Citations

Abstract Multiple myeloma (MM) is a heterogenous cancer that remains mostly incurable. A unifying feature of MM cells is a highly interconnected network of transcription factors and co-factors that coordinate the activity of super-enhancers to enforce myeloma cell identity. Targeting this network offers a promising avenue for therapeutic intervention across genetically diverse myeloma sub-types. Using integrated molecular and functional genomic approaches we identified Menin as a key driver of oncogenic gene expression in MM cells. Menin and its co-factor KMT2A bind at super-enhancers and maintain expression of essential myeloma genes, including IRF4. We demonstrate that Menin inhibitors, which have recently been approved for treatment of acute myeloid leukaemia, are highly active in myeloma cell lines and in vivo models. Combining Menin inhibitors with other super-enhancer targeting therapies such EP300/CREBBP inhibitors or immunomodulatory drugs (IMiDs) overcomes epigenetic plasticity in cells resistant to single agent treatment.

Abstract The Alzheimer's Disease Neuroimaging Initiative (ADNI) recently celebrated its 20th anniversary, reflecting two decades of major contributions to Alzheimer's research through open data sharing and longitudinal multimodal assessments. This review synthesizes 122 high‐impact studies using ADNI data or biospecimens from 2023 to mid‐2025 to clarify mechanisms of Alzheimer's disease (AD) progression. Studies describe impairment of glymphatic clearance and the impact of cerebral small vessel disease, trajectories of amyloid beta and tau deposition, inflammation, metabolic disturbances, synaptic dysfunction, and neurodegeneration, leading to cognitive impairment and neuropsychiatric symptoms. Multifactorial contributions from genetic and epigenetic influences, co‐pathologies and comorbidities, and mechanisms of resilience modulate disease progression. Finally, heterogeneity of clinical presentation and disease course is described in the context of multiple contributing factors, highlighting the complexity of AD. By integrating imaging, fluid biomarkers, genetics, and clinical measures, ADNI provides a comprehensive research dataset for unraveling mechanisms underlying AD progression.

Gephyrin is a postsynaptic scaffold protein essential for inhibitory neurotransmission. Gephyrin‐immunoglobulin G (IgG) was reported, decades ago, in a single case of paraneoplastic stiff‐person‐like syndrome, but its broader clinical relevance remains unknown. While investigating unclassified synaptic IgGs mimicking amphiphysin‐IgG, we identified gephyrin‐IgG in 3 patients using human protein microarray. Gephyrin specificity was confirmed using confocal tissue‐based immunofluorescence assay, cell‐based assay, and Western blot. The 3 patients, all female, had: encephalitis (2) and myeloneuropathy and breast cancer (1). All had inflammatory cerebrospinal fluid and abnormal magnetic resonance imaging, and improved following immunotherapy. Gephyrin‐IgG is associated with a treatable autoimmune neurological disease, sometimes paraneoplastic. ANN NEUROL 2026

Abstract Introduction: Surveillance biopsies after kidney transplantation provide an opportunity to assess early renal disease processes, including diabetic nephropathy, before clinical manifestation. This study aimed to identify proteomic alterations in renal allografts at 5 years post-transplant (5yrPT) and their associations with histologic features in diabetic/obese (DM/OB) versus non-diabetic/non-obese (nDM/nOB) recipients. Methods: We studied protocol biopsies from 17 DM/OB and 14 nDM/nOB kidney transplant recipients at Mayo Clinic (2000–2012). Laser capture microdissection followed by mass spectrometry was used for proteomic profiling. Histologic assessment included Banff and Tervaert scoring and morphometric analysis. Statistical comparisons were performed using ANOVA with Tukey post-hoc testing. Results: DM/OB recipients demonstrated greater histologic and metabolic injury at 5yrPT. Proteomic analysis identified 101 glomerular and 86 non-glomerular proteins differentially expressed between groups. Significant alterations were observed in proteins associated with mitochondrial dysfunction, including VDAC1 (fold change [FC] 2.6, p = 0.03), NDUFB9 (FC 0.15, p = 0.009), and NDUFA9 (FC 1.72, p = 0.01). Extracellular matrix remodeling proteins COL6A1, COL6A2, and COL6A3 were upregulated (FC 1.6–1.8, p < 0.05). Immune and inflammatory markers C9 (FC 1.6, p < 0.03) and TGFBI (FC 1.7, p < 0.001), as well as oxidative stress–related CLU, were increased. GGACT showed the greatest decrease (FC 0.30, p < 0.001), implicating altered energy metabolism. Conclusion: Distinct proteomic signatures at 5yrPT in DM/OB recipients highlight early mitochondrial, metabolic, immune, and extracellular matrix pathways involved in diabetic kidney disease. These changes precede clinical disease and identify candidate biomarkers and therapeutic targets to improve graft longevity.

