Retraction Notice to: Modulation of TNFα Activity by the microRNA Let-7 Coordinates Zebrafish Heart Regeneration.

[This retracts the article DOI: 10.1016/j.isci.2019.06.017.].

Retraction Notice to: Modulation of TNFa Activity by the microRNA Let-7 Coordinates Zebrafish Heart Regeneration.

[This retracts the article DOI: 10.1016/j.isci.2019.04.009.].

A Functional Precision Medicine Pipeline Combines Comparative Transcriptomics and Tumor Organoid Modeling to Identify Bespoke Treatment Strategies for Glioblastoma.

Li Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome caused by germline mutations in TP53. TP53 is the most common mutated gene in human cancer, occurring in 30-50% of glioblastomas (GBM). Here, we highlight a precision medicine platform to identify potential targets for a GBM patient with LFS. We used a comparative transcriptomics approach to identify genes that are uniquely overexpressed in the LFS GBM patient relative to a cancer compendium of 12,747 tumor RNA sequencing data sets, including 200 GBMs. STAT1 and STAT2 were identified as being significantly overexpressed in the LFS patient, indicating ruxolitinib, a Janus kinase 1 and 2 inhibitors, as a potential therapy. The LFS patient had the highest level of STAT1 and STAT2 expression in an institutional high-grade glioma cohort of 45 patients, further supporting the cancer compendium results. To empirically validate the comparative transcriptomics pipeline, we used a combination of adherent and organoid cell culture techniques, including ex vivo patient-derived organoids (PDOs) from four patient-derived cell lines, including the LFS patient. STAT1 and STAT2 expression levels in the four patient-derived cells correlated with levels identified in the respective parent tumors. In both adherent and organoid cultures, cells from the LFS patient were among the most sensitive to ruxolitinib compared to patient-derived cells with lower STAT1 and STAT2 expression levels. A spheroid-based drug screening assay (3D-PREDICT) was performed and used to identify further therapeutic targets. Two targeted therapies were selected for the patient of interest and resulted in radiographic disease stability. This manuscript supports the use of comparative transcriptomics to identify personalized therapeutic targets in a functional precision medicine platform for malignant brain tumors.

Prospective prediction of clinical drug response in high-grade gliomas using an ex vivo 3D cell culture assay.

BACKGROUND: Clinical outcomes in high-grade glioma (HGG) have remained relatively unchanged over the last 3 decades with only modest increases in overall survival. Despite the validation of biomarkers to classify treatment response, most newly diagnosed (ND) patients receive the same treatment regimen. This study aimed to determine whether a prospective functional assay that provides a direct, live tumor cell-based drug response prediction specific for each patient could accurately predict clinical drug response prior to treatment. METHODS: A modified 3D cell culture assay was validated to establish baseline parameters including drug concentrations, timing, and reproducibility. Live tumor tissue from HGG patients were tested in the assay to establish response parameters. Clinical correlation was determined between prospective ex vivo response and clinical response in ND HGG patients enrolled in 3D-PREDICT (ClinicalTrials.gov Identifier: NCT03561207). Clinical case studies were examined for relapsed HGG patients enrolled on 3D-PREDICT, prospectively assayed for ex vivo drug response, and monitored for follow-up. RESULTS: Absent biomarker stratification, the test accurately predicted clinical response/nonresponse to temozolomide in 17/20 (85%, P = .007) ND patients within 7 days of their surgery, prior to treatment initiation. Test-predicted responders had a median overall survival post-surgery of 11.6 months compared to 5.9 months for test-predicted nonresponders (P = .0376). Case studies provided examples of the clinical utility of the assay predictions and their impact upon treatment decisions resulting in positive clinical outcomes. CONCLUSION: This study both validates the developed assay analytically and clinically and provides case studies of its implementation in clinical practice.

Improving affirming care for sexual and gender minority veterans.

