Citations

GGGGCC (G 4 C 2 ) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Toxicity is thought to result from the accumulation of either repeat RNAs and/or dipeptide repeat proteins (DPRs) translated from repeat-containing transcripts through repeat-associated non-AUG (RAN) translation. To disentangle RNA from DPR toxicity, we mutated a CUG codon predominantly used to initiate DPR translation from all three reading frames. This mutation disrupted DPR synthesis while preserving the expression of repeat-containing RNAs. Despite the accumulation of RNA foci, behavioral deficits and pathological abnormalities, including p-TDP-43 inclusions, STING activation, motor neuron loss, neuroinflammation, and increased plasma neurofilament concentration, were alleviated in C9ORF72 mice. Base editing of the CUG codon also improved molecular phenotypes and survival in patient induced pluripotent stem cell–derived neurons, which highlights the potential of therapeutically targeting DPR production rather than repeat RNAs.

Abstract Background Relapsed medulloblastoma remains a significant therapeutic challenge as it is near universally fatal. The tumor microenvironment of medulloblastoma plays a critical role in tumor progression, influencing tumor growth, immune evasion, and therapeutic resistance. We hypothesized that defining tumor-immune interactions in diagnostic and relapsed medulloblastoma may uncover mechanisms of immune evasion and identify novel therapeutic targets. Methods We analyzed paired primary and recurrent RNA-sequencing data from 140 medulloblastoma patients to profile immune cell composition and validate spatial relationships within the TME. To identify key tumor-immune interactions, we developed a novel algorithm to detect receptor-ligand pairs using single-cell RNA-sequencing data. These interactions were validated across RNA and proteomic datasets. Their functional significance was empirically demonstrated in newly developed immunocompetent models of recurrent medulloblastoma that closely recapitulate the human disease. Results We observed a shift toward a heightened immunosuppressive TME at relapse. Using our algorithm, we identified biologically significant receptor-ligand interactions, most notably MIF-CD74, constitutively expressed at RNA and protein levels across medulloblastoma subgroups, at diagnosis and relapse. Disrupting MIF-CD74 interactions led to significant alterations in the tumor microenvironment, highlighting its functional significance. Conclusions Our multifaceted approach identified key tumor-immune interactions in medulloblastoma. Among these, MIF-CD74 was validated as a targetable interaction, demonstrating the utility of our integrative approach for identifying novel therapeutic targets across multiple tumor types.

Background and aims: Aberrations in telomere length can have important implications in cancer. Using a cohort of 1007 patients, we investigated whether leukocyte telomere length (LTL) in patients with colorectal cancer (CRC) is associated with survival. We also investigated whether some telomere maintenance genes are associated with survival in these patients. Methods: The Biobank for Gastrointestinal Health Research (BGHR), an ongoing project involving collection of biospecimens at the Mayo Clinic, was utilized to obtain data from patients diagnosed with stage II or III CRC. Blood samples were collected prior to chemotherapy/radiation and DNA was extracted for measuring median LTL. The main outcome measures were overall survival (OS) and disease-free survival (DFS) by disease stage. Results: A significant inverse relationship was observed with patient age and LTL (spearman correlation coefficient (r) = −0.48, 95%; p = 1.13 × 10−58). Females had significantly longer LTL than males (p = 3.97 × 10−5). The rs1317082 SNP in the TERC gene was significantly associated with both OS and DFS in combined stage II and stage III patients (p = 0.017 and p = 0.023, respectively). A statistically significant association of the OBFC1 SNP (rs9419958) was observed for OS for the combined stage II and stage III patients (p = 0.016). Importantly, LTL was significantly associated with both OS and DFS (p = 0.008 and 0.044 respectively) in combined stage II and stage III patients. Conclusions: Our results show that LTL is predictive of OS and DFS for stage II and III CRC patients, particularly over a longer follow-up, extending beyond five years after a diagnosis of CRC, and certain SNPs in genes involved in telomere maintenance are significantly associated with patient outcomes, independent of telomere length.

