Metabolic Rewiring by Loss of Sirt5 Promotes Kras-Induced Pancreatic Cancer Progression.

BACKGROUND & AIMS: SIRT5 plays pleiotropic roles via post-translational modifications, serving as a tumor suppressor, or an oncogene, in different tumors. However, the role SIRT5 plays in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) remains unknown. METHODS: Published datasets and tissue arrays with SIRT5 staining were used to investigate the clinical relevance of SIRT5 in PDAC. Furthermore, to define the role of SIRT5 in the carcinogenesis of PDAC, we generated autochthonous mouse models with conditional Sirt5 knockout. Moreover, to examine the mechanistic role of SIRT5 in PDAC carcinogenesis, SIRT5 was knocked down in PDAC cell lines and organoids, followed by metabolomics and proteomics studies. A novel SIRT5 activator was used for therapeutic studies in organoids and patient-derived xenografts. RESULTS: SIRT5 expression negatively regulated tumor cell proliferation and correlated with a favorable prognosis in patients with PDAC. Genetic ablation of Sirt5 in PDAC mouse models promoted acinar-to-ductal metaplasia, precursor lesions, and pancreatic tumorigenesis, resulting in poor survival. Mechanistically, SIRT5 loss enhanced glutamine and glutathione metabolism via acetylation-mediated activation of GOT1. A selective SIRT5 activator, MC3138, phenocopied the effects of SIRT5 overexpression and exhibited antitumor effects on human PDAC cells. MC3138 also diminished nucleotide pools, sensitizing human PDAC cell lines, organoids, and patient-derived xenografts to gemcitabine. CONCLUSIONS: Collectively, we identify SIRT5 as a key tumor suppressor in PDAC, whose loss promotes tumorigenesis through increased noncanonic use of glutamine via GOT1, and that SIRT5 activation is a novel therapeutic strategy to target PDAC.

Impact of a Mobile Phone Intervention to Reduce Sedentary Behavior in a Community Sample of Adults: A Quasi-Experimental Evaluation.

BACKGROUND: Greater time spent sedentary is linked with increased risk of breast, colorectal, ovarian, endometrial, and prostate cancers. Given steadily increasing rates of mobile phone ownership, mobile phone interventions may have the potential to broadly influence sedentary behavior across settings. OBJECTIVE: The purpose of this study was to examine the short-term impact of a mobile phone intervention that targeted sedentary time in a diverse community sample. METHODS: Adults participated in a quasi-experimental evaluation of a mobile phone intervention designed to reduce sedentary time through prompts to interrupt periods of sitting. Participants carried mobile phones and wore accelerometers for 7 consecutive days. Intervention participants additionally received mobile phone prompts during self-reported sitting and information about the negative health impact of prolonged sedentariness. The study was conducted from December 2012 to November 2013 in Dallas, Texas. Linear mixed model regression analyses were conducted to evaluate the influence of the intervention on daily accelerometer-determined estimates of sedentary and active time. RESULTS: Participants (N=215) were predominantly female (67.9%, 146/215) and nonwhite (black: 50.7%, 109/215; Latino: 12.1%, 26/215; other: 5.6%, 12/215). Analyses revealed that participants who received the mobile phone intervention had significantly fewer daily minutes of sedentary time (B=-22.09, P=.045) and more daily active minutes (B=23.01, P=.04) than control participants. CONCLUSIONS: A simple mobile phone intervention was associated with engaging in less sedentary time and more physical activity. Findings underscore the potential impact of mobile phone interventions to positively influence sedentary behavior and physical activity.

The association of incomplete glenoid component seating and periprosthetic glenoid radiolucencies after total shoulder arthroplasty.

BACKGROUND: Radiolucent lines surrounding prosthetic glenoid components are commonly seen after unconstrained total shoulder arthroplasty and can be a harbinger of subsequent glenoid component failure. Whether less than 100% glenoid seating is associated with the development of radiolucent lines around glenoid prostheses is unknown. This study investigated the association between incomplete glenoid component seating and periprosthetic glenoid radiolucencies. METHODS: Thirty-six unconstrained total shoulder arthroplasties were performed in 29 patients for primary glenohumeral osteoarthritis with a minimum 2-year follow-up. All were implanted with a partially cemented all-polyethylene glenoid prosthesis. Patients were evaluated with standardized plain films preoperatively and postoperatively and with thin-cut computed tomography (CT) scans at the latest follow-up. The Lazarus and Yian classifications were used to assess radiolucency and seating on radiographs and CT scans. Ratings were calculated for intraobserver and interobserver reliability and given κ, the Kendall coefficient, and interclass correlation coefficient values. RESULTS: At a mean of 43 months (range 24-26 months) after surgery, neither Lazarus plain film radiolucency scores (P = .78) nor Yian CT radiolucency scores (P = .68) were associated with Lazarus plain film seating scores. Neither Lazarus plain film radiolucency scores (P = .25) nor Yian CT radiolucency scores (P = .91) were associated with modified Lazarus CT scan seating scores. CT allowed for better intraobserver and interobserver reliability in all categories. CONCLUSION: Radiolucencies around a partially cemented glenoid component were not associated with the degree of component seating. Complete seating of the glenoid component is not necessary to achieve radiographic implant stability at a mean follow-up of 43 months.

