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1.  FGFR1 and NTRK3 actionable alterations in “Wild-Type” gastrointestinal stromal tumors 
Background
About 10–15% of adult, and most pediatric, gastrointestinal stromal tumors (GIST) lack mutations in KIT, PDGFRA, SDHx, or RAS pathway components (KRAS, BRAF, NF1). The identification of additional mutated genes in this rare subset of tumors can have important clinical benefit to identify altered biological pathways and select targeted therapies.
Methods
We performed comprehensive genomic profiling (CGP) for coding regions in more than 300 cancer-related genes of 186 GISTs to assess for their somatic alterations.
Results
We identified 24 GIST lacking alterations in the canonical KIT/PDGFRA/RAS pathways, including 12 without SDHx alterations. These 24 patients were mostly adults (96%). The tumors had a 46% rate of nodal metastases. These 24 GIST were more commonly mutated at 7 genes: ARID1B, ATR, FGFR1, LTK, SUFU, PARK2 and ZNF217. Two tumors harbored FGFR1 gene fusions (FGFR1–HOOK3, FGFR1–TACC1) and one harbored an ETV6–NTRK3 fusion that responded to TRK inhibition. In an independent sample set, we identified 5 GIST cases lacking alterations in the KIT/PDGFRA/SDHx/RAS pathways, including two additional cases with FGFR1–TACC1 and ETV6–NTRK3 fusions.
Conclusions
Using patient demographics, tumor characteristics, and CGP, we show that GIST lacking alterations in canonical genes occur in younger patients, frequently metastasize to lymph nodes, and most contain deleterious genomic alterations, including gene fusions involving FGFR1 and NTRK3. If confirmed in larger series, routine testing for these translocations may be indicated for this subset of GIST. Moreover, these findings can be used to guide personalized treatments for patients with GIST.
Trial registration NCT 02576431. Registered October 12, 2015
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-016-1075-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12967-016-1075-6
PMCID: PMC5157084  PMID: 27974047
Gene sequencing; Mutation; GIST; FGFR1; ETV6–NTRK3
2.  Importance of Radiation Oncologist Experience Among Patients With Head-and-Neck Cancer Treated With Intensity-Modulated Radiation Therapy 
Journal of Clinical Oncology  2016;34(7):684-690.
Purpose
Over the past decade, intensity-modulated radiation therapy (IMRT) has replaced conventional radiation techniques in the management of head-and-neck cancers (HNCs). We conducted this population-based study to evaluate the influence of radiation oncologist experience on outcomes in patients with HNC treated with IMRT compared with patients with HNC treated with conventional radiation therapy.
Methods
We identified radiation providers from Medicare claims of 6,212 Medicare beneficiaries with HNC treated between 2000 and 2009. We analyzed the impact of provider volume on all-cause mortality, HNC mortality, and toxicity end points after treatment with either conventional radiation therapy or IMRT. All analyses were performed by using either multivariable Cox proportional hazards or Fine-Gray regression models controlling for potential confounding variables.
Results
Among patients treated with conventional radiation, we found no significant relationship between provider volume and patient survival or any toxicity end point. Among patients receiving IMRT, those treated by higher-volume radiation oncologists had improved survival compared with those treated by low-volume providers. The risk of all-cause mortality decreased by 21% for every additional five patients treated per provider per year (hazard ratio [HR], 0.79; 95% CI, 0.67 to 0.94). Patients treated with IMRT by higher-volume providers had decreased HNC-specific mortality (subdistribution HR, 0.68; 95% CI, 0.50 to 0.91) and decreased risk of aspiration pneumonia (subdistribution HR, 0.72; 95% CI, 0.52 to 0.99).
Conclusion
Patients receiving IMRT for HNC had improved outcomes when treated by higher-volume providers. These findings will better inform patients and providers when making decisions about treatment, and emphasize the critical importance of high-quality radiation therapy for optimal treatment of HNC.
doi:10.1200/JCO.2015.63.9898
PMCID: PMC4872027  PMID: 26729432
3.  The evolving world of pseudoenzymes: proteins, prejudice and zombies 
BMC Biology  2016;14:98.
Pseudoenzymes are catalytically deficient variants of enzymes that are represented in all major enzyme families. Their regulatory functions in signalling pathways are shedding new light on the non-catalytic functions of active enzymes, and are suggesting new ways to target cellular signalling mechanisms with drugs.
doi:10.1186/s12915-016-0322-x
PMCID: PMC5106787  PMID: 27835992
4.  The impact of radiotherapy costs on clinical outcomes in breast cancer 
Background and Purpose
In cost-effective healthcare systems, the cost of services should parallel patient complexity or quality of care. The purpose of this study was to determine whether the cost of radiotherapy correlates with patient-related outcomes among a large cohort of breast cancer patients treated with adjuvant breast radiation.
