Phase II prospective randomized trial of weight loss prior to radical prostatectomy.

BACKGROUND:Obesity is associated with poorly differentiated and advanced prostate cancer and increased mortality. In preclinical models, caloric restriction delays prostate cancer progression and prolongs survival. We sought to determine if weight loss (WL) in men with prostate cancer prior to radical prostatectomy affects tumor apoptosis and proliferation, and if WL effects other metabolic biomarkers. METHODS:In this Phase II prospective trial, overweight and obese men scheduled for radical prostatectomy were randomized to a 5-8 week WL program consisting of standard structured energy-restricted meal plans (1200-1500 Kcal/day) and physical activity or to a control group. The primary endpoint was apoptotic index in the radical prostatectomy malignant epithelium. Secondary endpoints were proliferation (Ki67) in the radical prostatectomy tissue, body weight, body mass index (BMI), waist to hip ratio, body composition, and serum PSA, insulin, triglyceride, cholesterol, testosterone, estradiol, leptin, adiponectin, interleukin 6, interleukin 8, insulin-like growth factor 1, and IGF binding protein 1. RESULTS:In total 23 patients were randomized to the WL intervention and 21 patients to the control group. Subjects in the intervention group had significantly more weight loss (WL:-3.7 ± 0.5 kg; Control:-1.6 ± 0.5 kg; p = 0.007) than the control group and total fat mass was significantly reduced (WL:-2.1 ± 0.4; Control: 0.1 ± 0.3; p = 0.015). There was no significant difference in apoptotic or proliferation index between the groups. Among the other biomarkers, triglyceride, and insulin levels were significantly decreased in the WL compared with the control group. CONCLUSIONS:In summary, this short-term WL program prior to radical prostatectomy resulted in significantly more WL in the intervention vs. the control group and was accompanied by significant reductions in body fat mass, circulating triglycerides, and insulin. However, no significant changes were observed in malignant epithelium apoptosis or proliferation. Future studies should consider a longer term or more intensive weight loss intervention

Effects of Calorie Restriction and IGF-1 Receptor Blockade on the Progression of 22Rv1 Prostate Cancer Xenografts

Calorie restriction (CR) inhibits prostate cancer progression, partially through modulation of the IGF axis. IGF-1 receptor (IGF-1R) blockade reduces prostate cancer xenograft growth. We hypothesized that combining calorie restriction with IGF-1R blockade would have an additive effect on prostate cancer growth. Severe combined immunodeficient mice were subcutaneously injected with 22Rv1 cells and randomized to: (1) Ad libitum feeding/intraperitoneal saline (Ad-lib); (2) Ad-lib/20 mg/kg twice weekly, intraperitoneal ganitumab [anti-IGF-1R antibody (Ad-lib/Ab)]; (3) 40% calorie restriction/intraperitoneal saline (CR); (4) CR/ intraperitoneal ganitumab, (CR/Ab). CR and ganitumab treatment were initiated one week after tumor injection. Euthanasia occurred 19 days post treatment. Results showed that CR alone decreased final tumor weight, plasma insulin and IGF-1 levels, and increased apoptosis. Ganitumab therapy alone reduced tumor growth but had no effect on final tumor weight. The combination therapy (CR/Ab) further decreased final tumor weight and proliferation, increased apoptosis in comparison to the Ad-lib group, and lowered plasma insulin levels relative to the Ad-lib and Ad-lib/Ab groups. Tumor AKT activation directly correlated with plasma IGF-1 levels. In conclusion, whereas ganitumab therapy modestly affected 22Rv1 tumor growth, combining IGF-1R blockade with calorie restriction resulted in a significant decrease in final tumor weight and improved metabolic profile

Etude des déterminants structuraux de la sécrétion, de la bioactivité et de la spécificité de la gonadotropine équine, eLH/CG, dans le but de développer de nouvelles molécules à activité gonadotrope

L'élaboration de nouvelles molécules à activité gonadotrope, utilisables en zootechnie, nécessite une étude détaillée des régions nécessaires à l'activité hormonale. Cela impose également le développement de systèmes de production permettant d'obtenir une hormone recombinante biologiquement active in vivo en quantité suffisante. Les gonadotropines sont constituées par l'association non-covalente de deux sous-unités distinctes : a et b La sous-unité b confère la spécificité hormonale de chaque dimère a / b. Au cours de ce travail de thèse, nous avons étudié le rôle de la région C-terminale (séquence b 90-149) de la sous-unité beLH/CG supposée contenir les déterminants LH et FSH des gonadotropines. Les travaux effectués montrent que contrairement à l'hCG, le pont disulfure b26-110 n'est pas nécessaire au maintien du dimère de la eLH/CG et de la pLH, ni à l'expression de leurs activités biologiques. Par contre, l'absence de ce pont disulfure diminue de 30% la sécrétion de l'hormone par les cellules COS7. La mutation du pont disulfure b26-110 provoque une rétention intracellulaire de l'hormone. L'effet de la mutation du pont 26-110 sur la sécrétion de l'hormone est aboli lorsque les deux sous-unités sont liées en une seule chaîne (monocaténaire baeLH/CG). Par des délétions progressives de la région C-terminale de la sous-unité , nous avons identifié deux régions impliquées dans la sécrétion de la eLH/CG : d'une part la région b132-149 et d'autre part la région b104-109. La délétion de la séquence b110-149 n'affecte pas les bio activités LH et FSH in vitro de la eLH/CG (dimérique et/ou monocaténaire). Par contre, la mutation de la région b104-109 en alanine induit une chute de 80% de l'activité FSH in vitro de l'hormone. Ces travaux montrent que la région C-terminale de la sous-unité joue un rôle dans les processus de maturation et de sécrétion de la eLH/CG et est impliquée dans le déterminisme de l'activité FSH. Dans le but de développer des systèmes de production appropriés à la synthèse d'hormone recombinante, nous avons tenté de produire une eLH/CG monocaténaire (baeLH/CG) par transgénèse dans le lait de lapine. Cette hormone est produite a raison de 21 mg/l dans le lait et présente les mêmes activités LH et FSH in vitro que la eCG naturelle. Par contre, la baeLH/CG ne présente pas d'activité biologique in vivo du fait de son élimination très rapide après injection.TOURS-BU Sciences Pharmacie (372612104) / SudocSudocFranceF

