Medical-Legal Partnership Education Impacts Resident Physician Competencies Relating to Social Drivers of Health.

Medical-legal partnerships (MLPs) support patients and clinicians by streamlining legal and medical care and helping identify and address a subset of social drivers of health (SDOH). Less is known on the effect of MLPs on the competency of residents regarding SDOH. The aim of this study was to identify how integration of an MLP into a pediatric residency training program affected residents' experience understanding and addressing SDOH.

Creating a digital approach for promoting physical activity in pediatric pulmonary hypertension: A framework for future interventions.

Children with pulmonary hypertension (PH) often demonstrate limited exercise capacity. Data support exercise as an effective nonpharmacologic intervention among adults with PH. However, data on exercise training in children and adolescents are limited, and characteristics of the optimal exercise program in pediatric PH have not been identified. Exercise programs may have multiple targets, including muscle deficits which are associated with exercise limitations in both adult and pediatric PH. Wearable accelerometer sensors measure physical activity volume and intensity in the naturalistic setting and can facilitate near continuous data transfer and bidirectional communication between patients and the study team when paired with informatics tools during exercise interventions. To address the knowledge gaps in exercise training in pediatric PH, we designed a prospective, single arm, nonrandomized pilot study to determine feasibility and preliminary estimates of efficacy of a 16-week home exercise intervention, targeting lower extremity muscle mass and enriched by wearable mobile health technology. The exercIse Training in pulmONary hypertEnsion (iTONE) trial includes (1) semistructured exercise prescriptions tailored to the participant's baseline level of activity and access to resources; (2) interval goal setting fostering self-efficacy; (3) real time monitoring of activity via wearable devices; (4) a digital platform enabling communication and feedback between participant and study team; (5) multiple avenues to assess participant safety. This pilot intervention will provide information on the digital infrastructure needed to conduct home-based exercise interventions in PH and will generate important preliminary data on the effect of exercise interventions in youth with chronic cardiorespiratory conditions to power larger studies in the future.

Multilevel Factors Impacting Substance Use Treatment Access, Engagement, and Racial Equity Among Opioid Overdose Survivors in Boston, MA.

BACKGROUND: There are well-documented racial/ethnic inequities in drug-related overdoses and access to evidence-based opioid use services nationally and in Boston, MA. OBJECTIVE: To qualitatively explore the drivers of racial/ethnic inequities in access to opioid use disorder treatment and services in Boston. DESIGN: Semi-structured qualitative interviews. PARTICIPANTS: Using purposive sampling, researchers recruited 59 opioid overdose survivors in Boston who self-identified as Black, Hispanic or Latino/a/x, and/or White. APPROACH: Interviewers administered a socio-demographic and drug use survey, and used a semi-structured interview guide to explore experiences with and perspectives on substance use treatment and services. KEY RESULTS: Participants' racial/ethnic identities were distributed across three subgroups: non-Hispanic Black (n = 18; 31%), non-Hispanic White (n = 18; 31%), and Latino/a/x (n = 23; 39%). Qualitative analysis identified multiple themes that were organized into four social-ecological levels after analysis. At the individual level, some participants emphasized the importance of personal responsibility and individual motivation in determining access to services. Participants expressed a range of perspectives about using medication for opioid use disorder treatment; Black and Latino/a/x participants were more likely than White participants to have critical perspectives. At the interpersonal level, experiences of bias, stigma, and racism from staff in healthcare and treatment settings were common. At the program/process level, participants described challenges connecting to services following overdose and barriers within specific programs, with Black and Latino/a/x participants experiencing particular gaps. At the systems level, the limited availability of housing, employment, and mental health care negatively impacted treatment access and engagement. CONCLUSION: A racism lens was used during data interpretation to apply the themes at a broader population level. Through this lens, the identified barriers can be understood to have a disproportionate impact on people of color. Findings call for programmatic and policy solutions that address racism, break down stigma, and ensure equitable access to evidence-based services and social supports.