Materials and Methods
23,127 women with non-metastatic breast cancer undergoing radiotherapy after breast conservation surgery were identified from the Surveillance, Epidemiology, and End Results database from 2000-2009. Medicare reimbursements were used as a proxy for cost of radiotherapy, and Medicare claims were examined to identify local toxicities, and breast cancer-related endpoints. The impact of cost on these outcomes was studied with multivariable Fine-Gray models to account for competing risks.
Results
The median cost (and interquartile range) of a course of breast radiation was $8,100 ($6,700-$9,700). Increased radiation costs were not associated with the occurrence of treatment-related toxicities (all p-values > 0.05), ipsilateral breast recurrence (p=0.55), or breast cancer-related mortality (p=0.55).
Conclusion
Higher costs for adjuvant radiation in breast cancer were not associated with a decreased risk of patient-related outcomes, suggesting inefficiency in Medicare reimbursements. Future efforts should focus on prospective evaluation of alternative payment models for radiotherapy.
doi:10.1016/j.radonc.2015.10.004
PMCID: PMC4758206  PMID: 26472317
Breast cancer; radiation therapy; costs; outcomes
5.  Computerized Versus Motivational Interviewing Alcohol Interventions: Impact on Discrepancy, Motivation, and Drinking 
The authors conducted two randomized clinical trials with ethnically diverse samples of college student drinkers in order to determine (a) the relative efficacy of two popular computerized interventions versus a more comprehensive motivational interview approach (BASICS) and (b) the mechanisms of change associated with these interventions. In Study 1, heavy drinking participants recruited from a student health center (N = 74, 59% women, 23% African American) were randomly assigned to receive BASICS or the Alcohol 101 CD-ROM program. BASICS was associated with greater post-session motivation to change and self-ideal and normative discrepancy relative to Alcohol 101, but there were no group differences in the primary drinking outcomes at 1-month follow-up. Pre to post session increases in motivation predicted lower follow-up drinking across both conditions. In Study 2, heavy drinking freshman recruited from a core university course (N = 133, 50% women, 30% African American) were randomly assigned to BASICS, a web-based feedback program (e-CHUG), or assessment-only. BASICS was associated with greater post-session self-ideal discrepancy than e-CHUG, but there were no differences in motivation or normative discrepancy. There was a significant treatment effect on typical weekly and heavy drinking, with participants in BASICS reporting significantly lower follow-up drinking relative to assessment only participants. In Study 2, change in the motivation or discrepancy did not predict drinking outcomes. Across both studies, African American students assigned to BASICS reported medium effect size reductions in drinking whereas African American students assigned to Alcohol 101, e-CHUG, or assessment did not reduce their drinking.
doi:10.1037/a0021347
PMCID: PMC5070604  PMID: 21198224
brief alcohol intervention; motivation; discrepancy; computerized intervention; ethnicity; college alcohol use
6.  Improved Method to Stratify Elderly Patients With Cancer at Risk for Competing Events 
Journal of Clinical Oncology  2016;34(11):1270-1277.
Purpose
To compare a novel generalized competing event (GCE) model versus the standard Cox proportional hazards regression model for stratifying elderly patients with cancer who are at risk for competing events.
Methods
We identified 84,319 patients with nonmetastatic prostate, head and neck, and breast cancers from the SEER-Medicare database. Using demographic, tumor, and clinical characteristics, we trained risk scores on the basis of GCE versus Cox models for cancer-specific mortality and all-cause mortality. In test sets, we examined the predictive ability of the risk scores on the different causes of death, including second cancer mortality, noncancer mortality, and cause-specific mortality, using Fine-Gray regression and area under the curve. We compared how well models stratified subpopulations according to the ratio of the cumulative cause-specific hazard for cancer mortality to the cumulative hazard for overall mortality (ω) using the Akaike Information Criterion.
Results
In each sample, increasing GCE risk scores were associated with increased cancer-specific mortality and decreased competing mortality, whereas risk scores from Cox models were associated with both increased cancer-specific mortality and competing mortality. GCE models created greater separation in the area under the curve for cancer-specific mortality versus noncancer mortality (P < .001), indicating better discriminatory ability between these events. Comparing the GCE model to Cox models of cause-specific mortality or all-cause mortality, the respective Akaike Information Criterion scores were superior (lower) in each sample: prostate cancer, 28.6 versus 35.5 versus 39.4; head and neck cancer, 21.1 versus 29.4 versus 40.2; and breast cancer, 24.6 versus 32.3 versus 50.8.
Conclusion
Compared with standard modeling approaches, GCE models improve stratification of elderly patients with cancer according to their risk of dying from cancer relative to overall mortality.
doi:10.1200/JCO.2015.65.0739
PMCID: PMC5070568  PMID: 26884579
7.  Alcohol Craving and Demand Mediate the Relation between Posttraumatic Stress Symptoms and Alcohol-Related Consequences 
Objective
Posttraumatic stress (PTS) symptoms are associated with alcohol-related consequences, but there is a need to understand mediators that may help explain the reasons for this relationship. Individuals with PTS may experience elevated craving and alcohol reward value (demand), which may contribute to risk for alcohol-related consequences.
