Lower region-specific gray matter volume in females with atypical anorexia nervosa and anorexia nervosa.

OBJECTIVE: Few studies have focused on brain structure in atypical anorexia nervosa (atypical AN). This study investigates differences in gray matter volume (GMV) between females with anorexia nervosa (AN) and atypical AN, and healthy controls (HC). METHOD: Structural magnetic resonance imaging data were acquired for 37 AN, 23 atypical AN, and 41 HC female participants. Freesurfer was used to extract GMV, cortical thickness, and surface area for six brain lobes and associated cortical regions of interest (ROI). Primary analyses employed linear mixed-effects models to compare group differences in lobar GMV, followed by secondary analyses on ROIs within significant lobes. We also explored relationships between cortical gray matter and both body mass index (BMI) and symptom severity. RESULTS: Our primary analyses revealed significant lower GMV in frontal, temporal and parietal areas (FDR < .05) in AN and atypical AN when compared to HC. Lobar GMV comparisons were non-significant between atypical AN and AN. The parietal lobe exhibited the greatest proportion of affected cortical ROIs in both AN versus HC and atypical AN versus HC. BMI, but not symptom severity, was found to be associated with cortical GMV in the parietal, frontal, temporal, and cingulate lobes. No significant differences were observed in cortical thickness or surface area. DISCUSSION: We observed lower GMV in frontal, temporal, and parietal areas, when compared to HC, but no differences between AN and atypical AN. This indicates potentially overlapping structural phenotypes between these disorders and evidence of brain changes among those who are not below the clinical underweight threshold. PUBLIC SIGNIFICANCE: Despite individuals with atypical anorexia nervosa presenting above the clinical weight threshold, lower cortical gray matter volume was observed in partial, temporal, and frontal cortices, compared to healthy individuals. No significant differences were found in cortical gray matter volume between anorexia nervosa and atypical anorexia nervosa. This underscores the importance of continuing to assess and target weight gain in clinical care, even for those who are presenting above the low-weight clinical criteria.

Targeting ULK1 Decreases IFNγ-Mediated Resistance to Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICI) have transformed the treatment of melanoma. However, the majority of patients have primary or acquired resistance to ICIs, limiting durable responses and patient survival. IFNγ signaling and the expression of IFNγ-stimulated genes correlate with either response or resistance to ICIs, in a context-dependent manner. While IFNγ-inducible immunostimulatory genes are required for response to ICIs, chronic IFNγ signaling induces the expression of immunosuppressive genes, promoting resistance to these therapies. Here, we show that high levels of Unc-51 like kinase 1 (ULK1) correlate with poor survival in patients with melanoma and overexpression of ULK1 in melanoma cells enhances IFNγ-induced expression of immunosuppressive genes, with minimal effects on the expression of immunostimulatory genes. In contrast, genetic or pharmacologic inhibition of ULK1 reduces expression of IFNγ-induced immunosuppressive genes. ULK1 binds IRF1 in the nuclear compartment of melanoma cells, controlling its binding to the programmed death-ligand 1 promoter region. In addition, pharmacologic inhibition of ULK1 in combination with anti-programmed cell death protein 1 therapy further reduces melanoma tumor growth in vivo. Our data suggest that targeting ULK1 represses IFNγ-dependent immunosuppression. These findings support the combination of ULK1 drug-targeted inhibition with ICIs for the treatment of patients with melanoma to improve response rates and patient outcomes. IMPLICATIONS: This study identifies ULK1, activated downstream of IFNγ signaling, as a druggable target to overcome resistance mechanisms to ICI therapy in metastatic melanoma.

Identification of State Markers in Anorexia Nervosa: Replication and Extension of Inflammation Associated Biomarkers Using Multiplex Profiling in Anorexia Nervosa and Atypical Anorexia Nervosa.

Proteomics provides an opportunity for detection and monitoring of anorexia nervosa (AN) and its related variant, atypical-AN (atyp-AN). However, research to date has been limited by the small number of proteins explored, exclusive focus on adults with AN, and lack of replication across studies. This study performed Olink Proseek Multiplex profiling of 92 proteins involved in inflammation among females with AN and atyp-AN (N = 64), all < 90% of expected body weight, and age-matched healthy controls (HC; N=44). After correction for multiple testing, nine proteins differed significantly in the AN/atyp-AN group relative to HC group ( lower levels: CXCL1, HGF, IL-18R1, TNFSF14, TRANCE; higher levels: CCL23, Flt3L, LIF-R, MMP-1). The expression levels of three proteins ( lower IL-18R1, TRANCE; higher LIF-R) were uniquely disrupted in females with AN. No unique expression levels emerged for atyp-AN. Across the whole sample, twenty-one proteins correlated positively with BMI (ADA, AXIN1, CD5, CD244, CD40, CD6, CXCL1, FGF-21, HGF, IL-10RB, IL-12B, IL18, IL-18R1, IL6, LAP TGF-beta-1, SIRT2, STAMBP, TNFRSF9, TNFSF14, TRAIL, TRANCE) and six (CCL11, CCL23, FGF-19, IL8, LIF-R, OPG) were negatively correlated with BMI. Overall, our results replicate the prior study demonstrating a dysregulated inflammatory status in AN, and extend these results to atyp-AN (AN/atyp-AN all < 90% of expected body weight). Of the 27 proteins correlated with BMI, 18 were replicated from a prior study using similar methods, highlighting the promise of inflammatory protein expression levels as biomarkers of disease monitoring. Additional studies of individuals across the entire weight spectrum are needed to understand the role of inflammation in atyp-AN.