Citations

Context.— Treatments are available for common forms of systemic amyloidosis that show promise for extending and improving the quality of life for patients. Early diagnosis and accurate identification of amyloid fibril type are crucial for successful treatment, but the diagnosis and workup of amyloidosis is inconsistent among pathologists and laboratories. Thus, the goal of this guideline is to offer recommendations for proper testing and workup for amyloidosis to optimize patient care. Objective.— To establish evidence-based recommendations for appropriate laboratory testing to detect amyloidosis and identify the specific amyloidogenic protein. Design.— The College of American Pathologists convened a panel of experts to develop recommendations following the standards established by the National Academy of Medicine for developing trustworthy clinical practice guidelines. The panel conducted a systematic literature review addressing 6 key questions. Using the Grading of Recommendations Assessment, Development and Evaluation framework, recommendations were created based on the available evidence, certainty of that evidence, and key judgments as defined in the framework. Results.— Four conditional recommendations and 3 good practice statements were established to provide guidance for proper testing and workup of amyloidosis. Conclusions.— This guideline summarizes the available evidence on the diagnosis and workup of systemic amyloidosis in tissue samples, including the challenges and limitations of common approaches and techniques. Recommendations for pathologists and laboratories receiving these samples are provided.

Abstract Description Neutrophils heavily infiltrate the brain following acute and chronic brain insults. Neutrophils infiltrating brain tumors display a prolonged lifespan compared to blood neutrophils. We investigated presence and potential function of neutrophils in the brain following infection with Theiler’s Murine Encephalomyelitis (TMEV) and kainic acid-induced seizures. Both total myeloid cells and neutrophils started infiltrating the brain as early as day 1, peaked at day 3, and remained elevated at least 7 days post-infection. Further characterization of the neutrophils revealed upregulation of MHC-II, indicating a potential role in antigen presentation. We detected similar accumulation of total myeloid cells and neutrophils in the brain of mice following seizures. MHC-II expression was upregulated on infiltrating neutrophils. Given the sustained and unusual accumulation of neutrophils in the brain past innate time points, we evaluated the bone marrow niche for evidence of myelopoiesis. Frequencies of Lin-Sca-1+c-Kit + (LSK) were significantly higher in all bone marrow compartments in mice infected intracranially with TMEV. This increase in LSK cells concurred with an increase in frequencies of total myeloid cells. These changes were not observed when mice were infected with TMEV systemically. Our data highlights dysregulation of bone marrow hematopoiesis and a potential novel role of neutrophils in response to neuroinflammation following intracranial pathologies. Topic Categories Neuroimmunology (NEUR)

Abstract DAB2IP (Disabled homolog 2 interacting protein), a recognized tumor suppressor, plays a pivotal role in regulating various oncogenic pathways. Our previous research demonstrated that DAB2IP functions as a cell cycle regulator by facilitating PLK1-mediated mitosis progression. Here, we elucidate a novel function of DAB2IP in promoting DNA replication origin firing. Mechanistically, we identified that DAB2IP localizes to the nucleus, where it interacts with the histone acetyltransferase HBO1 and enhances the HBO1–PLK1 interaction. DAB2IP facilitates PLK1-mediated phosphorylation of HBO1, which subsequently promotes HBO1-directed acetylation of histone 3 at lysine 14 (H3K14Ac). This modification enables the loading of the minichromosome maintenance protein (MCM) complex onto chromatin, thereby supporting DNA replication and maintaining genome integrity. Additionally, we found that ATR regulates CDK1-mediated phosphorylation of DAB2IP, and that this phosphorylation is essential for the formation and activation of the HBO1-PLK1 complex. Ablation of DAB2IP phosphorylation results in increased genomic instability due to incomplete replication of genomic DNA, as evidenced by the accumulation of anaphase ultrafine bridges and 53BP1 nuclear bodies in G1 phase of the cell cycle. In summary, our findings underscore the critical regulatory role of DAB2IP in DNA replication initiation and genomic stability maintenance, providing new insights into its function in cellular homeostasis.

