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

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

Evaluation of Outcomes Following Surgical Treatment of Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS), a chronic disease of the apocrine bearing skin causing induration, pain, draining sinuses, and subcutaneous abscesses, significantly impairs patients quality of life (QOL). Full-thickness excision followed by skin grafting of the involved area can be curative. Herein, we evaluated the impact of this surgical treatment on QOL and depression symptomatology. Adult patients (≥18 years) who consented to participate filled out the dermatology quality of life (DLQI) and the Patient History Questionnaire (PHQ-9) at consent and at 1, 6, and 12 months post-initial evaluation and surgery. Demographics, HS, admission, and operative information were collected. Sixteen patients were included. Subjects were mainly white (81.3 %) and female (56.3%) with a median age of 38.2 (Interquartile range: 34.2-54.5); 62.5% were obese (BMI= 39.7 [28.4-50.6]). Half of the subjects presented with HS in 2 or more areas. Six patients were still undergoing surgeries at 6 months. One-, six-, and 12-month follow-up surveys were obtained from 14, 11, and 8 subjects for DQLI and from 14, 9, and 5 subjects for PHQ9. DLQI scores significantly decreased at 6 months compared to baseline, which indicates QOL improvement (10 [4-20] vs 15.5 [12-21.8], P = .036). Although not significant, PHQ9 scores tended to decrease. For those with the worst disease, DLQI significantly decreased at both 6 (P = .049) and 12 months (P = .047) compared to baseline. Despite a small sample size, our data suggest that aggressive surgical treatment improves the QOL of HS patients. Further studies are warranted to confirm our findings

Fall injuries, associated deaths, and 30-day readmission for subsequent falls are increasing in the elderly US population: a query of the WHO mortality database and National Readmission Database from 2010 to 2014.

PurposeClinicians anecdotally noted that elderly patients who suffered from traumatic injuries (falls or other injuries) often re-present and are readmitted with fall injuries. Herein, we hypothesized that fall injuries and fall-related deaths and readmissions are increasing over time, and assessed whether the overall rates of death, hospital admission, and 30-day readmission due to falls increased from 2010 to 2014 in the elderly population (≥65) in the US.Patients and methodsThe WHO mortality database and the National Readmission Database (NRD) were queried to assess rates of deaths and hospital admissions and 30-day readmissions associated with fall injuries in the elderly population that presented with trauma. Descriptive statistics were obtained. The generalized linear mixed modeling (GLMM) framework was utilized to examine the relationship between fixed-effect predictor variables and the dichotomous outcome, indicating readmission within 30 days of previous discharge while accounting for hospital clustering with a random intercept.ResultsFall-related death increased by 1.4% from 2010 to 2014. Similarly, the hospital admission rate increased by 2% and was mainly associated with increased admission of elderly 65-74 years old. Approximately 55% of the fall patients were placed in nursing facilities in 2010, and this rate increased by 3% from 2010 to 2014. Thirty-day readmission rates for fall and trauma patients remained stable from 2010 to 2014. However, the rate of fall patients readmitted within 30 days for a subsequent fall increased from 15.6% to 17.4% between 2010 and 2014.ConclusionOur data indicate a steady increase in deaths and admissions for fall injuries in the elderly population. Strikingly, the incidence of readmission for a subsequent fall is increasing. With the aging population, this trend is likely to continue and highlights the need for elderly social support systems and fall prevention programs