Mayo Clinic

Peritoneal fibrosis is one of the main causes of peritoneal dysfunction and withdrawal of patients from peritoneal dialysis (PD). Our previous study has shown that high‐glucose dialysis solution promotes glycolysis in peritoneal mesothelial cells, leading to mesothelial‐to‐mesenchymal transition (MMT) and peritoneal fibrosis. However, the molecular mechanisms remain unclear. Using single‐cell RNA sequencing (scRNA‐seq) analysis of cells from the effluent of patients undergoing PD from our previous study, we found that pyruvate kinase isozymes M2 (PKM2), a key rate‐limiting enzyme of glucose metabolism, was significantly upregulated in the mesothelial cells of patients with long‐term peritoneal dialysis (LPD). Using co‐immunoprecipitation, chromatin immunoprecipitation assay, and gene silencing techniques, we revealed that PKM2 promotes the expression of transcription factor SNAI2 by acetylating histone H3K9 (H3K9ac), thereby promoting the occurrence of MMT and hence peritoneal fibrosis. l‐cysteine, a known PKM2 inhibitor, blocked these responses and prevented PD‐induced peritoneal fibrosis. These results could provide a novel therapeutic strategy for treating peritoneal fibrosis.

Introduction Increased steatosis on preimplant liver frozen section is associated with delayed graft function and primary nonfunction. Efforts to standardize histologic assessment have proven difficult. Frozen section artifact and lipopeliosis complicate the detection of steatosis. We aimed to develop and validate an AI model to recognize large droplet fat and fat induced artifact (FIA)/lipopeliosis on preimplantation frozen section and to correlate the AI results with post-transplant clinical parameters. Methods The model was applied to 161 consecutive liver transplant specimens with preimplant slides. Results were correlated with traditional and Banff histologic assessment and clinical parameters. Results By traditional assessment, steatosis ranged from 0%–40%. The AI model identified a range of 0 to 15.9% steatosis. There was no difference in patient survival by any measures of steatosis. AI steatosis correlated with increased risk of early allograft dysfunction (OR = 1.63, P < .001), respiratory failure (OR = 1.21, P = .003), and more advanced fibrosis (OR = 1.18, P = .030), but was not correlated with graft or patient survival. FIA/lipopeliosis were identified in a range of 0 to 6.42%. In univariate analysis the percentage of FIA/lipopeliosis correlated with both graft and patient survival ( P = .044 and P = .009, respectively), but was not associated with increased risk of early allograft dysfunction, respiratory failure, or advanced fibrosis. Conclusions We developed an AI model that quantitates large droplet fat and FIA/lipopeliosis on frozen section slides and found a correlation with post-transplant outcomes. Further studies on larger, multi-institutional cohorts with higher fat containing donors are necessary to determine the role this model may have in organ acceptance decisions.

We report the presentation and management of a unique case of bilateral congenitally absent stapes footplates, with an open vestibule, in a pediatric patient. This case adds to the few prior reports of this rare anomaly and highlights the advanced diagnostic imaging capability of the Photon Counting Detector CT (PCD‐CT). image

Objectives The four‐repeat (4R) tauopathies are a group of neurodegenerative diseases, including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and globular glial tauopathy (GGT). This study aimed to characterize spatiotemporal atrophy progression using structural magnetic resonance imaging (MRI) and to examine its relationship with clinical course and neuropathology in a cohort of autopsy‐confirmed 4R tauopathies. Methods The study included 85 autopsied patients (54 with PSP, 28 with CBD, and 3 with GGT) who underwent multiple 3T MRI scans, as well as neuropsychological, neurological, and speech/language examinations, and standardized postmortem neuropathological evaluations. An unsupervised machine‐learning algorithm, Subtype and Stage Inference (SuStaIn), was applied to the cross‐sectional brain volumes to estimate spatiotemporal atrophy patterns and data‐driven subtypes and stages in each patient. The relationships among estimated subtypes, pathological diagnoses, and longitudinal changes in clinical testing were examined. Results The SuStaIn algorithm identified 2 distinct subtypes: (1) the subcortical subtype, in which atrophy progresses from the midbrain to the cortex, and (2) the cortical subtype, in which atrophy progresses from the frontal cortex to the subcortical regions. The subcortical subtype was more associated with typical PSP, whereas the cortical subtype was more associated with atypical PSP with a cortical distribution of pathology and CBD (p < 0.001). The cortical subtype had a faster rate of change on the PSP Rating Scale than the subcortical subtype (p < 0.05). Interpretation SuStaIn analysis revealed 2 MRI‐driven subtypes with distinct spatiotemporal atrophy patterns, clinical courses, and neuropathology. Our findings contribute to a comprehensive and improved understanding of disease progression and its relationship to tau pathology in 4R tauopathies. ANN NEUROL 2025