Lesbian, gay, bisexual, and transgender (LGBT) populations face a range of health disparities that all health care systems must address. In response to known health disparities, the LGBT Health Program of the Veterans Health Administration (VHA) developed policies supporting the provision of affirming care to LGBT veterans. To support policy implementation, the program launched the LGBT Veteran Care Coordinator (LGBT VCC) Program in 2016, requiring every VHA facility to appoint at least one clinical staff member to serve as an LGBT VCC. This quality improvement project reports on LGBT VCCs' perspectives on the state of affirming care at their facilities in the first year of the program. LGBT VCCs (n = 79) completed a brief online survey, including qualitative questions on barriers and facilitators to implementation, and general recommendations for the program. The Consolidated Framework for Implementation Research (CFIR) guided directed content analysis of reported facilitators and barriers. The highest proportion of facilitators and barriers reported by the LGBT VCCs were coded under leadership engagement, available resources, other personal attributes, organizational culture, and networking and communications. LGBT VCCs requested additional support in securing adequate designated administrative time, engaging with facility leadership, improving networking and communication, tailoring programing, and providing professional advancement opportunities. Organizing findings using the CFIR enabled the LGBT Health Program to effectively promote facilitators and address barriers experienced during the startup year of the LGBT VCC Program. The VHA's efforts to reduce LGBT veteran health disparities may serve as a model for other health care systems. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Maternal obesity in sheep impairs foetal hepatic mitochondrial respiratory chain capacity.

BACKGROUND: Changes in the nutritional environment in utero induced by maternal obesity (MO) lead to foetal metabolic dysfunction predisposing offspring to later-life metabolic diseases. Since mitochondria play a crucial role in hepatic metabolism and function, we hypothesized that MO prior to conception and throughout pregnancy programmes foetal sheep liver mitochondrial phenotype. MATERIAL AND METHODS: Ewes ate an obesogenic diet (150% requirements; MO), or 100% requirements (CTR), from 60 days prior to conception. Foetal livers were removed at 0.9 gestation. We measured foetal liver mitochondrial DNA copy number, activity of superoxide dismutase, cathepsins B and D and selected protein content, total phospholipids and cardiolipin and activity of mitochondrial respiratory chain complexes. RESULTS: A significant decrease in activities of mitochondrial complexes I, II-III and IV, but not aconitase, was observed in MO. In the antioxidant machinery, there was a significant increase in activity of total superoxide dismutase (SOD) and SOD2 in MO. However, no differences were found regarding autophagy-related protein content (p62, beclin-I, LC3-I, LC3-II and Lamp2A) and cathepsin B and D activities. A 21.5% decrease in total mitochondrial phospholipid was observed in MO. CONCLUSIONS: The data indicate that MO impairs foetal hepatic mitochondrial oxidative capacity and affects total mitochondrial phospholipid content. In addition, MO affects the regulation of foetal liver redox pathways, indicating metabolic adaptations to the higher foetal lipid environment. Consequences of in utero programming of foetal hepatic metabolism may persist and compromise mitochondrial bioenergetics in later life, and increase susceptibility to metabolic diseases.

A heretical view: rather than a solely placental protective function, placental 11ß hydroxysteroid dehydrogenase 2 also provides substrate for fetal peripheral cortisol synthesis in obese pregnant ewes.

