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Abstract Background Mosaic chromosomal alterations (mCAs) are large-scale somatic gains, losses, or copy-neutral loss of heterozygosity (CNLOH) detectable by genotyping of peripheral blood DNA. They represent a form of clonal hematopoiesis and are observed in 0.5-5% of cancer-free individuals. The presence of any autosomal mCA has been associated with >3-fold risk of hematological malignancies. In particular, mCAs occurring in regions related to lymphoid malignancies have an 11-fold increased risk of lymphoid malignancies and a 68.6-fold risk for chronic lymphocytic leukemia (CLL). Monoclonal B-cell lymphocytosis (MBL), the precursor state to CLL, is defined by <5×10⁹/L clonal B cells in otherwise healthy individuals and is classified as low-count (<0.5x109/L) or high-count (0.5-5x10⁹/L) based on clonal B-cell count. MBL is also associated with increased risk of lymphoid malignancy (beyond CLL), with 4.3-fold and 74-fold risk in individuals with low- and high-count MBL, respectively. We previously reported a significant enrichment of autosomal mCAs in MBL, demonstrating a 1.7-fold association in those with low-count MBL and a 50.5-fold association in those with high-count MBL. Whether mCAs independently predict lymphoid malignancy risk after accounting for MBL status is unknown. Here, we evaluated the impact of mCAs on risk of incident lymphoid malignancies in individuals with MBL and in individuals screened negative for MBL. Methods CLL-type MBL (CD5 positive) was identified using flow cytometry assay on peripheral blood. Participants were age ≥40, had no prior hematologic malignancy, and were enrolled through the Mayo Clinic Biobank or the Division of Hematology at Mayo Clinic, Rochester. Participants were followed for incident lymphoid malignancy, including CLL, with diagnoses confirmed by medical record review. mCAs with cell fraction >1% were detected from array-based genotyping of whole blood DNA. Cox proportional hazards models, adjusted for age and sex, estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of developing an incident lymphoid malignancy in individuals with autosomal mCA versus those without an autosomal mCA. Results In 4,331 participants with available MBL and mCA status, the median age was 67 years, and 45% were male. Flow cytometry identified 3,231 individuals who screened negative for MBL, 754 individuals with low-count MBL, and 346 individuals with high-count MBL. Autosomal mCAs were present in 6.5% of individuals without MBL, 7.6% with low-count MBL, and 71.1% with high-count MBL. Over a median follow-up of 6.9 years, 237 individuals developed an incident lymphoid malignancy. The most common types were CLL, multiple myeloma, and diffuse large B-cell lymphoma. Ignoring MBL status, the presence of an autosomal mCA was associated with increased risk of lymphoid malignancy (HR = 2.65; 95% CI: 1.45–4.86; P = 0.002), replicating previous results. However, after excluding individuals with MBL, this association attenuated; those with mCA alone did not have a significantly elevated risk (HR = 1.60; 95% CI: 0.57-4.52; P = 0.38) compared to individuals without MBL or mCA. We next examined the effect of mCAs among individuals with MBL. In those with low-count MBL, the most frequent mCA events were 13q loss (2.1%), 12 gain (1.9%), and 4q CNLOH (1.2%), and individuals with an mCA had a borderline significant risk of developing a lymphoid malignancy (HR = 2.78; 95% CI: 1.01–7.67; P = 0.049) compared to those without an mCA. Similarly, in those with high-count MBL, the most frequent mCA events were 13q loss/CNLOH (31.2%), 12 gain (13.0%), and 11q loss (4.9%), and the presence of an mCA conferred an increased risk compared to those without mCA (HR = 1.51; 95% CI: 1.09-2.08; P = 0.012). Conclusions Autosomal mCAs were more frequent in individuals with high-count MBL compared to those with low-count or no MBL. mCAs showed limited predictive value for lymphoid malignancy among individuals without MBL. In contrast, in individuals with low-count MBL, autosomal mCAs emerged as a potential biomarker for identifying those at risk of developing a lymphoid malignancy. In high-count MBL, mCAs were also a biomarker, but were driven by known chromosomal abnormalities identified through clinical testing. These findings suggest that the utility of mCAs as a predictive marker for lymphoid malignancy is contingent on the presence of MBL and may inform risk stratification and surveillance strategies in this population.