Objective: Percutaneous needle tenotomy (PNT) and ultrasonic debridement (UD) are minimally invasive interventions for the management of chronic tendinopathy. Despite their increasing use, no standardized, evidence-based rehabilitation guidelines currently exist to direct clinicians in post-procedural management. This systematic review aimed to characterize and synthesize reported rehabilitation protocols following PNT and UD for patellar, proximal hamstring, and gluteal tendinopathies. Design: Systematic Review Results: Twenty-seven studies met inclusion criteria, with patellar tendon procedures (n=13) being the most common, followed by gluteal (n=6), proximal hamstring (n=3), and multi-tendon protocols (n=5). Of the included studies, 21 (78%) utilized percutaneous needle tenotomy (PNT) and six (22%) used ultrasound debridement or Tenex. Exercise restrictions were mandated in 19 studies (70%), while 12 (44%) provided a detailed, structured rehabilitation program, frequently emphasizing eccentric loading for patellar and hamstring tendons. Weight-bearing limitations were uncommon, appearing in only three studies (11%). Fifteen studies (56%) combined the procedure with platelet-rich plasma (PRP). Pharmacological protocols also showed high variance, with NSAID restrictions ranging from 1 to 28 days and corticosteroid avoidance lasting between 10 days and one year. Overall, substantial variability remains regarding recommended activity progression, exercise initiation, and mechanical loading strategies across current research. Conclusion: PNT and UD appear effective for managing refractory tendinopathy, yet post-procedure rehabilitation guidelines remain inconsistent and supported by limited high-quality evidence. Future research should aim to identify key variables that guide individualized rehabilitation progressions, optimizing recovery timelines, and facilitating safe and efficient return to activity following PNT and UD procedures.

Delayed graft function (DGF) is a frequent complication after deceased donor kidney transplantation, yet its long-term impact remains understudied. Heterogeneous populations, short follow-up, and inadequate control of donor-related factors have limited prior studies. Using the Scientific Registry of Transplant Recipients (2005–2024), we evaluated the association between DGF and long-term graft outcomes, including a mate-kidney (same donor, discordant DGF status) analysis to isolate its independent effect. We identified 103,678 dialysis-dependent deceased donor kidney recipients maintained on tacrolimus and mycophenolate. Mixed-effects Cox models, adjusted for donor, recipient, immunologic, and procurement factors. DGF occurred in 30.1% of recipients and was associated with increased death-censored graft failure (HR 1.40; 95% CI 1.33–1.47) and overall graft failure (HR 1.27; 95% CI 1.23–1.31). DGF recipients had higher rejection rates at 6 (6.0% vs. 4.7%) and 12 months (8.9% vs. 7.3%), longer hospital stay, and higher 1-year rehospitalization. In the mate-kidney analysis (6,818 donors), DGF remained strongly associated with death-censored graft failure (HR 1.58; 95% CI 1.39–1.80) and overall graft failure (HR 1.35; 95% CI 1.25–1.46), confirming the independent effect of DGF. DGF is a strong predictor of adverse long-term outcomes irrespective of rejection and warrants targeted prevention strategies and intensified follow-up.

The NCCN Guidelines for Melanoma: Cutaneous provide strategies for the diagnosis, treatment, and follow-up of patients with cutaneous melanoma, which is among the most common cancers in the United States. The outcome of cutaneous melanoma is significantly influenced by stage at initial presentation. Generally, localized disease and smaller primary tumors have been associated with more favorable prognosis. Thus, the select content featured in this issue focuses on risk factors associated with cutaneous melanoma development and which should be considered during an initial assessment. These include (1) phenotypic predispositions, (2) personal medical history or comorbidities, (3) genetic predispositions, and (4) environmental factors.

ABSTRACT Background Readmission is considered as a surgical quality indicator. More data regarding predictors of readmission and outcomes after surgery for colorectal liver metastasis are needed. Using a propensity score match to create a 1:2 match of cases:controls for 90‐day. Readmission, the matching variables used for balance included age, tumor size, estimated blood loss, and type of resection (minor or major). T‐tests were used for continuous measures, Fisher's exact test was used for categorical data, and the Kaplan–Meier method was used to estimate survival. p < 0.05 was considered significant. Methods Retrospectively examined 935 patients with CLM from 2000 to 2018. Using a propensity score match to create a 1:2 match of cases:controls for 90‐day. Readmission, the matching variables used for balance included age, tumor size, estimated blood loss, and type of resection (minor or major). T‐tests were used for continuous measures, Fisher's exact test was used for categorical data, and the Kaplan–Meier method was used to estimate survival. p < 0.05 was considered significant. Results 935 patients were included in the initial sample with 896 eligible for inclusion in the propensity matching. The average age of the population was 59% and 59% male. Overall readmission rate was 8.0%. Median time to readmission was 14 days. In the propensity score matched sample, readmitted patients had higher rates of organ space infection (28% vs 2% and p < 0.0001), bile leak (26% vs 1% and p < 0.0001), and liver failure (9% vs 2% and p = 0.042). There was no difference in LOS (7 days versus six days and p = 0.40), overall survival (median 39.7 vs 41.0 months and p = 0.79), or rate of adjuvant therapy (68% for both and p > 0.99). Conclusion Patients readmitted for intermediate and late complications after surgery for CLM can recover and receive adjuvant therapy with no adverse effect on overall survival. Organ space infection, bile leak, and liver failure are highly associated with readmission.