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Differentiated thyroid cancer (DTC) affects thousands of lives worldwide every year. Typically, DTC is a treatable disease with a good prognosis. Yet, some patients are subjected to partial or total thyroidectomy and radioiodine therapy to prevent local disease recurrence and metastasis. Unfortunately, thyroidectomy and/or radioiodine therapy often worsen(s) the quality of life and might be unnecessary in indolent DTC cases. This clinical setting highlights the unmet need for a precise molecular diagnosis of DTC, which should dictate appropriate therapy. Here we propose a differential multi-omics model approach to distinguish normal gland from thyroid tumor and to indicate potential metastatic diseases in papillary thyroid cancer (PTC), a sub-class of DTC. Based on PTC patient samples, our data suggest that elevated nuclear and mitochondrial DNA mutational burden, intratumor heterogeneity, shortened telomere length, and altered metabolic profile reflect the potential for metastatic disease. Specifically, normal and tumor thyroid tissues from these patients had a distinct yet well-defined metabolic profile with high levels of anabolic metabolites and/or other metabolites associated with the energy maintenance of tumor cells. Altogether, this work indicates that a differential and integrated multi-omics approach might improve DTC management, perhaps preventing unnecessary thyroid gland removal and/or radioiodine therapy. Well-designed, prospective translational clinical trials will ultimately show the value of this targeted molecular approach.TRANSLATIONAL RELEVANCEIn this article, we propose a new integrated metabolic, genomic, and cytopathologic methods to diagnose Differentiated Thyroid Cancer when the conventional methods failed. Moreover, we suggest metabolic and genomic markers to help predict high-risk Papillary Thyroid Cancer. Both might be important tools to avoid unnecessary surgery and/or radioiodine therapy that can worsen the quality of life of the patients more than living with an indolent Thyroid nodule.Graphical Abstract

Background:We have previously shown that the long non-coding (lnc)RNA prostate cancer associated 3 (PCA3; formerly prostate cancer antigen 3) functions as a trans-dominant negative oncogene by targeting the previously unrecognized prostate cancer suppressor gene PRUNE2 (a homolog of the Drosophila prune gene), thereby forming a functional unit within a unique allelic locus in human cells. Here, we investigated the PCA3/PRUNE2 regulatory axis from early (tumorigenic) to late (biochemical recurrence) genetic events during human prostate cancer progression.Methods:The reciprocal PCA3 and PRUNE2 gene expression relationship in paired prostate cancer and adjacent normal prostate was analyzed in two independent retrospective cohorts of clinically annotated cases post-radical prostatectomy: a single-institutional discovery cohort (n=107) and a multi-institutional validation cohort (n=497). We compared the tumor gene expression of PCA3 and PRUNE2 to their corresponding expression in the normal prostate. We also serially examined clinical/pathological variables including time to disease recurrence.Results:We consistently observed increased expression of PCA3 and decreased expression of PRUNE2 in prostate cancer compared with the adjacent normal prostate across all tumor grades and stages. However, there was no association between the relative gene expression levels of PCA3 or PRUNE2 and time to disease recurrence, independent of tumor grades and stages.Conclusions:We concluded that upregulation of the lncRNA PCA3 and targeted downregulation of the protein-coding PRUNE2 gene in prostate cancer could be early (rather than late) molecular events in the progression of human prostate tumorigenesis but are not associated with biochemical recurrence. Further studies of PCA3/PRUNE2 dysregulation are warranted.Funding:We received support from the Human Tissue Repository and Tissue Analysis Shared Resource from the Department of Pathology of the University of New Mexico School of Medicine and a pilot award from the University of New Mexico Comprehensive Cancer Center. RP and WA were supported by awards from the Levy-Longenbaugh Donor-Advised Fund and the Prostate Cancer Foundation. EDN reports research fellowship support from the Brazilian National Council for Scientific and Technological Development (CNPq), Brazil, and the Associação Beneficente Alzira Denise Hertzog Silva (ABADHS), Brazil. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of New Mexico Comprehensive Cancer Center (CA118100) and the Rutgers Cancer Institute of New Jersey (CA072720).

Background:Lymphatic malformations (LMs) often pose treatment challenges due to a large size or a critical location that could lead to disfigurement, and there are no standardized treatment approaches for either refractory or unresectable cases.Methods:We examined the genomic landscape of a patient cohort of LMs (n = 30 cases) that underwent comprehensive genomic profiling using a large-panel next-generation sequencing assay. Immunohistochemical analyses were completed in parallel.Results:These LMs had low mutational burden with hotspot PIK3CA mutations (n = 20) and NRAS (n = 5) mutations being most frequent, and mutually exclusive. All LM cases with Kaposi sarcoma-like (kaposiform) histology had NRAS mutations. One index patient presented with subacute abdominal pain and was diagnosed with a large retroperitoneal LM harboring a somatic PIK3CA gain-of-function mutation (H1047R). The patient achieved a rapid and durable radiologic complete response, as defined in RECIST1.1, to the PI3Kα inhibitor alpelisib within the context of a personalized N-of-1 clinical trial (NCT03941782). In translational correlative studies, canonical PI3Kα pathway activation was confirmed by immunohistochemistry and human LM-derived lymphatic endothelial cells carrying an allele with an activating mutation at the same locus were sensitive to alpelisib treatment in vitro, which was demonstrated by a concentration-dependent drop in measurable impedance, an assessment of cell status.Conclusions:Our findings establish that LM patients with conventional or kaposiform histology have distinct, yet targetable, driver mutations.Funding:R.P. and W.A. are supported by awards from the Levy-Longenbaugh Fund. S.G. is supported by awards from the Hugs for Brady Foundation. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of Arizona Cancer Center (CA023074), the University of New Mexico Comprehensive Cancer Center (CA118100), and the Rutgers Cancer Institute of New Jersey (CA072720). B.K.M. was supported by National Science Foundation via Graduate Research Fellowship DGE-1143953.Clinical trial number:NCT03941782

Access to mental health (MH) care is of paramount concern to U.S. health care delivery systems, including the Veterans Health Administration. To improve access, there is a need to better focus existing MH resources toward care for those most in need of specialty-level MH treatment. This article provides early results of Project FLOW's (not an acronym) approach to developing and evaluating electronic medical record (EMR)-based criteria to identify clinically stable patients and promote their effective transition from specialty MH back to primary care (PC). Implementation utilized a blended facilitation approach consistent with Integrated Promoting Action on Research Implementation in Health Services (iPARIHS). The Reach Effectiveness Adoption Implementation Maintenance (RE-AIM) framework guided measurement of implementation outcomes. During FLOW, 424 unique MH patients transitioned from MH to PC; of those, only 9 (2.1%) returned to MH after that transition. Most of those patients (n = 335; 79.0%) were first identified on the MH FLOW report, but 89 (21.0%) were other MH patients. The total number of patients discharged due to recovery or stabilization was 411. The 335 patients represent 21.3% of all unique patients (n = 1,566) who met the EMR criteria during the project. The 411 recovered/stabilized patients are 16.4% of all unique MH patients (n = 2,504) treated at the site. These early results suggest that this EMR-based system, combined with sound clinical practices, can be used to identify MH patients who are candidates for transition and foster their effective transition to care management in PC. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Evaluation of immunogenic epitopes for universal vaccine development in the face of ongoing SARS-CoV-2 evolution remains a challenge. Herein, we investigate the genetic and structural conservation of an immunogenically relevant epitope (C662–C671) of spike (S) protein across SARS-CoV-2 variants to determine its potential utility as a broad-spectrum vaccine candidate against coronavirus diseases. Comparative sequence analysis, structural assessment, and molecular dynamics simulations of C662–C671 epitope were performed. Mathematical tools were employed to determine its mutational cost. We found that the amino acid sequence of C662–C671 epitope is entirely conserved across the observed major variants of SARS-CoV-2 in addition to SARS-CoV. Its conformation and accessibility are predicted to be conserved, even in the highly mutated Omicron variant. Costly mutational rate in the context of energy expenditure in genome replication and translation can explain this strict conservation. These observations may herald an approach to developing vaccine candidates for universal protection against emergent variants of coronavirus.

