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We describe a human lung disease caused by autosomal recessive, complete deficiency of the monocyte chemokine receptor C-C motif chemokine receptor 2 (CCR2). Nine children from five independent kindreds have pulmonary alveolar proteinosis (PAP), progressive polycystic lung disease, and recurrent infections, including bacillus Calmette Guérin (BCG) disease. The CCR2 variants are homozygous in six patients and compound heterozygous in three, and all are loss-of-expression and loss-of-function. They abolish CCR2-agonist chemokine C-C motif ligand 2 (CCL-2)-stimulated Ca2+ signaling in and migration of monocytic cells. All patients have high blood CCL-2 levels, providing a diagnostic test for screening children with unexplained lung or mycobacterial disease. Blood myeloid and lymphoid subsets and interferon (IFN)-γ- and granulocyte-macrophage colony-stimulating factor (GM-CSF)-mediated immunity are unaffected. CCR2-deficient monocytes and alveolar macrophage-like cells have normal gene expression profiles and functions. By contrast, alveolar macrophage counts are about half. Human complete CCR2 deficiency is a genetic etiology of PAP, polycystic lung disease, and recurrent infections caused by impaired CCL2-dependent monocyte migration to the lungs and infected tissues.
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Proteinosis Alveolar Pulmonar , Receptores CCR2 , Niño , Humanos , Pulmón/metabolismo , Macrófagos Alveolares/metabolismo , Proteinosis Alveolar Pulmonar/genética , Proteinosis Alveolar Pulmonar/diagnóstico , Receptores CCR2/deficiencia , Receptores CCR2/genética , Receptores CCR2/metabolismo , Reinfección/metabolismoRESUMEN
BACKGROUND: The actin cytoskeleton has a crucial role in the maintenance of the immune homeostasis by controlling various cellular processes, including cell migration. Mutations in TTC7A have been described as the cause of a primary immunodeficiency associated to different degrees of gut involvement and alterations in the actin cytoskeleton dynamics. OBJECTIVES: This study investigates the impact of TTC7A deficiency in immune homeostasis. In particular, the role of the TTC7A/phosphatidylinositol 4 kinase type III α pathway in the control of leukocyte migration and actin dynamics. METHODS: Microfabricated devices were leveraged to study cell migration and actin dynamics of murine and patient-derived leukocytes under confinement at the single-cell level. RESULTS: We show that TTC7A-deficient lymphocytes exhibit an altered cell migration and reduced capacity to deform through narrow gaps. Mechanistically, TTC7A-deficient phenotype resulted from impaired phosphoinositide signaling, leading to the downregulation of the phosphoinositide 3-kinase/AKT/RHOA regulatory axis and imbalanced actin cytoskeleton dynamics. TTC7A-associated phenotype resulted in impaired cell motility, accumulation of DNA damage, and increased cell death in dense 3-dimensional gels in the presence of chemokines. CONCLUSIONS: These results highlight a novel role of TTC7A as a critical regulator of lymphocyte migration. Impairment of this cellular function is likely to contribute to the pathophysiology underlying progressive immunodeficiency in patients.