SUDEP risk is influenced by longevity genomics: A polygenic risk score study Martins H, Mills JD, Pagni S, Gulcebi MI, Vakrinou A, Moloney PB, Clayton LM, Bellampalli R, Stamberger H, Weckhuysen S, Striano P, Zara F, Bagnall RD, Harris RV, Lawrence KM, Sadleir LG, Crompton DE, Friedman D, Laze J, Li L, Berkovic SF, Semsarian C, Scheffer IE, Devinsky O, Kuchenbaecker K, Balestrini S, Sisodiya SM. EBioMedicine. 2025 Aug;118:105841. doi: 10.1016/j.ebiom.2025.105841. Epub 2025 Jul 28. PMID: 40731221; PMCID: PMC12368338. Background: Sudden Unexpected Death in Epilepsy (SUDEP) is a rare and tragic outcome in epilepsy, identified by those with the condition as their most serious concern. Although several clinical factors are associated with elevated SUDEP risk, mechanisms underlying SUDEP are poorly understood, making individual risk prediction challenging, especially early in the disease course. We hypothesised that common genetic variation contributes to SUDEP risk. Methods: Genetic data from people who had succumbed to SUDEP was compared to data from people with epilepsy who had not succumbed to SUDEP and from healthy controls. Polygenic risk scores (PRSs) for longevity, intelligence and epilepsy were compared across cohorts. Reactome pathways and gene ontology terms implicated by the contributing single nucleotide polymorphisms (SNPs) were explored. In the subset of SUDEP cases with the necessary data available, a risk score was calculated using an existing risk prediction tool (SUDEP-3); the added value to this prediction of SNP-based genomic information was evaluated. Findings: Only European-ancestry participants were included. 161 SUDEP cases were compared to 768 cases with epilepsy and 1153 healthy controls. PRS for longevity was significantly reduced in SUDEP cases compared to disease (P =0.0096) and healthy controls (P=0.0016), as was PRS for intelligence (SUDEP cases compared to disease (P=0.0073) and healthy controls (P=0.00024)). The PRS for epilepsy did not differ between SUDEP cases and disease controls (P =0.76). SNP-determined pathway and gene ontology analysis highlighted those related to inter-neuronal communication as amongst the most enriched in SUDEP. Addition of PRS for longevity and intelligence to SUDEP-3 scores improved risk prediction in a subset of cases (38) and controls (703), raising the area-under-the-curve in a receiver-operator characteristic from 0·699 using SUDEP-3 alone to 0·913 when PRSs were added. Interpretation: Common genetic variation contributes to SUDEP risk, offering new approaches to improve risk prediction and to understand underlying mechanisms.

OBJECTIVE Lordotic devices have garnered increased attention for improving the segmental lordosis (SL) achieved with transforaminal lumbar interbody fusion (TLIF). However, it is unclear the degree to which surgeons maximize the "ideal" or listed lordosis of the interbody device. METHODS Patients undergoing one- or two-level TLIF for degenerative pathologies were identified and data were extracted on demographics, baseline lumbopelvic radiographic parameters, and TLIF details. The primary outcome of interest was the degree to which postoperative SL approximated the listed cage lordosis (Δtarget). Change in SL was a secondary outcome. Linear mixed-effects modeling was used to identify significant predictors of the percentage of ideal lordosis achieved. RESULTS A total of 239 treated levels were included (median patient age 66.6 years; 56.9% female); 151 levels were part of single-level TLIF constructs. The median segmental corrections were a 2.8° increase in SL and 2.8 mm in disc height. The median difference between listed cage lordosis and postoperative SL (Δtarget) was 0.5°. However, only 56.1% of levels achieved at least the listed cage lordosis. Linear mixed-effects modeling found that independent predictors of Δtarget were lower implant lordosis (estimate −1.01° [95% CI −1.15° to −0.87°] per degree, p < 0.001), greater preoperative SL (estimate 0.38° [95% CI 0.28°–0.48°] per degree, p < 0.001), greater preoperative PI (estimate 0.06° [95% CI 0.02°–0.11°] per degree, p = 0.007), and closer approximation of the anterior apophyseal ring of the caudal vertebrae (estimate −0.27° [95% CI −0.39° to −0.15°] per mm, p < 0.001). Similarly, independent predictors of postoperative SL were larger implant lordosis (estimate 0.16° [95% CI 0.05°–0.27°] per degree, p = 0.004), lower preoperative SL (estimate −0.70° [95% CI −0.79° to −0.62°] per degree, p < 0.001), greater preoperative PI (estimate 0.08° [95% CI 0.04°–0.12°] per degree, p < 0.001), and closer approximation of the anterior apophyseal ring of the cranial vertebrae (estimate −0.15° [95% CI −0.28° to −0.03°] per mm, p = 0.014). CONCLUSIONS The present results suggest that while lordosing, only 56% TLIF operations obtain the listed interbody lordosis ("target" lordosis). Anterior placement within the disc space is the only modifiable intraoperative technical factor for maximizing lordosis for a given interbody, highlighting the importance of effective disc space exenteration.