Trauma-focused psychotherapies, such as prolonged exposure and cognitive processing therapy, are the most effective forms of treatment for posttraumatic stress disorder. These treatments are commonly delivered in the Veterans Health Administration; however, dropout means that some veterans fail to benefit. Ending treatment prematurely is a common problem across psychotherapies, with on average, 20% to 25% of patients dropping out. The purpose of this study was to examine veterans' self-reported reasons for dropping out of prolonged exposure or cognitive processing therapy. Veterans who dropped out from prolonged exposure or cognitive processing therapy (N = 28) completed qualitative interviews about their experiences. Interviews were coded by 2 coders using grounded theory. Therapy-related barriers were the largest category reported, and included lack of buy-in to the rationale or specific therapy tasks, believing that treatment was not working, alliance issues, or switching to a different treatment. Practical barriers and finding treatment "too stressful" were also common reasons for dropout. This research provides information that can shape how PTSD treatments are delivered in health care settings. Therapy-related barriers were the largest group, suggesting that providers may need to find more effective ways to communicate the rationale for these therapies or to tailor them to individual patients' needs. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

We partnered with veteran-serving nonprofits in order to identify distressed rural veterans and provide them with a mental health workshop in community-based settings. Community organizations helped recruit veterans and provided space for 1-day (5-h) Acceptance and Commitment Therapy (ACT) group workshops conducted in rural locations. Qualitative interviews were conducted at 1- and 3-months post-intervention to assess acceptability. Quantitative measures were conducted at baseline, 1- and 3-months post-intervention to measure effectiveness. We successfully engaged community partners throughout every stage of the research and delivered workshops to thirty-one veterans in rural community-based locations. Veterans appreciated the structure, content, and environment of the workshops; most implemented ACT skills into their daily lives and some initiated new treatment following workshop participation. Quantitative measures showed improvements in functioning (Cohen's d ranging from .27 to .40), reintegration (Cohen's d = .45), meaning and purpose (Cohen's d = .40), and reductions in distress (Cohen's d ranging from .28 to .40) 3-months following workshop participation. Collaborating with rural veteran-serving nonprofit organizations holds promise for engaging hard-to-reach distressed veterans in mental health care.

Objective Innovative treatments and outcome measures are needed for binge-eating disorder (BED). This randomized controlled trial compared Integrative Cognitive-Affective Therapy (ICAT-BED), an individual psychotherapy targeting momentary behavioral and emotional precipitants of binge eating, with an established cognitive-behavioral guided self-help (CBTgsh) treatment using standard and ecological momentary assessment (EMA) outcome measures. Method A total of 112 participants were randomized to 17 weeks of treatment (21 sessions for ICAT-BED and 10 sessions for CBTgsh). Binge-eating frequency was assessed with the Eating Disorder Examination (EDE) as well as EMA using cell phone-based real-time, naturalistic assessment at end of treatment (EOT) and 6-month follow-up. Hypothesized maintenance mechanisms were assessed using self-report questionnaires. Results Binge-eating frequency as measured by the EDE and real-time assessment showed significant reductions at EOT and follow-up, with no significant differences between treatments. Hypothesized maintenance mechanisms, including emotion regulation, cognitive self-discrepancy, self-directed style, as well as measures of associated eating disorder psychopathology, depression, anxiety, impulsivity, and negative affect, showed similar improvement at EOT and follow-up with no differences between treatments. Abstinence rates at EOT (ICAT-BED: 57.1%; CBTgsh: 42.9%) and 6-month follow-up (ICAT-BED: 46.4%; CBTgsh: 42.9%) were not significantly different. Treatment retention was significantly higher for ICAT-BED (87.5%) than CBTgsh (71.4%). Discussion These findings suggest that ICAT-BED and CBTgsh were associated with similar improvements in binge eating, psychopathology, and putative maintenance mechanisms as measured by traditional self-report and momentary, naturalistic assessments and that these changes were generally sustained at 6-month follow-up.

BackgroundLymphatic malformations (LMs) often pose treatment challenges due to a large size or a critical location that could lead to disfigurement, and there are no standardized treatment approaches for either refractory or unresectable cases.MethodsWe examined the genomic landscape of a patient cohort of LMs (n=30 cases) that underwent comprehensive genomic profiling (CGP) using a large-panel next generation sequencing (NGS) assay. Immunohistochemical analyses were completed in parallel.ResultsThese LMs had low mutational burden with hotspot PIK3CA mutations and NRAS mutations being most frequent, and mutually exclusive. All LM cases with Kaposi sarcoma-like (kaposiform) histology had NRAS mutations. One index patient presented with subacute abdominal pain and was diagnosed with a large retroperitoneal lymphatic malformation harboring a somatic PIK3CA gain-of-function mutation (H1047R). The patient achieved a rapid and durable complete response to the PI3Kα inhibitor alpelisib within the context of a personalized N-of-1 clinical trial (NCT03941782). In translational correlative studies, canonical PI3Kα pathway activation was confirmed by immunohistochemistry and human LM-derived lymphatic endothelial cells carrying an allele with an activating mutation at the same locus were sensitive in vitro to alpelisib in a concentration-dependent manner.ConclusionsOur findings establish that LM patients with conventional or kaposiform histology have distinct, yet targetable, driver mutations.FundingR.P. and W.A. are supported by awards from the Levy-Longenbaugh Fund. S.G. is supported by awards from the Hugs for Brady Foundation. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of Arizona Cancer Center (CA023074), the University of New Mexico Comprehensive Cancer Center (CA118100), and the Rutgers Cancer Institute of New Jersey (CA072720). B.K.M. was supported by National Science Foundation via Graduate Research Fellowship DGE-1143953.Clinical trial numberNCT03941782

Lymphatic malformations (LMs) often pose treatment challenges due to a large size or a critical location that could lead to disfigurement, and there are no standardized treatment approaches for either refractory or unresectable cases.We examined the genomic landscape of a patient cohort of LMs (These LMs had low mutational burden with hotspotOur findings establish that LM patients with conventional or kaposiform histology have distinct, yet targetable, driver mutations.R.P. and W.A. are supported by awards from the Levy-Longenbaugh Fund. S.G. is supported by awards from the Hugs for Brady Foundation. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of Arizona Cancer Center (CA023074), the University of New Mexico Comprehensive Cancer Center (CA118100), and the Rutgers Cancer Institute of New Jersey (CA072720). B.K.M. was supported by National Science Foundation via Graduate Research Fellowship DGE-1143953.NCT03941782.

