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1.  Pyruvate sensitizes pancreatic tumors to hypoxia-activated prodrug TH-302 
Hypoxic niches in solid tumors harbor therapy-resistant cells. Hypoxia-activated prodrugs (HAPs) have been designed to overcome this resistance and, to date, have begun to show clinical efficacy. However, clinical HAPs activity could be improved. In this study, we sought to identify non-pharmacological methods to acutely exacerbate tumor hypoxia to increase TH-302 activity in pancreatic ductal adenocarcinoma (PDAC) tumor models.
Three human PDAC cell lines with varying sensitivity to TH-302 (Hs766t > MiaPaCa-2 > SU.86.86) were used to establish PDAC xenograft models. PDAC cells were metabolically profiled in vitro and in vivo using the Seahorse XF system and hyperpolarized 13C pyruvate MRI, respectively, in addition to quantitative immunohistochemistry. The effect of exogenous pyruvate on tumor oxygenation was determined using electroparamagnetic resonance (EPR) oxygen imaging. Hs766t and MiaPaCa-2 cells exhibited a glycolytic phenotype in comparison to TH-302 resistant line SU.86.86. Supporting this observation is a higher lactate/pyruvate ratio in Hs766t and MiaPaCa xenografts as observed during hyperpolarized pyruvate MRI studies in vivo. Coincidentally, response to exogenous pyruvate both in vitro (Seahorse oxygen consumption) and in vivo (EPR oxygen imaging) was greatest in Hs766t and MiaPaCa models, possibly due to a higher mitochondrial reserve capacity. Changes in oxygen consumption and in vivo hypoxic status to pyruvate were limited in the SU.86.86 model. Combination therapy of pyruvate plus TH-302 in vivo significantly decreased tumor growth and increased survival in the MiaPaCa model and improved survival in Hs766t tumors.
Using metabolic profiling, functional imaging, and computational modeling, we show improved TH-302 activity by transiently increasing tumor hypoxia metabolically with exogenous pyruvate. Additionally, this work identified a set of biomarkers that may be used clinically to predict which tumors will be most responsive to pyruvate + TH-302 combination therapy. The results of this study support the concept that acute increases in tumor hypoxia can be beneficial for improving the clinical efficacy of HAPs and can positively impact the future treatment of PDAC and other cancers.
Electronic supplementary material
The online version of this article (doi:10.1186/s40170-014-0026-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4310189  PMID: 25635223
Hypoxia; Hypoxia-activated prodrugs; TH-302; Tumor microenvironment; Metabolism; Pancreatic cancer; Functional imaging; Computational modeling
2.  Bioinspired amphiphilic phosphate block copolymers as non-fluoride materials to prevent dental erosion 
RSC advances  2014;4(90):49053-49060.
Inspired by the fact that certain natural proteins, e.g. casein phosphopeptide or amelogenin, are able to prevent tooth erosion (mineral loss) and to enhance tooth remineralization, a synthetic amphiphilic diblock copolymer, containing a hydrophilic methacryloyloxyethyl phosphate block (MOEP) and a hydrophobic methyl methacrylate block (MMA), was designed as a novel non-fluoride agent to prevent tooth erosion under acidic conditions. The structure of the polymer, synthesized by reversible addition-fragment transfer (RAFT) polymerization, was confirmed by gel permeation chromatography (GPC), Fourier transform infrared spectroscopy (FTIR), and nuclear magnetic resonance spectroscopy (NMR). While the hydrophilic PMOEP block within the amphiphilic block copolymer strongly binds to the enamel surface, the PMMA block forms a hydrophobic shell to prevent acid attack on tooth enamel, thus preventing/reducing acid erosion. The polymer treatment not only effectively decreased the mineral loss of hydroxyapatite (HAP) by 36–46% compared to the untreated control, but also protected the surface morphology of the enamel specimen following exposure to acid. Additionally, experimental results confirmed that low pH values and high polymer concentrations facilitate polymer binding. Thus, the preliminary data suggests that this new amphiphilic diblock copolymer has the potential to be used as a non-fluoride ingredient for mouth-rinse or toothpaste to prevent/reduce tooth erosion.
PMCID: PMC4235796  PMID: 25419457
3.  Improved Serum Leptin and Ghrelin Following Bariatric Surgery Predict Better Postoperative Cognitive Function 
Background and Purpose
Bariatric surgery is associated with improved cognitive function, but the mechanisms underlying these gains remain poorly understood. Disturbed leptin and ghrelin systems are common in obese individuals and are associated with impaired cognitive function in other samples. Bariatric surgery has been shown to improve serum leptin and ghrelin levels, and these changes may underlie postoperative cognitive improvements.
