Citations

Background Rheumatoid arthritis (RA) is an HLA-DR associated disease with a pivotal role of T cells in the pathogenesis. The mechanisms underlying the HLA association and the generation of a synovial T-cell response are unclear. We have hypothesized that the selection of the primary T-cell repertoire is a predisposing factor for rheumatoid synovitis. Methods The repertoire of T-cell receptors (TCR) expressed by circulating naive CD4 + CD45RO − T cells was compared in 10 patients with RA, 11 HLA-DR matched normal donors and 10 mismatched normal donors by determining the frequencies of TCR BV-BJ combinations in 3 different BV gene segment families. Clonally expanded synovium-specific CD4 T cells were identified in 8 patients by TCR BV-BJ-specific PCR of purified T-cell subsets followed by size fractionation and sequencing of the PCR product. The TCR BV-BJ repertoires of naive peripheral T cells and of synovial clones were compared. Results The repertoires of naive circulating CD4 + CD45RO − T cells were different in RA patients and in HLA-DR matched and unmatched controls, suggesting HLA-DR as well as disease-specific features of T-cell selection. To test the disease relevance of the shifts in the naive repertoire, CD4 T cells undergoing joint-specific clonal expansion were identified. The usage of BV-BJ gene combinations in these synovium-specific clones was biased and significantly different from the expected distribution with a preference for combinations favored in the naive TCR repertoire of RA patients. Conclusions These data suggest that primary T-cell selection in RA patients is of functional importance for the generation of synovium-specific T-cell responses. The synovial repertoire is influenced by aberrations in the naive T-cell repertoire that might indicate a defect in thymic education with the selection of high-affinity self-reactive T cells in RA.

Background Measles remains a public health threat in the United States with over 50,000 cases being reported from 1989 through 1991 with continued smaller outbreaks. Measles vaccine failure is in part to blame for these large-scale outbreaks. The human leukocyte antigen (HLA) genes are important determinants of immune response to measles virus and vaccine. To examine the influence that HLA polymorphisms may have on measles vaccine antibody response, we compared the distribution of HLA-DRB1 alleles between measles vaccine nonresponders and hyper-responders. Methods We determined the seroprevalence of measles antibody in 881 school children immunized with measles-mumps-rubella-II at age 15 months using a whole virus IgG EIA. We performed class II HLA-DR typing by PCR with sequence specific primers (PCR-SSP) on 81 nonresponders (IgG seronegative) and 65 hyper-responders (from the upper 10th percentile of IgG levels of all subjects). We then compared the distribution of alleles between nonresponders and hyper-responders. Results The distribution of HLA-DRB1 alleles among nonresponders compared to hyper-responders was significantly different ( p = 0.014). Nonresponders were significantly less likely to carry the HLA-DRB1*13 alleles than were hyper-responders (7.4% vs 16.2%; p = 0.02). Nonresponders also had an excess of HLA-DRB1*07 alleles (15.4% vs 6.2%; p = 0.015). Conclusions The absence of HLA-DRB1*13 alleles is associated with measles vaccine nonresponse. The absence of this allele has also been associated with susceptibility to other infectious diseases. The role of this gene in the immunogenetic response to infectious diseases requires further study.

ABSTRACT Objectives To evaluate the impact of semaglutide on body mass index (BMI) and cardiometabolic markers in adolescents with obesity and genetic variants associated with monogenic or syndromic obesity. Methods A retrospective chart review was conducted in adolescents with severe obesity who underwent multigene panel testing and were treated with semaglutide. Results Twenty‐seven adolescents (mean age 15 ± 1.9 years); BMI % of the 95th percentile 158 ± 29; (70% White) were treated with semaglutide for a mean of 10 ± 4.7 months. Participants were classified into three groups: (1) Dominant or Known Risk Variants ( n = 7); (2) Carriers of Rare Variants in Recessive Genes ( n = 10); and (3) Negative or Unmatched Genetic Findings ( n = 10). All groups showed reductions in BMI, which was not different between the groups. Adolescents with dominant or known risk variants experienced a significant decrease in BMI % of the 95th percentile (−17, (IQR −26 to −10) p = 0.022) and in BMI by −9.4% ± 7% ( p = 0.035). Significant improvements in median non‐HDL cholesterol (−16 mg/dL), total cholesterol (−15 mg/dL), and HbA1c (−0.3%) were noted in children with dominant or known risk variants ( p = 0.036). Conclusions Semaglutide was associated with significant reductions in BMI and cardiometabolic markers in adolescents (majority White) with dominant or known risk variants for monogenic obesity.

