TGF-/Smad signaling plays crucial roles in breast cancer cell invasion and breast tumor metastasis. Understanding how TGF-signaling is regulated in metastatic breast cancer cells will allow for development of novel targeted therapy and prognostic markers. In this research, we study the mechanisms through which 2 signaling molecules, G protein-coupled receptor kinase 2 (GRK2) and Breast Cancer Anti-estrogen Resistance 3 (BCAR3), antagonize Smad signaling in breast cancer cells. We also study for correlations between expressions of these factors in breast tumors to disease outcomes. Our results advance current understanding of an important aspect of breast cancer pathology, namely TGF--induced metastasis. They also define GRK2 and BCAR3 as novel prognostic markers of breast cancer disease relapse and metastasis.

关键词：(生物学);乳腺癌;细胞转移;磷酸化;疾病;反馈

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Heart disease is the leading cause of death in both the United States and Hawaii, including men and women of the Armed Forces. Furthermore, chest trauma in military men and women can lead to cardiac injury and cardiomyopathy. There is presently no good therapy for injured myocardium. Stem cells hold great promise in the field of regenerative medicine, and may be the key to developing new therapies to treat cardiac damage. Our prior study showed that blood stem cells can, to some extent, facilitate repair of cardiac damage in a mouse model of cardiac infarct. Adipose stem cells however, are more accessible and abundant than blood stem cells, and are multipotent(can produce several different tissues types other than adipose). The latter property may make directed re-programming of these cells into the cardiac lineage more efficient. The objectives for the present study are: (No. 1) Test the hypothesis that the multipotent adipose-derived stem cells will perform better than bone marrow- derived stem cells in facilitating recovery from heart disease. (No. 2) Test the hypotheses that cardiac-like progenitors, derived via reprogramming of different types of stem cells, will further enhance the therapeutic potential of stem cell-based methodologies in the treatment of heart disease and (No. 3), the delivery of re-programming factors into stem cells using a transposase-mediated gene delivery system will enhance the re-programming efficiency of stem cells towards the cardiac lineage. The results to date have confirmed that adipose stem cells may be re-programmed into the cardiac lineage with an efficiency of (approximately) 25, substantially higher than (approximately) 1efficiency we had previously observed for blood stem cells. We are presently working an analysis of the relative potential of adipose stem cells and reprogrammed adipose stem cells to facilitate recovery of induced infarcts in our murine model.

关键词：充血性心力衰竭;干细胞;脂肪组织;骨髓;基因

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Maintaining genomic stability is critical for organismal fitness. Consequently, the absence of tumor suppressor gene activity, such as p53, results in increased genomic instability and increased cancer predisposition. Homologous recombination (HR), as measured by the in vivo pun assay, is a DNA repair mechanism that our laboratory uses to measure genomic instability. We compared eyespot frequency in normal wild type mice, mice that are absent in p53 protein (null) and those that have the hotspot mutations R172H and R172P (equivalent to R175 in human breast cancer). Previously, we have shown that in the absence of p53 the normal frequency of spontaneous HR is significantly elevated. However, the mechanism by which p53 suppresses HR is unclear. The p53 R172P mutant mice retains limited transcriptional functionality (regulating cell cycle genes but not apoptotic genes) while the p53 R172H mutant mice lack any transcriptional activity but retain some protein: protein interaction capability. We observed significantly increased HR frequency in the p53 R172H mutant versus the p53 R172P mutant mice. This suggests that p53 regulation of cell cycle genes but not apoptotic genes may be responsible for its ability to suppress HR frequency. Also, the loss of key protein: protein interactions may have contributed to this suppression. It has been previously reported that p53 R172H mutant mice come down with early aggressive tumors compared to the p53 R172P mutant mice. This correlates with the increased HR frequency we observed in the R172H mutant mice implicating p53 suppression of genomic instability as a major mechanism for p53 tumor suppression. This work provides novel insight into the mechanism of cancer development in the absence or mutation of p53 and the mechanism of p53 control of HR in an in vivo system. p53 is often a targeted therapy and further insight into the function of p53 in DNA repair pathways can be vital to finding novel points of targeted therapy.