Eighty-four patients completed a computerized cognitive test battery prior to bariatric surgery and at 12 months postoperatively. Participants also submitted to an 8-hour fasting blood draw to quantify serum leptin and ghrelin concentrations at these same time points.
Baseline cognitive impairments and disturbed leptin and ghrelin levels improved at the 12-month follow-up compared to presurgery. Higher leptin levels were associated with worse attention/executive function at baseline; no such findings emerged for ghrelin. Regression analyses controlling for baseline factors and demographic characteristics showed that both decreased leptin and increased ghrelin following surgery was associated with better attention/executive function at the 12-month follow-up. These effects diminished after controlling for the postoperative change in body mass index (BMI); however, BMI change did not predict 12-month cognitive function.
Improvements in leptin and ghrelin levels following bariatric surgery appear to contribute to postoperative cognitive benefits. These gains may involve multiple mechanisms, such as reduced inflammation and improved glycemic control. Future studies that employ neuroimaging are needed to clarify the underlying mechanisms and determine whether the effects of bariatric surgery on leptin and ghrelin levels can attenuate adverse brain changes and/or risk of dementia in severely obese individuals.
PMCID: PMC4302179  PMID: 25628737
obesity; bariatric surgery; cognitive function; leptin; ghrelin
4.  PX-478, an inhibitor of hypoxia-inducible factor-1α, enhances radiosensitivity of prostate carcinoma cells 
Overexpression of hypoxia-inducible factor-1α (HIF-1α) in human tumors is associated with poor prognosis and poor outcome to radiation therapy. Inhibition of HIF-1α is considered as a promising approach in cancer therapy. The purpose of this study was to test the efficacy of a novel HIF-1α inhibitor PX-478 as a radiosensitizer under normoxic and hypoxic conditions in vitro. PC3 and DU 145 prostate carcinoma cells were treated with PX-478 for 20 hr, and HIF-1α protein level and clonogenic cell survival were determined under normoxia and hypoxia. Effects of PX-478 on cell cycle distribution and phosphorylation of H2AX histone were evaluated. PX-478 decreased HIF-1α protein in PC3 and DU 145 cells. PX-478 produced cytotoxicity in both cell lines with enhanced toxicity under hypoxia for DU-145. PX-478 (20 μmol/L) enhanced the radiosensitivity of PC3 cells irradiated under normoxic and hypoxic condition with enhancement factor (EF) 1.4 and 1.56, respectively. The drug was less effective in inhibiting HIF-1α and enhancing radiosensitivity of DU 145 cells compared to PC3 cells with EF 1.13 (normoxia) and 1.25 (hypoxia) at 50 μmol/L concentration. PX-478 induced S/G2M arrest in PC3 but not in DU 145 cells. Treatment of PC3 and DU 145 cells with the drug resulted in phosphorylation of H2AX histone and prolongation of γH2AX expression in the irradiated cells. PX-478 is now undergoing Phase I clinical trials as an oral agent. Although the precise mechanism of enhancement of radiosensitivity remains to be identified, this study suggests a potential role for PX-478 as a clinical radiation enhancer.
PMCID: PMC4277812  PMID: 18729192
PX-478; hypoxia; normoxia; HIF-1α; radiosensitivity
5.  Primary Amenorrhea in Anorexia Nervosa: Impact on Characteristic Masculine and Feminine Traits 
Animal studies indicate gonadal hormones at puberty have an effect on the development of masculine and feminine traits. However, it is unknown whether similar processes occur in humans. We examined whether women with anorexia nervosa (AN), who often experience primary amenorrhea, exhibit attenuated feminization in their psychological characteristics in adulthood due to the decrease/absence of gonadal hormones at puberty. Women with AN were compared on a number of psychological characteristics using General Linear Models based on the presence/absence of primary amenorrhea. Although women with primary amenorrhea exhibited lower anxiety scores than those without primary amenorrhea, in general, results did not provide evidence of attenuated feminization in women with AN with primary amenorrhea. Future research should utilize novel techniques and direct hormone measurement to explore the effects of pubertal gonadal hormones on masculine and feminine traits.
PMCID: PMC4266542  PMID: 24123541
Organizational effects; sex differences; amenorrhea; pubertal timing; anorexia nervosa
6.  Lifespan extension by dietary intervention in a mouse model of Cockayne Syndrome uncouples early postnatal development from segmental progeria 
Aging cell  2013;12(6):1144-1147.
