Search

BackgroundEarly childhood is a pivotal period for the development of healthy eating practices. One way to promote child health is to identify early modifiable factors that affect child eating and weight. Given the intergenerational transmission of eating behaviors, this study examined how mothers' eating behaviors were associated with child feeding practices, and whether child weight-for-length (z-WFL) moderated this relation, in a community sample.MethodsParticipants were 72 mother-child dyads. Maternal eating behaviors-emotional, external and restrained-were assessed 9-months postpartum, using the Dutch Eating Behavior Questionnaire. Child feeding-restrictive, pressure, and concern about overeating/overweight or undereating/underweight-was measured using the Infant Feeding Questionnaire, and child z-WFL were assessed 18-months postpartum. Linear regressions were used to test the main effect of maternal eating and the interaction effect of maternal eating and child z-WFL, on child feeding practices.ResultsMaternal restrained eating was associated with child pressure feeding, and contrarily with concerns about overeating/overweight. However, a significant interaction between child z-WFL and both maternal emotional and external eating were found with regard to concern about child undereating/underweight. Paradoxically, among children who weighed more, greater maternal emotional and greater external eating were associated with greater concern about child undereating/underweight.ConclusionsIn this community sample, mothers were more likely to report contradictory feeding practices and concerns, suggesting complicated relations among a mother's own eating behavior, her child's weight, and her perceptions of child eating and weight. This may indicate a need for better communication and support of infant feeding practices.Trial registrationData was collected as part of two grants (MAMAS Grant ID: HL097973-01; SEED Grant ID: HL116511-02) conducted at the University of California, San Francisco (UCSF). All subjects gave their informed consent for inclusion before they participated in the study. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by institutional review board at UCSF.

BackgroundEating disorders have serious psychological and physical consequences. Current evidence-based treatments for adolescents with eating disorders have modest effects, underscoring the need to improve current treatment approaches. Cognitive behavior therapy (CBT) and dialectical behavior therapy (DBT) have been proposed as alternative treatment options, with burgeoning research in this area. This review aims to summarize and critically analyze the current literature on the feasibility, acceptability, effectiveness, and efficacy of CBT and DBT for adolescent eating disorders, and then proposes areas of future research.MethodsPsycINFO and PubMed were searched using the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines to identify studies examining the feasibility, acceptability, effectiveness and/or efficacy of CBT or DBT for adolescent eating disorders.ResultsEligible studies (N = 50; CBT: n = 40, DBT: n = 10) indicated that both treatments are reasonably feasible, acceptable, and possibly effective for adolescent eating disorders across diagnoses and levels of care, though efficacy trials are lacking.ConclusionsCBT and DBT demonstrate promise as alternatives to family-based approaches for adolescent eating disorders. Adequately powered trials to establish the effectiveness and efficacy of CBT and DBT are needed, particularly ones that compare these treatments against other leading approaches. Despite high rates of relapse and likelihood for severe and enduring illness, there is a dearth of evidence-based treatment options for adolescents with eating disorders. Potentially viable but less well-studied treatments for adolescents with eating disorders include cognitive behavior therapy (CBT) and dialectical behavior therapy (DBT). This systematic review of CBT and DBT for adolescent eating disorders focuses on feasibility (i.e., how easy it was to implement the treatment), acceptability (i.e., how well the intervention was received by patients and therapists), effectiveness (i.e., how well the intervention performed under routine, real-world circumstances), and efficacy (i.e., how well the intervention performed in highly-controlled research settings). This review concludes that research supports the feasibility and acceptability of these approaches, as well as preliminary evidence of their effectiveness. However, the field is lacking studies that systematically compare CBT and DBT to other evidence-based approaches. Recommendations to advance research on CBT and DBT for adolescent eating disorders are provided, including a call for efficacy studies that clarify their performance compared to other leading approaches.

ObjectiveEarly response, as indicated by early weight gain, in family-based treatment (FBT) for adolescent anorexia nervosa (AN) predicts remission at end of treatment. However, little is known about what factors contribute to early response. Further, no previous studies have examined early response to separated forms of FBT.MethodData from a randomised clinical trial of conjoint FBT and separated FBT (parent-focused treatment, PFT) were analysed to examine the timing and amount of early weight gain that predicted remission and identify factors associated with early response.ResultsWeight gain of at least 2.80 kg in FBT (N = 55) and 2.28 kg in PFT (N = 51), by Session 5, were the best predictors of remission at end of treatment. Early response in FBT was predicted by greater paternal therapeutic alliance and lower paternal criticism. Early response in PFT was predicted by less severe eating-disorder symptoms and negative affect at baseline, lower maternal criticism, and greater adolescent therapeutic alliance.ConclusionsThe results confirm that early weight gain is an important prognostic indicator in both conjoint FBT and PFT and suggest that addressing negative emotion, parental criticism, and therapeutic alliance early in treatment could improve remission rates.