Exposure to glucocorticoid levels higher than appropriate for current developmental stages induces offspring metabolic dysfunction. Overfed/obese (OB) ewes and their fetuses display elevated blood cortisol, while fetal Adrenocorticotropic hormone (ACTH) remains unchanged. We hypothesized that OB pregnancies would show increased placental 11ß hydroxysteroid dehydrogenase 2 (11ß-HSD2) that converts maternal cortisol to fetal cortisone as it crosses the placenta and increased 11ß-HSD system components responsible for peripheral tissue cortisol production, providing a mechanism for ACTH-independent increase in circulating fetal cortisol. Control ewes ate 100% National Research Council recommendations (CON) and OB ewes ate 150% CON diet from 60 days before conception until necropsy at day 135 gestation. At necropsy, maternal jugular and umbilical venous blood, fetal liver, perirenal fat, and cotyledonary tissues were harvested. Maternal plasma cortisol and fetal cortisol and cortisone were measured. Fetal liver, perirenal fat, cotyledonary 11ß-HSD1, hexose-6-phosphate dehydrogenase (H6PD), and 11ß-HSD2 protein abundance were determined by Western blot. Maternal plasma cortisol, fetal plasma cortisol, and cortisone were higher in OB vs. CON (p < 0.01). 11ß-HSD2 protein was greater (p < 0.05) in OB cotyledonary tissue than CON. 11ß-HSD1 abundance increased (p < 0.05) in OB vs. CON fetal liver and perirenal fat. Fetal H6PD, an 11ß-HSD1 cofactor, also increased (p < 0.05) in OB vs. CON perirenal fat and tended to be elevated in OB liver (p < 0.10). Our data provide evidence for increased 11ß-HSD system components responsible for peripheral tissue cortisol production in fetal liver and adipose tissue, thereby providing a mechanism for an ACTH-independent increase in circulating fetal cortisol in OB fetuses.

Peer delivery of a brief cognitive-behavioral treatment for posttraumatic stress disorder: A hybrid effectiveness-implementation pilot study.

OBJECTIVE: Posttraumatic stress disorder (PTSD) treatment delivery by peer specialist providers could increase access to and engagement with PTSD treatment in low resource settings. The current pilot study tested the feasibility, acceptability, and initial effectiveness of a peer-delivered, brief cognitive-behavioral therapy for PTSD. METHOD: Four certified peer specialists delivered the intervention to 18 participants with probable PTSD. We assessed PTSD symptoms weekly and administered surveys and interviews at baseline and posttreatment. RESULTS: Our mixed-methods approach suggests that the intervention was feasible and acceptable, demonstrating high client satisfaction. We also found significant improvements in PTSD, depressive, anxiety, and general stress symptoms. CONCLUSIONS: Peer-delivered interventions may be a good fit for addressing posttraumatic stress symptoms for people accessing care in low resource settings. Future research should evaluate peer-delivered PTSD treatment as a strategy for both reducing symptoms and improving access and engagement in professional care.

Cardiac injury modulates critical components of prostaglandin E2 signaling during zebrafish heart regeneration.

The inability to effectively stimulate cardiomyocyte proliferation remains a principle barrier to regeneration in the adult human heart. A tightly regulated, acute inflammatory response mediated by a range of cell types is required to initiate regenerative processes. Prostaglandin E2 (PGE2), a potent lipid signaling molecule induced by inflammation, has been shown to promote regeneration and cell proliferation; however, the dynamics of PGE2 signaling in the context of heart regeneration remain underexplored. Here, we employ the regeneration-competent zebrafish to characterize components of the PGE2 signaling circuit following cardiac injury. In the regenerating adult heart, we documented an increase in PGE2 levels, concurrent with upregulation of cox2a and ptges, two genes critical for PGE2 synthesis. Furthermore, we identified the epicardium as the most prominent site for cox2a expression, thereby suggesting a role for this tissue as an inflammatory mediator. Injury also drove the opposing expression of PGE2 receptors, upregulating pro-restorative ptger2a and downregulating the opposing receptor ptger3. Importantly, treatment with pharmacological inhibitors of Cox2 activity suppressed both production of PGE2, and the proliferation of cardiomyocytes. These results suggest that injury-induced PGE2 signaling is key to stimulating cardiomyocyte proliferation during regeneration.

Understanding of evidence-based mental health care and the perceived importance of scientific information in a sample of U.S. adults.

OBJECTIVES: This online survey sought to qualitatively ascertain the extent to which a sample of U.S. adults understood the concept of evidence-based mental health care (EBMHC). Additional goals included assessing the perceived importance of scientific information in EBMHC, and examining whether understanding EBMHC and science values varied as a function of participant factors. METHOD: Participants (N = 221) defined EBMHC and rated the importance of scientific information. Open-ended EBMHC definitions were content-coded, and binomial logistic and linear regressions examined predictors of accurately defining EBMHC and of the perceived importance of scientific information. RESULTS: Participants endorsed seven definitions of EBMHC, and only 20% defined it accurately. Having greater knowledge about mental health conditions was associated with understanding EBMHC and with the higher perceived importance of scientific information. Greater help-seeking efficacy also predicted higher perceived importance of scientific information. CONCLUSIONS: Results support customized strategies to promote basic EBMHC education among U.S. adults.