Cockayne Syndrome (CS) is a rare autosomal recessive segmental progeria characterized by growth failure, lipodystrophy, neurological abnormalities and photosensitivity but without skin cancer predisposition. CS life expectancy ranges from 5 to 16 years for the two most severe forms (Types II and I, respectively). Mouse models of CS have thus far been of limited value due either to very mild phenotypes, or premature death during postnatal development prior to weaning. The cause of death in severe CS models is unknown but has been attributed to extremely rapid aging. Here, we found that providing mutant pups with soft food from as late as postnatal day 14 allowed survival past weaning with high penetrance independent of dietary macronutrient balance in a novel CS model (Csa-/- ∣ Xpa-/-). Survival past weaning revealed a number of CS-like symptoms including small size, progressive loss of adiposity and neurological symptoms, with a maximum lifespan of 19 weeks. Our results caution against interpretation of death before weaning as premature aging, and at the same time provide a valuable new tool for understanding mechanisms of progressive CS-related progeroid symptoms including lipodystrophy and neurodysfunction.
PMCID: PMC4266594  PMID: 23895664
DNA repair; Cockayne syndrome; CSA; XPA; segmental progeria; lifespan
7.  Hard Exercise, Affect Lability, and Personality Among Individuals with Bulimia Nervosa 
Eating behaviors  2013;14(4):10.1016/j.eatbeh.2013.07.004.
The current study explores the personality traits of compulsivity (e.g., sense of orderliness and duty to perform tasks completely) and restricted expression (e.g., emotion expression difficulties) as potential moderators of the relation between affect lability and frequency of hard exercise episodes in a sample of individuals with bulimic pathology. Participants were 204 adult females recruited in five Midwestern cities who met criteria for threshold or subthreshold bulimia nervosa (BN). Compulsivity was found to significantly moderate the relation between affect lability and number of hard exercise episodes over the past 28 days, such that among those with high compulsivity, level of affect lability was associated with the number of hard exercise episodes; whereas, among those with low compulsivity, affect lability was not associated with the number of hard exercise episodes. The same pattern of findings emerged for restricted expression; however, this finding approached, but did not reach statistical significance. As such, it appears that affect lability is differentially related to hard exercise among individuals with BN depending upon the level of compulsivity and, to a more limited extent, restricted expression. These results suggest that, for individuals with BN with either compulsivity or restricted expression, focusing treatment on increasing flexibility and/or verbal expression of emotions may help them in the context of intense, fluctuating affect.
PMCID: PMC3832258  PMID: 24183126
exercise; emotion regulation; bulimia nervosa; affect lability; compulsivity; emotion expression
8.  Examining Duration of Binge Eating Episodes in Binge Eating Disorder 
The primary goal of this paper is to examine and clarify characteristics of binge eating in individuals with binge eating disorder (BED), particularly the duration of binge eating episodes, as well as potential differences between individuals with shorter compared to longer binge eating episodes.
Two studies exploring binge eating characteristics in BED were conducted. Study 1 examined differences in clinical variables among individuals (N = 139) with BED who reported a short (< 2 hours) versus long (≥ 2 hours) average binge duration. Study 2 utilized an ecological momentary assessment (EMA) design to examine the duration and temporal pattern of binge eating episodes in the natural environment in a separate sample of nine women with BED.
Participants in Study 1 who were classified as having long duration binge eating episodes displayed greater symptoms of depression and lower self-esteem, but did not differ on other measures of eating disorder symptoms, compared to those with short duration binge eating episodes. In Study 2, the average binge episode duration was approximately 42 minutes, and binge eating episodes were most common during the early afternoon and evening hours, as well as more common on weekdays versus weekends.
Past research on binge episode characteristics, particularly duration, has been limited to studies of binge eating episodes in BN. This study contributes to the existing literature on characteristics of binge eating in BED.
PMCID: PMC3889648  PMID: 23881639
9.  Restrictive Eating Behaviors are a Non-Weight-Based Marker of Severity in Anorexia Nervosa 
The purpose of this study was to compare the type and frequency of restrictive eating behaviors across the two subtypes of anorexia nervosa (AN; restricting [ANr] and binge eating/purging [ANbp]) using ecological momentary assessment (EMA) and to determine whether subtype differences in restrictive eating behaviors were attributable to severity of the disorder or the frequency of binge eating.
Participants (N = 118) were women at least 18 years of age with full (n = 59) or sub-threshold (n = 59) AN who participated in a two week (EMA) protocol.