Background Several genetic syndromes that affect nerve development and functioning may involve the enteric nervous system and present clinically as dysmotility syndromes, typically in childhood. Aim To review the enteric neuromuscular manifestations, predominantly observed in adults, of neurofibromatosis type I at a tertiary referral center. Methods We conducted a medical records review at the Mayo Clinic and documented clinical manifestations and findings on radiology, pathology, and specialized motility tests of the esophagus, stomach, colon, and rectal evacuatory functions. The tests included scintigraphic gastrointestinal and colonic transit measurements, intraluminal esophageal, gastrointestinal, colonic, and anorectal manometry, and balloon expulsion test. Results Among 2406 with documented NF1, the gastrointestinal manifestations were obstruction or dysmotility, seen in 2% of the cohort. Thirteen patients had small bowel or colonic obstructions: 4 gastrointestinal stromal tumors, 3 malignant peripheral nerve sheath tumors, 3 neurofibromas, 1 diffuse ganglioneuromatosis, 1 schwannoma, and 1 inflammatory fibroid polyp. In addition, 38 patients had abnormal gut motility, including esophageal achalasia or spasm, delayed gastric emptying, slow colonic transit, and dyssynergic defecation. Gastric, small bowel, and colonic manometry were characterized by normal amplitude incoordinated contractions suggestive of neuropathy. In the few resected specimens, myenteric plexus proliferation or diffuse ganglioneuromatosis was identified histologically. Conclusions In addition to mechanical obstruction, typically due to benign tumors affecting smooth muscle or components of nerve (sheath or nerve fiber), patients with NF1 may present with dysmotility syndromes such as gastroparesis, slow colonic transit, or global dysmotility. Neuropathic dysmotility in NF1 can be identified by manometry and by histological evidence of myenteric plexus proliferation or diffuse ganglioneuromatosis.

Objectives Various mutations in hepatocellular carcinoma (HCC) carry prognostic implications. The objective of this study is to assess CT and MRI imaging features associated with Catenin Beta-1 (CTNNB1) mutation in HCC. Methods This retrospective, IRB- approved multi-reader, single-center study included treatment-naive, pathologic-proven HCC that underwent contrast-enhanced CT, MRI or both, with subsequent targeted tumor sequencing test. Preoperative CT and MRI were reviewed for the Liver Imaging Reporting and Data System (LI-RADS, LR) features and prognostic imaging features. Fisher’s exact test and multiple testing adjustment were used to assess the association of imaging features and CTNNB1 mutation status. Results Of the 160 HCCs included (median age 69 [IQR: 62, 75], 125 men), 58 (36%) had CTNNB1 mutation. Compared to wildtype, CTNNB1-mutated HCCs were more likely to be present as solitary lesion (CT: 26/43[60%] vs. 31/80 [40%], p = 0.024), have mosaic appearance (MRI: 9/34[26%] vs. 3/68[4.4%], p = 0.002), blood products in mass (CT: 7/43[16%] vs. 2/80[2.5%], p = 0.009; MRI: 12/34[35%] vs. 8/68[12%], p = 0.008), necrosis (CT: 16/43[37%] vs. 14/80[18]%, p = 0.026), intralesional arteries (CT: 26/43[60%] vs. 32/80[40%], p = 0.038). A subgroup of 98 high risk patients (hepatitis B, morphologic cirrhosis) were assigned LI-RADS categorization; majority of patients were assigned LR-5 (CT: 15/25[60%] vs. 21/52[40%]; MRI: 10/18[56%] vs. 19/44[43%]). No feature was significantly associated with CTNNB1 mutation status after multiple testing adjustment. Conclusion Compared to wildtype, CTNNB1-mutated HCCs are more likely to appear as solitary masses with mosaic, heterogeneous appearance containing blood products, necrosis and intralesional arteries. Majority of CTNNB1-mutated tumors were categorized as LR-5 in a subgroup of high risk patients. No imaging feature independently predicted CTNNB1-mutated HCCs.