Preaching to the Choir? Predictors of Engagement in a Community-Based Learning Collaborative.

This study examined predictors of engagement among 283 professionals from 34 agencies participating in three community-based learning collaboratives (CBLCs) on trauma-focused cognitive-behavioral therapy (TF-CBT). Only 50.2% of participants completed the CBLC, primarily due to not attending consultation calls or completing training cases. While higher engagement was associated with being trauma-informed and using more of the TF-CBT components prior to the CBLC, most predictors were not significant, perhaps due to ceiling effects. Positive attitudes and high organizational support were not sufficient to ensure engagement. Future research using longitudinal measurement of a wider range of predictors is needed.

Prospective Validation of an Ex Vivo, Patient-Derived 3D Spheroid Model for Response Predictions in Newly Diagnosed Ovarian Cancer.

Although 70-80% of newly diagnosed ovarian cancer patients respond to first-line therapy, almost all relapse and five-year survival remains below 50%. One strategy to increase five-year survival is prolonging time to relapse by improving first-line therapy response. However, no biomarker today can accurately predict individual response to therapy. In this study, we present analytical and prospective clinical validation of a new test that utilizes primary patient tissue in 3D cell culture to make patient-specific response predictions prior to initiation of treatment in the clinic. Test results were generated within seven days of tissue receipt from newly diagnosed ovarian cancer patients obtained at standard surgical debulking or laparoscopic biopsy. Patients were followed for clinical response to chemotherapy. In a study population of 44, the 32 test-predicted Responders had a clinical response rate of 100% across both adjuvant and neoadjuvant treated populations with an overall prediction accuracy of 89% (39 of 44, p < 0.0001). The test also functioned as a prognostic readout with test-predicted Responders having a significantly increased progression-free survival compared to test-predicted Non-Responders, p = 0.01. This correlative accuracy establishes the test's potential to benefit ovarian cancer patients through accurate prediction of patient-specific response before treatment.

Modulation of TNFα Activity by the microRNA Let-7 Coordinates Zebrafish Heart Regeneration.

The adult zebrafish is capable of regenerating heart muscle, resolving collagen tissue, and fully restoring heart function throughout its life. In this study, we show that the highly upregulated, epicardium-enriched microRNA let-7i functions in wound closure and cardiomyocyte proliferation. RNA sequencing experiments identified upregulated expression of members of the tumor necrosis factor (TNF) signaling pathway in the absence of let-7. Importantly, co-suppression of TNF and let-7 activity rescued epicardium migration and cardiomyocyte proliferation defects induced by depletion of let-7 alone. Sensitizing animals to low levels of TNF activity before injury culminated in repressed cardiomyocyte proliferation and wound closure defects, suggesting that levels of inflammation at the onset of injury are critical for heart regeneration. Our studies indicate that injury-induced reduction in TNF signaling by let-7 in the epicardium creates a pro-regenerative environment for cardiomyocyte proliferation during adult heart regeneration.

Rapid Communication: Reduced maternal nutrition during early- to mid-gestation elevates newborn lamb plasma cortisol concentrations and eliminates the neonatal leptin surge.