General estimating equations revealed that individuals with ANbp generally reported more frequent restrictive eating behaviors than individuals with ANr. These differences were mostly accounted for by greater severity of eating psychopathology, indicating that the presence and frequency of restrictive eating behaviors in AN may be non-weight-based markers of severity. Binge eating frequency did not account for these findings.
The present findings are especially interesting in light of the weight-based severity rating in the DSM-5.
PMCID: PMC4001723  PMID: 23868197
Anorexia nervosa; subtypes; dietary restriction; severity
10.  Picking and nibbling: Frequency and associated clinical features in bulimia nervosa, anorexia nervosa and binge eating disorder 
Picking and nibbling (P&N) is a newly studied eating behavior characterized by eating in an unplanned and repetitious manner in between meals and snacks. This behavior seems to be related to poorer weight loss outcomes after bariatric surgery for weight loss in severely obese patients, but clarification is still required regarding its value in other clinical samples.
The purpose of this study was to investigate the frequency of P&N across different eating disorder samples, as well as to examine its association with psychopathological eating disorder features.
Our sample included treatment-seeking adult participants, recruited for five different clinical trials: 259 binge eating disorder (BED); 264 bulimia nervosa (BN) and 137 anorexia nervosa (AN). Participants were assessed using the Eating Disorders Examination interview before entering the clinical trials.
P&N was reported by 44% of the BED; 57.6% of the BN and 34.3% of the AN participants. No association was found between P&N and BMI, the presence of compensatory behaviors, binge eating or any of the EDE subscales.
This study suggests that P&N behavior is highly prevalent across eating disorder diagnoses. Our findings suggest that P&N is not associated with psychopathology symptoms or other eating disordered behaviors.
PMCID: PMC4009470  PMID: 23922133
Picking and nibbling; eating behaviors;  eating disordered behaviors
11.  Sexual Functioning and Sex Hormones in Persons with Extreme Obesity and Seeking Surgical and Non-Surgical Weight Loss 
Many individuals with obesity are motivated to lose weight to improve weight-related comorbidities or psychosocial functioning, including sexual functioning. Few studies have documented rates of sexual dysfunction in persons with obesity.
This study investigated sexual functioning, sex hormones, and relevant psychosocial constructs in individuals with obesity who sought surgical and non-surgical weight loss.
University based health systems.
One hundred forty-one bariatric surgery patients (median BMI [25th percentile, 75th percentile] 44.6 [41.4, 50.1]) and 109 individuals (BMI = 40.0 [38.0, 44.0]) who sought nonsurgical weight loss participated. Sexual functioning was assessed by the Female Sexual Function Index (FSFI) and International Index of Erectile Function (IIEF). Hormones were assessed by blood assay. Quality of life, body image, depressive symptoms and marital adjustment were assessed by validated questionnaires.
Fifty-one percent of women presenting for bariatric surgery reported a sexual dysfunction; 36% of men presenting for bariatric surgery reported erectile dysfunction (ED). This is in contrast to 41% of women who sought nonsurgical weight loss and reported a sexual dysfunction and 20% of men who sought nonsurgical weight loss and reported ED. These differences were not statistically significant. Sexual dysfunction was strongly associated with psychosocial distress in women; these relationships were less strong and less consistent among men. Sexual dysfunction was unrelated to sex hormones, except for sex hormone binding globulin (SHGB) in women.
Women and men who present for bariatric surgery, as compared to individuals who sought non-surgical weight loss, were not significantly more likely to experience a sexual dysfunction. There were few differences in reproductive hormones and psychosocial constructs between candidates for bariatric surgery and individuals interested in non-surgical weight loss.
PMCID: PMC3864660  PMID: 24120985
Sexual Functioning; Quality of Life; Obesity
13.  Health Care Costs in Patients with Eating Disorders 
To examine health care costs among patients with eating disorders using the Blue Cross Blue Shield of North Dakota (BCBSND) claims database system.
Four groups of individuals enrolled between 1999 and 2005 were identified: 1) a group diagnosed with eating disorders at the beginning of the study period, in 2000 or 2001; 2) a group diagnosed with eating disorders later in the study period, in 2004 or 2005; 3) a comparison group with depression; and 4) a non-eating disordered comparison group.
Health care costs were high for patients diagnosed with an eating disorder during the period when the diagnosis was made but remained elevated in the years following. Such costs were consistently higher than those for the non-eating disordered comparison group, but similar to the depression comparison group.