Evaluation of immunogenic epitopes for universal vaccine development in the face of ongoing SARS-CoV-2 evolution remains a challenge. Herein, we investigate the genetic and structural conservation of an immunogenically relevant epitope (C662-C671) of spike (S) protein across SARS-CoV-2 variants to determine its potential utility as a broad-spectrum vaccine candidate against coronavirus diseases. Comparative sequence analysis, structural assessment, and molecular dynamics simulations of C662-C671 epitope were performed. Mathematical tools were employed to determine its mutational cost. We found that the amino acid sequence of C662-C671 epitope is entirely conserved across the observed major variants of SARS-CoV-2 in addition to SARS-CoV. Its conformation and accessibility are predicted to be conserved, even in the highly mutated Omicron variant. Costly mutational rate in the context of energy expenditure in genome replication and translation can explain this strict conservation. These observations may herald an approach to developing vaccine candidates for universal protection against emergent variants of coronavirus.

Made available in DSpace on 2022-04-28T19:41:58Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-07-27 Development of effective vaccines against coronavirus disease 2019 (COVID-19) is a global imperative. Rapid immunization of the entire human population against a widespread, continually evolving, and highly pathogenic virus is an unprecedented challenge, and different vaccine approaches are being pursued. Engineered filamentous bacteriophage (phage) particles have unique potential in vaccine development due to their inherent immunogenicity, genetic plasticity, stability, cost-effectiveness for large-scale production, and proven safety profile in humans. Herein we report the development and initial evaluation of two targeted phage-based vaccination approaches against SARS-CoV-2: dual ligand peptide-targeted phage and adeno-associated virus/phage (AAVP) particles. For peptide-targeted phage, we performed structure-guided antigen design to select six solvent-exposed epitopes of the SARS-CoV-2 spike (S) protein. One of these epitopes displayed on the major capsid protein pVIII of phage induced a specific and sustained humoral response when injected in mice. These phage were further engineered to simultaneously display the peptide CAKSMGDIVC on the minor capsid protein pIII to enable their transport from the lung epithelium into the systemic circulation. Aerosolization of these “dual-display” phage into the lungs of mice generated a systemic and specific antibody response. In the second approach, targeted AAVP particles were engineered to deliver the entire S protein gene under the control of a constitutive CMV promoter. This induced tissue-specific transgene expression, stimulating a systemic S protein-specific antibody response in mice. With these proof-of-concept preclinical experiments, we show that both targeted phage- and AAVP-based particles serve as robust yet versatile platforms that can promptly yield COVID-19 vaccine prototypes for translational development. Rutgers Cancer Institute of New Jersey Division of Cancer Biology Department of Radiation Oncology Rutgers New Jersey Medical School Center for Theoretical Biological Physics Rice University Department of Physics Institute of Biosciences Humanities and Exact Sciences São Paulo State University Public Health Research Institute Rutgers New Jersey Medical School Department of Neurology Harvard Medical School Department of Surgery Rutgers Robert Wood Johnson Medical School Department of Physics and Center for Theoretical Biological Physics Northeastern University RCSB Protein Data Bank Institute for Quantitative Biomedicine, Rutgers State University of New Jersey Department of Chemistry and Chemical Biology Rutgers State University of New Jersey RCSB Protein Data Bank San Diego Supercomputer Center and Skaggs School of Pharmacy & Pharmaceutical Sciences University of California San Diego Department of Biosciences Rice University Department of Chemistry Rice University Department of Physics and Astronomy Rice University Division of Hematology/Oncology Department of Medicine Rutgers New Jersey Medical School Department of Physics Institute of Biosciences Humanities and Exact Sciences São Paulo State University

Bacteriophage (phage) have attractive advantages as delivery systems compared with mammalian viruses, but have been considered poor vectors because they lack evolved strategies to confront and overcome mammalian cell barriers to infective agents. We reasoned that improved efficacy of delivery might be achieved through structural modification of the viral capsid to avoid pre- and postinternalization barriers to mammalian cell transduction. We generated multifunctional hybrid adeno-associated virus/phage (AAVP) particles to enable simultaneous display of targeting ligands on the phage's minor pIII proteins and also degradation-resistance motifs on the very numerous pVIII coat proteins. This genetic strategy of directed evolution bestows a next-generation of AAVP particles that feature resistance to fibrinogen adsorption or neutralizing antibodies and ability to escape endolysosomal degradation. This results in superior gene transfer efficacy in vitro and also in preclinical mouse models of rodent and human solid tumors. Thus, the unique functions of our next-generation AAVP particles enable improved targeted gene delivery to tumor cells.

Low treatment engagement is a barrier to implementation of empirically supported treatments for posttraumatic stress disorder (PTSD) among veterans. Understanding personality traits that predict dropout may help focus attempts to improve engagement. The current study included 90 veterans who served in recent conflicts in Iraq and/or Afghanistan and participated in a trial of cognitive processing therapy for PTSD. Goals were to characterize (a) personality correlates of PTSD, (b) patterns of engagement (i.e., attendance and homework completion), and (c) personality correlates of reduced engagement. Higher levels of PTSD symptoms were associated with a range of characteristics, including affective lability, r = .44 p.001; anxiety, r = .38, p.001; identity problems, r = .57, p.001; intimacy problems, r = .34, p = .001; low affiliation, r = .33, p = .002; oppositionality, r = .36, p = .001; restricted expression, r = .35, p = .001; and suspiciousness, r = .50, p.001. Notably, veterans with worse PTSD symptoms endorsed more cognitive dysregulation, r = .40, p.001; and less insecure attachment, r = .14, p = .190, than expected. Only 52.2% of veterans completed the 12-session course of treatment and 31.0% of participants completed fewer than six sessions. Personality traits did not predict attendance or homework completion. Disengagement continues to be a significant issue in trauma-focused treatment for veterans with PTSD. Understanding veteran-level factors, such as personality traits, may be useful considerations for future research seeking to understand and improve engagement.Spanish Abstracts by Asociación Chilena de Estrés Traumático (ACET) Patrones de desconexión del tratamiento y rasgos de personalidad asociados con el trastorno de estrés postraumático en Recientes Veteranos Estadounidenses que reciben terapia de procesamiento cognitivo DESCONEXIÓN DEL TRATAMIENTO Y PERSONALIDAD EN VETERANOS El bajo compromiso con el tratamiento es una barrera para la implementación de tratamientos con apoyo empírico para el trastorno de estrés postraumático (TEPT) entre los veteranos. Comprender los rasgos de personalidad que predicen el abandono puede ayudar a enfocar los intentos de mejorar el compromiso con el tratamiento en esta población. El estudio actual incluyó una muestra de 90 veteranos que habían servido en conflictos recientes en Irak y / o Afganistán y que estaban inscritos en el ensayo de terapia de procesamiento cognitivo para el TEPT. Los objetivos principales del estudio fueron (a) describir los correlatos de la personalidad y el TEPT de los veteranos, (b) caracterizar los patrones de compromiso (es decir, la asistencia y la finalización de la tarea), y (c) identificar los rasgos de personalidad asociados con el poco compromiso . Los niveles más altos de síntomas de TEPT se asociaron con una amplia gama de problemas de personalidad, incluida la labilidad afectiva, ansiedad, desregulación cognitiva, problemas de identidad, problemas de intimidad, baja afiliación, oposicionismo, expresión restringida y desconfianza. En particular, los veteranos con niveles más altos de síntomas de TEPT mostraron más desregulación cognitiva y menos problemas con el apego inseguro de lo esperado. Solo el 52.2% de los veteranos completaron el curso de tratamiento de 12 sesiones. Casi un tercio de los participantes (31.0%) completó menos de seis sesiones. Los rasgos de personalidad no fueron predictivos de la asistencia o la finalización de la tarea en el presente estudio. El abandono del tratamiento con apoyo empírico sigue siendo un problema importante en el tratamiento centrado en el trauma para los veteranos con TEPT. Comprender los factores a nivel de veteranos, como los rasgos de personalidad, puede ser una consideración útil para futuras investigaciones que buscan comprender y mejorar el compromiso con el tratamiento.

