiemetic efficacy of aprepitant plus standard therapy over more than one cycle of chemotherapy, we examined combined data from the multiple cycles extensions of two phase III clinical trials of oral aprepitant plus standard therapy for the prevention of chemotherapy-induced nausea and vomiting. Data were pooled from two multicentre, randomised, double-blind, placebo-controlled studies with identical design and treatment regimens.

Epoetin alfa corrects anemia and improves quality of life in patients with hematologic malignancies receiving non-platinum chemotherapy.

Anemia, a commonly occurring morbidity in patients with cancer, often leads to diminished quality of life (QOL). Numerous clinical trials have shown that epoetin alfa treatment improves hematologic and QOL variables in cancer patients. The clinical trial analysis reported here was performed to assess response to epoetin alfa in patients with hematologic malignancies.

Thyrotrophin receptor-specific memory T cell responses require normal B cells in a murine model of Graves' disease.

The role of B cells as antigen-presenting cells is being recognized increasingly in immune responses to infections and autoimmunity. We compared T cell responses in wild-type and B cell-deficient mice immunized with the thyrotrophin receptor (TSHR), the major autoantigen in Graves' disease. Three B cell-deficient mouse strains were studied: JHD (no B cells), mIgM (membrane-bound monoclonal IgM+ B cells) and (m + s)IgM (membrane-bound and secreted monoclonal IgM).

Thyrotropin receptor knockout mice: studies on immunological tolerance to a major thyroid autoantigen.

Graves' disease involves a breakdown in self-tolerance to the TSH receptor (TSHR). Central T cell tolerance is established by intrathymic deletion of immature T lymphocytes that bind with high affinity to peptides from autoantigens (like the TSHR) expressed ectopically in the thymus. In TSHR-knockout mice, tolerance cannot be induced to the TSHR, which should, therefore, be a foreign antigen for these animals.

Thyrotropin receptor-DNA vaccination of transgenic mice expressing HLA-DR3 or HLA-DQ6b.

Graves' disease in Caucasians is associated with the major histocompatibility (MHC) antigen HLA-DR3. One approach to studying the role of susceptibility genes involves the use of mice that lack murine MHC and instead express human HLA antigens. Although Graves' disease does not arise spontaneously in animals, thyrotropin receptor (TSHR) antibodies can be induced in mice by vaccination with TSHR-DNA in a plasmid.

Low-dose immunization with adenovirus expressing the thyroid-stimulating hormone receptor A-subunit deviates the antibody response toward that of autoantibodies in human Graves' disease.

Immunization with adenovirus expressing the TSH receptor (TSHR) induces hyperthyroidism in 25-50% of mice. Even more effective is immunization with a TSHR A-subunit adenovirus (65-84% hyperthyroidism). Nevertheless, TSHR antibody characteristics in these mice do not mimic accurately those of autoantibodies in typical Graves' patients, with a marked TSH-blocking antibody response.

Addition of the oral NK1 antagonist aprepitant to standard antiemetics provides protection against nausea and vomiting during multiple cycles of cisplatin-based chemotherapy.

Purpose: This analysis evaluated whether the antiemetic efficacy of the NK1 receptor antagonist aprepitant (EMEND trade mark, Merck, Whitehouse Station, NJ) plus standard antiemetics could be sustained for up to six cycles of cisplatin-based chemotherapy.

Patients And Methods: Patients receiving cisplatin > or = 70 mg/m2 were blindly assigned to receive one of the following three regimens: (1) aprepitant 375 mg 1 hour before cisplatin on day 1 and aprepitant 250 mg on days 2 to 5 (n = 35); (2) aprepitant 125 mg before cisplatin and aprepitant 80 mg on days 2 to 5 (n = 81); or (3) placebo before cisplatin on days 2 to 5 (n = 86). All groups received ondansetron 32 mg and dexamethasone 20 mg before cisplatin, and dexamethasone 8 mg on days 2 to 5.

Does thyrotropin cleave its cognate receptor?

A recent report of major pathophysiological significance, and opposed to present concepts, is that TSH (but not MS-1, a hamster monoclonal thyroid-stimulating antibody), cleaves the single-chain TSH receptor (TSHR) on the cell surface into its two-subunit form. We reassessed the issue using two approaches. First we wished to confirm the flow-cytometric assay previously used to quantitate TSHR cleavage.

Evidence that the C terminus of the A subunit suppresses thyrotropin receptor constitutive activity.

The TSH receptor (TSHR), unlike the LH receptor (LHR), has considerable ligand-independent adenylyl cyclase activity, a feature of pathophysiological importance. The TSHR ectodomain partially suppresses constitutive activity, an effect reversed by trypsin treatment of intact cells. Localizing the functional site of trypsin action would provide insight into how the TSHR ectodomain exerts its constraint.

The thyrotropin receptor autoantigen in Graves disease is the culprit as well as the victim.

Graves disease, a common organ-specific autoimmune disease affecting humans, differs from all other autoimmune diseases in being associated with target organ hyperfunction rather than organ damage. Clinical thyrotoxicosis is directly caused by autoantibodies that activate the thyrotropin receptor (TSHR). The etiology of Graves disease is multifactorial, with nongenetic factors playing an important role.

Phase II clinical trial of carboplatin and docetaxel in patients with metastatic ovarian cancer: active combination with low incidence of peripheral neuropathy.

During the past 2 decades there have been chemotherapeutic advances in the management of patients with advanced epithelial ovarian cancer. Nevertheless, new drug combinations aimed at increasing response and survival and decreasing toxicities are under investigation. The aim of this phase II study is to determine the feasibility, efficacy and toxicity of docetaxel at a dose of 75 mg/m2 in combination with Carboplatin at an area under the curve (AUC) of 6, as first line treatment in patients with advanced ovarian cancer.

Insight into antibody responses induced by plasmid or adenoviral vectors encoding thyroid peroxidase, a major thyroid autoantigen.

Plasmid and adenoviral vectors have been used to generate antibodies in mice that resemble human autoantibodies to the thyrotrophin receptor. No such studies, however, have been performed for thyroid peroxidase (TPO), the major autoantigen in human thyroiditis. We constructed plasmid and adenovirus vectors for in vivo expression of TPO.

A major role for non-major histocompatibility complex genes but not for microorganisms in a novel murine model of Graves' hyperthyroidism.

The etiology of Graves' disease is multifactorial. We investigated the role of genetic and environmental factors on the susceptibility to Graves' hyperthyroidism using a new murine model. Intramuscular injection of recombinant adenovirus expressing the thyrotropin receptor (AdCMVTSHR) induces Graves'-like hyperthyroidism (thyrotropin receptor [TSHR] antibodies, elevated thyroxine, and diffuse goiter) in more than 50% of female BALB/c mice.

The cysteine-rich amino terminus of the thyrotropin receptor is the immunodominant linear antibody epitope in mice immunized using naked deoxyribonucleic acid or adenovirus vectors.

Experimental Graves' disease is more effectively produced by immunization approaches involving in vivo TSH receptor (TSHR) expression than by conventional immunization with TSHR protein and adjuvant. Unlike conformational epitopes that are extremely difficult to define, linear epitopes can be readily assessed using synthetic peptides. TSHR linear epitopes are well characterized in conventionally immunized animals, but there is no information for animals vaccinated with TSHR DNA in plasmid or adenovirus vectors.