Harnessing Naturally Occurring Tumor Immunity: A Clinical Vaccine Trial in Prostate Cancer

International audienceBACKGROUND:Studies of patients with paraneoplastic neurologic disorders (PND) have revealed that apoptotic tumor serves as a potential potent trigger for the initiation of naturally occurring tumor immunity. The purpose of this study was to assess the feasibility, safety, and immunogenicity of an apoptotic tumor-autologous dendritic cell (DC) vaccine.METHODS AND FINDINGS:We have modeled PND tumor immunity in a clinical trial in which apoptotic allogeneic prostate tumor cells were used to generate an apoptotic tumor-autologous dendritic cell vaccine. Twenty-four prostate cancer patients were immunized in a Phase I, randomized, single-blind, placebo-controlled study to assess the safety and immunogenicity of this vaccine. Vaccinations were safe and well tolerated. Importantly, we also found that the vaccine was immunogenic, inducing delayed type hypersensitivity (DTH) responses and CD4+ and CD8+ T cell proliferation, with no effect on FoxP3+ regulatory T cells. A statistically significant increase in T cell proliferation responses to prostate tumor cells in vitro (p = 0.002), decrease in prostate specific antigen (PSA) slope (p = 0.016), and a two-fold increase in PSA doubling time (p = 0.003) were identified when we compared data before and after vaccination.CONCLUSIONS:An apoptotic cancer cell vaccine modeled on naturally occurring tumor immune responses in PND patients provides a safe and immunogenic tumor vaccine

Analisis Risiko Pelayanan Pasien Lama Terhadap Penyakit Diabetes Melitus Tipe 2 (Studi Kasus : RS Yadika Pondok Bambu Jakarta Timur)

Manajemen Risiko merupakan aktivitas manajemen didalam mempersiapkan strategi untuk merespon risiko atau kejadian yang tidak diinginkan muncul. RS Yadika Pondok Bambu dalam menjalankan kegiatan bisnis pelayanan Rumah sakit akan melewati tahapan didalam proses bisnis pelayanan Rumah sakit yaitu pendaftaran, pemeriksaan Pasien di ruang tunggu poliklinik Penyakit dalam,ketidakmampuan mendiagnosa pasien DM Type 2 dan Terapi. Penelitian ini menggunakan tahapan manajemen risiko yang dimulai dari Identifikas risiko disetiap tahapan proses bisnis penjualan perumahan dengan menggunakan diagram fishbone didapati ada 10 item risiko dari setiap tahapan yang terbagi dari 2 item risiko di tahapan pendaftaran, 3 item pemeriksaan Pasien di ruang tunggu poli Penyakit dalam, 2 item risiko ketidakmampuan mendiagnosa pasien DM Type 2 dan 3 item risiko di Terapi. Kemudian dilanjutkan dengan mengukur risiko dengan menghitung peluang dan dampak dari risiko tersebut dan dengan tabel Heat Map hasil perkalian antara peluang dan dampak dari risiko – risiko di setiap tahapan proses bisnis pelayanan Rumah Sakit diketahui bahwa nilai Risk Assesment Matrik berada dalam kategori tinggi dan sangat tinggi. Dan diakhiri dengan menggunakan diagram Treshold of Risk Level diketahui tekhnik pengelolaan risiko yaitu dengan Avoidance atau menghindari risiko tersebut yang dipergunakan merancang strategi untuk merespon risiko. Dan dari penelitian ini diperoleh strategi respon risiko untuk tahapan pendaftaran adalah sebelum melakukan pelayanan kepada pasien, Rumah sakit harus terlebih dahulu melakukan survey secara langsung dan teliti, komunikasi dan koordinasi dengan semua pihak pelayanan medis, penunjang medik, medical record dan Apoteker serta sosialisasi secara resmi serta transparan informasi sesuai prosedur yang berlaku kepada semua dokter Spesialis penyakit dalam dan pihak lain. Tahapan kedua yaitu pemeriksaan Pasien di ruang tunggu poliklinik Penyakit dalam dengan strategi respon risiko adalah mengkaji ulangruang tunggu yang sesuai dengan standart yang berlaku, pemeriksaan dasar yang sesuai dan ruang periksa yang sesuai dengan standar yang berlaku. Strategi Respon risiko tahapan keidakmampuan mendiagnosa penyakit DM type 2 adalah koordinasi dengan pihak dokter spesialis penyakit dalam agar memeriksa pasien sesuai dengan standar operasional prosedur (SOP) yang berlaku serta koordinasi dengan kepala penunjang medic untuk menyediakan pemeriksaan penunjang. Dan untuk tahapan terapi respon risikonya adalah perlu koordinasi antara apoteker dengan dokter spesialis penyakit dalam serta pasien dalam menyedikan terapi yang dibutuhkan. Kata kunci : manajemen risiko, proses bisnis, strategi respon risik