Significance The COVID-19 pandemic has had an unprecedented impact. Although several vaccines have received emergency use authorization, demand has created enormous logistical challenges—including supply, access, and distribution—that justify research for alternative strategies. Phage are viruses that only infect bacteria and can be safely administered to humans. Here, as a proof-of-concept study, we demonstrate that aerosol vaccination with lung-targeted phage particles displaying short SARS-CoV-2 S protein epitopes and subcutaneous vaccination with targeted AAVP particles carrying the entire S protein gene both elicit systemic and specific immune responses in immunocompetent mice. Given their unique attributes, including sturdiness, simple-to-engineer platform, cost-effectiveness for rapid large-scale production, and stability at room temperature, these phage-based approaches may become attractive tools for COVID-19 vaccine development., Development of effective vaccines against coronavirus disease 2019 (COVID-19) is a global imperative. Rapid immunization of the entire human population against a widespread, continually evolving, and highly pathogenic virus is an unprecedented challenge, and different vaccine approaches are being pursued. Engineered filamentous bacteriophage (phage) particles have unique potential in vaccine development due to their inherent immunogenicity, genetic plasticity, stability, cost-effectiveness for large-scale production, and proven safety profile in humans. Herein we report the development and initial evaluation of two targeted phage-based vaccination approaches against SARS-CoV-2: dual ligand peptide-targeted phage and adeno-associated virus/phage (AAVP) particles. For peptide-targeted phage, we performed structure-guided antigen design to select six solvent-exposed epitopes of the SARS-CoV-2 spike (S) protein. One of these epitopes displayed on the major capsid protein pVIII of phage induced a specific and sustained humoral response when injected in mice. These phage were further engineered to simultaneously display the peptide CAKSMGDIVC on the minor capsid protein pIII to enable their transport from the lung epithelium into the systemic circulation. Aerosolization of these “dual-display” phage into the lungs of mice generated a systemic and specific antibody response. In the second approach, targeted AAVP particles were engineered to deliver the entire S protein gene under the control of a constitutive CMV promoter. This induced tissue-specific transgene expression, stimulating a systemic S protein-specific antibody response in mice. With these proof-of-concept preclinical experiments, we show that both targeted phage- and AAVP-based particles serve as robust yet versatile platforms that can promptly yield COVID-19 vaccine prototypes for translational development.

Obsessive-compulsive disorder (OCD) and substance-use disorders (SUDs) co-occur at high rates, which is related to poorer psychosocial outcomes. Prior work suggests that, among veterans in the Veterans Health Administration (VHA), OCD is underdiagnosed and undertreated, which can compound negative effects of OCD and SUD co-occurrence. This study identified patterns of OCD and specific SUD co-occurrence and their effect on mental health and substance-use screening measures and mental healthcare utilization. Using VHA administrative data, we identified veterans with an OCD diagnosis from 2010 to 2016 (N = 38,157); 36.70% also had a SUD diagnosis. Specific SUD rates are alcohol-use disorder, 17.17%; cannabis-use disorder, 5.53%; opioid-use disorder, 3.60%; amphetamine-use disorder, 1.49%; cocaine-use disorder, 3.37%; and tobacco-use disorder, 26.50%. Veterans with co-occurring OCD and SUD used more mental health services throughout the data capture period. Findings suggest that OCD and SUD co-occur at high rates within the VHA, and that this is associated with more burden to the healthcare system. Targeted screening and treatment efforts may help address the needs of this population.

We partnered with veteran-serving nonprofits in order to identify distressed rural veterans and provide them with a mental health workshop in community-based settings. Community organizations helped recruit veterans and provided space for 1-day (5-h) Acceptance and Commitment Therapy (ACT) group workshops conducted in rural locations. Qualitative interviews were conducted at 1- and 3-months post-intervention to assess acceptability. Quantitative measures were conducted at baseline, 1- and 3-months post-intervention to measure effectiveness. We successfully engaged community partners throughout every stage of the research and delivered workshops to thirty-one veterans in rural community-based locations. Veterans appreciated the structure, content, and environment of the workshops; most implemented ACT skills into their daily lives and some initiated new treatment following workshop participation. Quantitative measures showed improvements in functioning (Cohen's d ranging from .27 to .40), reintegration (Cohen's d = .45), meaning and purpose (Cohen's d = .40), and reductions in distress (Cohen's d ranging from .28 to .40) 3-months following workshop participation. Collaborating with rural veteran-serving nonprofit organizations holds promise for engaging hard-to-reach distressed veterans in mental health care.

Research to improve access to mental healthcare often focuses on increasing timely referrals from primary care (PC) to specialty mental health (SMH). However, timely and appropriate transitions back to PC are indispensable for increasing access to SMH for new patients. We developed and implemented a formalized process to identify patients eligible for transition from SMH to PC. The FLOW intervention was piloted at a Veterans Health Administration community-based outpatient clinic. Qualitatively examine provider perspectives regarding patient transitions at initiation and termination of the FLOW project. Sixteen mental health providers and three PC staff completed qualitative interviews about the benefits and drawbacks of FLOW at initiation. Ten mental health providers and one PC staff completed interviews at 12-month follow-up. Primary benefits anticipated at initiation were that FLOW would increase access to SMH, provide acknowledgment of veterans’ recovery, and differentiate between higher and lower intensity mental health services. SMH providers reported additional perceived benefits at 12-month follow-up, including decreased stress over their caseloads and increased ability to deliver efficient, effective treatment. Anticipated drawbacks at initiation were that veterans would get inconsistent care, PC could not offer the same level of care as SMH, and veterans might view transition as a rejection by their SMH provider. Perceived drawbacks were similar at 12-month follow-up, but there was less frequent endorsement. Findings highlight need for sustained and frequent provider education regarding (i) the appropriate characteristics of individuals eligible for transition and (ii) established procedures to ensure care coordination during and after transition.