Method
We examined relationships between PTS status, craving, alcohol demand, and alcohol-related consequences in PTS-positive (n = 64) and PTS-negative (n = 200) college students (M age = 21.7; 77% women; 54% Caucasian; 34% African American) who endorsed past-month alcohol use. We tested craving and alcohol demand as mediators of the relation between PTS status and alcohol problems.
Results
Craving (B = .04, SE = .02, 95% CI = .01 – .10), demand intensity (B = .05, SE = .03, 95% CI = .0009 – .17), and demand elasticity (B = .05, SE = .03, 95% CI = .006 – .03) significantly mediated the association between PTS symptoms and alcohol problems. Craving remained a significant mediator in a multiple mediators model (B = .08, SE = .04, 95% CI = .03 – .19).
Conclusions
Craving and alcohol demand may partially explain the relation between PTS status and alcohol-related consequences. Craving may be especially salient for individuals with PTS symptoms, as it may lead to more severe alcohol-related consequences even in the absence of elevated alcohol consumption.
doi:10.1037/pha0000040
PMCID: PMC4573546  PMID: 26375513
Posttraumatic stress symptoms; craving; alcohol-related consequences; behavioral economics; alcohol demand
8.  A Randomized Controlled Trial of a Behavioral Economic Intervention for Alcohol and Marijuana Use 
Objective
A recent study demonstrated that a single 50-minute supplemental session that targeted the behavioral economic mechanisms of substance-free reinforcement and delayed reward discounting (Substance Free Activity Session: SFAS) enhanced the efficacy of a standard alcohol brief motivational intervention (BMI) for college drinkers. The purpose of the current study was to conduct a randomized controlled trial intended to replicate and extend the aforementioned study by focusing on both drug and alcohol misuse and reducing session length in order to enhance dissemination potential.
Method
Participants were 97 college students (58.8% women; 59.8% white/Caucasian & 30.9% African American; M age = 20.01, SD = 2.23) who reported at least one heavy drinking episode in the past month (M = 4.01 episodes). Most participants (62%) reported recent marijuana use (M = 12.22 days of past-month use). After completing a baseline assessment and an individual 30-minute alcohol-focused BMI, participants were randomized to either the 30-minute SFAS session or an education control session.
Results
A series of mixed model intent-to-treat analyses revealed that both groups reported drinking reductions and that participants in the BMI+SFAS group reported fewer days using marijuana at the 6-month follow-up.
Conclusions
These results do not support the incremental efficacy of the briefer SFAS for reducing drinking but suggest that it may improve marijuana outcomes. Future research is needed to identify the ideal length and timing of the SFAS supplement to BMIs.
doi:10.1037/pha0000025
PMCID: PMC4579003  PMID: 26191947
alcohol; marijuana; behavioral economics; motivational interventions; substance-free reinforcement
9.  Increased Risk of Additional Cancers Among Patients with Gastrointestinal Stromal Tumors: A Population-Based Study 
Cancer  2015;121(17):2960-2967.
Purpose
Most gastrointestinal stromal tumors (GIST) are considered non-hereditary or sporadic. However, single-institution studies suggest that GIST patients develop additional malignancies with increased frequencies. We hypothesized that we could gain greater insight into possible associations between GIST and other malignancies using a national cancer database inquiry.
Methods
Patients diagnosed with GIST (2001–2011) in the Surveillance, Epidemiology, and End Results database were included. Standardized prevalence ratios (SPRs) and standardized incidence ratios (SIRs) were used to quantify cancer risks incurred by GIST patients before and after GIST diagnoses, respectively, when compared with the general U.S. population.
Results
Of 6,112 GIST patients, 1,047 (17.1%) had additional cancers. There were significant increases in overall cancer rates: 44% (SPR=1.44) before diagnosis and 66% (SIR=1.66) after GIST diagnoses. Malignancies with significantly increased occurrence both before/after diagnoses included other sarcomas (SPR=5.24/SIR=4.02), neuroendocrine-carcinoid tumors (SPR=3.56/SIR=4.79), non-Hodgkin’s lymphoma (SPR=1.69/SIR=1.76), and colorectal adenocarcinoma (SPR=1.51/SIR=2.16). Esophageal adenocarcinoma (SPR=12.0), bladder adenocarcinoma (SPR=7.51), melanoma (SPR=1.46), and prostate adenocarcinoma (SPR=1.20) were significantly more common only before GIST. Ovarian carcinoma (SIR=8.72), small intestine adenocarcinoma (SIR=5.89), papillary thyroid cancer (SIR=5.16), renal cell carcinoma (SIR=4.46), hepatobiliary adenocarcinomas (SIR=3.10), gastric adenocarcinoma (SIR=2.70), pancreatic adenocarcinoma (SIR=2.03), uterine adenocarcinoma (SIR=1.96), non-small cell lung cancer (SIR=1.74), and transitional cell carcinoma of the bladder (SIR=1.65) were significantly more common only after GIST.
