The p53 transactivation domain 1 (TAD1) plays a critical role in inducing p53 mediated cell-cycle arrest and apoptosis in response to acute DNA damage caused by irradiation. During radiation therapy of cancers, this p53- induced apoptosis triggers various deleterious pathological side effects in normal tissues. Interestingly, recent studies from our laboratory have demonstrated that p53 TAD1 is completely dispensable for tumor suppression in diverse mouse cancer models. We hypothesize that specific inhibition of p53 TAD1 should ameliorate the p53-associated pathologies occurring in response to acute DNA damage, while keeping p53-mediated tumor suppression intact, thus allowing improvement in the therapeutic index of radiation therapy in cancer. Importantly, because the majority of cancers, such as advanced prostate cancers, have inactivated the p53 pathway, such inhibitors should not compromise the efficacy of treating tumors. We propose to perform high-throughput chemical library screens to identify specific inhibitor of p53 TAD1 that may be administered as adjuvants of chemotherapy and radiotherapy in the context of prostate cancer.

关键词：前列腺癌;逮捕(过程);化疗;脱氧核糖核的酸;放射疗法;治疗;组织(生物学)

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We aimed to develop a virus-Au NS assembly to specifically target breast cancer cells, and to use localized heat of NIR radiation of Au NS to destroy breast cancer cells in synergy with gene therapy. We proposed to develop virus-nanoshell assemblies by attaching adeno-associated virus (AAV) to gold nanoshells (Au NS) through chemical bonds. We have successfully completed majority of tasks 1 and 2 of our Statement of Work. Specifically, we have designed and synthesized a linker molecule with dual functionalities to be able to covalently attach AAV to Au NS surface. Au NS was successfully functionalized with the linker molecules. AAV capsid surface was modified with a benzaldehyde functional group. Using higher titer AAV8, we were able to confirm and quantify the successful conjugation. Recombinant AAV vectors encoding a gene under regulation of a heat-responsive promoter were generated. By combining breast cancer targeting, gene therapy, and hyperthermia, the virus- NS assemblies have the potential to greatly reduce the recurrence of cancer, reduce side effects, increase patient survival rates, and improve the quality of life of breast cancer patients.

关键词：乳腺癌;腺病毒;醛类;苄激进分子化学键;编码;基因治疗;高热;病毒

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关键词：细胞(生物学);脱氧核糖核的酸;前列腺癌;凋亡;克隆;药物

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The PT-304 study was prematurely terminated on October 1, 2012 primarily due to Precision receiving non-coverage forIn Vitro Chemosensitivity & Chemoresistance Asssays from Medicare. Additionally, our attempts to increase patient accrual throughout the duration of the study were unmet and ultimately the lack of subject recruitment negatively impacted the success of this study. A total of three-hundred-eighty-five (385) specimens were received by Precision accounting for both pre-treatment and post-treatment samples. Of the specimens received one-hundred-eighty-three (183) were terminated and one-hundred-twelve (112) were screen failures, the remaining two-hundred-two (202) specimens had drug assays completed of which the success rate following quality control was sixty percent. Three-hundred-twenty-seven (327) subjects were enrolled in the trial of which only one-hundred-thirty-four (134) were deemed evaluable. Upon notifying sites of the termination all active subjects were discontinued from participation. A total of thirty Principal Investigators were approved by the DoD to participate in this study, six investigator sites were prematurely closed prior to the termination of the study notification sent on October 1, 2012. Eleven additional sites have been officially closed with IRBs following the termination of the project and the remaining thirteen sites are in the process of closing. All sites are expected to be officially closed by the end of the calendar year with the Department of Defense.

关键词：腺癌;患者;治疗

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Vascular disruption agents (VDAs) have been shown to selectively destroy established tumor vasculature, which results in the ischemic death of up to 99of tumor cells. The weakness of VDA monotherapy is that it often leaves a rim of surviving tumor cells which can then regrow and spread. The overall goal of this study (addressed in Task 2) is to enhance VDA therapy by inducing hyperthermia, targeted to the neovascular endothelium, through the use of superparamagnetic iron oxide nanoparticles (SPIONs), in order to halt, or significantly slow down tumor growth. Therefore, the first aim of this study (Task 1) is to maximize the delivery of SPIONs to the tumor rim, through a combination of neovascular targeting and increased vascular permeability induced by the VDA. Covalent coupling of a primary amine on the antibody to a carboxyl on the SPIONs activated by EDC/Sulfo-NHS resulted in colloidally- stable particles that showed specific binding to VEGFR-2 expressing cells in vitro. Current in vivo results suggest a synergistic enhancement of SPION delivery to the tumor rim when VEGFR-2 targeting of PEG-coated particles and 15 min pre-administration of DMXAA (a VDA) are employed. The results suggest that the combination of targeting the neovasculature and increasing vascular permeability through the action of the VDA is an effective SPION delivery strategy. Quantitative chemical analysis of tumor samples are ongoing to obtain statistically-significant iron quantitation. In vitro testing of SPION heating in the presence of an alternating magnetic field has been successful and demonstrates that heating is optimized using 20 nm SPIONs. However, in vivo testing of hyperthermia therapy in mice receiving targeted SPIONs after DMXAA pre-treatment is currently on hold, pending a solution to the problem of poor long-term survival of the mice after DMXAA administration.