Cardiopulmonary exercise testing on adaptive equipment in children and adults with Friedreich ataxia.

INTRODUCTION/AIMS: Traditional exercise is often difficult for individuals with Friedreich ataxia (FRDA), and evidence is limited regarding how to measure exercise performance in this population. We evaluated the feasibility, reliability, and natural history of adaptive cardiopulmonary exercise test (CPET) performance in children and adults with FRDA. METHODS: Participants underwent CPET on either an arm cycle ergometer (ACE) or recumbent leg cycle ergometer (RLCE) at up to four visits (baseline, 2 weeks, 4 weeks, and 1 year). Maximum work, oxygen consumption (peak VO2), oxygen (O2) pulse, and anaerobic threshold (AT) were measured in those who reached maximal volition. Test-retest reliability was assessed with intraclass coefficients, and longitudinal change was assessed using regression analysis. RESULTS: In our cohort (N = 23), median age was 18 years (interquartile range [IQR], 14-23), median age of FRDA onset was 8 years (IQR 6-13), median Friedreich Ataxia Rating Scale score was 58 (IQR 54-62), and GAA repeat length on the shorter FXN allele (GAA1) was 766 (IQR, 650-900). Twenty-one (91%) completed a maximal CPET (n = 8, ACE and n = 13, RLCE). Age, sex, and GAA1 repeat length were each associated with peak VO2. Preliminary estimates demonstrated reasonable agreement between visits 2 and 3 for peak work by both ACE and RLCE, and for peak VO2, O2 pulse, and AT by RLCE. We did not detect significant performance changes over 1 year. DISCUSSION: Adaptive CPET is feasible in FRDA, a relevant clinical trial outcome for interventions that impact exercise performance and will increase access to participation as well as generalizability of findings.

Enhancing the health knowledge and health literacy of recently resettled refugees through classroom-based instructional methods.

Health education can elevate health literacy, which is associated with health knowledge, health-seeking behaviors and overall improved health outcomes. Refugees are particularly vulnerable to the effects of low health knowledge and literacy, which can exacerbate already poor health stemming from their displacement experience. Traditional learning methods including classroom-based instruction are typically how health-related information is presented to refugees. Through a series of interactive classes focused on specific health topics relevant to the resettled refugee population, this study evaluated the effectiveness of a classroom-based health education model in enhancing the health knowledge of recently resettled refugees. We used the Wilcoxon signed-rank test to evaluate differences in pre- and post-class knowledge through test performance. We found a significant improvement in health knowledge in two refugee groups: females and those who were employed. Culturally and socially sensitive considerations including language inclusiveness, class timing, transportation and childcare provisions are important when creating an educational program for individuals with refugee backgrounds. Developing focused approaches to instruction that enhance health knowledge could lead to better health literacy and ultimately improve health-related behaviors and outcomes in the refugee population.

Perspectives and recommendations of opioid overdose survivors experiencing unsheltered homelessness on housing, overdose, and substance use treatment in Boston, MA.

