induction-invasive-transitional-cell-bladder-carcinoma-immune-intact

Induction of Invasive Transitional Cell Bladder Carcinoma in Immune Intact Human MUC1 Transgenic Mice:  A Model for Immunotherapy Development

A preclinical model of invasive bladder cancer was developed in human mucin 1 (MUC1) transgenic (MUC1.Tg) mice for the purpose of evaluating immunotherapy ...

University of California, Davis

Cw-ESR distance measurement method is extremely valuable for studying the dynamics-function relationship of biomolecules. However, extracting distance distributions from experiments has been a highly technique-demanding procedure. It has never been conclusively identified, to our knowledge, that the problems involved in the analysis are ill posed and are best solved using Tikhonov regularization. We treat the problems from a novel point of view. First of all, we identify the equations involved and uncover that they are actually two linear first-kind Fredholm integral equations. They can be combined into one single linear inverse problem and solved in a Tikhonov regularization procedure. The improvement with our new treatment is significant. Our approach is a direct and reliable mathematical method capable of providing an unambiguous solution to the ill-posed problem. It need not perform nonlinear least-squares fitting to infer a solution from noise-contaminated data and, accordingly, substantially reduces the computation time and the difficulty of analysis. Numerical tests and experimental data of polyproline II peptides with variant spin-labeled sites are provided to demonstrate our approach. The high resolution of the distance distributions obtainable with our new approach enables a detailed insight into the flexibility of dynamic structure and the identification of conformational species in solution state.

Determination of interspin distance distributions by cw-ESR is a single linear inverse problem.

BACKGROUND: L-BLP25 antigen-specific cancer immunotherapeutic agent is currently in phase III clinical trials for non-small cell lung cancer. Using a novel human MUC1 transgenic (hMUC1.Tg) lung cancer mouse model, we evaluated effects of L-BLP25 combined with low-dose cyclophosphamide (CPA) pretreatment on Th1/Th2 cytokine production and antitumor activity. METHODS: A chemically-induced lung tumor model was developed in hMUC1.Tg C57BL/6 mice by administering 10 weekly 0.75-mg/g doses of the chemical carcinogen urethane by intraperitoneal injection. Serum cytokines associated with Th1/Th2 polarization and inflammation were measured by multiplex cytokine assay during tumorigenesis. Antitumor activity of L-BLP25 (10 mug) with CPA (100 mg/kg) pretreatment was evaluated following either one or two eight-week cycles of treatment by preparing lung whole mounts and counting tumor foci, and assessing IFN-gamma production by ELISpot assay. RESULTS: During the carcinogenesis phase, no detectable Th1- or Th2-associated cytokine responses were observed, but levels of pro-inflammatory cytokines were increased with distinctive kinetics. A single cycle of L-BLP25 consisting of eight weekly doses was ineffective, whereas adding a second cycle given during tumor progression showed a significant reduction in the incidence of tumor foci. Administering two cycles of L-BLP25 induced Th1 cytokines IL-12, IL-2 and IFNgamma at 24 h after the last dose, while Th2 and inflammatory cytokines were elevated to a lesser extent. CONCLUSIONS: Urethane-induced lung tumors in hMUC1.Tg mice can be used as a model to assess the efficacy of the MUC1 antigen-specific cancer immunotherapeutic agent L-BLP25. The results indicate that the antitumor response to L-BLP25 requires at least two cycles and pre-treatment with CPA. In addition, monitoring pro-inflammatory serum cytokines may be useful as a biomarker of L-BLP25 response. Taken together, the preclinical lung tumor model can be utilized for determining effective combinations of L-BLP25 with chemotherapy and/or other immunotherapies.

Antitumor effects of L-BLP25 Antigen-Specific tumor immunotherapy in a novel human MUC1 transgenic lung cancer mouse model.

Ospemifene is a selective estrogen receptor modulator (SERM), or estrogen receptor agonist/antagonist, that was recently approved by the US Food and Drug Administration for the treatment of dyspareunia associated with vulvar and vaginal atrophy, a chronic condition that affects up to 60% of postmenopausal women. Ospemifene is the first and only nonestrogen compound approved for this indication. Compared with other approved SERMs, such as tamoxifen, toremifene, bazedoxifene, and raloxifene, the estrogen-like effects of ospemifene in the vaginal epithelium are unique. This review first discusses the rationale for developing ospemifene, including its mechanism of action, and then focuses on the clinical development of ospemifene for the treatment of dyspareunia associated with vulvar and vaginal atrophy. Included are discussions of the effects of ospemifene on the endometrium, serum lipids, coagulation markers, bone, and breast cancer. In conclusion, ospemifene is a SERM with a unique estrogen agonist/antagonist tissue profile that was recently approved in the US for the treatment of dyspareunia associated with vulvar and vaginal atrophy in postmenopausal women. Ospemifene warrants further clinical investigation for the treatment and prevention of osteoporosis and breast cancer.

Chiao-Jung Kao

Department of Internal Medicine,
Division of Hematology and Oncology,
Department of Internal Medicine, Division of Hematology and Oncology

University of California, Davis

Induction of Invasive Transitional Cell Bladder Carcinoma in Immune Intact Human MUC1 Transgenic Mice: A Model for Immunotherapy Development

Chiao-Jung Kao

Department of Internal Medicine,Division of Hematology and Oncology,Department of Internal Medicine, Division of Hematology and Oncology

University of California, Davis

Induction of Invasive Transitional Cell Bladder Carcinoma in Immune Intact Human MUC1 Transgenic Mice: A Model for Immunotherapy Development

Department of Internal Medicine,
Division of Hematology and Oncology,
Department of Internal Medicine, Division of Hematology and Oncology