Introduction Many clinical practice guidelines (CPGs) claim to use Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, but its implementation varies. This suggests that CPG developers, methodologists and users would benefit from an instrument to evaluate the extent to which CPGs adhere to GRADE approach. Such a structured instrument is currently unavailable. Accordingly, this study will develop an evaluation instrument for assessing guideline adherence to the GRADE approach, which we have named ‘GRADE-Check’. The goal is to target items to which CPGs fail to adhere and that potentially have serious consequences resulting in inaccuracies in certainty of evidence and inappropriate direction or strength of recommendations, thereby discriminating across CPGs in issues of importance. Methods and analysis The panel will include up to 25 individuals with specific knowledge and expertise, including experienced authors, educators and methodologists on CPGs methodology and GRADE approach from relevant organisations. The instrument will focus on the key elements of GRADE, aiming for clarity for GRADE experts and non-GRADE experts to apply. The development process for GRADE-Check will consist of the following five phases: (1) recruitment of a panel of GRADE experts; (2) development of objectives and scope for the development of GRADE-Check and criteria for item selection; (3) generation of candidate items through a literature review and panel consultation; (4) panellist discussion to construct the initial draft and extended explanation manual and (5) user testing. Ethics and dissemination This study has been approved by the Medical Ethics Committee of Zhongnan Hospital of Wuhan University (no. (2025047K)). Our research findings will be published in peer-reviewed journal articles and presented at academic conferences. Additionally, the dissemination plan will include considerations for the development of implementation manuals, a dedicated project website and training tools.

Yao syndrome (YAOS) is a NOD2-associated autoinflammatory disease marked by periodic fevers, dermatitis, polyarthritis, distal extremity swelling, and nearly universal gastrointestinal symptoms. A recent study was the first to comprehensively assess the gastrointestinal symptoms and manifestations of YAOS, finding that most testing is normal, without gastrointestinal mucosal inflammation, and many patients have constipation and rectal evacuation disorders. Building on this foundation, this paper highlights future directions and research priorities in furthering the understanding of YAOS. These draw heavily from the literature on Crohn disease, which is also associated with NOD2 variants. These future research priorities include detailed genotype-phenotype correlation focusing on specific NOD2 variants, prospective, comprehensive gastrointestinal phenotyping, and multi-omics approaches to investigate genetic, microbiome, epigenetic, and environmental interactions underlying YAOS pathogenesis. Insights gained from such investigation may guide improved diagnostic criteria and targeted, personalized therapeutic development for patients with YAOS.

Importance Many patients are diagnosed with benign breast lesions; however, evidence- and consensus-based guidelines for the management of benign breast disease (BBD) are limited. Observations The American Society of Breast Surgeons (ASBrS) and the Society of Breast Imaging (SBI) developed guidelines for the management of benign fibroepithelial lesions (FELs) using a modified Delphi consensus methodology and public comment. There was strong consensus that core biopsy–proven concordant fibroadenomas without atypia only require excision if they were symptomatic, patient preferred, attained a certain size, or demonstrated substantive growth over time on clinical examination. There was strong consensus that when removing a fibroadenoma, complete excision without transection of the mass is recommended and surgeons should consider aesthetics, sensation, and other factors when selecting incision placement. Patients with core biopsy–proven concordant fibroadenomas do not require imaging follow-up and may return to age-appropriate screening. Many benign phyllodes tumors (BPTs) present as an FEL on core biopsy, and these lesions along with any lesions with suspicion of or concern for phyllodes tumors (PTs) require surgical excisional biopsy with complete excision of the mass. Re-excision of a BPT is not required for patients with a positive margin for BPT, but a margin re-excision may be considered if the mass was transected or there is concern of residual disease after excisional biopsy. Patients with BPT who have undergone excision do not require follow-up imaging and may return to age-appropriate screening. Conclusions and Relevance Evidence-informed, consensus and expert opinion-based guidelines for the management of benign FELs of the breast were developed. These guidelines provide clarification on the controversial management of benign FELs of the breast. Any practicing clinicians who treat patients with benign FELs should integrate these guidelines into treatment of their patients.

Abstract Transcription factors and their cofactors are major and selective nononcogene dependencies in multiple myeloma cells. By performing a gain-of-function perturbation screen in human multiple myeloma cell lines, we identified the inhibitor of DNA binding (ID) genes as putative suppressors of multiple myeloma cell fitness. Among them, ID2 was found to be downregulated in multiple myeloma patient cells and acted as a tumor suppressor by directly binding and repressing the basic helix-loop-helix factor TCF3, also known as E2A. Lower ID2 expression in multiple myeloma cells conferred a proliferative advantage by increasing TCF3 activity, leading to a dependency on this transcription factor. In contrast, ID2 overexpression reduced TCF3 binding to DNA, which resulted in cell-cycle arrest and a halt in multiple myeloma cell proliferation. The myeloma bone marrow milieu supported this process by further decreasing the expression of ID2 and enhancing TCF3 activity, partly via IL6, revealing a mechanism by which the tumor microenvironment affects multiple myeloma cell behavior. Significance: Multiple myeloma cells exploit the oncogenic and proliferative potential of TCF3 by downregulating the transcriptional regulator ID2, a process facilitated by the bone marrow microenvironment.