Health care costs remained elevated after a diagnosis of an eating disorder for an extended period of time.
PMCID: PMC4205564  PMID: 19172600
14.  A Fine-Grained Analysis of Eating Behavior in Women with Bulimia Nervosa 
In the current study we were interested in developing a typology of eating in patients with bulimia nervosa based on the size of the eating episode, whether the episode was followed by self-induced vomiting, and the degree of loss of control self-reported by participants.
Twenty-one adult women with bulimia nervosa, purging type, were evaluated using the Nutritional Data System for Research, the Eating Disorders Examination, and the Matrix.
The most common type of episode resembled what might be termed “normal” eating which involved the consumption of less than 1000 kcal with no sense of loss of control and no vomiting. There was an increase in severity of self-assessed loss of control in objectively large eating episodes with vomiting. Self-reported hunger prior to eating episodes did not seem to be predictive of subsequent behavior. Most people were engaged in other behaviors while eating.
The results of this study suggest a typology that included primarily four types of eating episodes. The results also suggest that when loss of control is assessed on a Likert-scale rather than as a dichotomous variable there is considerable variability in self-assessed degree of loss of control.
PMCID: PMC4201497  PMID: 21956763
bulimia nervosa; eating behavior; binge eating; vomiting; nutritional assessment
15.  Benefits of short-term dietary restriction in mammals 
Experimental gerontology  2013;48(10):1043-1048.
Dietary or calorie restriction (DR, CR), defined as reduced food intake without malnutrition, imparts many benefits in model organisms. Extended longevity is the most popularized benefit but the least clinically relevant due to the requirement for long-term food restriction. DR also promotes stress resistance and metabolic fitness. Emerging data in experimental models and in humans indicate that these benefits occur rapidly upon initiation of DR, suggesting potential clinical relevance. Here we review data on the ability of short-term DR to induce beneficial effects on clinically relevant endpoints including surgical stress, inflammation, chemotherapy and insulin resistance. The encouraging results obtained in these preclinical and clinical studies, and the general lack of mechanistic understanding, both strongly suggest the need for further research in this emerging area.
PMCID: PMC3745522  PMID: 23376627
16.  Bariatric Surgery Patients Exhibit Improved Memory Function 12 Months Post-Operatively 
Obesity surgery  2013;23(10):1527-1535.
Previous work from our group demonstrated improved memory function in bariatric surgery patients at 12 weeks post-operatively relative to controls. However, no study has examined longer term changes in cognitive functioning following bariatric surgery.
Materials and Methods
A total of 137 individuals (95 bariatric surgery patients, 42 obese controls) were followed prospectively to determine whether post-surgery cognitive improvements persist. Potential mechanisms of change were also examined. Bariatric surgery participants completed self-report measurements and a computerized cognitive test battery prior to surgery and at 12-week and 12-month follow-up; obese controls completed measures at equivalent time points.
Bariatric surgery patients exhibited cognitive deficits relative to well established standardized normative data prior to surgery, and obese controls demonstrated similar deficits. Analyses of longitudinal change indicated an interactive effect on memory indices, with bariatric surgery patients demonstrating better performance post-operatively than obese controls.
While memory performance was improved 12 months post-bariatric surgery, the mechanisms underlying these improvements were unclear and did not appear attributable to obvious post-surgical changes, such as reductions in BMI or co-morbid medical conditions. Future studies employing neuroimaging, metabolic biomarkers, and more precise physiological measurements are needed to determine the mechanisms underlying memory improvements following bariatric surgery.
PMCID: PMC3773052  PMID: 23636994
obesity; cognitive function; bariatric surgery; longitudinal assessment
17.  Associations between Retrospective versus Ecological Momentary Assessment Measures of Emotion and Eating Disorder Symptoms in Anorexia Nervosa 
Journal of psychiatric research  2013;47(10):1514-1520.
This study examined the unique associations between eating disorder symptoms and two emotion-related constructs (affective lability and anxiousness) assessed via distinct methodologies in anorexia nervosa (AN). Women (N=116) with full or subthreshold AN completed baseline emotion and eating disorder assessments, followed by two weeks of ecological momentary assessment (EMA). Hierarchical regressions were used to examine unique contributions of baseline and EMA measures of affective lability and anxiousness in accounting for variance in baseline eating disorder symptoms and EMA dietary restriction, controlling for age, body mass index, depression, and AN diagnostic subtype. Only EMA affective lability was uniquely associated with baseline eating disorder symptoms and EMA dietary restriction. Anxiousness was uniquely associated with baseline eating disorder symptoms regardless of assessment method; neither of the anxiousness measures was uniquely associated with EMA dietary restriction. Affective lability and anxiousness account for variance in global eating disorder symptomatology; AN treatments targeting these emotion-related constructs may prove useful.