Conclusion
This is the first population-based study to characterize the associations and temporal relationships between GIST and other cancers, both by site and histological type. These associations may carry important clinical implications for future cancer screening and treatment strategies.
doi:10.1002/cncr.29434
PMCID: PMC4545693  PMID: 25930983
GIST; Neoplasms; Second Primary; Multiple Primary Neoplasms; Neoplasms; Synchronous; Neoplasms; Metachronous; SEER
10.  Variation in the Cost of Radiation Therapy Among Medicare Patients With Cancer 
Journal of Oncology Practice  2015;11(5):403-409.
Factors unrelated to the individual patient accounted for the majority of variation in the cost of radiation therapy, suggesting potential inefficiency in health care expenditure.
Purpose:
Radiation therapy represents a major source of health care expenditure for patients with cancer. Understanding the sources of variability in the cost of radiation therapy is critical to evaluating the efficiency of the current reimbursement system and could shape future policy reform. This study defines the magnitude and sources of variation in the cost of radiation therapy for a large cohort of Medicare beneficiaries.
Patients and Methods:
We identified 55,288 patients within the SEER database diagnosed with breast, lung, or prostate cancer between 2004 and 2009. The cost of radiation therapy was estimated from Medicare reimbursements. Multivariable linear regression models were used to assess the influence of patient, tumor, and radiation therapy provider characteristics on variation in cost of radiation therapy.
Results:
For breast, lung, and prostate cancers, the median cost (interquartile range) of a course of radiation therapy was $8,600 ($7,300 to $10,300), $9,000 ($7,500 to $11,100), and $18,000 ($11,300 to $25,500), respectively. For all three cancer subtypes, patient- or tumor-related factors accounted for < 3% of the variation in cost. Factors unrelated to the patient, including practice type, geography, and individual radiation therapy provider, accounted for a substantial proportion of the variation in cost, ranging from 44% with breast, 43% with lung, and 61% with prostate cancer.
Conclusion:
In this study, factors unrelated to the individual patient accounted for the majority of variation in the cost of radiation therapy, suggesting potential inefficiency in health care expenditure. Future research should determine whether this variability translates into improved patient outcomes for further evaluation of current reimbursement practices.
doi:10.1200/JOP.2015.005694
PMCID: PMC4575405  PMID: 26265172
11.  The Reinforcing Properties of Ethanol are Quantitatively Enhanced in Adulthood by Peri-Adolescent Ethanol, but not Saccharin, Consumption in Female Alcohol-Preferring (P) Rats 
Alcohol (Fayetteville, N.Y.)  2015;49(5):513-518.
Alcohol drinking during adolescence is associated in adulthood with heavier alcohol drinking and an increased rate of alcohol dependence. Past research in our laboratory has indicated that peri-adolescent ethanol consumption can enhance the acquisition and reduce the rate of extinction of ethanol self-administration in adulthood. Caveats of the past research include reinforcer specificity, increased oral consumption during peri-adolescence, and a lack of quantitative assessment of the reinforcing properties of ethanol. The current experiments were designed to determine the effects of peri-adolescent ethanol or saccharin drinking on acquisition and extinction of oral ethanol self-administration and ethanol seeking, and to quantitatively assess the reinforcing properties of ethanol (progressive ratio). Ethanol or saccharin access by alcohol-preferring (P) rats occurred during postnatal day (PND) 30–60. Animals began operant self-administration of ethanol or saccharin after PND 85. After 10 weeks of daily operant self-administration, rats were tested in a progressive ratio paradigm. Two weeks later, self-administration was extinguished in all rats. Peri-adolescent ethanol consumption specifically enhanced the acquisition of ethanol self-administration, reduced the rate of extinction for ethanol self-administration, and quantitatively increased the reinforcing properties of ethanol during adulthood. Peri-adolescent saccharin consumption was without effect. The data indicate that ethanol consumption during peri-adolescence results in neuroadaptations that may specifically enhance the reinforcing properties of ethanol during adulthood. This increase in the reinforcing properties of ethanol could be a part of biological sequelae that are the basis for the effects of adolescent alcohol consumption on the increase in the rate of alcoholism during adulthood.
doi:10.1016/j.alcohol.2015.04.007
PMCID: PMC4468788  PMID: 26074425
alcoholism; adolescence; operant; self-administration; progressive ratio
12.  Indirect Reciprocity, Resource Sharing, and Environmental Risk: Evidence from Field Experiments in Siberia 
PLoS ONE  2016;11(7):e0158940.