Human epidemiological and animal studies show that maternal nutrient reduction (MNR) and maternal overnutrition/obesity (MO) alter fetal growth and development, predisposing offspring (F1) to endocrine and appetite dysregulation. Compared to F1 of control-fed ewes, F1 of MO ewes display hypercortisolemia at birth and fail to exhibit the neonatal leptin surge implicated in lifelong appetite regulation. Here, we determined if MNR also elevates newborn lamb plasma cortisol and eliminates the neonatal leptin surge. Starting 30 d prior to conception, nulliparous control (CON, n = 6) ewes ate 100% NRC recommendations through parturition. Nutrient-reduced (NR, n = 6) ewes ate a CON diet through day 27 of gestation. From gestational days 28 to 78, NR ewes ate 50% of the CON diet before realimentation to 100% NRC recommendations. Jugular blood was collected daily from lambs from birth (day 0) through postnatal day 10, to determine plasma cortisol and leptin. Newborn NR plasma cortisol concentrations were increased (P < 0.0001) vs. CON and were similar to concentrations in MO lambs. Plasma leptin concentrations were similar between groups through postnatal day 7. The leptin surge, seen in CON lambs on postnatal days 8 to 10 was not present in NR lambs. These data show that, similar to MO lambs, early pregnancy MNR elevates newborn lamb plasma cortisol and eliminates the neonatal leptin surge. In the light of the similar elevation of neonatal cortisol in MNR and MO lambs, we conclude that cortisol plays a central role in regulating the neonatal lamb leptin surge.

RegenDbase: a comparative database of noncoding RNA regulation of tissue regeneration circuits across multiple taxa.

Regeneration is an endogenous process of tissue repair that culminates in complete restoration of tissue and organ function. While regenerative capacity in mammals is limited to select tissues, lower vertebrates like zebrafish and salamanders are endowed with the capacity to regenerate entire limbs and most adult tissues, including heart muscle. Numerous profiling studies have been conducted using these research models in an effort to identify the genetic circuits that accompany tissue regeneration. Most of these studies, however, are confined to an individual injury model and/or research organism and focused primarily on protein encoding transcripts. Here we describe RegenDbase, a new database with the functionality to compare and contrast gene regulatory pathways within and across tissues and research models. RegenDbase combines pipelines that integrate analysis of noncoding RNAs in combination with protein encoding transcripts. We created RegenDbase with a newly generated comprehensive dataset for adult zebrafish heart regeneration combined with existing microarray and RNA-sequencing studies on multiple injured tissues. In this current release, we detail microRNA-mRNA regulatory circuits and the biological processes these interactions control during the early stages of heart regeneration. Moreover, we identify known and putative novel lncRNAs and identify their potential target genes based on proximity searches. We postulate that these candidate factors underscore robust regenerative capacity in lower vertebrates. RegenDbase provides a systems-level analysis of tissue regeneration genetic circuits across injury and animal models and addresses the growing need to understand how noncoding RNAs influence these changes in gene expression.

A Microvascularized Tumor-mimetic Platform for Assessing Anti-cancer Drug Efficacy.

Assessment of anti-cancer drug efficacy in in vitro three-dimensional (3D) bioengineered cancer models provides important contextual and relevant information towards pre-clinical translation of potential drug candidates. However, currently established models fail to sufficiently recapitulate complex tumor heterogeneity. Here we present a chip-based tumor-mimetic platform incorporating a 3D in vitro breast cancer model with a tumor-mimetic microvascular network, replicating the pathophysiological architecture of native vascularized breast tumors. The microfluidic platform facilitated formation of mature, lumenized and flow-aligned endothelium under physiological flow recapitulating both high and low perfused tumor regions. Metastatic and non-metastatic breast cancer cells were maintained in long-term 3D co-culture with stromal fibroblasts in a poly(ethylene glycol)-fibrinogen hydrogel matrix within adjoining tissue chambers. The interstitial space between the chambers and endothelium contained pores to mimic the "leaky" vasculature found in vivo and facilitate cancer cell-endothelial cell communication. Microvascular pattern-dependent flow variations induced concentration gradients within the 3D tumor mass, leading to morphological tumor heterogeneity. Anti-cancer drugs displayed cell type- and flow pattern-dependent effects on cancer cell viability, viable tumor area and associated endothelial cytotoxicity. Overall, the developed microfluidic tumor-mimetic platform facilitates investigation of cancer-stromal-endothelial interactions and highlights the role of a fluidic, tumor-mimetic vascular network on anti-cancer drug delivery and efficacy for improved translation towards pre-clinical studies.