Background Mild traumatic brain injury (mTBI) is a signature wound of Veterans of operations in Iraq and Afghanistan (i.e., OIF/OEF/OND). Most Veterans with mTBI also experience stress-based psychopathology (e.g., depression, posttraumatic stress disorder) and chronic pain. This combination – referred to as polytrauma - results in detrimental long-term effects on social, occupational, and community reintegration. This study will compare the efficacy of a one-day Acceptance and Commitment Training plus Education, Resources, and Support (ACT+ERS) workshop to a one-day active control group (ERS) on symptoms of distress and social, occupational, and community reintegration. We will also examine mediators and moderators of treatment response. Methods This is an ongoing randomized clinical trial. 212 OIF/OEF/OND Veterans with polytrauma are being recruited. Veterans are randomly assigned to a one-day ACT+ERS or a one-day ERS workshop with two individualized booster sessions approximately two- and four-weeks post-workshop. Veterans complete assessments prior to the workshop and again at six weeks, three months, and six months post-workshop. Of note, workshops were converted to a virtual format due to the COVID-19 pandemic. Results The primary outcomes are symptoms of distress and reintegration; secondary outcomes are post-traumatic stress disorder symptoms and pain interference. Secondary analyses will assess whether changes in avoidance at three months mediate changes in distress and reintegration at six months. Conclusion Facilitating the psychological adjustment and reintegration of Veterans with polytrauma is critical. The results of this study will provide important information about the impact of a brief intervention for Veterans with these concerns.

The current study protocol regards a partnered, mixed-methods, cluster-randomized stepped wedge trial of the implementation and effectiveness of the FLOW program. FLOW (not an acronym) is a collection of resources and strategies to assist in determining which recovered or stabilized specialty mental health (SMH) patients should transition back to primary care (PC) and tools to make the transition seamless. Transitioning appropriate patients to PC can increase access and timeliness of mental health care for newly referred mental health patients. Nine sites in one US region will be randomized to one of three waves in which they will receive implementation-facilitation to implement the FLOW program. Primary outcomes will include the reach of FLOW, provider adoption of the program, effectiveness in increasing access in SMH, implementation fidelity, and maintenance over time. A mixed-methods analysis of implementation factors associated with implementation success will also be conducted, including the following as possible predictors: staffing ratios, site resources, leadership and provider support for the program, and local champion characteristics. This study's results will provide evidence for the effectiveness of FLOW in increasing access and may provide generalizable information about characteristics of sites that are likely to be successful with implementing similar programs.

Objective The purpose of this investigation was to examine the indirect effects of Integrative Cognitive-Affective Therapy (ICAT-BN) and Cognitive-Behavioral Therapy-Enhanced (CBT-E) on bulimia nervosa (BN) treatment outcome through three hypothesized maintenance variables: emotion regulation, self-directed behavior, and self-discrepancy. Method Eighty adults with BN were randomized to 21 sessions of ICAT-BN or CBT-E. A regression-based bootstrapping approach was used to test the indirect effects of treatment on outcome at end of treatment through emotion regulation and self-directed behavior measured at mid-treatment, as well as the indirect effects of treatment at follow-up through emotion regulation, self-directed behavior, and self-discrepancy measured at end of treatment. Results No significant differences in outcome between treatment conditions were observed, and no significant direct or indirect effects were found. Examination of the individual paths within the indirect effects models revealed comparable treatment effects. Across treatments, improvements in emotion regulation and self-directed behavior between baseline and mid-treatment predicted improvements in global eating disorder scores but not binge eating and purging frequency at end of treatment. Baseline to end of treatment improvements in emotion regulation and self-directed behavior also predicted improvements in global eating disorder scores at follow-up. Baseline to end of treatment improvements in emotion regulation predicted improvements in binge eating and baseline to end of treatment increases in positive self-directed behavior predicted improvements in purging at follow-up. Discussion These findings suggest that emotion regulation and self-directed behavior are important treatment targets and that ICAT-BN and CBT-E are comparable in modifying these psychological processes among individuals with BN.

National Veterans Health Administration (VHA) data suggest that Veterans with obsessive-compulsive disorder (OCD) are often unrecognized and poorly treated. We investigated the experience of VHA mental health providers in treating Veterans with OCD and related disorders and perceptions of available resources. Psychiatrists, psychologists, social workers and nurses were invited through email distribution lists to complete an anonymous 25-question survey through www.surveymonkey.com from 10/20/14 to 12/19/14. Questions pertained to experience and knowledge of treating Veterans with OCD and related disorders, such as body dysmorphic disorder, hoarding disorder, trichotillomania and excoriation disorder. Of 166 completers, 81 (49%) had seen 10 or fewer Veterans with OCD and related disorders at the VHA, and 147 (88%) were seeing 10 or fewer of these patients at survey completion. Only 38 (23%) had received specialized training in treating these patients. Participant-recommended treatments for these conditions did not correspond with evidence-based practice: only 47% recommended exposure and response prevention. Most reported insufficient assessment and treatment resources for Veterans with OCD. Many VHA mental health providers lack sufficient knowledge and expertise in diagnosing and treating OCD and related disorders. Additional resources need to be developed to facilitate improved care for Veterans with OCD and related disorders.

Although loss of control (LOC) while eating is a core construct of bulimia nervosa (BN), questions remain regarding its validity and prognostic significance independent of overeating. We examined trajectories of objective and subjective binge eating (OBE and SBE, respectively; i.e., LOC eating episodes involving an objectively or subjectively large amount of food) among adults participating in psychological treatments for BN-spectrum disorders (n=80). We also explored whether changes in the frequency of these eating episodes differentially predicted changes in eating-related and general psychopathology and, conversely, whether changes in eating-related and general psychopathology predicted differential changes in the frequency of these eating episodes. Linear mixed models with repeated measures revealed that OBE decreased twice as rapidly as SBE throughout treatment and 4-month follow-up. Generalized linear models revealed that baseline to end-of-treatment reductions in SBE frequency predicted baseline to 4-month follow-up changes in eating-related psychopathology, depression, and anxiety, while changes in OBE frequency were not predictive of psychopathology at 4-month follow-up. Zero-inflation models indicated that baseline to end-of-treatment changes in eating-related psychopathology and depression symptoms predicted baseline to 4-month follow-up changes in OBE frequency, while changes in anxiety and self-esteem did not. Baseline to end-of-treatment changes in eating-related psychopathology, self-esteem, and anxiety predicted baseline to 4-month follow-up changes in SBE frequency, while baseline to end-of-treatment changes in depression did not. Based on these findings, LOC accompanied by objective overeating may reflect distress at having consumed an objectively large amount of food, whereas LOC accompanied by subjective overeating may reflect more generalized distress related to one's eating- and mood-related psychopathology. BN treatments should comprehensively target LOC eating and related psychopathology, particularly in the context of subjectively large episodes, to improve global outcomes.