INTRODUCTION: Opioid overdose causes one in four deaths among people experiencing homelessness in Boston, MA. To reduce overdose risks, the experience and perspectives of people experiencing homelessness should be incorporated into housing, overdose prevention, and substance use treatment efforts. METHODS: In 2021, we conducted qualitative interviews with 59 opioid overdose survivors to inform equitable access to treatment services. In response to policy debate surrounding a public drug scene near a key recruitment site, we conducted a targeted thematic analysis of transcribed interview data from a subset of participants experiencing unsheltered homelessness (n=29) to explore their perspectives and recommendations on housing, overdose prevention, and substance use treatment. RESULTS: Among 29 participants who identified as non-Hispanic Black (n=10), Hispanic/Latinx (n=10), or as non-Hispanic White (n=9), the median number of self-reported opioid overdoses in the past three months was 2.0 (SD 3.7). Three themes emerged from this targeted analysis: (1) Participants described inadequate housing resources and unwelcoming shelter environments. (2) Participants near a large public drug scene explained how unsheltered homelessness was chaotic, dangerous, and disruptive to recovery goals. (3) Participants provided recommendations for improving housing and addiction treatment systems and including their perspectives in the development of solutions to the intersecting housing and opioid overdose crises. CONCLUSIONS: The overdose prevention, housing and substance use treatment systems must address the needs of opioid overdose survivors experiencing unsheltered homelessness. Overdose survivors experiencing unsheltered homelessness described a chaotic public drug scene but resorted to residing in nearby encampments because the existing shelter, housing, and addiction treatment systems were unwelcoming, difficult to navigate, or unaffordable. Despite efforts to provide low-threshold housing in Boston, additional low-barrier housing services (i.e., including harm reduction resources and without "sobriety" requirements) could promote the health and safety of people who use drugs and are experiencing homelessness.

Child safety assessments during a caregiver's evaluation in emergency departments after intimate partner violence.

BACKGROUND: Physical abuse of children is reported to occur in 30%-60% of homes with intimate partner violence (IPV). IPV in adult victims presenting to emergency departments (EDs) represents a critical opportunity to evaluate for child safety. OBJECTIVES: The primary objective was to determine the frequency of child safety assessments (CSAs), defined as any documented inquiry about the presence of children in the household, when adults presented to EDs for IPV. The secondary aims were to assess (1) the impact of demographic factors, ED type, and social work (SW) involvement on the likelihood of CSAs; (2) the nature of children's exposure; and (3) the frequency of child protective services (CPS) reports. METHODS: We performed a chart review of encounters with ICD-10-CM codes for patients aged 18-60 with IPV presenting to three EDs in Connecticut from 2017 through 2019. RESULTS: CSAs were completed in 179/277 encounters (78.9%) and were more likely to be completed in encounters with SW involvement than without (162/171 [94.7%] vs. 17/56 [30.3%], p < 0.001). A total of 143 children lived in the home at the time of the incident; of the 107 children for whom the nature of exposure was known, 10 (9.3%) were physically involved and 26 (24.2%) were direct witnesses to the violence. CPS reports were made in 52.4% of the encounters in which children lived in the home. CONCLUSIONS: CSAs were omitted in one-fifth of encounters for IPV. Given the high prevalence of children involved in IPV episodes, ED encounters for IPV represent an opportunity to improve the safety of children.

A Path FORWARD: Development of a Comprehensive Multidisciplinary Clinic to Create Health and Wellness for the Child and Adolescent with a Fontan Circulation.

Today, it is anticipated most individuals diagnosed with single-ventricle malformation will survive surgical reconstruction through a successful Fontan operation. As greater numbers of patients survive, so has the recognition that individuals with Fontan circulation face a variety of challenges. The goal of a normal quality and duration of life will not be reached by all. The hurdles fall into a variety of domains. From a cardiovascular perspective, the Fontan circulation is fundamentally flawed by its inherent nature of creating a state of chronically elevated venous pressure and congestion, accompanied by a relatively low cardiac output. Ventricular dysfunction, atrioventricular valve regurgitation, and arrhythmia may directly impact cardiac performance and can progress with time. Problems are not limited to the cardiovascular system. Fontan circulatory physiology impacts a multitude of biological processes and health parameters outside the heart. The lymphatic circulation is under strain manifesting as variable degrees of protein-rich lymph loss and immune system dysregulation. Organ system dysfunction develops through altered perfusion profiles. Liver fibrosis is ubiquitous, and a process of systemic fibrogenesis in response to circulatory stressors may affect other organs as well. Somatic growth and development can be delayed. Behavioral and mental health problems are common, presenting as clinically important levels of anxiety and depression. Most striking is the high variability in prevalence and magnitude of these complications within the population, indicating the likelihood of additional factors enhancing or mitigating their emergence. We propose that optimal care for the individual with single ventricle and a Fontan circulation is ideally offered in a comprehensive multidisciplinary manner, with attention to elements that are beyond cardiac management alone. In this report, we share the concepts, our experiences, and perspectives on development of a clinic model-the "Fontan rehabilitation, wellness and resilience development" or FORWARD program. We provide insights into the mechanics of our multidisciplinary model of care and the benefits offered serving our growing population of individuals with a Fontan circulation and their families.

