RESUMEN
ABSTRACT: SETBP1 mutations are found in various clonal myeloid disorders. However, it is unclear whether they can initiate leukemia, because SETBP1 mutations typically appear as later events during oncogenesis. To answer this question, we generated a mouse model expressing mutated SETBP1 in hematopoietic tissue: this model showed profound alterations in the differentiation program of hematopoietic progenitors and developed a myeloid neoplasm with megakaryocytic dysplasia, splenomegaly, and bone marrow fibrosis, prompting us to investigate SETBP1 mutations in a cohort of 36 triple-negative primary myelofibrosis (TN-PMF) cases. We identified 2 distinct subgroups, one carrying SETBP1 mutations and the other completely devoid of somatic variants. Clinically, a striking difference in disease aggressiveness was noted, with patients with SETBP1 mutation showing a much worse clinical course. In contrast to myelodysplastic/myeloproliferative neoplasms, in which SETBP1 mutations are mostly found as a late clonal event, single-cell clonal hierarchy reconstruction in 3 patients with TN-PMF from our cohort revealed SETBP1 to be a very early event, suggesting that the phenotype of the different SETBP1+ disorders may be shaped by the opposite hierarchy of the same clonal SETBP1 variants.
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Sistema Hematopoyético , Enfermedades Mielodisplásicas-Mieloproliferativas , Trastornos Mieloproliferativos , Mielofibrosis Primaria , Animales , Ratones , Humanos , Mielofibrosis Primaria/genética , Trastornos Mieloproliferativos/genética , Mutación , Proteínas Portadoras/genética , Proteínas Nucleares/genéticaRESUMEN
In intrahepatic cholangiocarcinoma (iCCA), thrombospondin 1 (THBS1) and 2 (THBS2) are soluble mediators released in the tumor microenvironment (TME) that contribute to the metastatic spreading of iCCA cells via a lymphatic network by the trans-differentiation of vascular endothelial cells to a lymphatic-like phenotype. To study the direct role of THBS1 and THBS2 on the iCCA cells, well-established epithelial (HuCCT-1) and mesenchymal (CCLP1) iCCA cell lines were subjected to recombinant human THBS1 and THBS2 (rhTHBS1, rhTHBS2) for cellular function assays. Cell growth, cell adhesion, migration, and invasion were all enhanced in both CCLP1 and HuCCT-1 cells by the treatment with either rhTHBS1 or rhTHBS2, although they showed some variability in their intensity of speeding up cellular processes. rhTHBS2 was more intense in inducing invasiveness and in committing the HuCCT-1 cells to a mesenchymal-like phenotype and was therefore a stronger enhancer of the malignant behavior of iCCA cells compared to rhTHBS1. Our data extend the role of THBS1 and THBS2, which are not only able to hinder the vascular network and promote tumor-associated lymphangiogenesis but also exacerbate the malignant behavior of the iCCA cells.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Humanos , Neoplasias de los Conductos Biliares/metabolismo , Conductos Biliares Intrahepáticos/metabolismo , Proliferación Celular/genética , Colangiocarcinoma/metabolismo , Células Endoteliales/metabolismo , Trombospondina 1/genética , Trombospondina 1/metabolismo , Microambiente Tumoral , TrombospondinasRESUMEN
Mucopolysaccharidosis type I (MPSI) (OMIM #252800) is an autosomal recessive disorder caused by pathogenic variants in the IDUA gene encoding for the lysosomal alpha-L-iduronidase enzyme. The deficiency of this enzyme causes systemic accumulation of glycosaminoglycans (GAGs). Although disease manifestations are typically not apparent at birth, they can present early in life, are progressive, and include a wide spectrum of phenotypic findings. Among these, the storage of GAGs within the lysosomes disrupts cell function and metabolism in the cartilage, thus impairing normal bone development and ossification. Skeletal manifestations of MPSI are often refractory to treatment and severely affect patients' quality of life. This review discusses the pathological and molecular processes leading to impaired endochondral ossification in MPSI patients and the limitations of current therapeutic approaches. Understanding the underlying mechanisms responsible for the skeletal phenotype in MPSI patients is crucial, as it could lead to the development of new therapeutic strategies targeting the skeletal abnormalities of MPSI in the early stages of the disease.