Abstract The use of antibiotics in the hospice setting is complicated by differing patient goals, elevated side effects, and limited information regarding effectiveness. Here, we describe a case and apply the four-quadrant approach (4QA). This includes analyzing the case through the lenses of (1) medical indications related to improving function and reducing symptoms; (2) patient preferences, which vary among patients from complete avoidance of antibiotics to a therapeutic dosage to treat infection; (3) quality-of-life factors that include managing infectious symptoms versus antibiotic side effects; and (4) contextual features, which include antimicrobial resistance concerns and cost considerations. Antibiotics may be beneficial in some cases and should not be denied to patients enrolled in hospice care. More robust evidence-based information about outcomes is needed to inform discussions at the time of enrollment. Applying the 4QA to a case can help determine the best approach for each individual patient.

Background: Patients with cervical artery dissection (CAD) have a higher prevalence of cerebral aneurysms, likely due to underlying vasculopathies. Understanding risk factors and outcomes in this population may inform screening and management strategies. Methods: We conducted a post-hoc analysis of the STOP-CAD study, a multicenter international registry of patients with non-major trauma-related CAD across 63 centers. Cerebral aneurysms were identified based on medical history and intracranial vascular imaging obtained for dissection diagnosis. We compared demographic, clinical, laboratory, and imaging characteristics between patients with and without aneurysms. Variables with p<0.05 in univariate analysis were entered into a multivariable binary logistic regression to identify independent predictors. Clinical outcomes including ischemic stroke and symptomatic intracranial hemorrhage at follow-up were compared between both groups. Results: Out of 4023 patients included in the STOP-CAD study, 116 (2.9%) had at least one incidental cerebral aneurysm. In adjusted binary logistic regression, patients with cerebral aneurysm were more likely to have a history of migraine (aOR 1.78 95% CI 1.15-2.75, p=0.009), history of hypertension (aOR 1.65 95% CI 1.12-2.43, p = 0.010), known connective tissue disorder (aOR 3.47 95% CI 1.71-7.03), history of dissection (aOR 2.63 95% CI 1.31-5.28, p = 0.007), and a dissecting aneurysm at the site of the dissection (aOR 1.94 95% CI 1.25-3.01, p = 0.003). At follow-up, the presence of a cerebral aneurysm was not associated with ischemic stroke (7.8% vs. 5.6% p>0.1), but with a trend towards increased odds of symptomatic intracranial hemorrhage (3.4% vs. 1.2%, p = 0.062). Conclusions: Patients with CAD and concurrent incidental cerebral aneurysm were more likely to have a history of migraine headaches and markers of underlying vasculopathy and had a non-significantly increased risk of intracranial hemorrhage at follow-up. Further studies are needed to identify best practices for surveillance and risk stratification in this subgroup.