Cardiopulmonary Exercise Testing in Pediatric Patients With Hypertrophic Cardiomyopathy.

Background: Exercise stress testing (EST) in pediatric hypertrophic cardiomyopathy (HCM) patients has not well described in a large heterogenous cohort. Objectives: The objective of the study was to determine the clinical utility of EST in pediatric HCM. Methods: This was a retrospective single-center analysis of HCM patients younger than 21 years who had EST between January 1, 2000, and January 1, 2019. Clinical, demographic characteristics, and EST data were analyzed, using the last EST during the study or prior to the event in subjects with a primary outcome. The primary composite endpoint included cardiac death, transplant, or arrhythmia requiring implantable cardioverter-defibrillator placement. Outcome analysis was performed using Cox proportional hazard modeling. Results: The study cohort included 140 patients, 52% with a recognized genetic variant. There were 2 tests aborted due to safety concerns (ST-segment changes, ventricular ectopy). The median age at first EST was 13.6 years. Ninety percent of patients were tested using cycle ergometry, and 44% were on a beta-blocker. The median peak oxygen consumption was 37.1 mL/kg/min (IQR: 12.5 mL/kg/min) or 81.2% predicted, the mean anaerobic threshold was 21.8 Ml (IQR: 8.3 mL), and the median peak power was 2.6 ± 1.1 W/kg or 73.7% predicted. Ectopy during EST was seen in 44% of patients, and 8% had an abnormal blood pressure response to exercise. The endpoint was reached in 12 patients. The presence of any degree of ectopy was a predictor of the composite endpoint (hazard ratio: 5.8; 95% CI: 1.3-26.7). Conclusions: EST is clinically useful in select pediatric patients with HCM. Ectopy on EST is a risk factor for cardiac death, cardiac transplant, and arrhythmias requiring implantable cardioverter-defibrillator.

Normative Values for Cardiopulmonary Exercise Stress Testing Using Ramp Cycle Ergometry in Children and Adolescents.

OBJECTIVES: To provide sex, age, and race specific reference values for ramp cycle ergometer cardiopulmonary exercise test (CPET) in children in the US. STUDY DESIGN: Retrospective review was conducted of all cardiopulmonary CPET data from our Exercise Physiology Laboratory on healthy children and adolescents (6-18 years) with body mass index between the 5th and 95th percentiles and structurally normal hearts who performed a ramp cycle ergometry stress test between 1999 and 2015. Twenty-eight exercise variables were included: peak oxygen consumption, oxygen consumption at ventilatory anaerobic threshold, peak work rate, resting and peak heart rate and blood pressure, resting pulmonary function testing, and ventilatory responses to progressive exercise using breath-by-breath gas exchange. Owing to the nonlinear association between CPET results and age, fractional polynomials were used in the mixed-effects regression models to describe the sex- and age-specific normative values with 95% CIs, after adjusting for race and body mass index. RESULTS: We analyzed data on 1829 children (average age, 13.6 ± 2.6 years; 52% male). After 12 years of age, males generally had higher peak values for aerobic capacity and work rate. There were progressive increases with age for both sexes in resting pulmonary function and ventilatory response to exercise, peak aerobic and work rate, and oxygen pulse. Notably, there was an age-related decrease in ventilatory equivalents of oxygen and carbon dioxide at the ventilatory anaerobic threshold. CONCLUSIONS: Future research using prospective, inclusive, and statistically planned cohorts with standardized laboratory approaches and confirmed interoperability should be considered as a focus for validating normative pediatric CPET values in the future.