关键词：乳腺癌;脱氧核糖核的酸;基因;基因;热点;稳定性;肿瘤;复合反应

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Trastuzumab, a monoclonal antibody (mAb) targeting HER-2/neu, kills tumor cells by several mechanisms, including antibody-dependent cellular cytotoxicity (ADCC). Strategies that enhance the activity of ADCC effectors, including natural killer (NK) cells, may improve trastuzumab s efficacy. NK cells that encounter trastuzumabcoated, HER2-overexpressing breast cancer cells become activated and express CD137, a costimulatory receptor. CD137 activation, which is dependent on the Fc RIII receptor, occurred both in vitro and in the peripheral blood of women with HER2- expressing breast cancer following trastuzumab treatment. Stimulation of trastuzumab-activated NK cells with an agonistic mAb against CD137 killed breast cancer cells more efficiently in vitro.

关键词：乳腺癌;单克隆抗体;抗体;血液细胞(生物学);细胞毒素

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While much advancement has been made in breast cancer treatment, metastatic breast cancer remains an incurable disease. MUC1 is a glycoprotein expressed on normal glandular epithelial but is over-expressed and underglycosylated in over 90of human breast tumors and 100of metastatic lesions, which lead to its ranking by NCI as the second most targetable antigen. Vaccines against tumor antigens have several benefits, including the chance to eliminate metastatic lesions that express the vaccinating tumor antigen. To this end, we have proposed vaccinating with peptides from the MUC1 protein core, which is only visible to the immune system on the tumor- associated form of the protein. Previous work from our lab has demonstrated that this vaccine does elicit a MUC1-specific immune response that can only be functional if the immunosuppressive tumor microenvironment is altered to allow efficient killing of tumor cells. Thus, we investigated the effectiveness of MUC1 vaccination in combination with drugs known to inhibit immunosuppression to determine which drug is the most effective. Methods: Mice that are transgenic for human MUC1 (MUC1.Tg) mice were orthotopically injected with a syngenic breast cancer cell line expressing human MUC1 (Mtag.MUC1). Mice were vaccinated after palpable tumor formation with the vaccine cocktail, consisting of two MHC class I-restricted MUC1 tandem repeat peptides and a class II pan helper peptide mixed with GM-CSF and CpG ODN, in incomplete Freund s adjuvant. Previous work in our lab has shown that blocking the cyclooxygenase pathway (COX) resulted in an inhibition of immunosuppression. Thus we used the following drugs in combination with the MUC1-vaccine therapy: Indomethacin (COX1 and COX2 inhibitor), Celecoxib (COX2 inhibitor), 1-methyl tryptophan (indoleamine 2,3 dioxygenase inihibitor), and AH6809 (EP2 receptor antagonist). Mice were euthanized and tissue was collected post the final vaccination.

关键词：乳腺癌;糖蛋白;免疫抑制;转移;镇痛药;抗原

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Traditional herbal medicines are commonly used for HIV/ AIDS and other health conditions in Uganda and sub-Saharan Africa, often in parallel with programs that provide antiretroviral therapy (ART). In the 1990's an estimated 80of Ugandans living in rural villages used traditional healers for primary health care. A study of 137 HIV-infected Ugandans receiving ART found that 60used herbs concurrently with ART. In Uganda traditional herbal medicines are usually boiled extracts of herbs taken orally. Some potentially hepatotoxic traditional herbal medicines used in Uganda and sub-Saharan Africa include Hoodia gordonia, Phytolacca dioica, and herbs from the Asteraceae family. Little is known about the hepatotoxicity of other commonly used herbs or the contribution of herbs to the burden of liver fibrosis and hepatocellular carcinoma in sub-Saharan Africa, including when used concomitantly with ART. Data on the specific types of herbs taken by HIV-infected persons in Uganda is limited, as is information about their components, side effects, toxicities, and ART interactions. In Rakai, Uganda, liver toxicity associated with herbal medicine may be of particular concern given the high prevalence of significant liver disease (17) among HIV- infected persons in Rakai recently identified by transient elastography (FibroScanH Echosense, Paris, France). In the aforementioned study reported herbal medicine use was associated with a two-fold increased risk of significant liver disease, defined as a transient elastography score equivalent to METAVIR liver fibrosis stage 2 (portal fibrosis with few septa) or greater. The study presented here follows up on this prior investigation with an in-depth analysis of the herbs used by study participants and their relation to liver fibrosis.

关键词：纤维化;人类免疫缺陷病毒;肝疾病,医学;药理学

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This study is comprised of three trials, referred to as the Assessment of Chiropractic Treatment (or ACT). the most significant work during the last reporting period was the finalization of the protocol for ACT1 (RCT for low back pain and nested smoking cessation study) its movement into the military IRB process and the CRADA process, Further, protocols for Assessment of Chiropractic Trials study 2 (Pre/post differences in reflexes and reaction times in Special Operation Forces) and study 3 (RCT of strength, balance and likelihood of re-injury with combat ready troops, chiropractic manipulation therapy as compared to sham manipulation) have been finalized.

