Therapeutic efficacy of a synthetic epsin mimetic peptide in glioma tumor model: uncovering multiple mechanisms beyond the VEGF-associated tumor angiogenesis

Abstract

Binding of epsin ubiquitin-interacting motif (UIM) with ubiquitylated VEGFR2 is a critical mechanism for epsin-dependent VEGFR2 endocytosis and physiological angiogenesis. Deletion of epsins in vessel endothelium produces uncontrolled tumor angiogenesis and retards tumor growth in animal models. The aim of this study is to test the therapeutic efficacy and targeting specificity of a chemically-synthesized peptide, UPI, which compete for epsin binding sites in VEGFR2 and potentially inhibits Epsin-VEGFR2 interaction in vivo, in an attempt to reproduce an epsin-deficient phenotype in tumor angiogenesis. Our data show that UPI treatment significantly inhibits and shrinks tumor growth in GL261 glioma tumor model. UPI peptide specifically targets VEGFR2 signaling pathway revealed by genetic and biochemical approaches. Furthermore, we demonstrated that UPI peptide treatment caused serious thrombosis in tumor vessels and damages tumor cells after a long-term UPI peptide administration. Besides, we revealed that UPI peptides were unexpectedly targeted cancer cells and induced apoptosis. We conclude that UPI peptide is a potent inhibitor to glioma tumor growth through specific targeting of VEGFR2 signaling in the tumor vasculature and cancer cells, which may offer a potentially novel treatment for cancer patients who are resistant to current anti-VEGF therapies.

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Therapeutic efficacy of a synthetic epsin mimetic peptide in glioma tumor model: uncovering multiple mechanisms beyond the VEGF-associated tumor angiogenesis

Abstract

Binding of epsin ubiquitin-interacting motif (UIM) with ubiquitylated VEGFR2 is a critical mechanism for epsin-dependent VEGFR2 endocytosis and physiological angiogenesis. Deletion of epsins in vessel endothelium produces uncontrolled tumor angiogenesis and retards tumor growth in animal models. The aim of this study is to test the therapeutic efficacy and targeting specificity of a chemically-synthesized peptide, UPI, which compete for epsin binding sites in VEGFR2 and potentially inhibits Epsin-VEGFR2 interaction in vivo, in an attempt to reproduce an epsin-deficient phenotype in tumor angiogenesis. Our data show that UPI treatment significantly inhibits and shrinks tumor growth in GL261 glioma tumor model. UPI peptide specifically targets VEGFR2 signaling pathway revealed by genetic and biochemical approaches. Furthermore, we demonstrated that UPI peptide treatment caused serious thrombosis in tumor vessels and damages tumor cells after a long-term UPI peptide administration. Besides, we revealed that UPI peptides were unexpectedly targeted cancer cells and induced apoptosis. We conclude that UPI peptide is a potent inhibitor to glioma tumor growth through specific targeting of VEGFR2 signaling in the tumor vasculature and cancer cells, which may offer a potentially novel treatment for cancer patients who are resistant to current anti-VEGF therapies.

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Occupational radiation exposure and thyroid cancer incidence in a cohort of U.S. radiologic technologists, 1983-2013

Abstract

Although childhood exposure to ionizing radiation is a well-established risk factor for thyroid cancer, the risk associated with adulthood exposure remains unclear. We prospectively examined the association between cumulative, low-to-moderate dose occupational radiation exposure to the thyroid and thyroid cancer incidence in the U.S. Radiologic Technologists cohort. The study included 89,897 members who completed at least two of four mailed questionnaires and were cancer-free at the time of the first questionnaire. Cumulative occupational thyroid radiation dose (mean=57 mGy, range=0-1,600 mGy) was estimated based on self-reported work histories, historical data, and, during the years 1960 to 1997, 783,000 individual film badge measurements. During follow-up, we identified 476 thyroid cancer cases. We used Poisson regression to estimate excess relative risk of thyroid cancer per 100 milliGray (ERR/100 mGy) absorbed dose to the thyroid gland. After adjusting for attained age, sex, birth year, body mass index, and pack-years smoked, we found no association between thyroid dose and thyroid cancer risk (ERR/100 mGy= -0.05, 95% CI <-0.10, 0.34). In this large cohort study of radiologic technologists, protracted, low-to-moderate dose ionizing radiation exposure to the thyroid gland in adulthood was not associated with an increased risk of thyroid cancer. This article is protected by copyright. All rights reserved.

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Dietary Consumption of Antioxidant Vitamins and Subsequent Lung Cancer Risk: The Japan Public Health Center-based Prospective Study

Abstract

While many epidemiological studies have studied the association between lung cancer risk and fruits and vegetable consumption, the major sources of antioxidant vitamins, only a few have investigated the direct association with antioxidants in consideration of cancer subtypes and smoking status. Here, we examined the association between consumption of antioxidant vitamins and lung cancer risk in one of the largest prospective cohort studies in Japan. We investigated the association of dietary antioxidant vitamins intake, namely retinol, vitamin C, vitamin E, α-carotene, and β-carotene, and subsequent incidence of lung cancer among 38,207 men and 41,498 women in the Japan Public Health Center-based Prospective Study. Cox proportional hazard regression was performed with adjustment for potential confounders and by strata of cancer subtypes and smoking status. Antioxidant and other dietary intakes were assessed using a food frequency questionnaire (FFQ). During 1,233,096 person-years of follow-up between 1995 and 2013, a total of 1,690 lung cancer cases were newly diagnosed. In a multivariate regression model, while higher retinol intake was positively associated with overall lung cancer risk in men (HR 1.26; 95% CI 1.05-1.51; p_trend 0.003), the estimates were more evident with small cell carcinoma (HR 1.92; 95% CI 1.13-3.24; p_trend <0.001). Null associations were observed for other antioxidant vitamins. Our prospective study suggests that higher consumption of retinol may be associated with an increased risk of lung cancer in men, especially with small cell carcinoma, although confirmation is required. This article is protected by copyright. All rights reserved.