Integrating information from existing research, qualitative ethnographic interviews, and participant observation, we designed a field experiment that introduces idiosyncratic environmental risk and a voluntary sharing decision into a standard public goods game. Conducted with subsistence resource users in rural villages on the Kamchatka Peninsula in Northeast Siberia, we find evidence consistent with a model of indirect reciprocity and local social norms of helping the needy. When participants are allowed to develop reputations in the experiments, as is the case in most small-scale societies, we find that sharing is increasingly directed toward individuals experiencing hardship, good reputations increase aid, and the pooling of resources through voluntary sharing becomes more effective. We also find high levels of voluntary sharing without a strong commitment device; however, this form of cooperation does not increase contributions to the public good. Our results are consistent with previous experiments and theoretical models, suggesting strategic risks tied to rewards, punishments, and reputations are important. However, unlike studies that focus solely on strategic risks, we find the effects of rewards, punishments, and reputations are altered by the presence of environmental factors. Unexpected changes in resource abundance increase interdependence and may alter the costs and benefits of cooperation, relative to defection. We suggest environmental factors that increase interdependence are critically important to consider when developing and testing theories of cooperation
doi:10.1371/journal.pone.0158940
PMCID: PMC4956054  PMID: 27442434
13.  Help-Seeking for Alcohol-Related Problems in College Students: Correlates and Preferred Resources 
Despite the development of a variety of efficacious alcohol intervention approaches for college students, few student drinkers seek help. The present study assessed students’ history of help-seeking for alcohol problems as well as their estimates of how likely they would be to use various help-seeking resources, should they wish to change their drinking. Participants were 197 college students who reported recent heavy drinking (46% male, 68.5% White, 27.4% African-American). Participants completed measures related to their drinking and their use (both past use and likelihood of future use) of 14 different alcohol help-seeking options. Repeated measures ANOVAs revealed that students preferred informal help-seeking (e.g., talking to friends and family) over formal (e.g., talking with a counselor or medical provider) and anonymous resources (e.g., internet- or computer-based programs). Higher self-ideal discrepancy, greater depressive symptoms, and more alcohol-related consequences were positively associated with actual past help-seeking. Alcohol-related problems and normative discrepancy were negatively associated with hypothetical likelihood of utilizing all three help-seeking resources. These results suggest that heavy drinking college students prefer low-threshold intervention options including peer, family, computerized, and brief motivational interventions. Only 36 participants (18.3% of the sample) reported that they had utilized any of the help-seeking options queried, suggesting that campus prevention efforts should include both promoting low-threshold interventions and attempting to increase the salience of alcohol-related risk and the potential utility of changing drinking patterns.
doi:10.1037/a0021122
PMCID: PMC4912043  PMID: 21198220
help-seeking; college students; alcohol intervention; brief interventions; motivation to change
14.  Area Under the Curve as a Novel Metric of Behavioral Economic Demand for Alcohol 
Behavioral economic purchase tasks can be readily used to assess demand for a number of addictive substances including alcohol, tobacco and illicit drugs. However, several methodological limitations associated with the techniques used to quantify demand may reduce the utility of demand measures. In the present study, we sought to introduce area under the curve (AUC), commonly used to quantify degree of delay discounting, as a novel index of demand. A sample of 207 heavy drinking college students completed a standard alcohol purchase task and provided information about typical weekly drinking patterns and alcohol-related problems. Level of alcohol demand was quantified using AUC – which reflects the entire amount of consumption across all drink prices - as well as the standard demand indices (e.g., intensity, breakpoint, Omax, Pmax, and elasticity). Results indicated that AUC was significantly correlated with each of the other demand indices (rs = .42–.92), with particularly strong associations with Omax (r = .92). In regression models, AUC and intensity were significant predictors of weekly drinking quantity and AUC uniquely predicted alcohol-related problems, even after controlling for drinking level. In a parallel set of analyses, Omax also predicted drinking quantity and alcohol problems, although Omax was not a unique predictor of the latter. These results offer initial support for using AUC as an index of alcohol demand. Additional research is necessary to further validate this approach and to examine its utility in quantifying demand for other addictive substances such as tobacco and illicit drugs.
doi:10.1037/pha0000014
PMCID: PMC4461465  PMID: 25895013
Alcohol; Area under the curve; Behavioral economics; Demand; Purchase task
15.  Behavioral Economic Predictors of Brief Alcohol Intervention Outcomes 
Objective
The present study attempted to determine if behavioral economic indices of elevated alcohol reward value, measured before and immediately after a brief alcohol intervention, predict treatment response.
Method
Participants were 133 heavy drinking college students (49.6% female, 51.4% male; 64.3% Caucasian, 29.5% African American) who were randomized to one of three conditions: motivational interviewing plus personalized feedback (BMI), computerized personalized feedback intervention (e-CHUG), and assessment only.
Results
Baseline levels of alcohol demand significantly predicted drinks per week and alcohol problems at 1-month (demand intensity= maximum expenditure) and 6-month (relative discretionary expenditures on alcohol) follow-up. BMI and e-CHUG were associated with an immediate post-session reduction in alcohol demand (p < .001, ηρ2 = .29) that persisted at the 1-month follow-up, with greater post-session reductions in the BMI condition (p = .02, ηρ2 = .06). Reductions in demand intensity and Omax (maximum expenditure) immediately post-intervention significantly predicted drinking reductions at one-month follow up (p = .04, ΔR2 = .02 & p = .01, ΔR2 = .03, respectively). Reductions in relative discretionary expenditures on alcohol at 1-month significantly predicted drinking (p = .002, ΔR2 = .06,) and alcohol problem (p < .001, ΔR2 = .13) reductions at the 6-month follow-up.