PMCID: PMC3805055  PMID: 23880601
eating disorders; ecological momentary assessment; emotion; affective lability; anxiety; assessment
18.  Race/Ethnicity, Education, and Treatment Parameters as Moderators and Predictors of Outcome in Binge Eating Disorder 
Binge eating disorder (BED) is prevalent among individuals from minority racial/ethnic groups and among individuals with lower levels of education, yet the efficacy of psychosocial treatments for these groups has not been examined in adequately powered analyses. This study investigated the relative variance in treatment retention and post-treatment symptom levels accounted for by demographic, clinical, and treatment variables as moderators and predictors of outcome.
Data were aggregated from eleven randomized, controlled trials of psychosocial treatments for BED conducted at treatment sites across the United States. Participants were N = 1,073 individuals meeting criteria for BED including n = 946 Caucasian, n = 79 African American, and n = 48 Hispanic/Latino participants. Approximately 86% had some higher education; 85% were female. Multi-level regression analyses examined moderators and predictors of treatment retention, Eating Disorder Examination (EDE) global score, frequency of objective bulimic episodes (OBEs), and OBE remission.
Moderator analyses of race/ethnicity and education were non-significant. Predictor analyses revealed African Americans were more likely to drop out of treatment than Caucasians, and lower level of education predicted greater post-treatment OBEs. African Americans showed a small but significantly greater reduction in EDE global score relative to Caucasians. Self-help treatment administered in a group showed negative outcomes relative to other treatment types, and longer treatment was associated with better outcome.
Observed lower treatment retention among African Americans and lesser treatment effects for individuals with lower levels of educational attainment are serious issues requiring attention. Reduced benefit was observed for shorter treatment length and self-help administered in groups.
PMCID: PMC4175452  PMID: 23647283
binge eating disorder; race; ethnicity; socioeconomic status; treatment outcome
19.  Pyruvate Induces Transient Tumor Hypoxia by Enhancing Mitochondrial Oxygen Consumption and Potentiates the Anti-Tumor Effect of a Hypoxia-Activated Prodrug TH-302 
PLoS ONE  2014;9(9):e107995.
TH-302 is a hypoxia-activated prodrug (HAP) of bromo isophosphoramide mustard that is selectively activated within hypoxic regions in solid tumors. Our recent study showed that intravenously administered bolus pyruvate can transiently induce hypoxia in tumors. We investigated the mechanism underlying the induction of transient hypoxia and the combination use of pyruvate to potentiate the anti-tumor effect of TH-302.
The hypoxia-dependent cytotoxicity of TH-302 was evaluated by a viability assay in murine SCCVII and human HT29 cells. Modulation in cellular oxygen consumption and in vivo tumor oxygenation by the pyruvate treatment was monitored by extracellular flux analysis and electron paramagnetic resonance (EPR) oxygen imaging, respectively. The enhancement of the anti-tumor effect of TH-302 by pyruvate treatment was evaluated by monitoring the growth suppression of the tumor xenografts inoculated subcutaneously in mice. TH-302 preferentially inhibited the growth of both SCCVII and HT29 cells under hypoxic conditions (0.1% O2), with minimal effect under aerobic conditions (21% O2). Basal oxygen consumption rates increased after the pyruvate treatment in SCCVII cells in a concentration-dependent manner, suggesting that pyruvate enhances the mitochondrial respiration to consume excess cellular oxygen. In vivo EPR oxygen imaging showed that the intravenous administration of pyruvate globally induced the transient hypoxia 30 min after the injection in SCCVII and HT29 tumors at the size of 500–1500 mm3. Pretreatment of SCCVII tumor bearing mice with pyruvate 30 min prior to TH-302 administration, initiated with small tumors (∼550 mm3), significantly delayed tumor growth.
Our in vitro and in vivo studies showed that pyruvate induces transient hypoxia by enhancing mitochondrial oxygen consumption in tumor cells. TH-302 therapy can be potentiated by pyruvate pretreatment if started at the appropriate tumor size and oxygen concentration.
PMCID: PMC4177858  PMID: 25254649
20.  In Vivo Imaging of Tumor Physiological, Metabolic, and Redox Changes in Response to the Anti-Angiogenic Agent Sunitinib: Longitudinal Assessment to Identify Transient Vascular Renormalization 
Antioxidants & Redox Signaling  2014;21(8):1145-1155.