关键词：背压;疼痛;现役军事人员;反应时间;反射;治疗;吸烟;低背部疼痛,脊椎按摩疗法

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Malignant Pleural Mesothelioma (MPM) survival remains poor despite multidisciplinary treatment involving aggressive surgery, chemotherapy and adjuvant radiotherapy (RT). The large RT treatment volume, and concerns about the proximity of radiosensitive normal structures, restricts the tumoricidal dose of radiotherapy that can be delivered. These concerns limit the effectiveness of adjuvant RT. To overcome this limitation, an entirely novel radiation treatment schedule in combination with post-RT delivery of bone marrow-derived stem cells was examined to improve tumor control and facilitate normal tissue proliferation. A rat model of MPM was used. The RT regime consisted of 10 pulses of low-dose RT (0.2 Gy) using a 3 minute inter-pulse interval (PERT) to a daily dose of 2 Gy. The inclusion of post-RT stem cell therapy is to repopulate normal tissues in the RT field. RT tumor response was assessed by microPET/CT (Positron emission tomography/computed tomography) imaging. In vitro cell survival data was used to demonstrate PERT was not inferior to standard RT (2 Gy single continuous treatments). In vivo, The surgical procedure has been established and tumor model has been established and tumor volume determined by in situ with F18-FDG. Unexpected technological problems with respect to the microPET scanner have slowed the imaging aspect of the project. However, to date, we have demonstrated that RT is effective at reducing MPM tumor growth in vivo; and this is associated with recruitment of hematological stem cells. Studies are currently on-going to determine if PERT is superior to standard RT in MPM.

关键词：肿瘤;放射治疗;干细胞;电脑断层扫描;原位分析

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The VA Office of Inspector General Office of Healthcare Inspections conducted an inspection to assess the merit of allegations made by a complainant concerning management of chronic opioid therapy at the VA Maine Healthcare System Community Based Outpatient Clinic (CBOC) in Calais, Maine. We reviewed the following allegations: Providers did not adequately assess patients who were prescribed opioids for chronic pain. Providers did not adequately monitor patients who were prescribed opioid medications for misuse or diversion of the medications. Facility managers asked providers to write opioid prescriptions for patients they had not assessed. We substantiated the allegation that providers did not adequately assess patients who were prescribed opioids for chronic pain. Although providers performed initial pain assessments of patients, reassessments were not consistently documented at the minimum required frequency. We substantiated the allegation that providers did not adequately monitor patients who were prescribed opioids for misuse or diversion of the medications. One provider did not properly follow-up on a patient's positive urine drug test, and due to staffing constraints at the CBOC, patients often obtained prescriptions from multiple providers. We substantiated the allegation that facility managers asked providers to write opioid prescriptions for patients whom the providers had not assessed; however, VHA regulations do not require a provider to see a patient before writing an opioid prescription. We recommended that the facility Director implement procedures to ensure that providers comply with all elements of management of chronic pain patients on opioid therapy at the Calais CBOC, including those highlighted in this report, as required by VHA and local policies. The Veterans Integrated Service Network and Facility Directors concurred with the recommendation and provided an acceptable action plan. We will follow up on the planned actions until they are completed.

关键词：医疗补助;索赔;报销;医疗保健服务

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In breast cancer, myeloid cells recruitment into tumors following radiation therapy and chemotherapy is frequently observed in pre-clinical models. We therefore sought to determine the significance of myeloid cell recruitment following chemotherapy treatment and their role in therapeutic resistance. Using intravital imaging of tumors in live mice, we observed that the tumors of the polyoma middle T antigen (PyMT) mouse model of luminal breast cancer show a stage-dependent sensitivity to treatment with doxorubicin. Doxorubicin treatment recruits CCR2+Gr1+7/4+CD11b+ immature myeloid cells with monocytic morphology. Inhibition of this recruitment via orthotopic transplantation of Ccr2+/+ cancer cells from PyMT mice into Ccr2-/- mice enhances the response to doxorubicin. Furthermore, changes in tumor vasculature and tumor grade accompany this improved response, indicating that CCR2 signaling may play important roles in tumor proliferation and differentiation, angiogenesis, in addition to therapeutic response. The data herein presented show that antagonism of CCR2 signaling in combination with cytotoxic chemotherapy treatment may be a potentially powerful therapeutic strategy for the treatment of breast cancer.

关键词：化疗；细胞毒素；血管生成；抗原；骨髓；乳腺癌

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