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Iduronidasa , Mucopolisacaridosis I , Glicosaminoglicanos/metabolismo , Humanos , Iduronidasa/genética , Mucopolisacaridosis I/genética , Fenotipo , Calidad de VidaRESUMEN
BACKGROUND & AIMS: The microenvironment of intrahepatic cholangiocarcinoma (iCCA) is hypovascularized, with an extensive lymphatic network. This leads to rapid cancer spread into regional lymph nodes and the liver parenchyma, precluding curative treatments. Herein, we investigated which factors released in the iCCA stroma drive the inhibition of angiogenesis and promote lymphangiogenesis. METHODS: Quantitative proteomics was performed on extracellular fluid (ECF) proteins extracted both from cancerous and non-cancerous tissues (NCT) of patients with iCCA. Computational biology was applied on a proteomic dataset to identify proteins involved in the regulation of vessel formation. Endothelial cells incubated with ECF from either iCCA or NCT specimens were used to assess the role of candidate proteins in 3D vascular assembly, cell migration, proliferation and viability. Angiogenesis and lymphangiogenesis were further investigated in vivo by a heterotopic transplantation of bone marrow stromal cells, along with endothelial cells in SCID/beige mice. RESULTS: Functional analysis of upregulated proteins in iCCA unveils a soluble angio-inhibitory milieu made up of thrombospondin (THBS)1, THBS2 and pigment epithelium-derived factor (PEDF). iCCA ECF was able to inhibit in vitro vessel morphogenesis and viability. Antibodies blocking THBS1, THBS2 and PEDF restored tube formation and endothelial cell viability to levels observed in NCT ECF. Moreover, in transplanted mice, the inhibition of blood vessel formation, the de novo generation of the lymphatic network and the dissemination of iCCA cells in lymph nodes were shown to depend on THBS1, THBS2 and PEDF expression. CONCLUSIONS: THBS1, THBS2 and PEDF reduce blood vessel formation and promote tumor-associated lymphangiogenesis in iCCA. Our results identify new potential targets for interventions to counteract the dissemination process in iCCA. LAY SUMMARY: Intrahepatic cholangiocarcinoma is a highly aggressive cancer arising from epithelial cells lining the biliary tree, characterized by dissemination into the liver parenchyma via lymphatic vessels. Herein, we show that the proteins THBS1, THBS2 and PEDF, once released in the tumor microenvironment, inhibit vascular growth, while promoting cancer-associated lymphangiogenesis. Therefore, targeting THBS1, THBS2 and PEDF may be a promising strategy to reduce cancer-associated lymphangiogenesis and counteract the invasiveness of intrahepatic cholangiocarcinoma.
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Inductores de la Angiogénesis/metabolismo , Colangiocarcinoma/etiología , Linfangiogénesis/efectos de los fármacos , Trombospondina 1/farmacología , Trombospondinas/farmacología , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Colangiocarcinoma/fisiopatología , Modelos Animales de Enfermedad , Ratones , Proteómica/métodos , Proteómica/estadística & datos numéricos , Trombospondina 1/administración & dosificación , Trombospondinas/administración & dosificación , Microambiente Tumoral/efectos de los fármacosRESUMEN
BICD2 (BICD Cargo Adaptor 2, MIM*609797) mutations are associated with severe prenatal-onset forms of spinal muscular atrophy, lower extremity-predominant 2B (SMALED2B MIM 618291) or milder forms with childhood-onset (SMALED2A MIM 615290). Etiopathogenesis is not fully clarified and a wide spectrum of phenotypic presentations is reported, ranging from extreme prenatal forms with adverse outcome, to slow progressive late-onset forms. We report a fetus at 22 gestational weeks with evidence of Arthrogryposis Multiplex Congenita on ultrasound, presenting with fixed extended lower limbs and flexed upper limbs, bilateral clubfoot and absent fetal movements. A trio-based prenatal Exome Sequencing was performed, disclosing a de novo heterozygous pathogenic in frame deletion (NM_015250.3: c.1636_1638delAAT; p.Asn546del) in BICD2. After pregnancy termination, quantitative analysis on NeuN immunostained spinal cord sections of the ventral horns, revealed that neuronal density was markedly reduced compared to the one of an age-matched normal fetus and an age-matched type-I Spinal Muscular Atrophy sample, used as a comparative model. The present case, the first prenatally diagnosed and neuropathologically characterized, showed an early motor neuron loss in SMALED2B, providing further insight into the pathological basis of BICD2-opathies.
