Parallel Signaling through IRE1α and PERK Regulates Pancreatic Neuroendocrine Tumor Growth and Survival.

Master regulators of the unfolded protein response (UPR), IRE1α and PERK, promote adaptation or apoptosis depending on the level of endoplasmic reticulum (ER) stress. Although the UPR is activated in many cancers, its effects on tumor growth remain unclear. Derived from endocrine cells, pancreatic neuroendocrine tumors (PanNET) universally hypersecrete one or more peptide hormones, likely sensitizing these cells to high ER protein-folding stress. To assess whether targeting the UPR is a viable therapeutic strategy, we analyzed human PanNET samples and found evidence of elevated ER stress and UPR activation. Genetic and pharmacologic modulation of IRE1α and PERK in cultured cells, xenograft, and spontaneous genetic (RIP-Tag2) mouse models of PanNETs revealed that UPR signaling was optimized for adaptation and that inhibiting either IRE1α or PERK led to hyperactivation and apoptotic signaling through the reciprocal arm, thereby halting tumor growth and survival. These results provide a strong rationale for therapeutically targeting the UPR in PanNETs and other cancers with elevated ER stress. SIGNIFICANCE: The UPR is upregulated in pancreatic neuroendocrine tumors and its inhibition significantly reduces tumor growth in preclinical models, providing strong rationale for targeting the UPR in these cancers.

Elastase 3B mutation links to familial pancreatitis with diabetes and pancreatic adenocarcinoma.

While improvements in genetic analysis have greatly enhanced our understanding of the mechanisms behind pancreatitis, it continues to afflict many families for whom the hereditary factors remain unknown. Recent evaluation of a patient with a strong family history of pancreatitis sparked us to reexamine a large kindred originally reported over 50 years ago with an autosomal dominant inheritance pattern of chronic pancreatitis, diabetes and pancreatic adenocarcinoma. Whole exome sequencing analysis identified a rare missense mutation in the gene encoding pancreas-specific protease Elastase 3B (CELA3B) that cosegregates with disease. Studies of the mutant protein in vitro, in cell lines and in CRISPR-Cas9 engineered mice indicate that this mutation causes translational upregulation of CELA3B, which upon secretion and activation by trypsin leads to uncontrolled proteolysis and recurrent pancreatitis. Although lesions in several other pancreatitic proteases have been previously linked to hereditary pancreatitis, this is the first known instance of a mutation in CELA3B and a defect in translational control contributing to this disease.

Evolution of Mechanisms that Control Mating in Drosophila Males.

Genetically wired neural mechanisms inhibit mating between species because even naive animals rarely mate with other species. These mechanisms can evolve through changes in expression or function of key genes in sensory pathways or central circuits. Gr32a is a gustatory chemoreceptor that, in D. melanogaster, is essential to inhibit interspecies courtship and sense quinine. Similar to D. melanogaster, we find that D. simulans Gr32a is expressed in foreleg tarsi, sensorimotor appendages that inhibit interspecies courtship, and it is required to sense quinine. Nevertheless, Gr32a is not required to inhibit interspecies mating by D. simulans males. However, and similar to its function in D. melanogaster, Ppk25, a member of the Pickpocket family, promotes conspecific courtship in D. simulans. Together, we have identified distinct evolutionary mechanisms underlying chemosensory control of taste and courtship in closely related Drosophila species.

Motorcycle helmet effectiveness in reducing head, face and brain injuries by state and helmet law.