Velocity influences the relative contributions of visual and vestibular cues to self-acceleration.

Self-motion perception is based on the integration of visual (optic flow) and vestibular (inertial) sensory information. Previous research has shown that the relative contribution of visual and vestibular cues can change in real time based on the reliability of that information. The present study assessed whether initial velocity and acceleration magnitude influence the relative contribution of these cues to the detection of self-acceleration. Participants performed a simple response time task with visual and vestibular self-acceleration cues as targets. Visual optic flow was presented at three possible initial velocities of 3, 9, or 15 m/s, and accelerated to result in three possible final velocities of 21, 27, or 33 m/s. Corresponding vestibular cues were presented at magnitudes between 0.01 and 0.04 g. The self-acceleration cues were presented at three possible stimulus onset asynchronies (SOAs): visual-first (by 100 ms), in-sync, and vestibular-first (by 100 ms). We found that presenting the cues in-sync resulted in the fastest responses across all velocities and acceleration magnitudes. Interestingly, presenting the visual cue first resulted in a relative advantage over vestibular-first at the slowest initial velocity of 3 m/s, and vice versa for the fastest initial velocity of 15 m/s. The fastest overall responses for visual-first and in-sync were observed at 9 m/s. The present results support the hypothesis that velocity of optic flow can alter the relative contribution of visual and vestibular cues to the detection of self-acceleration.

Attention modulates event-related spectral power in multisensory self-motion perception.

Humans integrate visual and physical (vestibular and proprioceptive) cues to motion during self-motion perception. Theta and alpha-band oscillations have been associated with the processing of visual motion (e.g. optic flow). Alpha and beta-band oscillations have been shown to be associated with sensory-motor processing (e.g. walking). The present study examined modulation of theta, alpha, and beta oscillations while participants made heading direction judgments during a passive self-motion task which required selective attention to one of the simultaneously presented visual or physical motion stimuli. Attention to physical (while ignoring visual) motion produced a different time course of changes in spectral power compared to attention to visual (while ignoring physical) motion. We observed weaker theta event-related synchronization (ERS), as well as stronger beta and later onset of alpha event-related desynchronization (ERD) in the attend-physical condition compared to the attend-visual condition. We observed individual differences in terms of ability to perform the task. Specifically, some participants were not able to ignore or discount the visual input when visual and physical heading direction was incongruent; this was reflected by similar event-related spectral power for both conditions. The results demonstrated a possible electrophysiological signature of the time course of 1) cue conflict (congruency effects), 2) attention to specific motion cues, and 3) individual differences in perceptual weighting of motion stimuli (high-vs. low-accuracy effects).

No-cost gym visits are associated with lower weight and blood pressure among non-Latino black and Latino participants with a diagnosis of hypertension in a multi-site demonstration project.

Well documented, persistent racial/ethnic health disparities in obesity and hypertension in the US demonstrate the continued need for interventions that focus on people of color who may be at higher risk. We evaluated a demonstration project funded by the CDC's Racial/Ethnic Approaches to Community Health (REACH) program at four federally qualified health centers (FQHC) and YMCA fitness and wellness centers in Boston. No-cost YMCA memberships were offered from June 2014 to June 2015 to non-Latino black and Latino adults with a diagnosis of hypertension. YMCA visit data were merged with health data for 224 participants (n = 1265 health center visits). We assessed associations between gym visit frequency and weight, body mass index (BMI), systolic blood pressure (SBP), and diastolic blood pressure (DBP) using longitudinal time-varying linear fixed-effects models. The total number of gym visits over the entire program duration was 5.5, while the conditional total number of visits (after the first gym visit has been made) was 17.3. Having visited the gym at least 10 times before an FQHC exam was, on average, associated with lower weight (1.19 kg, p = 0.01), lower BMI (0.43 kg/m2, p = 0.01) and reductions in SBP (-3.20 mm Hg, p = 0.01) and DBP (-2.06 mm Hg p = 0.01). Having visited the gym an average of 1.4 times per month (study average) was associated with reductions in weight, BMI, and DBP. No-cost gym visits were associated with improved weight and blood pressure in hypertensive non-Latino black and Latino adults in this program. Additional evaluation is necessary to assess the sustainability of these effects.

