Citations

Abstract Effector gene expression in CD8+ T cells is tightly controlled at the epigenetic and transcriptional levels; however, crucial regulatory signals remain incompletely understood. In this study, we identify dual specificity phosphatase 2 (DUSP2) as a key epigenetic modulator of effector CD8+ T-cell state, by elucidating inhibition of BAF-mediated chromatin opening by DUSP2. Induced downregulation of DUSP2 in human CD8+ T cells enhances cytotoxicity and effector phenotypes by increasing chromatin accessibility through upregulation of BAF subunits, such as SMARCA4, and permitting binding of ETS1 to BAF subunit gene loci and those essential for effector programs. These findings uncover a previously unrecognized role of DUSP2 in the management of the chromatin landscape in effector CD8+ T cells and the epigenetic fine-tuning of their functionality, highlighting DUSP2 as a promising therapeutic target for T cell–based immunotherapy.

Abstract Background N‐methyl‐D‐aspartate receptor antibody encephalitis (NMDAR‐Ab‐E) is an autoantibody‐mediated disorder, characterized by acute development of neuropsychiatric symptoms, seizures, movement disorders, and autonomic instability. Objectives To describe acute seizure semiology and electroencephalogram (EEG) findings in patients with a first episode of NMDAR‐Ab‐E. Methods Medical records and EEG results were retrospectively evaluated from 14 adult patients with definite NMDAR‐Ab‐E, recruited between April 2009 and September 2017, and followed up until October 2024. Results A total of 92.8% (13/14) were women with a mean age of 29.6 years. 85.7% (12/14) patients experienced seizures. Focal and/or generalized seizures were described at presentation or in the first days of the illness in 57% (8/14). EEGs showed diffuse slowing in 13/14 and this coexisted with epileptiform activity in 10/13; fast frequencies in 7/13 (potentially owing to a benzodiazepine effect); and asymmetric focal slowing in 6/13. Six patients had periods of rhythmic slow activity (focal or diffuse), without evolution to electrographic seizures. An extreme delta brush (EDB) pattern was recorded in 2/13 patients, and this was associated with non‐convulsive status epilepticus in one of these individuals. Significance Most patients in this case series of NMDAR‐Ab‐E were young adult females with early focal and/or generalized seizures. Diffuse slowing in theta/delta range was the most common EEG finding, with or without epileptiform discharges, focal slowing, superimposed fast activities, and focal or diffuse rhythmic slowing. An EDB pattern was rare. Even with non‐specific findings, EEG seems to be a sensitive tool to aid diagnosis and decision‐making in NMDAR‐Ab‐E.

Objective: To evaluate the institutional learning curve of robotic liver resection (RLR), its association with surgical complexity and outcomes in an international multicenter cohort. Summary of Background Data: RLR is increasingly adopted worldwide, but the dynamics of the learning process and its impact on surgical outcomes remain poorly defined. Methods: This international, multicenter, retrospective cohort study included consecutive patients who underwent RLR between 06/2013 and 12/2024 across 22 expert centers. Based on the first 150 cases at each center, three phases were used to define the learning curve: operative time for competency, major complications for proficiency, and textbook outcome for mastery. Risk-adjusted generalized additive models were used to assess the learning process. Benchmark performance was compared to international reference values. Results: Among 2,331 patients, the most common indications were hepatocellular carcinoma (36%), benign lesions (23%) and colorectal liver metastases (21%). Operative time decreased after achieving competency (case #62), from 240 to 220 minutes ( P <0.001). Major morbidity reached a plateau during the proficiency phase (cases #63–138; 9% vs. 11%, P =0.144), while progression to mastery (cases #139–150) was associated with a higher rate of textbook outcome (76% vs. 87%, P =0.021). In contrast, conversion (5.1% vs. 4.9% vs. 2%), bile leak (4.0% vs. 5.3% vs. 3.8%), and 90-day mortality (0.7% vs. 0.9% vs. 0.9%) remained low and stable across all learning phases. Importantly, benchmark criteria for operative time, hospital stay, and textbook outcome were met across all complexity groups, including during the early learning phase. Conclusions: Robotic liver surgery shows progressive outcome improvement with early achievement of benchmark-level results and stable performance across increasing complexity. These findings indicate that, in experienced centers, RLR can be safely implemented and integrated into clinical practice, supporting its key role in modern hepatobiliary surgery.