Glioblastoma persists as a uniformly deadly diagnosis for patients and effective therapeutic options are gravely needed. Recently, targeted gene therapy approaches are re-emerging as attractive experimental clinical agents. Our ligand-directed hybrid virus of adeno-associated virus and phage (AAVP) is a targeted gene delivery vector that has been used in several formulations displaying targeting ligand peptides to deliver clinically applicable transgenes. Here we compared different constructs side-by-side in a tumor model, an orthotopic model of xenograft human glioblastoma cells stereotactically-implanted in immunodeficient mice. We have used divergent therapeutic strategies for two AAVP constructs, both displaying a double-cyclic RGD4C motif ligand specific for alpha V integrins expressed in tumor vascular endothelium but carrying different genes of interest for the treatment of intracranial xenografted tumors. One construct delivered tumor necrosis factor (TNF), a purely cytotoxic gene for anti-tumor activity (RGD4C-AAVP-TNF); in the other construct, we delivered Herpes simplex virus thymidine kinase (HSVtk) for in tandem molecular-genetic imaging and targeted therapy (RGD4C-AAVP- HSVtk) utilizing ganciclovir (GCV) for suicide gene therapy. Both AAVP constructs demonstrated anti-tumor activity, with damage to the tumor-associated neovasculature and induction of cell death evident after treatment. In addition, the ability to monitor transgene expression with a radiolabeled HSVtk substrate pre and post GCV treatment demonstrated the theranostic potential of RGD4C-AAVP-HSVtk. We conclude that targeted AAVP constructs delivering either cytotoxic TNF or theranostic HSVtk followed by suicide gene therapy with GCV have comparable preclinical efficacy, at least in this standard experimental model. The results presented here provide a blueprint for future studies of targeted gene delivery against human glioblastomas and other brain tumors.

Two of the primary components within Integrative Cognitive Affective Therapy (ICAT) are self-discrepancy and self-directed style. Self-discrepancy includes both actual:ideal (discrepancy between oneself and who one wishes they were) and actual:ought (discrepancy between oneself and who one believes they ought to be). Self-directed style in ICAT refers to a variety of behaviors emitted by a person toward the self including self-blaming and self-affirming. This study explored main effects and interactions between self-discrepancy and self-directed style in relation to global eating disorder (ED) psychopathology, depressive symptoms, and anxiety. Eighty treatment-seeking adults from the Midwest with BN or subthreshold BN completed interviews and self-report measures. Self-affirm and self-blame were associated with ED psychopathology, depressive symptoms, and anxiety. Actual:ideal discrepancy was related to anxiety and actual:ought discrepancy was related to anxiety and depressive symptoms. Interactions were found between self-affirm and actual:ought discrepancy as well as self-blame and actual:ought discrepancy for depressive symptoms. High actual:ought was related to increased depressive symptoms regardless of levels of self-affirm or self-blame. Effect sizes for models were medium-to-large with anxiety models demonstrating the largest effects. This study provides further evidence supporting the ICAT model and treatment, which targets self-discrepancies, self-directed styles, and related emotional states.

Nanomedicines have significant potential for cancer treatment. Although the majority of nanomedicines currently tested in clinical trials utilize simple, biocompatible liposome-based nanocarriers, their widespread use is limited by non-specificity and low target site concentration and thus, do not provide a substantial clinical advantage over conventional, systemic chemotherapy. In the past 20years, we have identified specific receptors expressed on the surfaces of tumor endothelial and perivascular cells, tumor cells, the extracellular matrix and stromal cells using combinatorial peptide libraries displayed on bacteriophage. These studies corroborate the notion that unique receptor proteins such as IL-11Rα, GRP78, EphA5, among others, are differentially overexpressed in tumors and present opportunities to deliver tumor-specific therapeutic drugs. By using peptides that bind to tumor-specific cell-surface receptors, therapeutic agents such as apoptotic peptides, suicide genes, imaging dyes or chemotherapeutics can be precisely and systemically delivered to reduce tumor growth in vivo, without harming healthy cells. Given the clinical applicability of peptide-based therapeutics, targeted delivery of nanocarriers loaded with therapeutic cargos seems plausible. We propose a modular design of a functionalized protocell in which a tumor-targeting moiety, such as a peptide or recombinant human antibody single chain variable fragment (scFv), is conjugated to a lipid bilayer surrounding a silica-based nanocarrier core containing a protected therapeutic cargo. The functionalized protocell can be tailored to a specific cancer subtype and treatment regimen by exchanging the tumor-targeting moiety and/or therapeutic cargo or used in combination to create unique, theranostic agents. In this review, we summarize the identification of tumor-specific receptors through combinatorial phage display technology and the use of antibody display selection to identify recombinant human scFvs against these tumor-specific receptors. We compare the characteristics of different types of simple and complex nanocarriers, and discuss potential types of therapeutic cargos and conjugation strategies. The modular design of functionalized protocells may improve the efficacy and safety of nanomedicines for future cancer therapy.

This study examined self-discrepancy, a construct of theoretical relevance to eating disorder (ED) psychopathology, across different types of EDs. Individuals with anorexia nervosa (AN; n = 112), bulimia nervosa (BN; n = 72), and binge eating disorder (BED; n = 199) completed semi-structured interviews assessing specific types of self-discrepancies. Results revealed that actual:ideal (A:I) discrepancy was positively associated with AN, actual:ought (A:O) discrepancy was positively associated with BN and BED, and self-discrepancies did not differentiate BN from BED. Across diagnoses, A:O discrepancy was positively associated with severity of purging, binge eating, and global ED psychopathology. Further, there were significant interactions between diagnosis and A:O discrepancy for global ED psychopathology and between diagnosis and A:I discrepancy for binge eating and driven exercise. These results support the importance of self-discrepancy as a potential causal and maintenance variable in EDs that differentiates among different types of EDs and symptom severity. Copyright © 2016 John Wiley & Sons, Ltd and Eating Disorders Association.

We previously isolated an IL-11–mimic motif (CGRRAGGSC) that binds to IL-11 receptor (IL-11R) in vitro and accumulates in IL-11R–expressing tumors in vivo . This synthetic peptide ligand was used as a tumor-targeting moiety in the rational design of BMTP-11, which is a drug candidate in clinical trials. Here, we investigated the specificity and accessibility of IL-11R as a target and the efficacy of BMTP-11 as a ligand-targeted drug in lung cancer. We observed high IL-11R expression levels in a large cohort of patients ( n = 368). In matching surgical specimens (i.e., paired tumors and nonmalignant tissues), the cytoplasmic levels of IL-11R in tumor areas were significantly higher than in nonmalignant tissues ( n = 36; P = 0.003). Notably, marked overexpression of IL-11R was observed in both tumor epithelial and vascular endothelial cell membranes ( n = 301; P in vitro cell death in a representative panel of human lung cancer cell lines. BMTP-11 treatment attenuated the growth of subcutaneous xenografts and reduced the number of pulmonary tumors after tail vein injection of human lung cancer cells in mice. Our findings validate BMTP-11 as a pharmacologic candidate drug in preclinical models of lung cancer and patient-derived tumors. Moreover, the high expression level in patients with non-small cell lung cancer is a promising feature for potential translational applications.