Undergraduate Neuroscience Education in the U.S.: Quantitative Comparisons of Programs and Graduates in the Broader Context of Undergraduate Life Sciences Education.

The impact of undergraduate neuroscience programs on the broader landscape of life sciences education has not been described. Using data from the National Center for Education Statistics, we found that the number of undergraduate neuroscience programs in the U.S. continues to grow. Within any given institution, neuroscience programs exist alongside a small number of other life sciences undergraduate programs, suggesting that neuroscience is one of few major options from which students can choose from at many institutions. Neuroscience majors constitute a substantial proportion of all life sciences graduates at many institutions, and in several cases, neuroscience majors were the majority of life sciences graduates. Thus, neuroscience programs contribute substantially to life sciences education, and neuroscience is a highly attractive major among undergraduate students where these programs are available. These data have implications for institutions with existing neuroscience programs as well as for institutions seeking to establish a new program.

A Quantitative Examination of Undergraduate Neuroscience Majors Applying and Matriculating to Osteopathic Medical School.

Undergraduates choose to become neuroscience majors for a number of reasons including future career goals. Faculty and administration of undergraduate neuroscience programs understand that many neuroscience majors have aspirations of applying and matriculating to medical school (Prichard, 2015); however a quantitative understanding of this particular student population remains unknown, especially in the context of the national growth in undergraduate neuroscience education (Ramos et al., 2011). In the present report, we use medical school application data to establish a novel quantitative understanding of the number of neuroscience majors that apply and matriculate to osteopathic medical school. Our data indicate that a substantial number of neuroscience majors do indeed apply and matriculate to medical school compared to other majors in the life sciences, math and physical sciences, and humanities. These data are relevant to faculty and administration of undergraduate neuroscience programs and suggest that when programmatic, curricular, and training decisions are made, they should be made in the context of the diverse motivations and professional goals of neuroscience majors including careers in medicine. Finally, our novel quantitative approach of determining student motivation and professional goals based on application/matriculation data, can complement traditional methods such as surveys and questionnaires and can be used to determine the extent to which neuroscience majors apply to other professional and graduate degree programs.

The Effectiveness of Simulator Motion in the Transfer of Performance on a Tracking Task Is Influenced by Vision and Motion Disturbance Cues.

OBJECTIVE: To examine the importance of platform motion to the transfer of performance in motion simulators. BACKGROUND: The importance of platform motion in simulators for pilot training is strongly debated. We hypothesized that the type of motion (e.g., disturbance) contributes significantly to performance differences. METHODS: Participants used a joystick to perform a target tracking task in a pod on top of a MOOG Stewart motion platform. Five conditions compared training without motion, with correlated motion, with disturbance motion, with disturbance motion isolated to the visual display, and with both correlated and disturbance motion. The test condition involved the full motion model with both correlated and disturbance motion. We analyzed speed and accuracy across training and test as well as strategic differences in joystick control. RESULTS: Training with disturbance cues produced critical behavioral differences compared to training without disturbance; motion itself was less important. CONCLUSION: Incorporation of disturbance cues is a potentially important source of variance between studies that do or do not show a benefit of motion platforms in the transfer of performance in simulators. APPLICATION: Potential applications of this research include the assessment of the importance of motion platforms in flight simulators, with a focus on the efficacy of incorporating disturbance cues during training.

Control over the strength of connections between modules: a double dissociation between stimulus format and task revealed by Granger causality mapping in fMRI.