Abstract Background Machine perfusion represents the most significant breakthrough in liver transplantation (LT) since the discovery of cyclosporin. Yet, the optimal perfusion strategy remains unsettled. Randomized trials demonstrate that hypothermic oxygenated perfusion (HOPE) improves graft survival and function and reduces ischemic cholangiopathy, whereas normothermic machine perfusion (NMP) decreases post-transplant injury. Real-world comparisons are lacking and challenging due to heterogeneity in donor-recipient risk profiles and regional differences. Aims To compare real-world outcomes of HOPE and NMP in LT. Methods We analyzed consecutive NMP-preserved LTs from seven North American centers between 2021 and 2024. We compared NMP to the European HOPE-REAL cohort, comprising HOPE-treated LTs from 22 centers between 2012 and 2021. Analyses were stratifyied by graft type and risk category and adjusted for donor age, donor risk index, and balance of risk score using entropy balancing. Results A total of 470 NMP and 1202 HOPE-treated grafts were analyzed, revealing major differences in risk profiles (Figure 1). In NMP, death-censored graft survivals at 1, 2, and 3 years were &gt;95% in donation after brain death (DBD) and &gt;94% in donation after circulatory death (DCD) grafts. Comparable outcomes were observed in the HOPE cohort with &gt;93%, in DBD, and &gt;87% in DCD after up to 3 years, despite significantly higher donor age and longer functional warm ischemia in the HOPE DCD cohort (Figure 2). After risk adjustment, death-censored graft survival remained similar between both modalities (Table 1). Non-anastomotic biliary stricture rates after DCD-LT were comparable (8.5% vs. 12.4%), independent of whether continuous or end-ischemic NMP was performed. Conclusion This first transatlantic real-world report demonstrates excellent outcomes with both NMP and HOPE despite higher graft risk in Europe. Machine perfusion is the new standard of care in LT, while further understanding is needed regarding the distinct benefits of each modality across risk profiles.Figure 1.Graft risk in NMP and HOPE stratified by graft type. Benchmark case was defined as primary transplant with MELD &lt;20 and BAR score &lt;9, extended criteria as either BMI &gt;30kg/m2, donor age &gt;65 years, CIT &gt;12h. DCD grafts were categorized as definedFor image description, please refer to the figure legend and surrounding text. Figure 2.Death-censored graft survival in liver transplantation following NMP and HOPE stratified by graft type. Abbreviations: NMP (Normothermic Machine Perfusion), HOPE (Hypothermic Oxygenated Perfusion), DBD (Donation after Brain Death), DCD (Donation after circulatory death)For image description, please refer to the figure legend and surrounding text. Table 1.Risk-adjusted comparison of death-censored graft survival between NMP and HOPE.For image description, please refer to the figure legend and surrounding text.

Abstract Background Indocyanine green (ICG) fluorescence imaging is increasingly incorporated into robotic liver resections (RLR), yet clinical practice regarding timing, dosage, and staining techniques is divergent. Aims This international expert survey aimed to characterize current practices for ICG in RLR. Methods Experts in RLR were invited to participate based on surgical volume (experience of 50 RLR and 30 annual RLR). A 74-item questionnaire was developed following a literature search and reviewed by a steering committee. The survey addressed indications, timing, dosage, imaging technology, benefits, limitations, training, and future directions of ICG use. Responses collected between September and October 2025 were analyzed. Results Seventy experts from 19 countries completed the survey, corresponding to an 88% response rate. Centers performed a median of 180 annual liver resections, including 55 RLR. Most experts used ICG (96%) during RLR. Anatomical demarcation (91%), tumor localization (60%), and biliary anatomy assessment (60%) were the most frequent indications. 60% of experts use preoperative ICG, while intraoperative ICG is mainly administered for demarcation (67%) and biliary tract visualization (40%). Considerable heterogeneity exists in dosage, timing, and staining techniques, particularly in cirrhotic livers and for tumor localization. Only half of the experts had standard operating procedures, whereas 64% expressed the need for a higher degree of standardization. Reported benefits of ICG use included improved anatomical orientation, margin assessment, lesion detection, and support during complex resections. Perceived limitations included background fluorescence, tissue penetration and variable staining in diseased parenchyma. 80% anticipated improved outcomes with combined ICG and three-dimensional image-guidance. Conclusion ICG fluorescence is widely used in RLR and is an important cornerstone for precision-guided robotic liver surgery. Standardized clinical practice guidelines, structured training, and technological improvements in imaging and navigation systems are claimed to optimize its clinical use.

