Nandakumar, Renu

Abstract Background XK disease is a multisystem neurodegenerative disorder caused by mutations in the XK gene that codes for the lipid scramblase XK. Objective The aim was to describe the lipidomic spectrum in postmortem brain tissue from XK patients. Methods We measured the levels of 593 lipid species in the caudate nucleus (CN), putamen, and dorsolateral prefrontal cortex (DLPFC) from postmortem tissues of 5 XK patients and 6 controls. Results In XK patients, we observed increased levels of triacylglycerol, monoacylglycerol, phosphatidylserine, and ceramide in the CN. Acylated phosphatidylglycerol levels were reduced in both the CN and putamen. Acyl carnitine, dihydrosphingomyelin, and monosialodihexosylganglioside were reduced, whereas N ‐acyl phosphatidylethanolamine was increased in the DLPFC. N ‐Acyl serine was reduced in all three regions. Conclusions Our findings provide initial evidence of abnormal sphingolipid and phospholipid concentrations in the brains of XK patients and may provide insights into mechanisms of neurodegeneration in this disease. © 2026 International Parkinson and Movement Disorder Society.

Abstract Germinal center B-cell lymphomas frequently exhibit monoallelic loss-of-function mutations in the histone acetyltransferases CREBBP and p300, which contribute to lymphoma development, disrupt normal germinal center biology, and promote immune evasion. This study evaluates YF2, a histone acetyltransferase activator that increases CREBBP/p300 activity, as a potential therapeutic approach for B-cell lymphoma. YF2 binds the bromodomain of CREBBP/p300, increasing their auto-acetylation and enzymatic activity. It also induces cytotoxicity in B-cell lymphoma cell lines, with a stronger response in those carrying CREBBP / EP300 mutations. Additionally, YF2 increases the acetylation of key CREBBP/p300 substrates, including H3K27, p53, and BCL6, leading to enhanced apoptosis and altered B-cell diTerentiation. YF2 is well tolerated in vivo and extends survival in both cell line- and patient-derived xenograft mouse models. Moreover, YF2 exposure upregulates antigen-presentation markers and reshapes the immune microenvironment, strengthening responses to immune checkpoint blockade. Taken together, these findings support pharmacologic activation of CREBBP/p300 with YF2 as a compelling therapeutic strategy for B-cell lymphoma. Significance YF2 stimulates CREBBP/p300 activity to normalize B-cell diTerentiation and enhance immune recognition, oTering a potential approach to limit lymphoma progression and strengthen immunotherapy responses.

Introduction: Sarcopenia, characterized by loss of muscle mass and function, is prevalent in heart failure (HF) and associated with poor outcomes. We investigated alterations in sarcopenia index (SI), a surrogate marker of skeletal muscle mass, in HF, left ventricular assist device (LVAD) and heart transplant (HT) and assessed its relationship with inflammation and digestive tract (gut and oral) microbiota. Hypothesis: Sarcopenia will be associated with increased inflammation, dysbiotic microbial signatures, higher HF class, and earlier time post-HT or post LVAD. Methods: We enrolled 460 HF, LVAD and HT patients. Repeated measures pre and post procedures were obtained in a subset of LVAD and HT patients. Sarcopenia index (serum Creatinine/Cystatin C) and inflammatory biomarkers (C-reactive protein, interleukin-6, tumor necrosis factor-alpha) were measured in 271 and 622 blood samples, respectively. Gut and saliva microbiota were assessed via 16S rRNA sequencing among 335 stool and 341 saliva samples. Multivariable regression models were used to assess the relationship between SI and i) New York Heart Association class; ii) pre- vs. post-LVAD or HT; iii) biomarkers of inflammation and microbial diversity. Results: Median (interquartile range) ln-SI was -0.13(-0.32,0.05). Ln-SI decreased across worsening HF class, further declined within the 1-month after LVAD and HT and rebounded over time to the levels of symptomatic HF. Ln-SI demonstrated an inverse correlation with inflammation (r=-0.28, p<0.0001), and a positive correlation with gut (r=0.26, p<0.0001) and oral microbial diversity (r=0.24, p<0.0001). Presence of the gut taxa Roseburia inulinivorans was associated with increased SI. Conclusions: SI levels decreased in symptomatic HF and remained decreased long-term after LVAD and HT. SI levels covaried with inflammation, gut and oral microbiota in a similar fashion.