BackgroundKinase inhibition in the mitogen activated protein kinase (MAPK) pathway is a standard therapy for cancer patients with activating BRAF mutations. However, the anti-tumorigenic effect and clinical benefit are only transient, and tumors are prone to treatment resistance and relapse. To elucidate mechanistic insights into drug resistance, we have established an in vitro cellular model of MAPK inhibitor resistance in malignant melanoma.MethodsThe cellular model evolved in response to clinical dosage of the BRAF inhibitor, vemurafenib, PLX4032. We conducted transcriptomic expression profiling using RNA-Seq and RT-qPCR arrays. Pathways of melanogenesis, MAPK signaling, cell cycle, and metabolism were significantly enriched among the set of differentially expressed genes of vemurafenib-resistant cells vs control. The underlying mechanism of treatment resistance and pathway rewiring was uncovered to be based on non-genomic adaptation and validated in two distinct melanoma models, SK-MEL-28 and A375. Both cell lines have activating BRAF mutations and display metastatic potential.ResultsDownregulation of dual specific phosphatases, tumor suppressors, and negative MAPK regulators reengages mitogenic signaling. Upregulation of growth factors, cytokines, and cognate receptors triggers signaling pathways circumventing BRAF blockage. Further, changes in amino acid and one-carbon metabolism support cellular proliferation despite MAPK inhibitor treatment. In addition, treatment-resistant cells upregulate pigmentation and melanogenesis, pathways which partially overlap with MAPK signaling. Upstream regulator analysis discovered significant perturbation in oncogenic forkhead box and hypoxia inducible factor family transcription factors.ConclusionsThe established cellular models offer mechanistic insight into cellular changes and therapeutic targets under inhibitor resistance in malignant melanoma. At a systems biology level, the MAPK pathway undergoes major rewiring while acquiring inhibitor resistance. The outcome of this transcriptional plasticity is selection for a set of transcriptional master regulators, which circumvent upstream targeted kinases and provide alternative routes of mitogenic activation. A fine-woven network of redundant signals maintains similar effector genes allowing for tumor cell survival and malignant progression in therapy-resistant cancer.

Objective: Among those with bulimia nervosa, weight suppression has been associated with illness severity and treatment prognosis. Although significant weight loss is known to reduce metabolic rate, the relation between weight suppression and resting energy expenditure (REE) in bulimia nervosa has not been examined. This study tested the hypothesis of an inverse relation between weight suppression and REE in a sample of women with bulimia nervosa (N = 84). Methods: In primary analyses, linear regressions were conducted between weight suppression and REE, corrected for fat‐free mass. In follow‐up, exploratory analyses, stepwise linear regressions were conducted to explore the main and interaction effects of weight history and weight suppression on REE. Results: Neither traditional (TWS) nor developmental weight suppression (DWS) correlated with REE. Results from exploratory analyses, however, revealed a medium‐to‐large inverse relation between several weight history variables and REE (highest past weight, sr2 = 0.05; lowest postmorbid weight, sr2 = 0.07; current weight, sr2 = 0.05). Additionally, DWS interacted with current (sr2 = 0.08) and highest premorbid (sr2 = 0.05) z‐BMI to influence REE with a medium‐to‐large effect. For individuals low in current and premorbid z‐BMIs, higher DWS associated with lower REE levels. However, for individuals at higher premorbid z‐BMIs, higher DWS unexpectedly associated with greater REE levels. Discussion: In this sample of women with bulimia nervosa, reduced REE associated with higher weights across all timepoints. If the interaction effect between DWS and z‐BMI history persists in future studies, this may indicate unique challenges faced by individuals low in z‐BMI and high in DWS related to weight gain and normalization of eating. [ABSTRACT FROM AUTHOR]

OBJECTIVE:Family-based treatment (FBT) is an efficacious treatment for adolescent eating disorders, yet it is not routinely implemented in clinical practice. Given that consumers play a role in treatment selection, this study sought to examine families' perspectives on FBT and remission markers associated with increased treatment satisfaction across families. METHOD:Participants were 40 adolescents and 43 caregivers who received outpatient FBT. FBT helpfulness was assessed using a treatment follow-up questionnaire, and eating disorder symptomatology was assessed using percent expected body weight (%EBW) and the eating disorder examination (EDE). Regression analyses were used to assess whether changes in symptoms from baseline to end-of-treatment (EOT) were significantly associated with helpfulness reports. RESULTS:On average, patients and their parents perceived FBT as "quite helpful" and "extremely helpful," respectively. Improvements in all EDE subscales, with the exception of restraint, were significantly associated with adolescent report of helpfulness (all p