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Actinas , Fosfatidilinositol 3-Quinasas , Humanos , Animales , Ratones , Muerte Celular , Mutación , Movimiento Celular/genética , Daño del ADN , Proteínas , 1-Fosfatidilinositol 4-QuinasaRESUMEN
Orchestrated recruitment of neutrophils to inflamed tissue is essential during the initiation of inflammation. Inflamed areas are usually hypoxic, and adaptation to reduced oxygen pressure is typically mediated by hypoxia pathway proteins. However, it remains unclear how these factors influence the migration of neutrophils to and at the site of inflammation during their transmigration through the blood-endothelial cell barrier, as well as their motility in the interstitial space. Here, we reveal that activation of hypoxia-inducible factor 2 (HIF2α) as a result of a deficiency in HIF prolyl hydroxylase domain protein 2 (PHD2) boosts neutrophil migration specifically through highly confined microenvironments. In vivo, the increased migratory capacity of PHD2-deficient neutrophils resulted in massive tissue accumulation in models of acute local inflammation. Using systematic RNA sequencing analyses and mechanistic approaches, we identified RhoA, a cytoskeleton organizer, as the central downstream factor that mediates HIF2α-dependent neutrophil motility. Thus, we propose that the novel PHD2-HIF2α-RhoA axis is vital to the initial stages of inflammation because it promotes neutrophil movement through highly confined tissue landscapes.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Movimiento Celular , Microambiente Celular , Neutrófilos/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Inflamación/genética , Inflamación/metabolismo , Ratones , Ratones Noqueados , RNA-SeqRESUMEN
Angioleiomyomas are uncommon, noncancerous, smooth muscle tumors that primarily arise from blood vessels. Previous studies have yielded limited data due to the lack of interdisciplinary approaches or restricted patient pools. This study aims to provide a comprehensive analysis of angioleiomyomas, including the demographic, clinical, radiological, and histopathological features, with a large number of patients. Conducted as a retrospective investigation at a single center from January 2005 to June 2023, this study involved 142 patients. Relevant information was extracted from electronic medical records, covering clinical, radiological, histological, and demographic details. Angioleiomyomas mostly occurred at age 59 (1-87), predominately affect females (53%) and commonly arise in subcutaneous tissue (85%) and the lower limbs (76%). MRI findings revealed characteristic signals, with a high prevalence of the solid histologic type (65%), often displaying a reticular sign. Smooth muscle Actin was universally present (n = 95/95), while Desmin and Caldesmon showed positive expression in 83% (n = 71/85) and 98% (n = 92/94) of cases, respectively. This study presents an updated and comprehensive analysis of angioleiomyomas. Typically appearing as well-defined nodules in the extremities, these tumors can be effectively diagnosed using MRI, though histopathological analysis is generally essential for confirmation. Treatment primarily involves straightforward excision, with notable low complication and recurrence rates.
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Chondroblastoma is a rare benign cartilaginous tumor that accounts for approximately 1% of bone tumors, but it can be associated with lung metastasis in extremely rare cases, leading to a poor prognosis and death. Herein, we report the case of a 19-year-old male patient who presented with an aggressive chondroblastoma of the proximal humerus and bilateral lung metastasis. The patient was treated with wide local resection, partial metastasectomy, and denosumab. Denosumab treatment was effective in controlling metastatic progression and preventing local recurrence.
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Neoplasias Óseas , Condroblastoma , Denosumab , Húmero , Neoplasias Pulmonares , Humanos , Masculino , Neoplasias Óseas/secundario , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Denosumab/uso terapéutico , Condroblastoma/tratamiento farmacológico , Adulto Joven , Húmero/patología , Conservadores de la Densidad Ósea/uso terapéuticoRESUMEN
INTRODUCTION: Ulnocarpal impaction syndrome causes pain on the ulnar side of the wrist. Various surgical techniques have been described. Ulnar shortening osteotomy is now a standard treatment. However, it is associated with complications such as non-union of the osteotomy site. The main study objective was to report the rate of radiographic consolidation after ulnar shortening osteotomy with a cutting guide. MATERIAL AND METHODS: This multicenter retrospective study of 30 cases reported clinical and radiographic criteria at a minimum 6 month's follow-up. RESULTS: The non-union rate was 3.4%. One case presented non-union of the osteotomy site. 87% of patients were satisfied or very satisfied with the procedure. Mean VAS pain rating was 2.7 ± 2.4. Mean QuickDASH and PRWE scores were 24.7 ± 19.2 and 28.6 ± 25. Mean strength on Jamar dynamometer was 27.4 ± 8.9 kg. One patient developed complex regional pain syndrome. Five patients required plate removal for hardware-related discomfort. DISCUSSION: Ulna shortening osteotomy with the Aptus Wrist plate provides a standardized approach to the surgical treatment of ulnocarpal impaction syndrome. Compared with other series in the literature, the procedure provided satisfactory consolidation and clinical results.