Context.— Pathology is essential to global health care, yet disparities remain in access to education and training. The College of American Pathologists (CAP) Foundation addresses these gaps through grants and awards that support trainees, early-career pathologists, and initiatives promoting equity worldwide. Since 2015, total funding has increased from $18,400 to $84,098, an astounding 357%. Objective.— To evaluate the CAP Foundation Grants and Awards Program during a 10-year period, assessing financial investment, award distribution, recipient characteristics, and impact. Design.— A mixed-methods retrospective study integrated (1) quantitative analysis of program data, (2) qualitative feedback from awardees, and (3) a quantitative award impact survey of past CAP Foundation awardees. Variables included demographics, award type, funding amounts, geographic distribution, and career stage. Surveys assessed professional development, mentorship, and long-term engagement with CAP. Results.— From 2015 to 2024, a total of 744 applicants submitted 760 applications, resulting in 355 awards across 14 categories. Applications increased more than 8-fold, peaking in 2023, with surges during the COVID-19 pandemic. Medical student applications grew from 1 in 2020 to 17 in 2024 (76% annual growth); 9 of 12 Medical Student Travel Award recipients (75%) entered pathology residency. Geographic disparities were noted, with smaller residency programs showing higher per capita application rates. Among 174 survey respondents, 129 (74%) reported networking benefits, 127 (73%) learning benefits, and 99 (57%) mentorship benefits, though only 49 (28%) sustained long-term mentoring relationships. Conclusions.— The CAP Foundation’s awards program has expanded access, supported career development, and fostered future pathologists. Strengthening long-term mentorship and bridging education-to-practice gaps may further enhance its impact.

Context.— Distinguishing benign from malignant processes in small lung biopsy specimens is challenging, particularly in the presence of architectural distortion and crush artifacts. Mimics include reactive type II pneumocytes in peribronchiolar metaplasia or organizing pneumonia and benign mucinous elements, including goblet cells and submucosal glands, which can mimic adenocarcinoma with mucinous features. Objective.— To understand whether caudal-type homeobox 2 (CDX2) and cytokeratin 20 (CK20) immunoreactivity is specific to malignant epithelial processes and evaluate their expression in a range of benign, premalignant, and malignant pulmonary lesions. Design.— We assessed CDX2 and CK20 immunohistochemistry in 48 cases of interstitial lung disease with reactive type II pneumocytes, 13 foci of atypical adenomatous hyperplasia, 11 bronchiolar adenomas, 4 adenocarcinomas in situ, 25 minimally invasive adenocarcinomas, 39 pulmonary adenocarcinomas with mucinous features, 6 mucoepidermoid carcinomas, and 1 squamous papilloma with goblet cell hyperplasia. Results.— No expression of CDX2 or CK20 was observed in reactive processes, goblet cells, bronchial glands, atypical adenomatous hyperplasia, or bronchiolar adenomas. In adenocarcinomas with mucinous features (n = 39), 9 (23%) were CK20-reactive and 8 (20%) were CDX2-reactive. A minority of nonmucinous and mucinous minimally invasive adenocarcinomas (n = 25) showed immunoreactivity (3 [12%] for each marker), while all in situ adenocarcinomas were negative. Conclusions.— Our findings demonstrate that CDX2 and CK20 are not expressed in benign or reactive type II pneumocytes and are specific for malignancy, particularly adenocarcinomas with mucinous features. Immunoreactivity with either marker in small biopsy specimens can support a diagnosis of malignancy, especially in morphologically equivocal or limited samples. Absence of staining does not exclude malignancy, but immunoreactivity with CDX2 and/or CK20 provides strong supportive evidence for a malignant process.