Importance Inherited pathogenic variants (PVs) in known predisposition genes can greatly increase breast cancer risk, but the combined impact of PV status, family history, and other factors on breast cancer risk in the general US population has not been well described. Objective To evaluate population-based breast cancer risk estimates for those with established PVs overall and stratified by first-degree family history of breast cancer and other factors. Design, Setting, and Participants This study used pooled data from 13 US-based breast cancer case-control studies participating in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Enrollment for individual studies occurred between 1976 and 2013, and results are based on data released March 2023, with analyses conducted from June 2022 to July 2025. Exposures PVs, breast cancer family history, self-reported race and ethnicity, and established risk factors. Main Outcomes and Measures Breast cancer rate ratios for PVs in 7 genes were estimated from the CARRIERS consortium. PV status and incidence and mortality statistics were combined using the Individualized Coherent Absolute Risk Estimation (iCARE) model to estimate conditional cumulative breast cancer risks and 95% CIs, stratified by family history and standardized to the US population. Models that incorporated population-based data and published estimates for established epidemiologic risk factors were also evaluated. Results A total of 67 692 women were studied, including 33 841 who were diagnosed with breast cancer. PVs in ATM , BRCA1 , BRCA2 , CHEK2 , and PALB2 were strongly associated with breast cancer risk, with BRCA1 and PALB2 PVs showing evidence of heterogeneity by family history. In models considering PVs, family history, and established risk factors, the estimated cumulative risks of breast cancer by age 50 years ranged from 2.4% (95% CI, 2.4-2.4) in women with no PVs and no family history to 35.5% (95% CI, 21.6-55.1) in PALB2 PV carriers with a family history. Among women who have not been diagnosed with breast cancer by age 50 years, the cumulative risk of breast cancer by age 80 years ranged from 11.1% (95% CI, 11.0-11.2) in noncarriers with no family history to 70.5% (95% CI, 52.8-83.5) for PALB2 carriers with a family history. PV-specific cumulative risk estimates varied across subgroups defined by race and ethnicity and potentially modifiable epidemiologic risk factors. Conclusions and Relevance In this study, population-based estimates of cumulative breast cancer risk for established PVs, as informed by the CARRIERS case-control sample, varied by family history and potentially modifiable risk factors. These estimates provide guidance for identifying individuals who will most benefit from enhanced screening and prevention strategies.

Abstract With the rapid advancements in large language model technology and the emergence of bioinformatics‐specific language models (BioLMs), there is a growing need for a comprehensive analysis of the current landscape, computational characteristics, and diverse applications. This survey aims to address this need by providing a thorough review of BioLMs, focusing on their evolution, classification, and distinguishing features, alongside a detailed examination of training methodologies, datasets, and evaluation frameworks. We explore the wide‐ranging applications of BioLMs in critical areas such as disease diagnosis, drug discovery, and vaccine development, highlighting their impact and transformative potential in bioinformatics. We identify key challenges and limitations inherent in BioLMs, including data privacy and security concerns, interpretability issues, biases in training data and model outputs, and domain adaptation complexities. Finally, we highlight emerging trends and future directions, offering valuable insights to guide researchers and clinicians toward advancing BioLMs for increasingly sophisticated biological and clinical applications.

Background The eccentric stenosis morphology in patients with intracranial atherosclerotic stenosis (ICAS) has a critical impact on the efficacy of endovascular treatment. This study aimed to establish a rabbit model of eccentric carotid atherosclerotic stenosis that mimics the pathophysiological and morphological characteristics of eccentric plaques in humans. Methods Rabbits received localized cryoinjury of the right carotid artery after 2 weeks of a high fat, high cholesterol diet, followed by an additional 8 weeks on the same diet. On the experimental endpoint, comprehensive analyses of the model’s pathological changes were conducted using serum lipid analysis, DSA, optical coherence tomography (OCT), histopathological analysis, and immunohistochemistry. Results The high fat, high cholesterol diet significantly elevated serum lipid levels in rabbits. Hematoxylin and eosin staining results at 24 hours postoperatively revealed focal intimal damage induced by 5 s of cryoinjury. After localized cryoinjury and high fat, high cholesterol diet feeding, DSA results demonstrated significant carotid stenosis, with a stenosis degree of 47±5% and a length of approximately 9 mm. OCT images revealed eccentric fibrous plaque formation at the stenotic site. Morphological analysis of the plaque samples demonstrated a plaque eccentricity index of 0.66±0.05 and a plaque burden of 60.68±7.41%. Histopathological analysis showed that atherosclerotic lesions developed in all rabbits of the model group. Among them, three rabbits had intermediate lesions, one rabbit had atheroma, and eight rabbits had fibroatheroma. Conclusions This study successfully established a rabbit model of eccentric carotid atherosclerotic stenosis, providing a novel experimental platform for transformation research of neurointerventional devices.