Somatic mutations in UBA1 involving hematopoietic stem and myeloid cells have been reported in patients with the newly defined VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Here, we report clinical hematologic manifestations and unique bone marrow (BM) features in 16 patients with VEXAS. All patients were male and had a history of severe autoinflammatory and rheumatologic manifestations and a somatic UBA1 mutation (p.Met41). Ten patients had hematologic disorders: myelodysplastic syndrome (MDS; 6 of 16), multiple myeloma (2 of 16), monoclonal gammopathy of undetermined significance (2 of 16), and monoclonal B-cell lymphocytosis (2 of 16), and a few of those patients had 2 co-existing clonal processes. Although macrocytic anemia (100%) and lymphopenia (80%) were prevalent in all patients with VEXAS, thrombocytopenia and neutropenia were more common in patients with progression to MDS. All BMs in VEXAS patients had prominent cytoplasmic vacuoles in myeloid and erythroid precursors. In addition, most BMs were hypercellular with myeloid hyperplasia, erythroid hypoplasia, and varying degrees of dysplasia. All patients diagnosed with MDS were lower risk (low blast count, very good to intermediate cytogenetics) according to standard prognostic scoring with no known progression to leukemia. In addition, 10 of 16 patients had thrombotic events, including venous thromboembolism and arterial stroke. Although VEXAS presents symptomatically as a rheumatologic disease, morbidity and mortality are associated with progression to hematologic disease. Given the increased risk of developing MDS and multiple myeloma, surveillance for disease progression is important.

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Background and Purpose Oestrogen receptor alpha (ERα) binds to different ligand which can function as complete/partial oestrogen‐agonist or antagonist. This depends on the chemical structure of the ligands which modulates the transcriptional activity of the oestrogen‐responsive genes by altering the conformation of the liganded‐ERα complex. This study determined the molecular mechanism of oestrogen‐agonistic/antagonistic action of structurally similar ligands, bisphenol (BP) and bisphenol A (BPA) on cell proliferation and apoptosis of ERα + ve breast cancer cells. Experimental Approach DNA was measured to assess the proliferation and apoptosis of breast cancer cells. RT‐PCR and ChIP assays were performed to quantify the transcripts of TFF1 gene and recruitment of ERα and SRC3 at the promoter of TFF1 gene respectively. Molecular docking was used to delineate the binding modes of BP and BPA with the ERα. PCR‐based arrays were used to study the regulation of the apoptotic genes. Key Results BP and BPA induced the proliferation of breast cancer cells; however, unlike BPA, BP failed to induce apoptosis. BPA consistently acted as an agonist in our studies but BP exhibited mixed agonistic/antagonistic properties. Molecular docking revealed agonistic and antagonistic mode of binding for BPA and BP respectively. BPA treatment resembled E2 treatment in terms of PCR‐based regulation of apoptotic genes whereas BP was similar to 4OHT treatment. Conclusions and Implications The chemical structure of ERα ligand determines the agonistic or antagonistic biological responses by the virtue of their binding mode, conformation of the liganded‐ERα complex and the context of the cellular function.

Immunoglobulin G4-related disease is a fibroinflammatory systemic disease that is characterized by focal or diffuse organ infiltration by immunoglobulin G4-bearing plasma cells. Immunoglobulin G4-related disease may affect any organ, and a high index of suspicion is necessary for early detection to avoid irreversible fibrosis, organ dysfunction, and death. Tumor-forming lesions are common radiological features of immunoglobulin G4-related disease that need to be differentiated from malignancies. The diagnostic approach requires the integration of clinical, biochemical, and radiographic manifestations with classic histopathologic features, which remain crucial to diagnosis. The histology of immunoglobulin G4-related disease is determined by a dense lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis in the presence of increased immunoglobulin G4-positve plasma cells. Although immunoglobulin G4-related disease forms a distinct, clinically independent disease category, many questions and problems remain unanswered, especially on its pathogenesis and the role of immunoglobulin G4. Advances in the understanding of immunoglobulin G4-related disease are likely to change the diagnostic approach in the future and create potential targets for therapeutic purposes. Here we describe the concept of immunoglobulin G4-related disease and the most recent knowledge in the clinico-pathological characteristics on this emerging disease. This study can guide clinicians in early diagnosis and prevent unnecessary surgical resections.