Despite the success of chimeric antigen receptor T (CART) cell therapy in hematological malignancies, durable remissions remain low. Here, we report CART senescence as a potential resistance mechanism in 41BB-costimulated CART cell therapy. To mimic cancer relapse, we utilized an in vitro model with repeated CART cell activation cycles followed by rest periods. Using CD19-targeted CART cells with costimulation via 4-1BB-CD3ζ (BBζ) or CD28-CD3ζ (28ζ), we showed that CART cells undergo functional, phenotypical, and transcriptomic changes of senescence, which is more prominent in BBζ. We then utilized two additional independent strategies to induce senescence through MYC activation and irradiation. Induction of senescence impaired BBζ activity but improved 28ζ activity in preclinical studies. These findings were supported by analyses of independent patient data sets; senescence signatures in CART cell products were associated with non-response to BBζ but with improved clinical outcomes in 28ζ treatment. In summary, our study identifies senescence as a potential mechanism of failure predominantly in 41BB-costimulated CART cells.

Monoclonal antibodies targeting CD38 are a therapeutic mainstay in multiple myeloma (MM). While they have contributed to improved outcomes, most patients still experience disease relapse, and little is known about tumor-intrinsic mechanisms of resistance to these drugs. Antigen escape has been implicated as a mechanism of tumor cell evasion in immunotherapy. Yet, it is unknown whether MM cells can develop permanent resistance to anti-CD38 antibodies by acquiring genomic events leading to biallelic disruption of the CD38 gene locus. Here, we analyzed whole genome and whole exome sequencing data from 701 newly diagnosed patients, 67 patients at relapse with naivety to anti-CD38 antibodies, and 50 patients collected at relapse following anti-CD38 antibodies. We report a loss of CD38 in 20% (10/50) of patients post-CD38 therapy, three of which exhibited a loss of both copies. Two of these cases showed convergent evolution where distinct subclones independently acquired similar advantageous variants. Functional studies on missense mutations involved in biallelic CD38 events revealed that two variants, L153H and C275Y, decreased binding affinity and antibody-dependent cellular cytotoxicity of the commercial antibodies Daratumumab and Isatuximab. However, a third mutation, R140G, conferred selective resistance to Daratumumab, while retaining sensitivity to Isatuximab. Clinically, patients with MM are often rechallenged with CD38 antibodies following disease progression and these data suggest that next generation sequencing may play a role in subsequent treatment selection for a subset of patients.

A diagnosis‐to‐ablation time of < 1 year and < 3 years is associated with a significantly lower risk of atrial fibrillation reccurence compared to a time of > 1 year and > 3 years in atrial fibrillation patients awaiting ablation procedures. image

Numerous factors including social determinants of health, knowledge gaps, economic challenges, workforce limitations, and health system deficiencies are associated with significant disparities in access to health care services and health outcomes for people with epilepsy (PWE). The American Epilepsy Society (AES) and the International League Against Epilepsy—North America (ILAE-NA) established a joint task force to explore and develop recommendations to address health care disparities experienced by PWE. The task force gathered foundational knowledge through meetings, public and patient organization comments and discussions to develop consensus recommendations. We enumerate the recommendations and discuss the rationale behind them to reduce disparities in epilepsy care through comprehensive research, inclusive clinical practices, robust advocacy, and targeted educational initiatives. While our recommendations are focused on the United States, we acknowledge that similar barriers and limitations exist for PWE globally and that these also need to be addressed within their local domains and with attention to unique factors therewithin.

Hyperdiploid multiple myeloma (Hy‐MM) is a common (50% of MM cases), but frequently under‐recognized subtype of MM. Hy‐MM is characterized by the presence of multiple trisomies of the odd numbered chromosomes (with the exception of chromosomes 13 and 17), leading to an average chromosome count of 53. Despite its prevalence, Hy‐MM tends to receive less attention compared to high‐risk subtypes. Thus, gaps in our understanding of Hy‐MM remain underscoring the need for continued research ultimately to aid in targeted therapies and personalized treatment strategies to improve outcomes in this subgroup.