Objective To describe the frequency of self-weighing and reactions to prescribed weekly weighing among individuals with eating disorder (ED) diagnoses, and to compare individuals weighing more or less frequently on mass index (BMI) and the Eating Disorder Examination (EDE) subscales. Method Baseline EDE and demographics from five studies (N = 758). Results Self-weighing was most frequent among individuals with anorexia nervosa (AN), followed by those with bulimia nervosa (BN) and binge eating disorder (BED). On average, participants reacted moderately negative to prescribed weekly weighing. No relationship between weighing frequency and BMI was evident in any sample. There was indication of greater pathology (i.e., restraint, shape concern, weight concern, global) in AN with more frequent weighing. In BN, mixed evidence emerged to support a relationship between more frequent weighing and higher shape concern, weight concern, and global score. In BED, higher restraint was found in those who weighed versus those who did not. Discussion Weighing frequency in each eating disorder (ED) sample was to some extent associated with greater ED severity, but not BMI. Future research should examine relationships between self-weighing, reactions to changing weighing frequency, and ED symptomatology in both ED and non-ED groups to understand the impact of self-weighing in heterogeneous populations. © 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016)

A hybrid vector of adeno-associated virus and phage (termed AAVP) has been introduced as a platform for systemic ligand-directed delivery of transgenes to tumors over the past decade. A series of studies have evaluated the AAVP platform for potential theranostic or purely therapeutic applications in several tumor models. Sufficient ligand-directed tumor targeting consistently resulted in specific molecular-genetic imaging and/or anti-tumor responses to 'suicide' transgene delivery. However, efforts to optimize transduction efficiency are still ongoing. Here, we set out to expand the translational utility of AAVP by combining it with gold (Au) nanoparticles in order to generate a 'transducing matrix' for improved targeted gene delivery in solid phase. Targeted AAVP-based solid-phase transduction is superior to conventional transduction in soluble (aqueous) environments. This transducing matrix is stable and can be further modified with additional attributes (for example, magnetization) for targeted imaging and therapeutic gene delivery. Notably, it spontaneously assembles around cells in vitro to markedly enhance transduction capabilities compared with AAVP alone. This versatile nanoplatform may enable new applications of AAVP for transgene delivery in translational settings including, for example, efforts toward complex tissue patterning.

Valproic acid (VPA) is a broad-spectrum antiepileptic drug indicated for monotherapy and adjunctive therapy of seizures, and complex manic episodes associated with bipolar disorder [1]. While uncommon due to monitoring, VPA can cause toxicity at supratherapeutic levels [1, 2]. Traditional treatment for VPA toxicity is primarily supportive care, however activated charcoal, l -carnitine, and hemodialysis have been successful in removing free VPA [2]. An interaction between carbapenem antibiotics and VPA is well-established and listed in respective package inserts as a combination to be avoided due to decreased VPA efficacy [1, 3]. Recent literature suggests co-administration of meropenem with VPA reduces mean plasma VPA levels by 50–80% [4, 6]. This case report describes the successful use of carbapenems to intentionally lower toxic VPA levels in a 42 year old female that presented to the emergency department with VPA toxicity from an overdose with divalproex sodium.

Little is known about the diagnosis and treatment of obsessive-compulsive disorder (OCD) in the Veterans Health Administration (VHA). This study examined diagnostic rates of OCD in a national sample of veterans as well as clinical comorbidities and mental health service use following an OCD diagnosis. This study used administrative data extracted from VHA medical records to identify patients with an OCD diagnosis between 2010 and 2011 (N = 20,364). Descriptive analyses examined demographic, clinical, and system-level variables associated with OCD diagnosis as well as mental health service use in a subset of patients newly diagnosed with OCD (n = 5,229). The OCD diagnosis rate in VHA medical records was 0.31% of VHA patients seen in 2010-2011. Examination of new-onset OCD diagnoses in 2010-2011 revealed that OCD was most likely to be diagnosed by physicians (48.6%) and behavioral health providers (31.9%), predominantly in mental health settings (87.5%). In the year following OCD diagnosis, veterans had an average of 3.9 individual psychotherapy and 3.5 psychiatric medication visits. These findings suggest that OCD is likely underrecognized and inadequately treated in the VHA and highlight the need for improved diagnostic and treatment services for veterans with OCD. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Translation of drug candidates into clinical settings requires demonstration of preclinical efficacy and formal toxicology analysis for filling an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA). Here, we investigate the membrane-associated glucose response protein 78 (GRP78) as a therapeutic target in leukemia and lymphoma. We evaluated the efficacy of the GRP78-targeted proapoptotic drug bone metastasis targeting peptidomimetic 78 (BMTP-78), a member of the D (KLAKLAK)2-containing class of agents. BMTP-78 was validated in cells from patients with acute myeloid leukemia and in a panel of human leukemia and lymphoma cell lines, where it induced dose-dependent cytotoxicity in all samples tested. Based on the in vitro efficacy of BMTP-78, we performed formal good laboratory practice toxicology studies in both rodents (mice and rats) and nonhuman primates (cynomolgus and rhesus monkeys). These analyses represent required steps towards an IND application of BMTP-78 for theranostic first-in-human clinical trials.

Low engagement in posttraumatic stress disorder (PTSD) psychotherapy is a common problem in the U.S. Department of Veteran Affairs (VA), with up to half of veterans who are referred to an evidence-based psychotherapy failing to engage in that treatment. Prior research has focused on identifying general barriers to mental health treatment rather than barriers specific to evidence-based treatments for PTSD. The purpose of the current study was to identify barriers for veterans who referred specifically for evidence-based psychotherapy (i.e., cognitive processing therapy or prolonged exposure) but who did not attend any sessions of those psychotherapies. Qualitative interviews (N = 24) were used to gain a better understanding of the experiences and attitudes of these veterans. Most veterans reported multiple barriers to treatment engagement (M = 4.2 barriers), suggesting that an accumulation of barriers contributes to poor engagement. Barriers fell into 5 categories: practical, knowledge, emotional, therapy-related, and VA-system-related. The most-endorsed category, mentioned by two thirds of the sample, was VA-system-related barriers, including inefficiencies and delays, negative experiences with VA staff and providers, discomfort with the VA environment, and difficulty navigating the VA system. Veterans' experienced barriers to beginning PE and CPT were diverse but, overall, highlighted the need to transform the VA to a more patient-centered model of care. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Evidence-based treatments for posttraumatic stress disorder (PTSD) can reduce symptoms and improve veterans' psychological health. Unfortunately, many veterans leave treatment before receiving maximum benefit. Fear of emotions is related to severity of PTSD, and changes in fear of emotions are correlated with changes in PTSD symptoms. This study built upon the literature linking greater fear of emotions to PTSD severity by examining whether pretreatment fear of emotions, measured by the Affect Control Scale, was associated with completion of cognitive processing therapy (CPT) and severity of posttreatment PTSD in a sample of 89 U.S. veterans who had served in Afghanistan and Iraq. About 60% of veterans completed 10 or more therapy sessions. A logistic regression on 51 of the 89 subjects that more fear of anxiety at pretreatment was associated with decreased likelihood of completing treatment, OR = 0.93, 95% CI [0.87, 1.00]. Of those veterans who completed treatment, higher fear of anger at pretreatment was negatively related to severity of PTSD posttreatment (β = -.29, p = .037), in a model with the other predictors. Assessing veterans for fear of anxiety and anger before CPT and teaching emotion regulation skills to those in need may reduce treatment dropout.

