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Mechanisms of hematopoietic clonal dominance in VEXAS syndrome
No full textClonal dominance characterizes hematopoiesis during aging and increases susceptibility to blood cancers and common non-malignant disorders. VEXAS syndrome is a recently discovered adult-onset autoinflammatory disease burdened by a high mortality rate and caused by dominant hematopoietic clones bearing somatic mutations in the UBA1 gene. However, pathogenic mechanisms driving clonal dominance are unknown. Moreover, the lack of disease models hampers the development of disease-modifying therapies. Here, we performed immunophenotypic characterization of hematopoiesis and single-cell transcriptomics in a cohort of 9 male patients with VEXAS syndrome, revealing pervasive inflammation across all lineages. Hematopoietic stem/progenitor cells (HSPCs) in patients are skewed toward myelopoiesis and acquire senescence-like programs. Humanized models of VEXAS syndrome, generated by inserting the causative mutation in healthy HSPCs through base editing, recapitulated proteostatic defects, cytologic alterations, and senescence signatures of patients’ cells, as well as disease hematologic and inflammatory hallmarks. Competitive transplants of human UBA1-mutant and wild-type HSPCs showed that while mutant cells are more resilient to the inflammatory milieu, likely through the acquisition of the senescence-like state, wild-type ones are progressively exhausted and overwhelmed by VEXAS clones, overall impairing functional hematopoiesis and leading to bone marrow failure. Our study unveils the mechanism of clonal dominance, provides models for preclinical investigation of therapeutic strategies, and might have implications for clinical management of VEXAS syndrome
A tug-of-war in intraductal papillary mucinous neoplasms management: Comparison between 2017 International and 2018 European guidelines
No full textThe dataset includes data collected at the Division of Pancreatic Surgery of San Raffaele Scientific Institute, Milan, Italy and at HPB Disease Unit of Karolinska Hospital in Stockholm, Sweden.
Demographics, symptoms, clinical history, diagnostic work-up (including laboratory, radiologic and endoscopic data), type of surgery, and pathology data were prospectively collected. All patients were preoperatively discussed in conference [14] . High-risk stigmata (HRS) and worrisome features (WF) of IG and absolute indications (AI) and relative indications (RI) of EG were retrospectively applied. HRS include jaundice, solid mass, main pancreatic duct (MPD) ≥10 mm, enhancing nodules ≥5 mm and cytology positive for high-grade dysplasia or adeno- carcinoma. WF include cyst size ≥30 mm, MPD size of 5–9 mm, pancreatitis, enhancing mural nodule 37 U/mL and cyst growth rate > 5 mm/2 years. AI include jaundice, MPD ≥10 mm, enhancing nodules ≥5 mm, solid mass and cytology positive for high-grade dysplasia or adenocar- cinoma. RI include cyst size ≥40 mm, MPD size of 5–9.9 mm, pan- creatitis, enhancing mural nodule 37 U/mL, new onset of diabetes and cyst growth rate > 5 mm/year
Tfr2 Genetic Deletion Makes Transfusion-Independent a Murine Model of Transfusion-Dependent β-Thalassemia
No full textβ-thalassemia is a genetic disorder caused by mutations in the β-globin gene, and characterized by anemia, ineffective erythropoiesis and iron overload. Patients affected by the most severe transfusion-dependent form of the disease (TDT) require lifelong blood transfusions and iron chelation therapy, a symptomatic treatment associated with several complications. Other therapeutic opportunities are available, but none is fully effective and/or applicable to all patients, calling for the identification of novel strategies. Transferrin receptor 2 (TFR2) balances red blood cells production according to iron availability, being an activator of the iron-regulatory hormone hepcidin in the liver and a modulator of erythropoietin signaling in erythroid cells. Selective Tfr2 deletion in the BM improves anemia and iron-overload in non-TDT mice, both as a monotherapy and, even more strikingly, in combination with iron restricting approaches. However, whether Tfr2 targeting might represent a therapeutic option for TDT has never been investigated so far. Here, we prove that BM Tfr2 deletion improves anemia, erythrocytes morphology and ineffective erythropoiesis in the Hbbth1/th2 murine model of TDT. This effect is associated with a decrease in the expression of α-globin, which partially corrects the unbalance with β-globin chains and limits the precipitation of misfolded hemoglobin, and with a decrease in the activation of unfolded protein response. Remarkably, BM Tfr2 deletion is also sufficient to avoid long-term blood transfusions required for survival of Hbbth1/th2 animals, preventing mortality due to chronic anemia and reducing transfusion-associated complications, such as progressive iron-loading. Altogether, these findings prove that TFR2 targeting might represent a promising therapeutic option also for TDT
Brain and cervical spinal cord MRI correlates of sensorimotor impairment in patients with multiple sclerosis
No full textSpinal cord (SC) involvement, particularly cervical SC (cSC) atrophy and lesions, is increasingly recognized as a key determinant of disability in multiple sclerosis (MS), yet its role in specific sensorimotor impairments remains underexplored. This cross-sectional multiparametric MRI study aimed to assess the relative contribution of brain and cSC lesion burden and atrophy to global disability and specific sensorimotor functions in MS.