Aims: The tumor microenvironment is characterized by a highly reducing redox status, a low pH, and hypoxia. Anti-angiogenic therapies for solid tumors frequently function in two steps: the transient normalization of structurally and functionally aberrant tumor blood vessels with increased blood perfusion, followed by the pruning of tumor blood vessels and the resultant cessation of nutrients and oxygen delivery required for tumor growth. Conventional anatomic or vascular imaging is impractical or insufficient to distinguish between the two steps of tumor response to anti-angiogenic therapies. Here, we investigated whether the noninvasive imaging of the tumor redox state and energy metabolism could be used to characterize anti-angiogenic drug-induced transient vascular normalization. Results: Daily treatment of squamous cell carcinoma (SCCVII) tumor-bearing mice with the multi-tyrosine kinase inhibitor sunitinib resulted in a rapid decrease in tumor microvessel density and the suppression of tumor growth. Tumor pO2 imaging by electron paramagnetic resonance imaging showed a transient increase in tumor oxygenation after 2–4 days of sunitinib treatment, implying improved tumor perfusion. During this window of vascular normalization, magnetic resonance imaging of the redox status using an exogenously administered nitroxide probe and hyperpolarized 13C MRI of the metabolic flux of pyruvate/lactate couple revealed an oxidative shift in tumor redox status. Innovation: Redox-sensitive metabolic couples can serve as noninvasive surrogate markers to identify the vascular normalization window in tumors with imaging techniques. Conclusion: A multimodal imaging approach to characterize physiological, metabolic, and redox changes in tumors is useful to distinguish between the different stages of anti-angiogenic treatment. Antioxid. Redox Signal. 21, 1145–1155.
PMCID: PMC4142786  PMID: 24597714
21.  Patient reports of cognitive problems are not associated with neuropsychological test performance in bariatric surgery candidates 
Recent work shows that cognitive deficits are common in bariatric surgery candidates and associated with reduced weight loss at 12 months post-operatively. As pre-operatively neuropsychological assessment is not available for all patients at all sites, many care providers ask patients to self-report their level of cognitive dysfunction. However, the accuracy of patient self-report of cognitive abilities has not been empirically examined.
Longitudinal Assessment of Bariatric Surgery (LABS), United States; Medical Center
Eighty-one bariatric surgery candidates completed self-report measures of cognitive functioning and neuropsychological tests of memory and other cognitive abilities.
Analyses found no association between subjective report of cognitive function and objective performance on neuropsychological testing. However, persons with history of major depressive disorder reported experiencing greater cognitive deficits.
These findings suggest that bariatric surgery candidates have little insight into their current level of cognitive function. Future work is needed to confirm these findings and identify brief, objective measures of cognitive function that are sensitive to deficits in bariatric surgery candidates.
PMCID: PMC3610809  PMID: 23245496
Bariatric; Cognition; Self-report; Memory; Executive Function
22.  Reporting weight change: Standardized reporting accounting for baseline weight 
Although it is recognized that a standardized approach to reporting weight change is essential to permit meaningful comparisons among cohorts and across studies, consensus is lacking.
Propose a method of reporting weight change allowing meaningful comparisons among studies of patients who underwent bariatric surgery and to demonstrate its utility using an example from the Longitudinal Assessment of Bariatric Surgery (LABS).
Relationships among several measures of weight change are described. Results from an observational, longitudinal cohort study of adults undergoing bariatric surgery and from simulation studies are used to illustrate the proposed method.
University Hospitals
Baseline weight is a critical parameter when assessing weight change. Men undergoing a bariatric procedure other than gastric bypass or adjustable band tended to have greater weight loss twelve months after surgery than men undergoing gastric bypass when not accounting for baseline weight, but the opposite was found when results were adjusted for baseline weight. Simulation results show that with relatively modest sample sizes, the adjusted weight loss was significantly different between the two groups of men.
A consistent metric for reporting weight loss following bariatric surgery is essential to interpret outcomes across studies and among subgroups. The baseline weight adjusted % weight loss (A%WL) uses a standard population, e.g., the LABS cohort, to account for differences between cohorts with respect to baseline weight and its use can change the interpretation of results compared to an unadjusted measure.