Abstract Background Icotrokinra is the first targeted oral peptide that selectively blocks the IL-23 receptor (IL-23R) and precisely inhibits the IL-23 pathway. In ANTHEM-UC—a Phase 2b, randomised, double-blind, placebo (PBO)-controlled, dose-ranging study in adults with moderately to severely active ulcerative colitis (UC)—all doses of icotrokinra achieved the primary endpoint of clinical response and delivered clinically meaningful improvements across key secondary endpoints at Week (W)12,1 which were maintained or improved at W28.2 Here we report the impact of icotrokinra on systemic and tissue biomarkers of inflammatory burden in UC. Methods Participants were randomised (1:1:1:1) to receive once-daily icotrokinra 100 mg, 200 mg, 400 mg, or PBO. Clinical inflammatory biomarkers, C-reactive protein (CRP) and faecal calprotectin (FCP), along with serum IL-23 pathway biomarkers (IL-22, IL-17A, and IL-17F) were used to determine the impact of icotrokinra on systemic inflammation. Gene expression changes in colonic biopsies were used to confirm tissue IL-23 pathway engagement and dampening of tissue inflammation with icotrokinra. Results At the W12 primary timepoint, all doses of icotrokinra attenuated levels of serum CRP and FCP (Figure 1). All doses of icotrokinra, but not PBO, markedly reduced serum levels of IL-22, IL-17A, and IL-17F at W12 relative to baseline. Greater reductions in these serum biomarkers of IL-23 pathway activation were observed with the 200 mg and 400 mg doses relative to the 100 mg dose (Figure 1, nominal p &lt; 0.05). All doses of icotrokinra, but not PBO, markedly reduced expression of gene sets associated with the IL-23–driven inflammation in tissue at W12 relative to baseline (Figure 2, nominal p &lt; 0.0001). With icotrokinra treatment, the tissue transcriptome more closely resembled that of healthy individuals, with decreased expression of gene sets associated with UC-relevant inflammatory cell types and increased expression of genes characteristic of healthy epithelial cells. Importantly, dampening of systemic and tissue inflammation with icotrokinra was sustained at W28 (Figures 1 & 2). Conclusion We show for the first time that blocking the IL-23R can inhibit IL-23-mediated inflammatory signaling in UC patients. Icotrokinra treatment induced a sustained (W28) reduction in systemic and tissue biomarkers of inflammatory burden in UC. Furthermore, icotrokinra induced transcriptional changes that are consistent with dampening of IL-23–driven inflammation and normalization of the tissue transcriptome. While all once-daily doses of icotrokinra attenuated systemic and tissue inflammation, greater reduction of systemic inflammatory burden was observed with the 200 mg and 400 mg doses of icotrokinra. References: 1. Abreu MT, et al. United European Gastroenterol J. 2025 10;13(suppl 8):172-3. 2. Jairath V, et al. Am J Gastroenterol. 2025 120;10(suppl 2):S312. Conflict of interest: Louis, Edouard: Education and Research Grants for my department: Abbvie, Takeda, Janssen, Pfizer, Fresenius-Kabi, Celltrion, EG pharma, Sandoz, Falk Personal Fees for conferences, advisory boards and consultancy: Abbvie, Takeda, Ferring, Pfizer, Janssen, Lilly, Galapagos, Celltrion, Arena, BMS, Falk, Biokuris, Fresenius-Kabi, Thabor Jairath, Vipul: Consulting fees from AbbVie, Alimentiv, Amgen, Anaptys Bio, Asahi Kasei, Asieris, Astra Zeneca, Attovia, Blackbird Labs, Bristol Myers Squibb, Boehringer Ingleheim, Biomebank, Caldera, Calluna, Catalytic Health, Celltrion, Ensho, Enthera, Exeliome Biosciences, Ferring, Fresenius Kabi, Gilead, Granite Bio, GSK, Johnson & Johnson, Lilly, Merck, Mountainfield, MRM Health, Nxera, Organon, OSE Immunotherapeutics, Pendopharm, Pioneering Medicine, Pfizer, Prometheus, Roche/Genentech, Sanofi, SCOPE, Shattuck Labs, Sorriso, Spyre, Synedgen, Takeda, Teva, Tillotts, Union Therapeutics, Ventus, Ventyx, Vividion, Xencor, Zealand Pharma. Siegmund, Britta: Consultant for AbbVie, Abivax, Boehringer Ingelheim, Bristol Myers Squibb, Dr. Falk Pharma, Eli Lilly, Endpoint Health, Galapagos, Johnson & Johnson, Materia Prima, MSD, Pfizer, Takeda, Wedbush Securities speaker for AbbVie, AlfaSigma, Bristol Myers Squibb, CED Service GmbH, Dr. Falk Pharma, Eli Lilly, Ferring, Galapagos, Johnson & Johnson, MD Education, MSD, Pfizer, Tr1xBio grant from Pfizer. Kannan, Arun K: Employee and shareholder of Johnson & Johnson Zeeman, Martha: Employee and shareholder of Johnson & Johnson Hart, Amy: Employee and shareholder of Johnson & Johnson Strawn, David: Employee and shareholder of Johnson & Johnson Venkat, Swati: Employee and shareholder of Johnson & Johnson Tomsho, Lynn: Employee and shareholder of Johnson & Johnson Mcrae, Bradford: Employee and shareholder of Johnson & Johnson Ruane, Darren: Employee and shareholder of Johnson & Johnson Surace, Lindsey: Employee and shareholder of Johnson & Johnson Erondu, Ngozi: Employee and shareholder of Johnson & Johnson Zhan, Joyce: Employee and shareholder of Johnson & Johnson Chen, Minhu: I have received speaker honoraria from Takeda China, Xian Janssen, and AbbVie China, as well as research funding from Takeda (China). Chachu, Karen: Advisory board for Johnson & Johnson consultant for OptumRx Matsuoka, Katsuyoshi: Grant: Abbvie Inc., Mochida Pharmaceutical Co., Ltd., ZERIA Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., JIMRO Co., Ltd. Personal Fees: Mitsubishi Tanabe Pharma, Janssen Pharmaceutical K.K., Abbvie Inc., EA Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., ZERIA Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Inc., Kyorin Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Gilead Sciences, Celltrion Healthcare, Bristol-Myers Squibb Limdi, Jimmy: Speaker/consultancy fees from AbbVie, Abivax, Arena, BioHit, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Galapagos, Johnson & Johnson, MSD, Pfizer, Takeda research support from Galapagos, Takeda Rydzewska, Grazyna: Speaker and consultant fees from AbbVie, AlfaSigma, AstraZeneca, Bayer, Biocodex, Bristol Myers Squibb, Ferring, Johnson & Johnson, Lilly, PRO.MED.Pl, Recordati, Sanprobi, SOBI, Takeda travel/accommodation meeting expenses from AbbVie, Ferring, Takeda Abreu, Maria Teresa: Grant/Research Support: Janssen, Prometheus Bioscience, Takeda Consultant: Janssen, Prometheus Bioscience, Takeda Gilead, Eli Lilly, AbbVie Inc., Bristol Myers, Imedex, Loftus Jr, Edward V: Consultant/advisory board member for AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly and Company, Genentech, Gilead Sciences, Johnson & Johnson, Pfizer, Takeda, UCB.