Monitoring Treatment Progress and Providing Feedback is Viewed Favorably but Rarely Used in Practice.

Numerous trials demonstrate that monitoring client progress and using feedback for clinical decision-making enhances treatment outcomes, but available data suggest these practices are rare in clinical settings and no psychometrically validated measures exist for assessing attitudinal barriers to these practices. This national survey of 504 clinicians collected data on attitudes toward and use of monitoring and feedback. Two new measures were developed and subjected to factor analysis: The monitoring and feedback attitudes scale (MFA), measuring general attitudes toward monitoring and feedback, and the attitudes toward standardized assessment scales-monitoring and feedback (ASA-MF), measuring attitudes toward standardized progress tools. Both measures showed good fit to their final factor solutions, with excellent internal consistency for all subscales. Scores on the MFA subscales (Benefit, Harm) indicated that clinicians hold generally positive attitudes toward monitoring and feedback, but scores on the ASA-MF subscales (Clinical Utility, Treatment Planning, Practicality) were relatively neutral. Providers with cognitive-behavioral theoretical orientations held more positive attitudes. Only 13.9 % of clinicians reported using standardized progress measures at least monthly and 61.5 % never used them. Providers with more positive attitudes reported higher use, providing initial support for the predictive validity of the ASA-MF and MFA. Thus, while clinicians report generally positive attitudes toward monitoring and feedback, routine collection of standardized progress measures remains uncommon. Implications for the dissemination and implementation of monitoring and feedback systems are discussed.

Individualized Progress Measures Are More Acceptable to Clinicians Than Standardized Measures: Results of a National Survey.

Despite research supporting measurement-based care grounded in standardized progress measures, such measures are underutilized by clinicians. Individualized measures of client-specific targets present an alternative, but little is known about their acceptability or use. We compared attitudes toward and use of standardized and individualized progress measures in a national sample of 504 clinicians. Clinicians reported neutral to positive attitudes toward both types of measures, but strongly preferred and were more likely to use individualized measures. Clinician attitudes, theoretical orientation, and work setting predicted assessment preferences and practices. Implications for dissemination and implementation of measurement-based care are discussed.

Outcome Measure Scores Predict Discharge Destination in Patients With Acute and Subacute Stroke: A Systematic Review and Series of Meta-analyses.

BACKGROUND AND PURPOSE: To identify the association between outcome measure score and discharge destination in adults following acute or subacute stroke in the United States. METHODS: A systematic literature search was performed in 3 databases using the PRISMA guidelines. Cohort studies were selected that included patients with acute or subacute stroke, which explored the relationship between scores on outcome measures and discharge destination. Four meta-analyses were performed. RESULTS: Nine articles met the inclusion criteria for systematic review and 5 for the series of meta-analyses. For every 1-point increase on the Functional Independence Measure (FIM), a patient is approximately 1.08 times more likely to be discharged home than to institutionalized care (odds ratio [OR] = 1.079; 95% confidence interval [CI], 1.056- 1.102). Patients with stroke who performed above-average (FIM ≥80; NIH Stroke Scale [NIHSS] score ≤5; etc) are 12 times (OR = 12.08; 95% CI, 3.550-41.07) more likely to discharge home. Patients who perform poorly (FIM ≤39; NIHSS score ≥14), experience discharge to institutionalized care 3.4 times (OR = 3.385; 95% CI, 2.591-4.422) more likely than home, with skilled nursing facility admission more likely than inpatient rehabilitation facility. Patients who perform average (FIM = 40-79; NIHSS score = 6-13) are 1.9 times (OR = 1.879; 95% CI, 1.227-2.877) more likely to be discharged to institutionalized care. DISCUSSION AND CONCLUSION: Outcome measure scores are strong predictors of discharge destination among patients with stroke and provide an objective means of early discharge planning. Discharge decisions should be made with consideration for patient-specific biopsychosocial factors that may supersede isolated results of the outcome measures, and further research needs to assess the success of the location that a patient is referred at discharge.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A194).