PMCID: PMC3686891  PMID: 23337770
obesity; bariatric surgery; weight change
23.  Cognitive Function Predicts 24-Month Weight Loss Success Following Bariatric Surgery 
Clinically significant cognitive impairment, particularly in attention/executive and memory function, is found in many patients undergoing bariatric surgery. These difficulties have previously been linked to decreased weight loss 12 months post-surgery, but more protracted examination of this relationship has not yet been conducted.
The current study prospectively examined the independent contribution of cognitive function to weight loss 24 months following bariatric surgery. Given the rapid rate of cognitive improvement observed following surgery, postoperative cognitive function (i.e., cognition 12 weeks following surgery, controlling for baseline cognition) was expected to predict lower body mass index (BMI) and higher percent total weight loss (%WL) at 24-month follow-up.
Data were collected by three sites of the Longitudinal Assessment of Bariatric Surgery (LABS) parent project.
Fifty-seven individuals enrolled in the LABS project undergoing bariatric surgery completed cognitive evaluation at baseline, 12 weeks, and 24 months. %WL and BMI were calculated for 24-month postoperative follow-up.
Better cognitive function 12 weeks following surgery predicted higher %WL and lower BMI at 24 months, and specific domains of attention/executive and memory function were robustly related to decreased BMI and greater %WL at 24 months.
Results demonstrate that cognitive performance shortly after bariatric surgery predicts greater long-term %WL and lower BMI 24 months following bariatric surgery. Further work is needed to clarify the degree to which this relationship is mediated by adherence to postoperative guidelines.
PMCID: PMC3788845  PMID: 23816443
memory; cognition; executive function; adherence
24.  Predicting group cognitive-behavioral therapy outcome of binge eating disorder using empirical classification 
Behaviour research and therapy  2013;51(9):10.1016/j.brat.2013.05.001.
The purpose of this study was to use empirical classification based on Latent Profile Analysis to identify subgroups of binge eating disorder (BED) and to evaluate the extent to which these subgroups were predictive of treatment outcome in group cognitive–behavioral therapy (CBT). The Eating Disorder Examination (EDE), Structured Clinical Interview for DSM-IV, and Inventory of Depressive Symptomatology-Self-Report were administered to 259 participants at baseline in a 15-session CBT trial (190 of whom received active treatment). The best fitting model included three profiles: dietary restraint only (DRO; n = 96; 51%); low dietary restraint (LDR; n = 52; 27%); and dietary restraint plus psychopathology (DRP; n = 42; 22%). Regression analyses revealed that after controlling for baseline score and treatment condition, EDE Global scores were lower for the DRO compared to the LDR profile at one year follow-up (p = .047). Class assignment was not predictive of EDE binge eating frequency or abstinence at end of treatment or follow-up. These results suggest that meaningful empirical classes based on eating disorder symptoms, psychopathology, dietary restraint, and BMI can be identified in BED and that these classes may be useful in predicting long-term group CBT outcome.
PMCID: PMC3813468  PMID: 23820157
Binge eating; Cognitive–behavioral therapy; Empirical classification; Prognosis
25.  Personality-Based Subtypes of Anorexia Nervosa: Examining Validity and Utility Using Baseline Clinical Variables and Ecological Momentary Assessment 
Behaviour research and therapy  2013;51(8):512-517.
This study sought to empirically derive and validate clinically relevant personality-based subtypes of anorexia nervosa (AN).
Women (N=116) with full or subthreshold AN completed baseline measures of personality, clinical variables, and eating disorder (ED) symptoms, followed by two weeks of ecological momentary assessment (EMA). A latent profile analysis was conducted to identify personality subtypes, which were compared on baseline clinical variables and EMA variables.
The best-fitting model supported three subtypes: underregulated, overregulated, and low psychopathology. The underregulated subtype (characterized by high stimulus seeking, self-harm, and oppositionality) displayed greater baseline ED symptoms, as well as lower positive affect and greater negative affect, self-discrepancy, and binge eating in the natural environment. The overregulated subtype (characterized by high compulsivity and low stimulus seeking) was more likely to have a lifetime obsessive-compulsive disorder diagnosis and exhibited greater perfectionism; levels of negative affect, positive affect, and self-discrepancy in this group were intermediate between the other subtypes. The low psychopathology subtype (characterized by normative personality) displayed the lowest levels of baseline ED symptoms, co-occurring disorders, and ED behaviors measured via EMA.
Findings support the validity of these personality-based subtypes, suggesting the potential utility of addressing within-diagnosis heterogeneity in the treatment of AN.
PMCID: PMC3721308  PMID: 23792181
eating disorders; personality; ecological momentary assessment; affect; empirical classification; latent profile analysis

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