Abstract This review aims to update recent advancements in the management and treatment of olfactory neuroblastoma (ONB) based on discussions and topics highlighted during the 2024 North American Skull Base Society session “Literature Review: What's New in Olfactory Neuroblastoma?” A systematic review was conducted using PubMed/MEDLINE, focusing on relevant studies published between January 2022 and June 2024. Data were organized into themes: prognostication and staging, surgical concepts, biomarkers/genomics, imaging, syndrome of inappropriate antidiuretic hormone release and hyponatremia, chemotherapy, and radiotherapy. Out of 289 initial records, 46 studies met eligibility criteria. Key findings include the proposed integration of Hyams grading and dural infiltration with traditional staging for better prognostic accuracy, a shift toward less invasive surgical techniques while maintaining clear resection margins, and the identification of biomarkers for improved diagnosis and targeted therapy. Advanced imaging modalities like DOTA-peptide tomography (positron emission tomography–computed tomography/magnetic resonance imaging) were highlighted for their diagnostic value. Variability in induction chemotherapy outcomes underscores the need for personalized treatment plans, and new radiotherapy techniques offer promising results with improving morbidity. Recent advancements in ONB management have enhanced prognostic accuracy, molecular diagnostics, imaging techniques, and treatment outcomes. Continuous research is necessary to optimize these strategies and further improve patient survival and quality of life.

CD25 is a subunit of the interleukin-2 (IL-2) receptor on T cells and natural killer (NK) cells. Acute leukemias with oncogenic tyrosine kinases often include CD25 + leukemia subpopulations, which portend poor clinical outcomes for patients; however, acute leukemia cells do not respond to IL-2. Here, we identified CD25 and its phosphorylation by protein kinase Cδ (PKCδ) as central elements of a feedback loop that stabilized fluctuations in oncogenic tyrosine kinase signaling in acute lymphoblastic and myeloid leukemia. Genetic ablation of CD25 in murine and patient-derived xenograft (PDX) models of acute leukemias reduced clonal fitness, colony formation, and leukemia-initiation capacity in serial transplant recipients. Oncogenic tyrosine kinase signaling in leukemia cells stimulated NF-κB–mediated CD25 expression, whereas PKCδ-mediated phosphorylation of CD25 suppressed oncogenic tyrosine kinase signaling through inhibitory phosphatases, such as PTPN6. Interactome analyses and mass spectrometry–based global phosphoproteomic analyses showed that CD25 deletion abolished the phosphatase activity of PTPN6, resulting in enhanced activation of tyrosine kinases and NF-κB. Four injections of a CD25 antibody-drug conjugate induced complete remission in mice transplanted with PDX refractory leukemia. These findings highlight the dependency of tyrosine kinase–driven leukemias on robust feedback control and the role of PKCδ and CD25 in assembling its components.

Convergent framework for future POC cancer diagnostics aligning clinical needs (why), enabling technologies (how), and translational bridges. It integrates lab-on-chip biosensing and analytics for decentralized, early, longitudinal care.

Neutrophils and neutrophil extracellular traps (NETs) contribute to early neuromyelitis optica (NMO) histopathology initiated by IgG targeting astrocytic aquaporin-4 (AQP4) water channels. Yet, the mechanisms underlying neutrophil recruitment and their pathogenic roles in disease progression remain unclear. To investigate molecular-cellular events preceding classical complement cascade activation in a mouse NMO model, we continuously infused, via spinal subarachnoid route, a non-complement-activating mouse monoclonal AQP4-IgG. Parenchymal infiltration of netting neutrophils containing C5a ensued with microglial activation and motor impairment but no blood-brain barrier leakage. Motor impairment and neuronal dysfunction both reversed when AQP4-IgG infusion stopped. Two-photon microscopy and electron microscopy–based reconstructions revealed physical interaction of infiltrating neutrophils with microglia. Ablation of either peripheral neutrophils or microglia attenuated the motor deficit, highlighting their synergistic pathogenic roles. Of note, mice lacking complement receptor C5aR1 exhibited reduction in neutrophil infiltration, microglial lysosomal activation, neuronal lipid droplet burden, and motor impairment. Pharmacological inhibition of C5aR1 recapitulated this protection. Immunohistochemical analysis of an NMO patient’s spinal cord revealed disease-associated microglia surrounding motor neurons in nondestructive lesions. Our study identifies neutrophil-derived C5a signaling through microglial C5aR1 as a key early driver of reversible motor neuron dysfunction in the precytolytic phase of NMO.