BACKGROUND: Despite evidence that motorcycle helmets reduce morbidity and mortality, helmet laws and rates of helmet use vary by state in the U.S. METHODS: We pooled data from eleven states: five with universal laws requiring all motorcyclists to wear a helmet, and six with partial laws requiring only a subset of motorcyclists to wear a helmet. Data were combined in the Crash Outcome Data Evaluation System's General Use Model and included motorcycle crash records probabilistically linked to emergency department and inpatient discharges for years 2005-2008. Medical outcomes were compared between partial and universal helmet law settings. We estimated adjusted relative risks (RR) and 95 % confidence intervals (CIs) for head, facial, traumatic brain, and moderate to severe head/facial injuries associated with helmet use within each helmet law setting using generalized log-binomial regression. RESULTS: Reported helmet use was higher in universal law states (88 % vs. 42 %). Median charges, adjusted for inflation and differences in state-incomes, were higher in partial law states (emergency department $1987 vs. $1443; inpatient $31,506 vs. $25,949). Injuries to the head and face, including traumatic brain injuries, were more common in partial law states. Effectiveness estimates of helmet use were higher in partial law states (adjusted-RR (CI) of head injury: 2.1 (1.9-2.2) partial law single vehicle; 1.4 (1.2, 1.6) universal law single vehicle; 1.8 (1.6-2.0) partial law multi-vehicle; 1.2 (1.1-1.4) universal law multi-vehicle). CONCLUSIONS: Medical charges and rates of head, facial, and brain injuries among motorcyclists were lower in universal law states. Helmets were effective in reducing injury in both helmet law settings; lower effectiveness estimates were observed in universal law states.

Underreporting of driver alcohol involvement in United States police and hospital records: capture-recapture estimates.

This paper analyzes what portion of US nonfatal crashes are alcohol-involved and how well police and hospitals detect involvement. A capture recapture model estimated alcohol involvement from levels detected by police and hospitals and the extent of detection overlap. We analyzed 550,933 Crash Outcome Data Evaluation System driver records from 2006-2008 police crash report censuses probabilistically linked to hospital inpatient and emergency department (ED) discharge censuses for CT, KY (admissions only), MD, NE, NY, SC, and UT. We computed national estimates from NHTSA's General Estimates System.Nationally an estimated 7.5% of drivers in nonfatal crashes and 12.9% of nonfatal crashes were alcohol-involved. (Crashes often involve multiple drivers but rarely are two alcohol-involved.) Police correctly identified an estimated 32% of alcohol-involved drivers in non-fatal crashes including 48% in injury crashes. Excluding KY, police in the six states reported 47% of alcohol involvement for cases treated in EDs and released and 39% for admitted cases. In contrast, hospitals reported 28% of involvement for ED cases and 51% for admitted cases. Underreporting varied widely between states. Police reported alcohol involvement for 44% of those who hospitals reported were alcohol-involved, while hospitals reported alcohol involvement for 33% of those who police reported were alcohol-involved. Police alcohol reporting completeness rose with police-reported driver injury severity. At least one system reported 62% of alcohol involvement. Police and hospitals need to communicate better about alcohol involvement. Despite the proven effectiveness of brief alcohol intervention, EDs rarely detect, much less intervene with crash-involved drinking drivers. Both police and EDs particularly need to assess alcohol involvement in minor injury better.

Factors associated with asthma control among adults in five New England states, 2006-2007.

BACKGROUND: Despite the National Asthma Education and Prevention Program (NAEPP) guidelines that specify the goals of asthma control and management strategies, the number of patients with uncontrolled asthma remains high, and factors associated with uncontrolled asthma are unknown. OBJECTIVE: The aim was to examine the relationship between asthma control and socio-demographic characteristics, health-care access and use, asthma education, and medication use among adults with active asthma residing in New England. METHODS: Data from the 2006-2007 Behavior Risk Factor Surveillance System Adult Asthma Call-Back Survey were analyzed using multinomial logistic regression. Asthma control was categorized as "well controlled," "not well controlled," or "very poorly controlled" according to the NAEPP guidelines. RESULTS: Of the respondents (n = 3079), 30% met the criteria for well-controlled asthma, 46% for not well-controlled asthma, and 24% for very poorly controlled asthma. Being of Hispanic ethnicity (odds ratio [OR] = 4.0; 95% confidence interval [CI] = 1.2-13.7), unemployed or unable to work (OR = 17.9; 95% CI = 6.0-53.4), high school educated or less (OR = 2.8; 95% CI = 1.6-4.7), current smokers (OR = 2.5; 95% CI = 1.3-5.1), or being unable to see a doctor or specialist for asthma care or unable to buy medication for asthma because of cost (OR = 7.6; 95% CI = 3.4-17.1) were associated with very poorly controlled asthma. In addition, having Coronary Obstructive Pulmonary Disease (COPD) (OR = 2.6; 95% CI = 1.5-4.5), two or more routine checkups for asthma (OR = 4.5; 95% CI = 2.3-8.9), or an emergency department visit, urgent care facility visit, and hospitalization in the past year (OR = 3.9; 95% CI = 2.1-7.3) were also associated with having very poorly controlled asthma. Using controller medication in the past year (OR = 2.6; 95% CI = 1.6-4.2) and taking a course on how to manage asthma (OR = 3.0; 95% CI = 1.2-7.8) were significantly associated with poor asthma control. CONCLUSION: The high prevalence (70%) of not well-controlled asthma and poorly controlled asthma in this study emphasizes the need to identify factors associated with poor asthma control for development of targeted intervention. A health policy of increasing asthma education, health-care access, and smoking cessation may be effective and result in better asthma control and management.