Conclusions
These results suggest that behavioral economic reward value indices may function as risk factors for poor intervention response and as clinically-relevant markers of change in heavy drinkers.
doi:10.1037/ccp0000032
PMCID: PMC4658255  PMID: 26167945
Alcohol; Behavioral Economics; Brief Interventions; Demand Curve; Alcohol-Related Expenditures; College Students
16.  Behavioral Economic Analysis of Cue-elicited Craving for Alcohol 
Addiction (Abingdon, England)  2010;105(9):1599-1607.
Rationale
Craving as a motivational determinant of drug use remains controversial because of ambiguous empirical findings. A behavioral economic approach may clarify the nature of craving, theorizing that subjective craving functionally reflects an acute increase in a drug’s value. The current study tested this hypothesis via a multidimensional assessment of alcohol demand over the course of an alcohol cue reactivity procedure.
Method
Heavy drinkers (n = 92) underwent exposures to neutral (water) cues followed by personalized alcohol cues. Participants were assessed for craving, alcohol demand, affect, and salivation following each exposure.
Findings
Alcohol versus neutral cues significantly increased craving and multiple behavioral economic measures of the relative value of alcohol, including alcohol consumption under conditions of zero cost (intensity), maximum expenditure on alcohol (Omax), persistence in drinking to higher prices (breakpoint) and proportionate price insensitivity (normalized Pmax). Craving was significantly correlated with demand measures at levels ranging from .21 – .43.
Conclusions
These findings support the potential utility of a behavioral economic approach to understanding the role of environmental stimuli in alcohol-related decision making. Specifically, they suggest that the behavioral economic indices of demand may provide complementary motivational information that is related to though not entirely redundant with measures of subjective craving.
doi:10.1111/j.1360-0443.2010.03004.x
PMCID: PMC4853028  PMID: 20626376
17.  Changes to coral health and metabolic activity under oxygen deprivation 
PeerJ  2016;4:e1956.
On Hawaiian reefs, the fast-growing, invasive algae Gracilaria salicornia overgrows coral heads, restricting water flow and light, thereby smothering corals. Field data shows hypoxic conditions (dissolved oxygen (DO2) < 2 mg/L) occurring underneath algal mats at night, and concurrent bleaching and partial tissue loss of shaded corals. To analyze the impact of nighttime oxygen-deprivation on coral health, this study evaluated changes in coral metabolism through the exposure of corals to chronic hypoxic conditions and subsequent analyses of lactate, octopine, alanopine, and strombine dehydrogenase activities, critical enzymes employed through anaerobic respiration. Following treatments, lactate and octopine dehydrogenase activities were found to have no significant response in activities with treatment and time. However, corals subjected to chronic nighttime hypoxia were found to exhibit significant increases in alanopine dehydrogenase activity after three days of exposure and strombine dehydrogenase activity starting after one overnight exposure cycle. These findings provide new insights into coral metabolic shifts in extremely low-oxygen environments and point to ADH and SDH assays as tools for quantifying the impact of hypoxia on coral health.
doi:10.7717/peerj.1956
PMCID: PMC4841221  PMID: 27114888
Montipora capitata; Anoxia; Hypoxia; Enzyme activity; Alanopine dehydrogenase; Strombine dehydrogenase; Ecological resilience; Coral metabolism; Corals; Hawaii
18.  Aspiration pneumonia after concurrent chemoradiotherapy for head-and-neck cancer 
Cancer  2014;121(8):1303-1311.
Background
Aspiration pneumonia represents an under-reported complication of chemoradiotherapy in head-and-neck cancer. This study evaluated the incidence, risk factors, and mortality of aspiration pneumonia in a large cohort of head-and-neck cancer patients treated with concurrent chemoradiotherapy.
Methods
Patients with head-and-neck cancer diagnosed between 2000 and 2009 were identified from the SEER-Medicare database. Aspiration pneumonia was identified from Medicare billing claims. The cumulative incidence, risk factors, and survival after aspiration pneumonia were estimated and compared to a non-cancer population.
Results
Of 3,513 head-and-neck cancer patients, 801 patients developed aspiration pneumonia at a median time of 5 months after initiating treatment. The 1- and 5-year cumulative incidence of aspiration pneumonia was 15.8% and 23.8% for head-and-neck cancer patients and 3.6% and 8.7% for non-cancer controls, respectively. Among cancer patients multivariate analysis identified independent risk factors (p<0.05) for aspiration pneumonia including hypopharyngeal and nasopharyngeal tumors, male gender, older age, increased comorbidity, no surgery prior to radiation, and care received at a teaching hospital. Among cancer patients who experienced aspiration pneumonia, 674 (84%) were hospitalized of which 301 (45%) were admitted to an intensive care unit. Thirty-day mortality after hospitalization for aspiration pneumonia was 32.5%. Aspiration pneumonia was associated with a 42% increased risk of death (HR=1.42, p<0.001) after controlling for confounders.
