Metastatic model of HPV+ oropharyngeal squamous cell carcinoma demonstrates heterogeneity in tumor metastasis

Human papillomavirus induced (HPV+) cancer incidence is rapidly rising, comprising 60–80% of oropharyngeal squamous cell carcinomas (OPSCCs); while rare, recurrent/metastatic disease accounts for nearly all related deaths. An in vivo pre-clinical model for these invasive cancers is necessary for testing new therapies. We characterize an immune competent recurrent/metastatic HPV+ murine model of OPSSC which consists of four lung metastatic (MLM) cell lines isolated from an animal with HPV+ OPSCC that failed cisplatin/radiation treatment. These individual metastatic clonal cell lines were tested to verify their origin (parental transgene expression and define their physiological properties: proliferation, metastatic potential, heterogeneity and sensitivity/resistance to cisplatin and radiation. All MLMs retain expression of parental HPV16 E6 and E7 and degrade P53 yet are heterogeneous from one another and from the parental cell line as defined by Illumina expression microarray. Consistent with this, reverse phase protein array defines differences in protein expression/activation between MLMs as well as the parental line. While in vitro growth rates of MLMs are slower than the parental line, in vivo growth of MLM clones is greatly enhanced. Moreover, in vivo resistance to standard therapies is dramatically increased in 3 of the 4 MLMs. Lymphatic and/or lung metastasis occurs 100% of the time in one MLM line. This recurrent/metastatic model of HPV+ OPSCC retains the characteristics evident in refractory human disease (heterogeneity, resistance to therapy, metastasis in lymph nodes/lungs) thus serving as an ideal translational system to test novel therapeutics. Moreover, this system may provide insights into the molecular mechanisms of metastasis

Beyond deficiency:Potential benefits of increased intakesof vitamin K for bone and vascular health

Vitamin K is wellknown for its role in the synthesisof a number of blood coagulationfactors.During recent years vitaminK-dependent proteins werediscovered to be of vital importancefor bone and vascular health.Recommendations for dietary vitaminK intake have been made onthe basis of the hepatic requirementsfor the synthesis of bloodcoagulation factors.Accumulatingevidence suggests that the requirementsfor other functions thanblood coagulation may be higher.This paper is the result of a closedworkshop (Paris,November 2002)in which a number of Europeanvitamin K experts reviewed theavailable data and formulated theirstandpoint with respect to recommendeddietary vitamin K intakeand the use of vitamin K-containingsupplements

The consistency of care for older patients with a hip fracture:are the results of the integrated orthogeriatric treatment model of the Centre of Geriatric Traumatology consistent 10 years after implementation?

Summary: In the past 10 years after implementation, the orthogeriatric treatment model led in general to consistent outcomes for 1555 older adults in terms of most of the complications and mortality. Surgery was more often delayed to 24–48 h after arrival at the hospital, while the length of hospital stay shortened. Introduction: Since 1 April 2008, patients aged ≥ 70 years presenting themselves with a hip fracture at Ziekenhuisgroep Twente (ZGT) have been treated according to the orthogeriatric treatment model. The aim of this study was to investigate if outcomes of the orthogeriatric treatment model are consistent over the first 10 years after implementation. Methods: Between 1 April 2008 and 31 December 2016, patients aged ≥ 70 years who were surgically treated at ZGT for a hip fracture were included and divided into three periods equally distributed in time. Patient characteristics, in-hospital logistics, complications, and mortality data were compared between the three periods. Results: A total of 1555 patients were included. There was a shift in the surgical treatment for the fractured neck of femur from dynamic hip screw/cannulated screws to hemiarthroplasty (p < 0.001). Surgery within 24 h after arrival to the hospital decreased (p < 0.001), while surgery within 48 h stayed the same (p = 0.085). Length of hospital stay significantly decreased over time (p < 0.001). Complication rates were consistent except for the number of postoperative anemia, delirium, and urinary tract infections. Mortality rates did not change over the years. Conclusions: The orthogeriatric treatment model leads in general to consistent outcomes concerning mortality and most of the complications, except for postoperative anemia, delirium, and urinary tract infections. Inconsistent complication rates were influenced by altered diagnosis and treatment protocols. Length of hospital stay reduced, while time to surgery was more often delayed to 24–48 h. Monitoring clinical outcomes of the orthogeriatric treatment model over time is recommended in order to optimize and maintain the quality of care for this frail patient population

Small portion sizes in worksite cafeterias: do they help consumers to reduce their food intake?

Background:Environmental interventions directed at portion size might help consumers to reduce their food intake.Objective:To assess whether offering a smaller hot meal, in addition to the existing size, stimulates people to replace their large meal with a smaller meal.Design:Longitudinal randomized controlled trial assessing the impact of introducing small portion sizes and pricing strategies on consumer choices.Setting/participants:In all, 25 worksite cafeterias and a panel consisting of 308 consumers (mean age39.18 years, 50% women).Intervention:A small portion size of hot meals was offered in addition to the existing size. The meals were either proportionally priced (that is, the price per gram was comparable regardless of the size) or value size pricing was employed.Main outcome measures:Daily sales of small and the total number of meals, consumers self-reported compensation behavior and frequency of purchasing small meals.Results:The ratio of small meals sales in relation to large meals sales was 10.2%. No effect of proportional pricing was found B0.11 (0.33), P0.74, confidence interval (CI): 0.76 to 0.54). The consumer data indicated that 19.5% of the participants who had selected a small meal often-to-always purchased more products than usual in the worksite cafeteria. Small meal purchases were negatively related to being male (B0.85 (0.20), P0.00, CI: 1.24 to 0.46, n178).Conclusion:When offering a small meal in addition to the existing size, a percentage of consumers that is considered reasonable were inclined to replace the large meal with the small meal. Proportional prices did not have an additional effect. The possible occurrence of compensation behavior is an issue that merits further attention. © 2011 Macmillan Publishers Limited All rights reserved

Associative Learning Contributes to the Persistence of Fatigue-Like Behavior in Male Mice in a Model of Cancer Survivorship

Persistent fatigue is a debilitating side effect that impacts a significant proportion of cancer survivors for which there is not yet an FDA-approved treatment. While certainly a multi-factorial problem, persistent fatigue could be due, in part, to associations learned during treatment. Therefore, we sought to investigate the role of associative learning in the persistence of fatigue using a preclinical model of cancer survivorship. For this purpose, we used a murine model of human papilloma virus-related head and neck cancer paired with a curative regimen of cisplatin-based chemoradiation in male C57BL/6J mice. Fatigue-like behavior was assessed by measuring variations in voluntary wheel running using a longitudinal design. Treatment robustly decreased voluntary wheel running, and this effect persisted for more than a month posttreatment. However, when wheels were removed during treatment, to minimize treatment-related fatigue, mice showed a more rapid return to baseline running levels. We confirmed that the delayed recovery observed in mice with continual wheel access was not due to increased treatment-related toxicity, in fact running attenuated cisplatin-induced kidney toxicity. Finally, we demonstrated that re-exposure to a treatment-related olfactory cue acutely re-instated fatigue. These data provide the first demonstration that associative processes can modulate the persistence of cancer-related fatigue-like behavior

Role of RhoA and rho kinase in lysophosphatidic acid-induced endothelial barrier dysfunction.

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