Quality-of-life and cost-benefit analysis of a home environmental assessment program in Connecticut.

BACKGROUND: The National Asthma Education Prevention Program's (NAEPP) Expert Panel Report 3 (EPR3) guidelines have stressed the need for environmental control measures for asthma, but there is limited evidence of their efficacy. OBJECTIVE: To examine the effectiveness of an in-home asthma intervention program for children and adults in Connecticut, we conducted a panel study to analyze quality-of-life indicators for asthmatic patients and the cost-benefit relationship in preventive care versus acute care. METHODS: The Asthma Indoor Reduction Strategies (AIRS) program was developed to reduce acute asthma episodes and improve asthma control through patient education and a home environmental assessment. Follow-up was conducted at 2-week, 3-month, and 6-month intervals. Measured quality-of-life indicators included number of unscheduled acute care visits, days absent from school/work due to asthma, times rescue inhaler used, and number of symptom-free days. Repeated measures analysis of variance (ANOVA) was used to determine whether significant differences exist in quality-of-life indicators at follow-up compared to that at the initial visit. Cost-benefit analysis was conducted by tabulating costs associated with physician office visits and emergency department (ED) visits due to asthma for children and adults separately. RESULTS: Twenty percent of participants in the program met the criteria for well-controlled asthma, 16% for not well-controlled asthma, and 64% for very poorly controlled asthma. At 6 months follow-up, the mean number of unscheduled acute care visits, days absent from school/work due to asthma, and times rescue inhaler used in the past week decreased by 87%, 82%, and 74%, respectively, whereas the mean number of symptom-free days increased by 27% compared to the initial visit. Furthermore, the percent of participants with very poorly controlled asthma decreased from 64% at initial visit to 13% at 6 months follow-up. All changes were statistically significant at p < 0.05. A net savings of $26,720 per 100 participants was estimated at 6 months follow-up due to decreases in unscheduled acute care visits for adults and children. CONCLUSION: Significant improvement in quality-of-life and decreases in healthcare resource utilization and costs were found after implementation of the AIRS program in Connecticut.

Dual-energy X-ray absorptiometry and evaluation of the osteoporosis self-assessment tool in men with rheumatoid arthritis.

Males with rheumatoid arthritis (RA) are at risk for osteoporosis but infrequently undergo dual-energy X-ray absorptiometry (DXA). We examined the frequency of DXA in males enrolled in the Veterans Affairs Rheumatoid Arthritis Registry. The Osteoporosis Self-Assessment Tool (OST) index, a formula using age and weight, was calculated for all subjects. DXA was performed on 282 (35.5%) of the males who were younger (p < 0.01), had lower mean OST index score (p < 0.05), and were more likely to have been prescribed prednisone (p < 0.01) than subjects without DXA. Low bone mass (T-score < -1) was present in 73% of subjects with DXA; 37% of subjects with low-risk OST index scores had normal bone mineral density (BMD) compared with 5.6% of those with high-risk OST index scores (p < 0.01). There was a significant but modest correlation between BMD and the OST index (r = 0.17, p < 0.01). No OST score had a sensitivity and specificity of more than 80%. Association between OST index and BMD was strongest in non-Hispanic whites, subjects older than 60 yr, and smokers. DXA was underutilized in males with RA. The OST index correlated with low bone mass but could not reliably predict osteoporosis in this population.