Abstract The brain avidly consumes glucose to fuel neurophysiology. Cancers of the brain, such as glioblastoma (GBM), relinquish physiological integrity and gain the ability to proliferate and invade healthy tissue. How brain cancers rewire glucose utilization to drive aggressive growth remains elusive. Here, we infused 13C-labeled glucose into patients and mice with brain cancer, coupled with quantitative metabolic flux analysis, to map the fates of glucose-derived carbon in tumor vs. cortex. Through the first direct and comprehensive measurements of carbon and nitrogen labeling in both cortex and glioma tissues, we uncover profound metabolic transformations. In human cortex, glucose carbons fuel essential physiologic processes including TCA cycle oxidation and neurotransmitter synthesis. Conversely, gliomas downregulate these processes and scavenge alternative carbon sources such as amino acids from the environment, repurposing glucose-derived carbons to generate molecules needed for proliferation and invasion. Targeting this metabolic rewiring in mice through dietary amino acid modulation selectively alters GBM metabolism, slows tumor growth, and augments the efficacy of standard-of-care treatments. These findings illuminate how aggressive brain tumors exploit glucose to suppress normal physiological activity in favor of malignant expansion and offer potential therapeutic strategies to enhance treatment outcomes.

The treatment landscape of invasive early-stage and metastatic breast cancer is evolving constantly. These NCCN Guidelines Insights focus on recent updates included in the most recent version (version 5.2025) of the NCCN Guidelines for Breast Cancer specific to workup, locoregional therapy, surveillance, and systemic neoadjuvant/adjuvant therapy recommendations for invasive, nonmetastatic breast cancer.

The NCCN Guidelines for Prostate Cancer provide a framework on which to base decisions for patients with prostate cancer across the disease spectrum. The Guidelines sections included in this article focus on metastatic castration-sensitive prostate cancer (mCSPC), nonmetastatic castration-resistant prostate cancer (CRPC), and metastatic CRPC (mCRPC). For patients with mCSPC, disease characteristics, such as whether metastases arose synchronously or metachronously and the degree of metastatic burden, impact therapy decisions, including how much treatment intensification is appropriate and when prostate-directed and/or metastasis-directed therapy should be considered. In the mCRPC setting, androgen deprivation therapy is continued with the sequential or concurrent addition of certain androgen receptor pathway inhibitors, chemotherapies, immunotherapies, radiopharmaceuticals, and/or targeted therapies. The NCCN Prostate Cancer Panel emphasizes a shared decision-making approach in all disease settings based on patient preferences, prior treatment exposures, biomarkers, the extent and location of metastases, symptoms, and potential side effects.

Introduction Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) used to treat type 2 diabetes mellitus (T2D), has potential associations with higher rates of diabetic retinopathy (DR) complications including proliferative DR (PDR) and diabetic macular edema (DME). The purpose of this study was to determine whether an association exists between semaglutide and PDR and treatment-requiring DR/DME. Research design and methods This was a retrospective cohort study of 14 databases (six administrative claims and eight electronic health records) in the Observational Health Data Sciences and Informatics Evidence Network. Adults with T2D on semaglutide, other GLP-1RA (dulaglutide, exenatide), or non-GLP-1RA medications (empagliflozin, sitagliptin, glipizide) from 1 December 2017 to 31 December 2023 were included. The association between semaglutide and PDR or treatment-requiring DR/DME was assessed using an active-comparator cohort design comparing new users of semaglutide as second-line T2D treatment to those on other GLP-1RAs and non-GLP-1RAs. Propensity score-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs). Network-wide HR estimates were generated using a random-effects meta-analysis. Results The study included 810 390 new semaglutide users for T2D. PDR risk for semaglutide was similar to dulaglutide (HR 0.81, 95% CI 0.42 to 1.54, p=0.51), empagliflozin (HR 0.83, 95% CI 0.53 to 1.30, p=0.41) and sitagliptin (HR 0.83, 95% CI 0.45 to 1.55, p=0.57) but was lower than glipizide (HR 0.59, 95% CI 0.39 to 0.88, p=0.01). The risk for treatment-requiring DR/DME for semaglutide was similar to empagliflozin (HR 0.66, 95% CI 0.43 to 1.02, p=0.06) but lower than dulaglutide (HR 0.53, 95% CI 0.31 to 0.91, p=0.02), sitagliptin (HR 0.46, 95% CI 0.26 to 0.81, p=0.008) and glipizide (HR 0.55, 95% CI 0.33 to 0.91, p=0.02). Conclusions and relevance We did not identify increased risk for either PDR or treatment-requiring DR/DME comparing semaglutide with other GLP-1RAs or non-GLP-1RAs. Patients with T2D should still undergo close eye care follow-up, particularly when initiating new antihyperglycemic medications.