Gene expression of vitamin D metabolic enzymes at baseline and in response to vitamin D treatment in thyroid cancer cell lines.

The association between vitamin D and thyroid cancer is unclear. It is unknown if CYP27A1 or CYP2R1 are present in normal thyroid or cancer cells and there is limited information regarding response to treatment with vitamin D. SV40 immortalized follicular cells (N-thy) and six thyroid cancer cell lines were treated with 10 µM vitamin D(3), 0.1 µM 1,25(OH)(2)D(3) or vehicle × 24 h. CYP27A1, CYP2R1, CYP27B1 and CYP24A1 mRNA were measured using quantitative real-time-PCR before and after treatment. Cell proliferation was also evaluated in TPC1 and C643 cells after treatment with D(3), 25(OH)D(3) and 1,25(OH)(2)D(3). Baseline CYP27A1 and CYP27B1 mRNA were present in all cells, CYP2R1 was higher and CYP24A1 mRNA was lower in cancer cell lines versus N-thy. TPC1 cells had increased CYP24A1 mRNA levels when treated with both D(3) (3.49, p < 0.001) and 1,25(OH)(2)D(3) (5.05, p < 0.001). C643 cells showed increased CYP24A1 mRNA expression when treated with 1,25(OH)(2)D(3) (5.36, p < 0.001). D(3), 25(OH)D(3) and 1,25(OH)(2)D(3) all significantly decreased cell proliferation in TPC1 and C643 cells. Overall, both cancerous and N-thy cell lines express CYP27A1 and CYP2R1 in addition to CYP27B1, establishing the potential to metabolize D(3) to 1,25(OH)(2)D(3). Additionally, vitamin D(3), 25(OH)D(3) and 1,25(OH)(2)D(3) all had an antiproliferative effect on two thyroid cancer cell lines.

Cyclin-dependent kinase 5 is amplified and overexpressed in pancreatic cancer and activated by mutant K-Ras.

PURPOSE: To evaluate the nature of cyclin-dependent kinase 5 (CDK5) hyperactivity in pancreatic cancer progression. EXPERIMENTAL DESIGN: We used genetic, biochemical, and molecular biology methods to investigate the nature and function of overexpression of CDK5 and its activators p35 and p39 during the progression of pancreatic cancer. RESULTS: Amplification of the CDK5 gene or either of its main activators, p35 and p39, was observed in 67% of human pancreatic ductal adenocarcinoma (PDAC). CDK5, p35, and p39 were rarely expressed in pancreatic ducts whereas more than 90% of PDACs had increased levels of CDK5 and p35. Increased levels of CDK5, p35, and p39 protein were observed in several pancreatic cancer cell lines. Inhibition of CDK5 kinase activity using a CDK5 dominant-negative mutant or the drug roscovitine significantly decreased the migration and invasion of pancreatic cancer cells in vitro. Increased CDK5 kinase activity was also observed in immortalized human pancreatic nestin-expressing (HPNE) cells expressing a mutant form of K-Ras (G12D) compared with HPNE cells expressing native K-Ras. G12D K-Ras increased cleavage of p35 to p25, a stable and greater activator of CDK5, thus implicating a role for CDK5 in early progression of PDAC. Inhibition of the signaling cascade downstream of mutant K-Ras (G12D) that involves mitogen-activated protein/extracellular signal-regulated kinase, phosphoinositide 3-kinase, or CDK5 decreased p25 protein levels. CONCLUSION: These results suggest that mutant K-Ras acts in concert with CDK5 and its activators to increase malignant progression, migration, and invasion of pancreatic cancer cells.

The impact of weight and fat mass loss and increased physical activity on physical function in overweight, postmenopausal women: results from the Women on the Move Through Activity and Nutrition study.

OBJECTIVE: The aim of this study was to determine whether changes in leisure time physical activity (LTPA) and body composition reflect concomitant changes in 400-meter walk time. METHODS: Data were collected at the baseline and 48-month visits in the Women on the Move Through Activity and Nutrition study. At baseline, participants (n = 508) were randomized to the lifestyle intervention or health education group. The lifestyle intervention focused on weight (7%-10%) and waist circumference reduction through healthy lifestyle behavior change. Change in walk time over 48 months was the primary outcome. Secondary measures included change in LTPA and body composition measures including, body weight, body mass index, waist circumference, and dual-energy x-ray absorptiometry--derived fat and lean mass. RESULTS: Increased LTPA and reductions in body weight, body mass index, waist circumference, and fat mass were associated with decreased walk time from baseline to 48 months (P < 0.01). After stratification by group, LTPA was no longer significantly related to walk time in the health education group. CONCLUSIONS: Increased LTPA and weight loss resulted in improved physical function, as measured by the 400-meter walk, in a group of overweight, postmenopausal women. These findings support the use of the 400-meter walk to evaluate progress in physical activity or weight loss programs.