Abstract Background Intracranial mesenchymal tumors, FET::CREB fusion-positive (ICMT), show fusions involving FET RNA-binding protein family genes (EWSR1 or FUS) and CREB family of transcription factors (ATF1, CREB1, or CREM). The methylation signature(s), gene expression characteristics, and clinical behavior of this important tumor type require further characterization. Methods We study the methylation profiles of 81 ICMT cases (61 newly profiled cases and 20 cases from publicly available sources). Clinicopathologic and genomic data were recorded for each case when available. Results ICMT showed a relatively distinct methylation signature compared to related tumors. Among the 65 cases where fusion types were documented, the identified fusions included EWSR1::ATF1 (25 cases), EWSR1::CREB1 (12 cases), EWSR1::CREM (21 cases), FUS::CREM (3 cases), and SMARCA2::CREM (4 cases). We confirmed the prior description of 2 distinct subgroups of ICMT (subclasses A and B). The majority of the cases belonged to subclass A (n = 69; 85%), which showed a higher median age compared to subclass B patients (26 years vs. 15 years). Subclass B cases (n = 12; 15%) showed shorter progression-free survival (P &lt; 0.01). Gene expression analysis of ICMT showed key overexpressed markers in ICMT, with significant CREM overexpression regardless of fusion type, when compared to either meningioma alone or a larger group of CNS tumors. Conclusions This work provides further characterization of ICMT as an important CNS mesenchymal neoplasm that is prone to tumor recurrence, showing 2 prognostically relevant methylation subclasses and warranting diagnostic distinction from other epigenetically and histologically related tumors. ICMTs show substantial overexpression of the CREM gene, independent of fusion type.