ABSTRACT A central paradox in cancer immunotherapy is that patients harboring apparently exhausted or dysfunctional CD8 + T cells can exhibit rapid and durable responses to immune checkpoint inhibition (ICI). Although such rebound responses do not occur in all ICI-treated patients, resolving this paradox is essential for identifying and therapeutically maximizing reversible T cell exhaustion before clinical benefit is achieved. Here, we identify malic enzyme 1 (ME1) as a key molecular determinant of a latent, epigenetically poised effector CD8 + T cell state that is both necessary and sufficient for responsiveness to ICI. Genetic loss of ME1 abolishes therapeutic efficacy despite intact checkpoint blockade, whereas enforced ME1 expression enables robust antitumor responses even in otherwise ICI-resistant tumor models. Chromatin accessibility profiling, together with bulk and single-cell transcriptomic analyses, demonstrates that ME1 preserves effector readiness by maintaining latent effector capacity as a measurable biological state. These findings also experimentally ground a mechanistically interpretable dynamical model of T cell exhaustion, in which latent effector capacity, E(t), evolves according to a first-order differential equation shaped by activation history and decay. By defining latent effector capacity as a quantifiable, history-dependent state variable, our findings further enable the rational design of AI-driven models to predict patient-specific responsiveness and optimize therapeutic strategies in T cell–based immunotherapy. Together, our results redefine exhaustion as a state of masked potential governed by history-dependent latent effector capacity and provide a unified framework explaining rapid functional rebound, therapeutic heterogeneity, and the boundary between reversible and irreversible T cell exhaustion.

Background: Acute transverse myelitis (ATM) is an inflammatory disorder of the spinal cord with heterogeneous etiologies, including autoimmune, infectious, paraneoplastic, and drug-induced causes. Tumor necrosis factor-alpha (TNF-α) inhibitors have been infrequently associated with inflammatory central nervous system events, including transverse myelitis. TNF-inhibitor-associated myelitis typically presents with short-segment lesions, a normal brain MRI, and partial responsiveness to corticosteroids. Longitudinally extensive transverse myelitis (LETM) and steroid-refractory cases are uncommon. Case Presentation: A 39-year-old woman with psoriatic arthritis treated with etanercept for two years presented with subacute progressive bilateral lower-extremity sensory loss and weakness. MRI revealed a T2 hyperintense spinal cord lesion extending from T11 to L1 with gadolinium enhancement, consistent with transverse myelitis, while brain MRI was normal. Cerebrospinal fluid analysis showed lymphocytic pleocytosis, elevated protein, oligoclonal bands, and increased kappa free light chains. Extensive infectious, metabolic, paraneoplastic, and autoimmune testing, including aquaporin-4 and MOG antibodies, was negative. Despite high-dose intravenous corticosteroids and the discontinuation of etanercept, the patient experienced clinical worsening with lesion expansion, meeting criteria for LETM, and developed urinary retention. She subsequently underwent plasma exchange, resulting in radiologic improvement and moderate clinical recovery. Conclusions: This case highlights an atypical presentation of TNF-inhibitor-associated myelitis characterized by a biphasic course, longitudinally extensive spinal cord involvement, steroid refractoriness, and responsiveness to plasma exchange. These features suggest either an unusually severe TNF-inhibitor-related inflammatory phenotype or a TNF-inhibitor-triggered antibody-mediated demyelinating process. Reports of TNF-inhibitor-associated myelitis evolving into longitudinally extensive, steroid-refractory disease remain limited, and this presentation may broaden the recognized clinical spectrum of TNF-α-related CNS inflammatory events. Close neurologic follow-up and heightened awareness of severe CNS complications associated with TNF-α inhibitors are warranted.

Abstract We present chromosome-level, phased diploid genome assemblies of two widely used human fibroblast cell lines: BJ (46,XY) and IMR-90 (46,XX). Using Oxford Nanopore, PacBio HiFi, and Hi-C sequencing data, we generated assemblies spanning 5.9 and 6.0 Gbp with diploid quality values exceeding QV 60. To validate structural integrity, we developed KaryoScope, an alignment-free tool for generating computational karyograms from k-mer feature databases. We identify &gt;50 000 structural variants relative to T2T-CHM13v2.0, the majority of which are heterozygous and cell-line-specific. Combining reference-based and de novo gene annotation, we uncover a previously unreported 1 Mbp homozygous duplication at the 16p11.2 locus in BJ, demonstrating that even karyotypically normal cell lines can harbor clinically relevant submicroscopic rearrangements. We show that mapping publicly available short-read, RNA-seq, and ChIP-seq data to sample-matched diploid assemblies substantially improves read alignment and enables haplotype phasing of 23%–28% of short reads. The BJ and IMR-90 assemblies and associated variant calls are publicly available as a resource for the research community.