Effects of health savings account-eligible plans on utilization and expenditures.

OBJECTIVE: To assess the impact of a health savings account (HSA)-eligible plan on utilization and expenditures in an employer-sponsored Midwestern health plan which offered a traditional plan from 2003 through 2004 that was fully replaced by an HSA-eligible plan in 2005 and 2006. STUDY DESIGN: Retrospective pre-post design with a control group. METHODS: Medical and pharmacy claims of plan members younger than 65 years who were continuously enrolled throughout the 4-year study period were used to evaluate the impact of switching to the HSA-eligible plan. Expenditure and utilization measures were compared with those for a control group covered by employers in the same industry and geographic location, while controlling for patient characteristics. RESULTS: The HSA-eligible plan was associated with significantly lower total expenditures (-17.4%), fewer and less costly office visits (-13.6% and -20.3%, respectively), fewer emergency department (ED) visits (-20.1%), lower pharmacy expenditures (-29.2%), lower expenses per drug (-27.9%), a reduced likelihood of mammograms (odds ratio [OR] = 0.55, P <.05) and Papanicolaou tests (OR = 0.66, P <.05), and a borderline significant reduction in routine physical exams (OR = 0.76, P <.10). The HSA-eligible plan also was associated with increased outpatient facility expenditures (5.1%, P <.05). CONCLUSION: Employer-sponsored HSA-eligible plans appear to be associated with lower healthcare expenditures and/or utilization, particularly for office visits, ED visits, and pharmacy. However, they also may discourage preventive care, leading to increased long-term medical costs. Employers offering HSA-eligible plans should ensure that there are no financial barriers for preventive services.

Bone presence between the central peg's radial fins of a partially cemented pegged all poly glenoid component suggest few radiolucencies.

BACKGROUND: Cement penetration problems and/or cement-induced bone necrosis may contribute to glenoid component failures. An all polyethylene component was developed that promotes biologic fixation between radial fins of its central peg and utilizes minimal cement fixation for its peripheral pegs, but it has little published data. We hypothesized better bone presence between the radial fins would be associated with less overall radiolucencies. This study's purpose was to utilize computed tomography (CT) and plain films to assess for bone between the central peg's radial fins and to assess overall component radiolucencies. MATERIALS AND METHODS: Thirty-five of 48 consecutively performed total shoulder arthroplasties (TSA) for primary glenohumeral osteoarthritis were in patients able to participate a minimum 2 years after surgery. All had reamed humeral head bone packed between radial fins of the central peg and minimal cement for the peripheral pegs. Thin cut (0.625 mm) CT scans, standardized plain films, Simple Shoulder Tests (SST), and Constant scores were obtained. A musculoskeletal radiologist calculated Yian CT scores, bone presence between fins on CT, and Lazarus radiolucency scores. RESULTS: At a mean of 43 months, by CT: 1) better Yian scores correlated with more bone between fins, and 2) bone was present in 6/6 inter-fin compartments in 23/35 shoulders, averaging 4.5/6 overall. Mean Lazarus radiolucency score was 0.45. Mean SST and Constant scores were 10.3 and 81.3, respectively. CONCLUSION: TSA utilizing autologous bone in inter-fin compartments of the central peg and minimal peripheral peg cement maintained bone presence a minimum 2 years post-op. More bone imparted fewer overall component radiolucencies.

Issues in accelerometer methodology: the role of epoch length on estimates of physical activity and relationships with health outcomes in overweight, post-menopausal women.

BACKGROUND: Current accelerometer technology allows for data collection using brief time sampling intervals (i.e., epochs). The study aims were to examine the role of epoch length on physical activity estimates and subsequent relationships with clinically-meaningful health outcomes in post-menopausal women. METHODS: Data was obtained from the Woman On the Move through Activity and Nutrition Study (n = 102). Differences in activity estimates presented as 60s and 10s epochs were evaluated using paired t-tests. Relationships with health outcomes were examined using correlational and regression analyses to evaluate differences by epoch length. RESULTS: Inactivity, moderate- and vigorous-intensity activity (MVPA) were significantly higher and light-intensity activity was significantly lower (all P < 0.001) when presented as 10s epochs. The correlation between inactivity and self-reported physical activity was stronger with 10s estimates (P < 0.03); however, the regression slopes were not significantly different. Conversely, relationships between MVPA and body weight, BMI, whole body and trunk lean and fat mass, and femoral neck bone mineral density was stronger with 60s estimates (all P < 0.05); however, regression slopes were similar. CONCLUSION: These findings suggest that although the use of a shorter time sampling interval may suggestively reduce misclassification error of physical activity estimates, associations with health outcomes did not yield strikingly different results. Additional studies are needed to further our understanding of the ways in which epoch length contributes to the ascertainment of physical activity in research studies. TRIAL REGISTRATION: Clinical Trials Identifier: NCT00023543.