Conclusions
This study found that nearly one-quarter of elderly patients will develop aspiration pneumonia within 5 years of chemoradiotherapy for head-and-neck cancer. A better understanding of mitigating factors will help identify patients at risk for this potentially lethal complication.
doi:10.1002/cncr.29207
PMCID: PMC4774546  PMID: 25537836
Aspiration pneumonia; chemoradiotherapy; head and neck neoplasms; Surveillance, Epidemiology and End Results Program; Medicare
19.  Brief Intervention to Reduce Hazardous Drinking and Enhance Coping among OEF/OIF/OND Veterans 
Hazardous drinking among US Military combat veterans is an important public health issue. Because recent combat veterans are difficult to engage in specialty mental health and substance abuse care, there is a need for opportunistic interventions administered in settings visited by recent combat veterans such as primary care. This paper describes a brief (single-session) intervention that was recently developed and tested in a sample of veterans of Operations Enduring Freedom, Iraqi Freedom and New Dawn (OEF/OIF/OND). The intervention consists of a counseling session delivered in a Motivational Interviewing style using a packet of personalized feedback about alcohol misuse, symptoms of PTSD and depression, as well as coping skills. The treatment is described and data from a single case treated with this intervention are presented.
doi:10.1037/a0036771
PMCID: PMC4498587  PMID: 26170531
20.  Abundance and recruitment data for Undaria pinnatifida in Brest harbour, France: Model versus field results 
Data in Brief  2016;7:540-545.
The data presented in this article are related to the research article entitled “A modelling approach to explore the critical environmental parameters influencing the growth and establishment of the invasive seaweed Undaria pinnatifida in Europe” [1]. This article describes raw simulation data output from a novel individual-based model of the invasive kelp species Undaria pinnatifida. It also includes field data of monthly abundance and recruitment values for a population of invasive U. pinnatifida (in Brest harbour, France) that were used to validate the model. The raw model output and field data are made publicly available in order to enable critical analysis of the model predictions and to inform future modelling efforts of the study species.
doi:10.1016/j.dib.2016.02.075
PMCID: PMC4802417  PMID: 27054156
Macroalgae; Individual-based model; Invasive species; Seaweed; Kelp; Undaria pinnatifida; Recruitment; Abundance
21.  Comparative genomics and functional analysis of the 936 group of lactococcal Siphoviridae phages 
Scientific Reports  2016;6:21345.
Genome sequencing and comparative analysis of bacteriophage collections has greatly enhanced our understanding regarding their prevalence, phage-host interactions as well as the overall biodiversity of their genomes. This knowledge is very relevant to phages infecting Lactococcus lactis, since they constitute a significant risk factor for dairy fermentations. Of the eighty four lactococcal phage genomes currently available, fifty five belong to the so-called 936 group, the most prevalent of the ten currently recognized lactococcal phage groups. Here, we report the genetic characteristics of a new collection of 936 group phages. By combining these genomes to those sequenced previously we determined the core and variable elements of the 936 genome. Genomic variation occurs across the 936 phage genome, such as genetic elements that (i) lead to a +1 translational frameshift resulting in the formation of additional structures on the phage tail, (ii) specify a double neck passage structure, and (iii) encode packaging module-associated methylases. Hierarchical clustering of the gene complement of the 936 group phages and nucleotide alignments allowed grouping of the ninety 936 group phages into distinct clusters, which in general appear to correspond with their geographical origin.
doi:10.1038/srep21345
PMCID: PMC4759559  PMID: 26892066
22.  Analysis of the N-terminal region of human MLKL, as well as two distinct MLKL isoforms, reveals new insights into necroptotic cell death 
Bioscience Reports  2016;36(1):e00291.
We show that mixed lineage kinase domain-like (MLKL) isoform 2, which lacks the pseudokinase domain and activation loop phosphorylation sites, is a more potent activator of cell death compared with MLKL isoform 1. Both MLKL isoforms are expressed in human monocyte-derived macrophages.
The pseudokinase mixed lineage kinase domain-like (MLKL) is an essential effector of necroptotic cell death. Two distinct human MLKL isoforms have previously been reported, but their capacities to trigger cell death have not been compared directly. Herein, we examine these two MLKL isoforms, and further probe the features of the human MLKL N-terminal domain that are required for cell death. Expression in HEK293T cells of the N-terminal 201 amino acids (aa) of human MLKL is sufficient to cause cell death, whereas expression of the first 154 aa is not. Given that aa 1–125 are able to initiate necroptosis, our findings indicate that the helix that follows this region restrains necroptotic activity, which is again restored in longer constructs. Furthermore, MLKL isoform 2 (MLKL2), which lacks much of the regulatory pseudokinase domain, is a much more potent inducer of cell death than MLKL isoform 1 (MLKL1) in ectopic expression studies in HEK293T cells. Modelling predicts that a C-terminal helix constrains the activity of MLKL1, but not MLKL2. Although both isoforms are expressed by human monocyte-derived macrophages at the mRNA level, MLKL2 is expressed at much lower levels. We propose that it may have a regulatory role in controlling macrophage survival, either in the steady state or in response to specific stimuli.
doi:10.1042/BSR20150246
PMCID: PMC4725247  PMID: 26704887
cell death; isoform; macrophage; mixed lineage kinase domain-like; MLKL; necroptosis
23.  The Atomic Structure of the Phage Tuc2009 Baseplate Tripod Suggests that Host Recognition Involves Two Different Carbohydrate Binding Modules 
mBio  2016;7(1):e01781-15.