A total of 151 MS patients and 69 age- and sex-matched healthy controls underwent 3T brain and cSC MRI and clinical evaluations including Expanded Disability Status Scale (EDSS), pyramidal and sensory functional system (P-FS, S-FS) scores, motor performance tests (9-hole peg test [9-HPT], finger tapping test [FTT], timed 25-foot walk test [T25FWT]), and vibration detection threshold (VDT). Random forest models identified MRI features most predictive of disability milestones (EDSS ≥3.0, ≥4.0, and ≥6.0), functional system impairments, and motor/sensory test performance.
Across all outcomes, cSC gray matter cross-sectional area (GM CSA) emerged as the most informative variable, outperforming brain volumetric and lesion metrics. GM CSA was the strongest predictor of progressive MS phenotype and higher EDSS scores (AUC up to 0.900). It also best explained impairments in lower limb motor function (T25FWT), upper limb repetitive motor performance (FTT), and vibratory sensation (VDT). In contrast, 9-HPT impairment, a more complex dexterity task, was associated with a broader combination of cSC and brain abnormalities, including lesion burden and cortical and deep gray matter atrophy.
VDT impairment was linked to volume loss in both cSC GM and white matter (WM), supporting the role of dorsal columns and posterior horns in somatosensory processing. Brain metrics, particularly thalamic volume, also contributed to VDT variability.
The findings highlight the predominant role of cSC GM atrophy as a structural correlate of sensorimotor impairment and disability in MS, especially at higher levels of functional decline. These results support integrating spinal cord MRI, particularly quantification of GM damage, into routine clinical assessments to enhance prognostic accuracy and guide personalized interventions in MS management
Testis Molecular Pathways in CAIS Unveil Testosterone/Estradiol on Germ Cell Tumor Risk in Non-Obstructive Azoospermia
No full textSupporting information and datasets to the paper titled "Testis Molecular Pathways in CAIS Unveil Testosterone/Estradiol on Germ Cell Tumor Risk in Non-Obstructive Azoospermia". DOI: 10.1210/clinem/dgaf40
Molecular and Phenotypic blueprint of human hematopoiesis links proliferation stress to stem cell aging
No full textHematopoietic stem/progenitor cell (HSPC) aging has long been associated with myeloid skewing, reduced clonal output, and impaired regenerative capacity, but quantitative immunophenotypic and functional analysis across the human lifespan has been lacking. Here, we provide a comprehensive phenotypic, transcriptional, and functional dissection of human hematopoiesis from youth to advanced age. Although primitive hematopoietic stem cell (HSC) numbers were stable during aging, overall cellularity declined, especially for erythroid and lymphoid lineages. HSPC from older individuals exhibited repopulating frequencies comparable to those from younger donors in both primary and secondary xenografts; however, aged HSC displayed impaired differentiation, chromatin and cell-cycle dysregulation, and poor tolerance to activation-induced proliferative stress, resulting in DNA damage and senescence-like features post-xenotransplantation. Importantly, imposing proliferative stress on young human HSPCs in vivo recapitulated key aging-associated phenotypic and functional declines. Together, our findings identify dysregulated activation responses as a defining feature of HSPC aging and establish proliferative stress–based xenotransplantation models as powerful platforms for investigating age-related hematopoietic dysfunctions.
This work is published on Journal of Experimental Medicine (doi: 10.1084/jem.20251805)
All the data generated in this study have been deposited in the San Raffaele Open Research Data Repository under accession code doi: 10.17632/72ty5v9djn.1
The RNA and ATAC sequencing data generated and discussed in this study have been deposited in NCBI's Gene Expression Omnibus (Edgar et al., 2002) and are accessible through GEO SuperSeries GSE311225, which contains the following data: GSE243327 (RNA-seq), GSE311221 (ATAC-seq).
The code used to process and to generate the images of RNAseq data in this manuscript is available at: http://www.bioinfotiget.it/gitlab/custom/LetteraScala_Ageing/bulk_RNAseq.