The specialty choices of graduates from Brighton and Sussex Medical School: a longitudinal cohort study

BACKGROUND Since 2007 junior doctors in the UK have had to make major career decisions at a point when previously many had not yet chosen a specialty. This study examined when doctors in this new system make specialty choices, which factors influence choices, and whether doctors who choose a specialty they were interested in at medical school are more confident in their choice than those doctors whose interests change post-graduation. METHODS Two cohorts of students in their penultimate year at one medical school (n = 227/239) were asked which specialty interested them as a career. Two years later, 210/227 were sent a questionnaire measuring actual specialty chosen, confidence, influence of perceptions of the specialty and experiences on choice, satisfaction with medicine, personality, self-efficacy, and demographics. Medical school and post-graduation choices in the same category were deemed 'stable'. Predictors of stability, and of not having chosen a specialty, were calculated using bootstrapped logistic regression. Differences between specialties on questionnaire factors were analysed. RESULTS 50% responded (n = 105/277; 44% of the 239 Year 4 students). 65% specialty choices were 'stable'. Factors univariately associated with stability were specialty chosen, having enjoyed the specialty at medical school or since starting work, having first considered the specialty earlier. A regression found doctors who chose psychiatry were more likely to have changed choice than those who chose general practice. Confidence in the choice was not associated with stability. Those who chose general practice valued lifestyle factors. A psychiatry choice was associated with needing a job and using one's intellect to help others. The decision to choose surgical training tended to be made early. Not having applied for specialty training was associated with being lower on agreeableness and conscientiousness. CONCLUSION Medical school experiences are important in specialty choice but experiences post-graduation remain significant, particularly in some specialties (psychiatry in our sample). Career guidance is important at medical school and should be continued post-graduation, with senior clinicians supported in advising juniors. Careers advice in the first year post-graduation may be particularly important, especially for specialties which have difficulty recruiting or are poorly represented at medical school

Cross-priming of cyclin B1, MUC-1 and survivin-specific CD8(+ )T cells by dendritic cells loaded with killed allogeneic breast cancer cells

INTRODUCTION: The ability of dendritic cells (DCs) to take up whole tumor cells and process their antigens for presentation to T cells ('cross-priming') is an important mechanism for induction of tumor specific immunity. METHODS: In vitro generated DCs were loaded with killed allogeneic breast cancer cells and offered to autologous naïve CD8(+ )T cells in 2-week and/or 3-week cultures. CD8(+ )T cell differentiation was measured by their capacity to secrete effector cytokines (interferon-γ) and kill breast cancer cells. Specificity was measured using peptides derived from defined breast cancer antigens. RESULTS: We found that DCs loaded with killed breast cancer cells can prime naïve CD8(+ )T cells to differentiate into effector cytotoxic T lymphocytes (CTLs). Importantly, these CTLs primed by DCs loaded with killed HLA-A*0201(- )breast cancer cells can kill HLA-A*0201(+ )breast cancer cells. Among the tumor specific CTLs, we found that CTLs specific for HLA-A2 restricted peptides derived from three well known shared breast tumor antigens, namely cyclin B1, MUC-1 and survivin. CONCLUSION: This ability of DCs loaded with killed allogeneic breast cancer cells to elicit multiantigen specific immunity supports their use as vaccines in patients with breast cancer

Design of a combinatorial DNA microarray for protein-DNA interaction studies

BACKGROUND: Discovery of precise specificity of transcription factors is an important step on the way to understanding the complex mechanisms of gene regulation in eukaryotes. Recently, double-stranded protein-binding microarrays were developed as a potentially scalable approach to tackle transcription factor binding site identification. RESULTS: Here we present an algorithmic approach to experimental design of a microarray that allows for testing full specificity of a transcription factor binding to all possible DNA binding sites of a given length, with optimally efficient use of the array. This design is universal, works for any factor that binds a sequence motif and is not species-specific. Furthermore, simulation results show that data produced with the designed arrays is easier to analyze and would result in more precise identification of binding sites. CONCLUSION: In this study, we present a design of a double stranded DNA microarray for protein-DNA interaction studies and show that our algorithm allows optimally efficient use of the arrays for this purpose. We believe such a design will prove useful for transcription factor binding site identification and other biological problems