BackgroundVascular progenitor cells (VPCs) derived from embryonic stem cells (ESCs) are a valuable source for cell- and tissue-based therapeutic strategies. During the optimization of endothelial cell (EC) inductions from mouse ESCs using our staged and chemically-defined induction methods, we found that cell seeding density but not VEGF treatment between 10 ng/mL and 40 ng/mL was a significant variable directing ESCs into FLK1+ VPCs during stage 1 induction. Here, we examine potential contributions from cell-to-cell signaling or cellular metabolism in the production of VPCs from ESCs seeded at different cell densities.MethodsUsing 1D 1H-NMR spectroscopy, transcriptomic arrays, and flow cytometry, we observed that the density-dependent differentiation of ESCs into FLK1+ VPCs positively correlated with a shift in metabolism and cellular growth.ResultsSpecifically, cell differentiation correlated with an earlier plateauing of exhaustive glycolysis, decreased lactate production, lower metabolite consumption, decreased cellular proliferation and an increase in cell size. In contrast, cells seeded at a lower density of 1,000 cells/cm2 exhibited increased rates of glycolysis, lactate secretion, metabolite utilization, and proliferation over the same induction period. Gene expression analysis indicated that high cell seeding density correlated with up-regulation of several genes including cell adhesion molecules of the notch family (NOTCH1 and NOTCH4) and cadherin family (CDH5) related to vascular development.ConclusionsThese results confirm that a distinct metabolic phenotype correlates with cell differentiation of VPCs.

BackgroundAmong breast cancers, the triple-negative breast cancer (TNBC) subtype has the worst prognosis with no approved targeted therapies and only standard chemotherapy as the backbone of systemic therapy. Unique metabolic changes in cancer progression provide innovative therapeutic opportunities. The receptor tyrosine kinases (RTKs) epidermal growth factor receptor (EGFR), and MET receptor are highly expressed in TNBC, making both promising therapeutic targets. RTK signaling profoundly alters cellular metabolism by increasing glucose consumption and subsequently diverting glucose carbon sources into metabolic pathways necessary to support the tumorigenesis. Therefore, detailed metabolic profiles of TNBC subtypes and their response to tyrosine kinase inhibitors may identify therapeutic sensitivities.MethodsWe quantified the metabolic profiles of TNBC cell lines representing multiple TNBC subtypes using gas chromatography mass spectrometry. In addition, we subjected MDA-MB-231, MDA-MB-468, Hs578T, and HCC70 cell lines to metabolic flux analysis of basal and maximal glycolytic and mitochondrial oxidative rates. Metabolic pool size and flux measurements were performed in the presence and absence of the MET inhibitor, INC280/capmatinib, and the EGFR inhibitor, erlotinib. Further, the sensitivities of these cells to modulators of core metabolic pathways were determined. In addition, we annotated a rate-limiting metabolic enzymes library and performed a siRNA screen in combination with MET or EGFR inhibitors to validate synergistic effects.ResultsTNBC cell line models displayed significant metabolic heterogeneity with respect to basal and maximal metabolic rates and responses to RTK and metabolic pathway inhibitors. Comprehensive systems biology analysis of metabolic perturbations, combined siRNA and tyrosine kinase inhibitor screens identified a core set of TCA cycle and fatty acid pathways whose perturbation sensitizes TNBC cells to small molecule targeting of receptor tyrosine kinases.ConclusionsSimilar to the genomic heterogeneity observed in TNBC, our results reveal metabolic heterogeneity among TNBC subtypes and demonstrate that understanding metabolic profiles and drug responses may prove valuable in targeting TNBC subtypes and identifying therapeutic susceptibilities in TNBC patients. Perturbation of metabolic pathways sensitizes TNBC to inhibition of receptor tyrosine kinases. Such metabolic vulnerabilities offer promise for effective therapeutic targeting for TNBC patients.

Background and Purpose: Neurotransmission and neuroinflammation are controlled by local increases in both extracellular ATP and the endocannabinoid 2‐arachidonoyl glycerol (2‐AG). While it is known that extracellular ATP stimulates 2‐AG production in cells in culture, the dynamics and molecular mechanisms that underlie this response remain poorly understood. Detection of real‐time changes in eCB levels with the genetically encoded sensor, GRABeCB2.0, can address this shortfall. Experimental Approach: 2‐AG and arachidonoylethanolamide (AEA) levels in Neuro2a (N2a) cells were measured by LC‐MS, and GRABeCB2.0 fluorescence changes were detected using live‐cell confocal microscopy and a 96‐well fluorescence plate reader. Key Results: 2‐AG and AEA increased GRABeCB2.0 fluorescence in N2a cells with EC50 values of 81 and 58 nM, respectively; both responses were reduced by the cannabinoid receptor type 1 (CB1R) antagonist SR141617 and absent in cells expressing the mutant‐GRABeCB2.0. ATP increased only 2‐AG levels in N2a cells, as measured by LC‐MS, and induced a transient increase in the GRABeCB2.0 signal within minutes primarily via activation of P2X7 receptors (P2X7R). This response was dependent on diacylglycerol lipase β activity, partially dependent on extracellular calcium and phospholipase C activity, but not controlled by the 2‐AG hydrolysing enzyme, α/β‐hydrolase domain containing 6 (ABHD6). Conclusions and Implications: Considering that P2X7R activation increases 2‐AG levels within minutes, our results show how these molecular components are mechanistically linked. The specific molecular components in these signalling systems represent potential therapeutic targets for the treatment of neurological diseases, such as chronic pain, that involve dysregulated neurotransmission and neuroinflammation. [ABSTRACT FROM AUTHOR]