WES data generated and discussed in this study are available at the European Nucleotide Archive (ENA) under the following accession code: PRJEB9390
History of Peripartum Depression Moderates the Association Between Estradiol Polygenic Risk Scores and Basal Ganglia Volumes in Major Depressive Disorder
No full textThe neurobiological differences between women who have experienced a peripartum episode and those who have only had episodes outside of this period are not well understood. Our findings demonstrate that women who have experienced a peripartum episode are neurobiologically distinct from women who have no history of PPD in a cluster within the basal ganglia, an area important for motivation, decision making, and emotional processing. Furthermore, we show that the genetic load for estradiol has a differing effect in this area based on PPD status, which supports the claim that PPD is associated with sensitivity to sex steroid hormones
FKBP12 inhibits hepcidin expression by modulating BMP receptors interaction and ligand responsiveness in hepatocytes
No full textThe expression of the iron regulatory hormone hepcidin in hepatocytes is regulated by the BMP-SMAD pathway through the type I receptors ALK2 and ALK3, the type II receptors ACVR2A and BMPR2, and the ligands BMP2 and BMP6. We previously
identified the immunophilin FKBP12 as a new hepcidin inhibitor that acts by blocking ALK2. Both the physiologic ALK2 ligand BMP6 and the immunosuppressive drug Tacrolimus (TAC) displace FKBP12 from ALK2 and activate the signaling. However,
the molecular mechanism whereby FKBP12 regulates BMP-SMAD pathway activity and thus hepcidin expression remains unclear. Here, we show that FKBP12 acts by modulating BMP receptor interactions and ligand responsiveness. We first demonstrate that in primary murine hepatocytes TAC regulates hepcidin expression exclusively via FKBP12. Downregulation of the BMP receptors reveals that ALK2, to a lesser extent ALK3, and ACVR2A are required for hepcidin upregulation in response to both BMP6 and TAC. Mechanistically, TAC and BMP6 increase ALK2 homooligomerization and ALK2–ALK3 hetero-oligomerization and the interaction between ALK2 and the type II receptors. By acting on the same receptors, TAC and BMP6 cooperate in BMP pathway activation and hepcidin expression both in vitro and in vivo. Interestingly, the activation state of ALK3 modulates its interaction with FKBP12, which may explain the cell-specific activity of FKBP12. Overall, our results identify the mechanism whereby FKBP12 regulates the BMP-SMAD pathway and hepcidin expression in hepatocytes, and suggest that FKBP12–ALK2 interaction is a potential pharmacologic target in disorders caused by defective BMP-SMAD signaling and characterized by low hepcidin and high BMP6 expression.
Complete data files relative to the manuscript "Pettinato M. et al., FKBP12 inhibits hepcidin expression by modulating BMP receptors interaction and ligand responsiveness in hepatocytes. Am J Hematol. 2023 Aug;98(8):1223-1235. doi: 10.1002/ajh.26961. Epub 2023 May 18. PMID: 37199280"
Altering the biophysical properties of ERC1/ELKS–driven condensates interferes with cell motility
No full textCell migration is orchestrated by molecular networks supporting motility. The scaffolds ERC1/ELKS and Liprin-α1 sustain cell migration and invasion by assembling dynamic plasma membrane-associated platforms. ERC1/ELKS forms cytoplasmic condensates with liquid–like behavior. In this study we tested whether the ability of ERC1 to form condensates is relevant to its function in cell motility. We identified the shortest N-terminal region of ERC1 sufficient to drive phase separation in vitro and in cells. Fluorescence recovery after photobleaching confirmed the dynamic behavior of ERC1(1-244) condensates. Surprisingly, deletion of ERC1(1-244) including an intrinsically disordered region did not abolish the ability of ERC1DΔN to form condensates. Although the interactions of ERC1ΔN with partners were unaffected, the biophysical properties of ERC1ΔN condensates were altered, with consequences on cell motility. These findings highlight the importance of ERC1/ELKS to assemble functional networks, and show that altering the properties of ERC1–driven condensates interferes with tumor cell motility
Commutability of Lombardy Region EQA Control Materials for Enzymes, Calcium, and Creatinine
No full textThis dataset contains raw, replicate-level measurements generated in a multicenter study assessing the commutability of External Quality Assessment (EQA) control materials across routine clinical chemistry platforms. No post-processing, outlier removal, bias calculations, uncertainty propagation, or commutability classifications are included here; all values are as reported by the participating instruments in the single analytical run per site.
Study design (for data context)
Setting: Ten routine clinical laboratories participating in the Lombardy Regional EQA program.
Analytes (measurands): ALP, ALT, AST, CK, LDH, CHE, creatinine, calcium.
Specimens: Three lyophilized control materials (CM-1/CM-2/CM-3) and fifteen human serum pools. Each site performed one analytical run. CMs were measured in six replicates; pools in three replicates. Routine calibration and IQC preceded each ru