关键词：乳腺癌;铁氧化物;磁场;转移;纳米粒子;胺类;抗体;血管;心血管系统

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关键词：位置依赖性;体位;折叠,侧卧位睡眠呼吸障碍

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There is no cure for metastatic breast cancer, which kills 40,000 American women (and 500 men) each year: all presently available treatments are palliative. Gene therapy techniques are used to introduce chimeric immunoglobulin-T cell receptors (IgTCR) into autologous patient T cells to create designer T cells that redirect the T cell immune system in a new type of immuno-gene therapy against breast cancer. Designer T cells have been created against the carcinoembryonic antigen (CEA) that is prominently present on many metastatic breast tumors (30-60). This exceeds the fraction that are Her2/neu overexpressing (20-25), making CEA an even better immune target for attacking breast cancer. Building on a prior study of CEA designer T cells in breast and colon cancer, 2nd generation designer T cells were created by incorporating into the IgTCR a CD28 co-stimulation cassette that was shown to oppose activation-induced cell death (AICD) of the T cells after tumor contact. This advanced generation modification leads to improved designer T cell survival and improved anti-tumor potency in preclinical models. Although the 2nd generation designer T cells produce interleukin 2 (IL2) growth factor on contact with tumor, interleukin 2 (IL2) supplementation is anticipated still to be required for optimal clinical therapeutic effect. However, the CBER/FDA has mandated a Phase I.

关键词：(生物学);乳腺癌;细胞临床医学;结肠癌

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Proton beam radiotherapy is a form of external beam radiation that offers better precision for localized dosage than other types of external beam radiotherapy. Because proton beams deposit most of their energy during the final portion of their trajectory, they diminish the risk of damage to tissue surrounding the tumor and thus allow for higher treatment doses with fewer side effects. Proton beam radiotherapy has been used in research applications since the 1950s and entered clinical practice in the United States in 1990. No randomized controlled trials and only a few well-conducted cohort studies have compared proton beam radiation to other treatments. In the absence of evidence of clinical superiority, proton beam radiotherapy has gained acceptance based on a theoretical advantage for the treatment of specific cancers.

关键词：放射治疗,质子束流;辐射剂量;癌症;临床医学;医疗;肿瘤;治疗;医疗保险

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The continued increase in expenditures for prescribed medicines persists as a concern for both consumers of health care and policymakers. Prescribed drugs are commonly used to treat mental health disorders; and the Affordable Care Act will expand mental health insurance coverage. This Statistical Brief presents estimates based on the 2009 Household Component of the Medical Expenditure Panel Survey (MEPS-HC) on use and expenses for the therapeutic class of prescribed psychotherapeutic agents and its subclasses: antidepressants and antipsychotics. The Brief provides estimates on the number of persons with at least one prescription drug purchase by age and gender, the number of prescriptions, total and out-of-pocket expenses, as well as average expenditures per person. Estimates in this Brief are based on reports of prescribed medicines purchased or received during the year. Medications administered only as part of ambulatory visits or inpatient stays are not included. Two prior Statistical Briefs, 357 and 358, present estimates of expenditures for prescribed medicines to treat mental health disorders in children (5-17 years old) and young adults (18-26 years old). All differences between estimates noted in the text are statistically significant at the 0.05 level or better.

关键词：卫生保健支出;处方药;心理;成年人;年龄;抗抑郁药

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The patient was an obese male in his 60s who presented to the facility's emergency department in May 2010 complaining of worsening shortness of breath. He presented with a low-grade fever and an oxygen saturation of 85 percent on room air. Per the patient's report, an outside facility had treated him for pneumonia 3 days prior; however, he reported feeling worse. He denied any significant past medical history, and no information was available in his EHR because he received his care at non-VA facilities. While in the emergency department, the patient was started on antibiotics and placed on supplemental oxygen via nasal cannula, which increased his oxygen saturation to 98 percent. He was admitted to the telemetry unit for treatment of pneumonia. The plan of care included antibiotics, bronchodilators, and oxygen therapy. On admission to the telemetry unit, a RN noted that the patient had labored breathing. On the morning of the first hospital day, a respiratory therapist (RT) administered a breathing treatment, noted the patient's decrease in oxygen saturation, and increased his supplemental oxygen. Shortly after administering the breathing treatment, the RT noted another decrease in the patient's oxygen saturation and placed him on a high flow nasal cannula. Throughout the day, the RT administered breathing treatments as scheduled and increased supplemental oxygen as necessary, per the physician's order. The patient's oxygen saturation continued to decrease, and the patient was placed on a Venturi mask. On the second hospital day, an RN noted that the patient had crackles (abnormal breath sounds caused by fluid in the lungs) in his upper chest. The patient's oxygen saturation continued to decrease and he was placed on a non-rebreather mask. In the evening, the RT attempted to administer another breathing treatment; however, the patient refused. The night RN noted coarse breath sounds and an oxygen saturation of 88 percent on the non-rebreather mask. The patients oxygen saturation continued to decrease further, and the RN notified the medical officer of the day (MOD). The MOD ordered an arterial blood gas and intravenous furosemide. The night RN noted the patients oxygen saturation was 90 percent. In the early morning hours of the third hospital day, the patient had an unwitnessed fall and was found face down in the bathroom. A nurse noted that he was cyanotic and had agonal respiration, with palpable pulse. A code was called, and the MOD responded and attempted endotracheal (ET) intubation unsuccessfully. The patient was then transferred to the intensive care unit accompanied by the MOD, the nursing supervisor on duty (NOD), and the RT. The NOD performed ET intubation and correct placement was confirmed by the MOD, who checked for the presence of exhaled carbon dioxide. Efforts at resuscitation were unsuccessful, and at 3:50 a.m., the patient was pronounced dead.

关键词：卫生保健;检验;临床医学;退伍军人(军人);气道管理

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