ABSTRACT
The Gram-positive bacterium Lactococcus lactis, used for the production of cheeses and other fermented dairy products, falls victim frequently to fortuitous infection by tailed phages. The accompanying risk of dairy fermentation failures in industrial facilities has prompted in-depth investigations of these phages. Lactococcal phage Tuc2009 possesses extensive genomic homology to phage TP901-1. However, striking differences in the baseplate-encoding genes stimulated our interest in solving the structure of this host’s adhesion device. We report here the X-ray structures of phage Tuc2009 receptor binding protein (RBP) and of a “tripod” assembly of three baseplate components, BppU, BppA, and BppL (the RBP). These structures made it possible to generate a realistic atomic model of the complete Tuc2009 baseplate that consists of an 84-protein complex: 18 BppU, 12 BppA, and 54 BppL proteins. The RBP head domain possesses a different fold than those of phages p2, TP901-1, and 1358, while the so-called “stem” and “neck” domains share structural features with their equivalents in phage TP901-1. The BppA module interacts strongly with the BppU N-terminal domain. Unlike other characterized lactococcal phages, Tuc2009 baseplate harbors two different carbohydrate recognition sites: one in the bona fide RBP head domain and the other in BppA. These findings represent a major step forward in deciphering the molecular mechanism by which Tuc2009 recognizes its saccharidic receptor(s) on its host.
IMPORTANCE
Understanding how siphophages infect Lactococcus lactis is of commercial importance as they cause milk fermentation failures in the dairy industry. In addition, such knowledge is crucial in a general sense in order to understand how viruses recognize their host through protein-glycan interactions. We report here the lactococcal phage Tuc2009 receptor binding protein (RBP) structure as well as that of its baseplate. The RBP head domain has a different fold than those of phages p2, TP901-1, and 1358, while the so-called “stem” and “neck” share the fold characteristics also found in the equivalent baseplate proteins of phage TP901-1. The baseplate structure contains, in contrast to other characterized lactococcal phages, two different carbohydrate binding modules that may bind different motifs of the host’s surface polysaccharide.
doi:10.1128/mBio.01781-15
PMCID: PMC4742702  PMID: 26814179
24.  Flicking the molecular switch underlying MLKL-mediated necroptosis 
Molecular & Cellular Oncology  2015;2(3):e985550.
The pseudokinase domain of the necroptosis effector mixed lineage kinase domain-like (MLKL) functions as a latch to restrain the unleashing of its N-terminal 4-helix bundle (4HB) domain. Cell death mediated by the 4HB domain relies on membrane association and oligomerization, which can be inhibited by an ATP-mimetic small molecule that binds the pseudokinase domain of MLKL.
doi:10.4161/23723556.2014.985550
PMCID: PMC4905300  PMID: 27308464
25.  Epidemiology of Gastrointestinal Stromal Tumors in the Era of Histology Codes: Results of a Population-Based Study 
To date, all population-based epidemiologic data on gastrointestinal stromal tumor (GIST) in the United States predate the 2001 implementation of GIST-specific histology coding. As such, results from previous studies were limited due to inclusion of non-GIST abdominal or gastrointestinal sarcomas. We utilized a national cancer registry with modern day histological codes to gain greater insight into the true epidemiology of GIST in the United States. We identified 6,142 patients diagnosed with GIST between 2001 and 2011 in the Surveillance, Epidemiology, and End Results database. Incidence, survival, demographic risk factors, and prognostic factors were analyzed. Annual age-adjusted incidence rose from 0.55/100,000 in 2001 to 0.78/100,000 in 2011 and increased with age, peaking among 70-79 year olds (3.06/100,000). GIST was also more common in males than females [rate ratio (RR)=1.35], non-Hispanics than Hispanics (RR=1.23), and blacks (RR=2.07) or Asians/Pacific Islanders (RR=1.50) than whites. The study period had 5-year overall and GIST-specific survival rates of 65% and 79%, respectively. The 5-year overall survival rates for those with localized, regional, and metastatic disease at diagnosis were 77%, 64%, and 41%, respectively. Multivariate analyses demonstrated that older age at diagnosis, male sex, black race, and advanced stage at diagnosis were independent risk factors of worse overall survival. Multivariate analysis also showed the four aforementioned characteristics, along with earlier year of diagnosis, to be independent risk factors of worse GIST-specific survival. As the first population-based, epidemiological study of histologically confirmed disease, our findings provide a robust representation of GIST in the era of immunohistochemical diagnoses.
doi:10.1158/1055-9965.EPI-14-1002
PMCID: PMC4294949  PMID: 25277795

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