Racial And Socioeconomic Differences Affect Outcomes in Elderly Burn Patients

BackgroundRace and socioeconomic status influence outcomes for adult and pediatric burn patients, yet the impact of these factors on elderly patients (Medicare eligible, 65 years of age) remains unknown.MethodsData pooled from three verified burn centers from 2004 to 2014 were reviewed retrospectively. Age, race, gender, percent total body surface area (%TBSA) burn, mortality, length of stay (LOS), LOS per %TBSA burn, and zip code which provided Census data on race, poverty, and education levels within a community were collected. Data were analyzed using logistic and generalized linear models in SAS version 9.4 (SAS Institute, Cary, NC, USA).ResultsOur population was mainly Caucasian (63%), African American (18%), Hispanic (7.6%), and Asian (3.5%). Mean age was 76.3 ± 8.3 years, 52.5% were male. Mean %TBSA was 9 ± 13.8%; 15% of the patients sustained an inhalation injury. The mortality rate was 14.4%. Inhalation injury was significantly associated with mortality and discharge to a skilled nursing facility (SNF) (p < 0.05). Race was significantly associated with socioeconomic disparities and affected LOS/TBSA, but not discharge to SNF or mortality on univariate analysis. Poverty level, education level, and insurance status (others vs. public) independently predicted SNF discharge, while median income and insurance type independently predicted LOS/TBSA.ConclusionIn this elderly cohort, race did not predict standard markers of burn outcome (mortality and discharge to SNF). Socioeconomic status independently predicted LOS and discharge to SNF, suggesting a relationship between socioeconomic status and recovery from a burn injury. Better understanding of racial and socioeconomic disparities is necessary to provide equitable treatment of all patients

A Prospective Comparison of Frailty Scores and Fall Prediction in Acutely Injured Older Adults.

BackgroundElderly (65 and older) fall-related injuries are a significant cause of morbidity and mortality. Although frailty predicts poor outcomes in geriatric trauma, literature comparing frailty scoring systems remains limited. Herein, we evaluated which frailty scoring system best predicts falls over time in the elderly.Materials and methodsAcute surgical patients 65 y and older were enrolled and prospectively observed. Demographics and frailty, assessed using the FRAIL Scale, Trauma Specific Frailty Index (TSFI), and Canadian Frailty Scale (CSHA-CFS), were collected at enrollment and 3 mo intervals following discharge for 1 y. Surveys queried the total number and timing of falls. Changes in frailty over time were assessed by logistic regression and area under the curve (AUC).ResultsFifty-eight patients were enrolled. FRAIL Scale and CSHA-CFS scores did not change over time, but TSFI scores did (P ≤ 0.01). Worsening frailty was observed using TSFI at 6 (P ≤ 0.01) and 12 mo (P ≤ 0.01) relative to baseline. Mortality did not differ based on frailty using any frailty score. Increasing frailty scores and time postdischarge was associated with increased odds of a fall. AUC estimates with 95% CI were 0.72 [0.64, 0.80], 0.81 [0.74, 0.88], and 0.76 [0.68, 0.84] for the FRAIL Scale, TSFI, and CSHA-CFS, respectively.ConclusionsThe risk of falls postdischarge were associated with increased age, time postdischarge, and frailty in our population. No scale appeared to significantly outperform the other by AUC estimation. Further study on the longitudinal effects of frailty is warranted

Effect of a Low-Fat Fish Oil Diet on Proinflammatory Eicosanoids and Cell-Cycle Progression Score in Men Undergoing Radical Prostatectomy

We previously reported that a 4-6 week low-fat fish oil (LFFO) diet did not affect serum IGF-1 levels (primary outcome) but resulted in lower omega-6 to omega-3 fatty acid ratios in prostate tissue and lower prostate cancer proliferation (Ki67) as compared to a Western diet (WD). In this post-hoc analysis, the effect of the LFFO intervention on serum pro-inflammatory eicosanoids, LTB4 and 15(S)-HETE, and the cell cycle progression (CCP) score were investigated. Serum fatty acids and eicosanoids were measured by gas chromatography and ELISA. CCP score was determined by RT-PCR. Associations between serum eicosanoids, Ki67, and CCP score were evaluated using partial correlation analyses. BLT1 (LTB4 receptor) expression was determined in prostate cancer cell lines and prostatectomy specimens. Serum omega-6 fatty acids and 15(S)-HETE levels were significantly reduced, and serum omega-3 levels were increased in the LFFO group relative to the WD group, whereas there was no change in LTB4 levels. The CCP score was significantly lower in the LFFO compared to the WD group. The 15(S)-HETE change correlated with tissue Ki67 (R=0.48; p<0.01) but not with CCP score. The LTB4 change correlated with the CCP score (r=0.4; p=0.02) but not with Ki67. The LTB4 receptor BLT1 was detected in prostate cancer cell lines and human prostate cancer specimens. In conclusion, a LFFO diet resulted in decreased 15(S)-HETE levels and lower CCP score relative to a WD. Further studies are warranted to determine whether the LFFO diet anti-proliferative effects are mediated through the LTB4/BLT1 and 15(S)-HETE pathways