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Placas Óseas , Osteotomía , Cúbito , Humanos , Osteotomía/métodos , Cúbito/cirugía , Estudios Retrospectivos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Satisfacción del Paciente , Articulación de la Muñeca/cirugía , Articulación de la Muñeca/fisiopatología , Articulación de la Muñeca/diagnóstico por imagen , Radiografía , Anciano , Dimensión del Dolor , Adulto JovenRESUMEN
Mesenchymal chondrosarcomas are extremely rare and aggressive tumors that primarily affect patients between the ages of 20 and 30. These neoplasms are typically found in the lower limbs and cranial region. Their occurrence within soft tissues is exceedingly rare, and the initial presentation often includes immediate metastatic dissemination. Given the extraordinarily low prevalence of extraskeletal mesenchymal chondrosarcoma, treatment approaches remain non-standardized. Surgical resection combined with neoadjuvant chemotherapy or radiotherapy is the most commonly favored strategy by medical teams. In this case report, we present the case of a 72-year-old patient with no specific medical history, who presented with a non-metastatic extraskeletal mesenchymal chondrosarcoma located in the popliteal fossa. The therapeutic intervention encompassed surgical resection followed by adjuvant radiotherapy. After 18 months of follow-up period, there was no evidence of local recurrence or distant metastases. The disparity between the patient's clinical characteristics and the existing medical literature may provide new insights into understanding this neoplastic entity.
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The study of iron reinforcements used in the construction of Notre-Dame de Paris offers a glimpse into the innovation that took place on this building site in the mid-12th century, adapting metal to create a novel architecture. The restoration of the monument after the 2019 fire offered unique possibilities to investigate its iron armatures and to sample 12 iron staples from different locations (tribunes, nave aisles and upper walls). Six of them were dated thanks to the development of an innovative methodology based on radiocarbon dating. They reveal that Notre-Dame is the first known Gothic cathedral where iron was massively used as a proper construction material to bind stones throughout its entire construction, leading to a better understanding of the master masons' thinking. Moreover, a metallographic study and slag inclusion chemical analyses of the staples provide the first study of iron supply for a great medieval Parisian building yard, renewing our understanding of iron circulation, trade and forging in the 12th and 13th century capital of the French kingdom. The highlighting of numerous welds in all iron staples and the multiple provenances sheds light on the activity of the iron market in this major medieval European city and the nature of the goods that circulated, and questions the possible importance of recycling.
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Incendios , Refuerzo en Psicología , Humanos , Materiales de ConstrucciónRESUMEN
To reach inflamed tissues from the circulation, neutrophils must overcome physical constraints imposed by the tissue architecture, such as the endothelial barrier or the three-dimensional (3D) interstitial space. In these microenvironments, neutrophils are forced to migrate through spaces smaller than their own diameter. One of the main challenges for cell passage through narrow gaps is the deformation of the nucleus, the largest and stiffest organelle in cells. Here, we showed that chemokines, the extracellular signals that guide cell migration in vivo, modulated nuclear plasticity to support neutrophil migration in restricted microenvironments. Exploiting microfabricated devices, we found that the CXC chemokine CXCL12 enhanced the nuclear pliability of mouse bone marrow-derived neutrophils to sustain their migration in 3D landscapes. This previously uncharacterized function of CXCL12 was mediated by the atypical chemokine receptor ACKR3 (also known as CXCR7), required protein kinase A (PKA) activity, and induced chromatin compaction, which resulted in enhanced cell migration in 3D. Thus, we propose that chemical cues regulate the nuclear plasticity of migrating leukocytes to optimize their motility in restricted microenvironments.
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Núcleo Celular , Neutrófilos , Ratones , Animales , Movimiento Celular , Transducción de Señal , CromatinaRESUMEN
Adenomatous polyposis coli (APC) is a tumor suppressor whose mutations underlie familial adenomatous polyposis (FAP) and colorectal cancer. Although its role in intestinal epithelial cells is well characterized, APC importance in T cell biology is ill defined. APC regulates cytoskeleton organization, cell polarity, and migration in various cell types. Here, we address whether APC plays a role in T lymphocyte migration. Using a series of cell biology tools, we unveiled that T cells from FAP patients carrying APC mutations display impaired adhesion and motility in constrained environments. We further dissected the cellular mechanisms underpinning these defects in APC-depleted CEM T cell line that recapitulate the phenotype observed in FAP T cells. We found that APC affects T cell motility by modulating integrin-dependent adhesion and cytoskeleton reorganization. Hence, APC mutations in FAP patients not only drive intestinal neoplasms but also impair T cell migration, potentially contributing to inefficient antitumor immunity.