Arsenic exposure and outcomes of antimonial treatment in visceral leishmaniasis patients in bihar, India:a retrospective cohort study

Funding: This work was supported by a Clinical PhD Fellowship to MRP (090665) and a Principal Research Fellowship to AHF (079838) from the Wellcome Trust (http://www.wellcome.ac.uk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Natural killer cells attenuate cytomegalovirus-induced hearing loss in mice

<div><p>Congenital cytomegalovirus (CMV) infection is the most common non-hereditary cause of sensorineural hearing loss (SNHL) yet the mechanisms of hearing loss remain obscure. Natural Killer (NK) cells play a critical role in regulating murine CMV infection via NK cell recognition of the Ly49H cell surface receptor of the viral-encoded m157 ligand expressed at the infected cell surface. This Ly49H NK receptor/m157 ligand interaction has been found to mediate host resistance to CMV in the spleen, and lung, but is much less effective in the liver, so it is not known if this interaction is important in the context of SNHL. Using a murine model for CMV-induced labyrinthitis, we have demonstrated that the Ly49H/m157 interaction mediates host resistance in the temporal bone. BALB/c mice, which lack functional Ly49H, inoculated with mCMV at post-natal day 3 developed profound hearing loss and significant outer hair cell loss by 28 days of life. In contrast, C57BL/6 mice, competent for the Ly49H/m157 interaction, had minimal hearing loss and attenuated outer hair cell loss with the same mCMV dose. Administration of Ly49H blocking antibody or inoculation with a mCMV viral strain deleted for the m157 gene rendered the previously resistant C57BL/6 mouse strain susceptible to hearing loss to a similar extent as the BALB/c mouse strain indicating a direct role of the Ly49H/m157 interaction in mCMV-dependent hearing loss. Additionally, NK cell recruitment to sites of infection was evident in the temporal bone of inoculated susceptible mouse strains. These results demonstrate participation of NK cells in protection from CMV-induced labyrinthitis and SNHL in mice.</p></div

Dietary soy and meat proteins induce distinct physiological and gene expression changes in rats

This study reports on a comprehensive comparison of the effects of soy and meat proteins given at the recommended level on physiological markers of metabolic syndrome and the hepatic transcriptome. Male rats were fed semi-synthetic diets for 1 wk that differed only regarding protein source, with casein serving as reference. Body weight gain and adipose tissue mass were significantly reduced by soy but not meat proteins. The insulin resistance index was improved by soy, and to a lesser extent by meat proteins. Liver triacylglycerol contents were reduced by both protein sources, which coincided with increased plasma triacylglycerol concentrations. Both soy and meat proteins changed plasma amino acid patterns. The expression of 1571 and 1369 genes were altered by soy and meat proteins respectively. Functional classification revealed that lipid, energy and amino acid metabolic pathways, as well as insulin signaling pathways were regulated differently by soy and meat proteins. Several transcriptional regulators, including NFE2L2, ATF4, Srebf1 and Rictor were identified as potential key upstream regulators. These results suggest that soy and meat proteins induce distinct physiological and gene expression responses in rats and provide novel evidence and suggestions for the health effects of different protein sources in human diets

Simulating hemispatial neglect with virtual reality

<p>Abstract</p> <p>Background</p> <p>Hemispatial neglect is a cognitive disorder defined as a lack of attention for stimuli contra-lateral to the brain lesion. The assessment is traditionally done with basic pencil and paper tests and the rehabilitation programs are generally not well adapted. We propose a virtual reality system featuring an eye-tracking device for a better characterization of the neglect that will lead to new rehabilitation techniques.</p> <p>Methods</p> <p>This paper presents a comparison of eye-gaze patterns of healthy subjects, patients and healthy simulated patients on a virtual line bisection test. The task was also executed with a reduced visual field condition hoping that fewer stimuli would limit the neglect.</p> <p>Results</p> <p>We found that patients and healthy simulated patients had similar eye-gaze patterns. However, while the reduced visual field condition had no effect on the healthy simulated patients, it actually had a negative impact on the patients. We discuss the reasons for these differences and how they relate to the limitations of the neglect simulation.</p> <p>Conclusion</p> <p>We argue that with some improvements the technique could be used to determine the potential of new rehabilitation techniques and also help the rehabilitation staff or the patient's relatives to better understand the neglect condition.</p