Drawing on theoretical and computational work with the localist dual route reading model and results from behavioral studies, Besner et al. (2011) proposed that the ability to perform tasks that require overriding stimulus-specific defaults (e.g., semantics when naming Arabic numerals, and phonology when evaluating the parity of number words) necessitate the ability to modulate the strength of connections between cognitive modules for lexical representation, semantics, and phonology on a task- and stimulus-specific basis. We used functional magnetic resonance imaging to evaluate this account by assessing changes in functional connectivity while participants performed tasks that did and did not require such stimulus-task default overrides. The occipital region showing the greatest modulation of BOLD signal strength for the two stimulus types was used as the seed region for Granger causality mapping (GCM). Our GCM analysis revealed a region of rostromedial frontal cortex with a crossover interaction. When participants performed tasks that required overriding stimulus type defaults (i.e., parity judgments of number words and naming Arabic numerals) functional connectivity between the occipital region and rostromedial frontal cortex was present. Statistically significant functional connectivity was absent when the tasks were the default for the stimulus type (i.e., parity judgments of Arabic numerals and reading number words). This frontal region (BA 10) has previously been shown to be involved in goal-directed behavior and maintenance of a specific task set. We conclude that overriding stimulus-task defaults requires a modulation of connection strengths between cognitive modules and that the override mechanism predicted from cognitive theory is instantiated by frontal modulation of neural activity of brain regions specialized for sensory processing.

Is eye gaze direction always determined without intent?

It is widely assumed that processing of gaze direction occurs "automatically," in the sense that it is reflexive (unfolds in the absence of intention). We assessed this view in a task in which participants saw a schematic face in which the eyes were gazing left or right, along with a second directional target (an arrow in Experiment 1; a directional word in Experiment 2). The eyes and other directional target were sometimes congruent and other times incongruent. On each trial, participants were cued with a tone to respond to either the direction the eyes were gazing, or the direction the noneye target indicated. The time between the onset of the task cue and the onset of the face was manipulated so that on half the trials the face and the cue were presented at the same time. Regardless of the type of target, the congruency effect was the same size at the zero SOA as it was at the 750 SOA, suggesting that eyes were not processed until participants knew what task to perform. These results are consistent with the claim that processing of gaze direction is, at least some of the time, secondary to an intent (i.e., it is not reflexive).

CBP Activity Mediates Effects of the Histone Deacetylase Inhibitor Butyrate on WNT Activity and Apoptosis in Colon Cancer Cells.

Mutations in the WNT/beta-catenin pathway are responsible for initiating the majority of colorectal cancers (CRCs). We have previously shown that hyperactivation of this signaling by histone deacetylase inhibitors (HDACis) such as butyrate, a fermentation product of dietary fiber, promotes CRC cell apoptosis. The extent of association between beta-catenin and the transcriptional coactivator CREB-binding protein (CBP) influences WNT/catenin signaling and, therefore, colonic cell physiology. CBP functions as a histone acetylase (HAT); therefore, we hypothesized that the modulation of WNT/catenin activity by CBP modifies the ability of the HDACi butyrate to hyperinduce WNT signaling and apoptosis in CRC cells. Our findings indicate that CBP affects the hyperinduction of WNT activity by butyrate. ICG-001, which specifically blocks association between CBP and beta-catenin, abrogates the butyrate-triggered increase in the number of CRC cells with high levels of WNT/catenin signaling. Combination treatment of CRC cells with ICG-001 and butyrate results in cell type-specific effects on apoptosis. Further, both butyrate and ICG-001 repress CRC cell proliferation, with additive effects in suppressing cell growth. Our study strongly suggests that ICG-001-like agents would be effective against butyrate/HDACi-resistant CRC cells. Therefore, ICG-001-like agents may represent an important therapeutic option for CRCs that exhibit low-fold hyperactivation of WNT activity and apoptosis in the presence of HDACis. The findings generated from this study may lead to approaches that utilize modulation of CBP activity to facilitate CRC therapeutic or chemopreventive strategies.