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Inflammatory potential of diet and risk of pancreatic cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial

Abstract

Inflammation plays a central role in pancreatic cancer etiology and can be modulated by diet. We aimed to examine the association between the inflammatory potential of diet, assessed with the Dietary Inflammatory Index (DII®), and pancreatic cancer risk in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial prospective cohort. Our study included 101,449 participants aged 52 to 78 years at baseline who completed both baseline questionnaire and a diet history questionnaire. Energy-adjusted DII (E-DII) scores were computed based on food and supplement intake. Cox proportional hazards models and time dependent Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with participants in the lowest E-DII quintile (most anti-inflammatory scores) as referent. After a median 8.5 years of follow-up, 328 pancreatic cancer cases were identified. E-DII scores were not associated with pancreatic cancer risk in the multivariable model (HR_Q5vsQ1 =0.94; 95% CI=0.66-1.35; P-trend=0.43). Time significantly modified the association (P-interaction=0.01). During follow up <4 years, there was suggestive evidence of an inverse association between E-DII and pancreatic cancer (HR_Q5vsQ1=0.60; 95% CI=0.35-1.02; P-trend=0.20) while there was a significant positive trend in the follow up ≥4 years (HR_Q5vsQ1 =1.31; 95% CI=0.83-2.08; P-trend=0.03). Similar results were observed for E-DII from food only. Our study does not support an association between inflammatory potential of diet and pancreatic cancer risk; however, heterogeneous results were obtained with different follow-up times. These divergent associations may result from the influences of undetected disease in the short-term. This article is protected by copyright. All rights reserved.

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Clinical evidence of prevention strategies for capecitabine-induced hand-foot syndrome

Abstract

Hand-foot syndrome (HFS) is the most common adverse effect of capecitabine-containing chemotherapy. The purpose of this study was to assess the efficacies of various prevention and treatment strategies for capecitabine-induced HFS. Searches of the PubMed and Embase databases were performed to identify relevant studies. The risk ratio (RR) with the corresponding 95% confidence interval (CI) was used as an effect measure to evaluate the efficacies of these prevention and treatment strategies. Publication bias was evaluated using Begg's and Egger's tests. Overall and subgroup analyses were conducted. All statistical analyses were conducted with Stata software version 12.0. Seventeen eligible studies were included. Our results indicated that celecoxib was significantly associated with a lower incidence of grade ≥2 capecitabine-induced HFS without heterogeneity (RR=0.43, 95% CI=0.23–0.81, I²=0.0%). However, pyridoxine and topical urea/lactic acid were not effective toward preventing capecitabine-induced grade 1, 2, 3, ≥1, or ≥2 HFS. Moreover, pyridoxine was not effective in treating capecitabine-induced HFS. Similar results were obtained by subgroup analysis. Our results indicate that celecoxib has potential prophylactic efficacy for capecitabine-induced HFS. However, pyridoxine and topical urea/lactic acid are not associated with a decrease in the incidence of capecitabine-induced HFS. This article is protected by copyright. All rights reserved.

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Occupational radiation exposure and thyroid cancer incidence in a cohort of U.S. radiologic technologists, 1983-2013

Abstract

Although childhood exposure to ionizing radiation is a well-established risk factor for thyroid cancer, the risk associated with adulthood exposure remains unclear. We prospectively examined the association between cumulative, low-to-moderate dose occupational radiation exposure to the thyroid and thyroid cancer incidence in the U.S. Radiologic Technologists cohort. The study included 89,897 members who completed at least two of four mailed questionnaires and were cancer-free at the time of the first questionnaire. Cumulative occupational thyroid radiation dose (mean=57 mGy, range=0-1,600 mGy) was estimated based on self-reported work histories, historical data, and, during the years 1960 to 1997, 783,000 individual film badge measurements. During follow-up, we identified 476 thyroid cancer cases. We used Poisson regression to estimate excess relative risk of thyroid cancer per 100 milliGray (ERR/100 mGy) absorbed dose to the thyroid gland. After adjusting for attained age, sex, birth year, body mass index, and pack-years smoked, we found no association between thyroid dose and thyroid cancer risk (ERR/100 mGy= -0.05, 95% CI <-0.10, 0.34). In this large cohort study of radiologic technologists, protracted, low-to-moderate dose ionizing radiation exposure to the thyroid gland in adulthood was not associated with an increased risk of thyroid cancer. This article is protected by copyright. All rights reserved.

http://ift.tt/2mZ6KjQ