Background Behavioral intervention studies in patients with an implantable cardioverter-defibrillator (ICD) show promise in improving psychosocial outcomes but inconclusive effects on cardiovascular outcome. We assessed the effects of cognitive behavioral stress management (CBSM) on mood state and potentially arrhythmogenic cardiovascular responses to mental stress in ICD patients, in support of further larger scale arrhythmia trials. Methods A total of 103 ICD recipients were randomly assigned to 10-week programs of CBSM or “Patient Education” (ED). Of these, 83 patients continued to either CBSM (n = 44) or ED (n = 39) intervention. Study end points were mood change, heart rate variability (HRV), double product elevation (DP = heart rate × systolic blood pressure) by math and anger-recall stress, and arrhythmia up to 6 months follow-up. Results Adjusting for multiple testing, CBSM was associated with moderate effect size reductions in tension/anxiety (P = 0.010), anger/hostility (P = 0.020), perceived stress (P = 0.037), and total mood disturbance (P = 0.025), greatest immediately following intervention (P < 0.05), and partially attributable to increased negative mood following ED (P < 0.01). No significant intervention effects on high frequency or low frequency spectral power of HRV, DP responses, or cardiac arrhythmias were demonstrated. Conclusions CBSM intervention in ICD recipients resulted in reduced anxiety, anger, and perceived stress, not sustained at 6 months follow-up, and without conclusive effect on cardiac autonomic or hemodynamic responses to mental stress, or arrhythmia. Findings support conduct of larger behavioral intervention arrhythmia trial, with consideration of reinforcement training and targeting of subgroup responders to therapy.

Human prostate cancer often metastasizes to bone, but the biological basis for such site-specific tropism remains largely unresolved. Recent work led us to hypothesize that this tropism may reflect pathogenic interactions between RAGE, a cell surface receptor expressed on malignant cells in advanced prostate cancer, and proteinase 3 (PR3), a serine protease present in inflammatory neutrophils and hematopoietic cells within the bone marrow microenvironment. In this study, we establish that RAGE–PR3 interaction mediates homing of prostate cancer cells to the bone marrow. PR3 bound to RAGE on the surface of prostate cancer cells in vitro, inducing tumor cell motility through a nonproteolytic signal transduction cascade involving activation and phosphorylation of ERK1/2 and JNK1. In preclinical models of experimental metastasis, ectopic expression of RAGE on human prostate cancer cells was sufficient to promote bone marrow homing within a short timeframe. Our findings demonstrate how RAGE–PR3 interactions between human prostate cancer cells and the bone marrow microenvironment mediate bone metastasis during prostate cancer progression, with potential implications for prognosis and therapeutic intervention. Cancer Res; 77(12); 3144–50. ©2017 AACR.

The goal of this study was to examine associations between dimensions of emotion dysregulation and eating disorder (ED) symptoms in bulimia nervosa (BN). This investigation used baseline data from a BN treatment study that included 80 adults (90% women) with full or subthreshold BN. Participants completed the Difficulties in Emotion Regulation Scale (DERS) and the Eating Disorders Examination (EDE) interview. The EDE global score was significantly correlated with the DERS total score, as well as several DERS subscales: Nonacceptance, Impulse, and Strategies. Further, the DERS Goals subscale was found to be uniquely associated with frequency of purging and driven exercise, although none of the subscales were associated with frequency of objective binge eating. Findings indicate that emotion dysregulation is associated with ED symptoms in BN, suggesting the utility of interventions that address emotion regulation skills deficits in the treatment of the disorder.

Adult muscle size and fibre-type composition are heritable traits that vary substantially between individuals. We used inbred mouse strains in which soleus muscle mass varied by an order of magnitude to explore whether properties of muscle spindles can also be influenced by genetic factors. Skip-serial cross-sections of soleus muscles dissected from 15 male mice of BEH, BEL, C57BL/6J, DUH, LG/J and SM/J strains were analysed for number of muscle spindles and characteristics of intrafusal and extrafusal fibres following ATPase staining. The BEL and DUH strains determined the range of: soleus mean size, a 10-fold difference from 2.1 to 22.3 mg, respectively; the mean number of extrafusal fibres, a 2.5-fold difference from 497 to 1249; and mean fibre-cross-sectional area, three-fold difference, e.g. for type 1 fibres, from 678 to 1948 μm2. The range of mean proportion of type 1 fibres was determined by C57BL/6J (31%) and DUH (64%) strains. The mean number of spindles per muscle ranged between nine (LG/J) and 13 (BEL) (strain effect P < 0.02). Genetic correlations between spindle count and muscle weight or properties of extrafusal fibres were weak and not statistically significant. However, there was a strong correlation between the proportion of spindles with more than one bag2 fibre and the proportion of extrafusal fibres that were of type 1, and strain-dependent variation in the numbers of such spindles was statistically significant. The numbers of intrafusal fibres per spindle ranged from 2 to 8, with the most common complement of four found in 75.6% of spindles. There were no significant differences between the strains in the mean numbers of intrafusal fibres; however, the variance of the number was significantly less for the C57BL/6J strain than for any of the others. We conclude that abundance of muscle spindles and their intrafusal-fibre composition are substantially determined by genetic factors, which are different from those affecting muscle size and properties of the extrafusal fibres.

BackgroundThe purpose of this investigation was to compare a new psychotherapy for bulimia nervosa (BN), integrative cognitive-affective therapy (ICAT), with an established treatment, ‘enhanced’ cognitive-behavioral therapy (CBT-E).MethodEighty adults with symptoms of BN were randomized to ICAT or CBT-E for 21 sessions over 19 weeks. Bulimic symptoms, measured by the Eating Disorder Examination (EDE), were assessed at baseline, at the end of treatment (EOT) and at the 4-month follow-up. Treatment outcome, measured by binge eating frequency, purging frequency, global eating disorder severity, emotion regulation, self-oriented cognition, depression, anxiety and self-esteem, was determined using generalized estimating equations (GEEs), logistic regression and a general linear model (intent-to-treat).ResultsBoth treatments were associated with significant improvement in bulimic symptoms and in all measures of outcome, and no statistically significant differences were observed between the two conditions at EOT or follow-up. Intent-to-treat abstinence rates for ICAT (37.5% at EOT, 32.5% at follow-up) and CBT-E (22.5% at both EOT and follow-up) were not significantly different.ConclusionsICAT was associated with significant improvements in bulimic and associated symptoms that did not differ from those obtained with CBT-E. This initial randomized controlled trial of a new individual psychotherapy for BN suggests that targeting emotion and self-oriented cognition in the context of nutritional rehabilitation may be efficacious and worthy of further study.