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Artrogriposis/genética , Predisposición Genética a la Enfermedad , Proteínas Asociadas a Microtúbulos/genética , Atrofia Muscular Espinal/genética , Artrogriposis/diagnóstico , Artrogriposis/diagnóstico por imagen , Artrogriposis/patología , Feto , Asesoramiento Genético/tendencias , Humanos , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/diagnóstico por imagen , Atrofia Muscular Espinal/patología , Mutación Missense/genética , Patología Molecular , Linaje , Secuenciación del ExomaRESUMEN
Mesenchymal stromal cells (MSCs) represent an essential component of the bone marrow (BM) niche and display disease-specific alterations in several myeloid malignancies. The aim of this work was to study possible MSC abnormalities in Philadelphia-negative myeloproliferative neoplasms (MPNs) in relationship to the degree of BM fibrosis. MSCs were isolated from BM of 6 healthy donors (HD) and of 23 MPN patients, classified in 3 groups according to the diagnosis and the grade of BM fibrosis: polycythemia vera and essential thrombocythemia (PV/ET), low fibrosis myelofibrosis (LF-MF), and high fibrosis MF (HF-MF). MSC cultures were established from 21 of 23 MPN patients. MPN-derived MSCs did not exhibit any functional impairment in their adipogenic/osteogenic/chondrogenic differentiation potential and displayed a phenotype similar to HD-derived MSCs but with a decreased expression of CD146. All MPN-MSC lines were negative for the patient-specific hematopoietic clone mutations (JAK2, MPL, CALR). MSCs derived from HF-MF patients displayed a reduced clonogenic potential and a lower growth kinetic compared to MSCs from HD, LF-MF, and PV/ET patients. mRNA levels of hematopoiesis regulatory molecules were unaffected in MSCs from HF-MF compared to HD. Finally, in vitro ActivinA secretion by MSCs was increased in HF-MF compared to LF-MF patients, in association with a lower hemoglobin value. Increased ActivinA immunolabeling on stromal cells and erythroid precursors was also observed in HF-MF BM biopsies. In conclusion, higher grade of BM fibrosis is associated with functional impairment of MSCs and the increased secretion of ActivinA may represent a suitable target for anemia treatment in MF patients.
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Activinas/metabolismo , Médula Ósea/metabolismo , Células Madre Mesenquimatosas/metabolismo , Trastornos Mieloproliferativos/metabolismo , Mielofibrosis Primaria/metabolismo , Adulto , Anciano , Médula Ósea/patología , Diferenciación Celular/fisiología , Células Cultivadas , Estudios de Cohortes , Femenino , Humanos , Masculino , Células Madre Mesenquimatosas/patología , Persona de Mediana Edad , Trastornos Mieloproliferativos/patología , Policitemia Vera/metabolismo , Policitemia Vera/patología , Mielofibrosis Primaria/patología , Trombocitemia Esencial/metabolismo , Trombocitemia Esencial/patologíaRESUMEN
Bone formation starts near the end of the embryonic stage of development and continues throughout life during bone modeling and growth, remodeling, and when needed, regeneration. Bone-forming cells, traditionally termed osteoblasts, produce, assemble, and control the mineralization of the type I collagen-enriched bone matrix while participating in the regulation of other cell processes, such as osteoclastogenesis, and metabolic activities, such as phosphate homeostasis. Osteoblasts are generated by different cohorts of skeletal stem cells that arise from different embryonic specifications, which operate in the pre-natal and/or adult skeleton under the control of multiple regulators. In this review, we briefly define the cellular identity and function of osteoblasts and discuss the main populations of osteoprogenitor cells identified to date. We also provide examples of long-known and recently recognized regulatory pathways and mechanisms involved in the specification of the osteogenic lineage, as assessed by studies on mice models and human genetic skeletal diseases.
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Osteoblastos/citología , Osteogénesis , Células Madre/citología , Animales , Huesos/citología , Huesos/embriología , Epigénesis Genética , Humanos , Osteogénesis/genética , Transducción de SeñalRESUMEN
In nonalcoholic steatohepatitis animal models, an increased lipid droplet size in hepatocytes is associated with fibrogenesis. Hepatocytes with large droplet (Ld-MaS) or small droplet (Sd-MaS) macrovesicular steatosis may coexist in the human liver, but the factors associated with the predominance of one type over the other, including hepatic fibrogenic capacity, are unknown. In pre-ischemic liver biopsies from 225 consecutive liver transplant donors, we retrospectively counted hepatocytes with Ld-MaS and Sd-MaS and defined the predominant type of steatosis as involving ≥50% of steatotic hepatocytes. We analyzed a donor Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 polymorphism, hepatic expression of proteins involved in lipid metabolism by RT-PCR, hepatic stellate cell (HSC) activation by α-SMA immunohistochemistry and, one year after transplantation, histological progression of fibrosis due to Hepatitis C Virus (HCV) recurrence. Seventy-four livers had no steatosis, and there were 98 and 53 with predominant Ld-MaS and Sd-MaS, respectively. In linear regression models, adjusted for many donor variables, the percentage of steatotic hepatocytes affected by Ld-MaS was inversely associated with hepatic expression of Insulin Induced Gene 1 (INSIG-1) and Niemann-Pick C1-Like 1 gene (NPC1L1) and directly with donor PNPLA3 variant M, HSC activation and progression of post-transplant fibrosis. In humans, Ld-MaS formation by hepatocytes is associated with abnormal PNPLA3-mediated lipolysis, downregulation of both the intracellular cholesterol sensor and cholesterol reabsorption from bile and increased hepatic fibrogenesis.
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Péptidos y Proteínas de Señalización Intracelular/genética , Lipasa/genética , Proteínas de la Membrana/genética , Proteínas de Transporte de Membrana/genética , Enfermedad del Hígado Graso no Alcohólico/genética , Adulto , Anciano , Femenino , Regulación de la Expresión Génica/genética , Hepacivirus/genética , Hepatocitos/virología , Humanos , Gotas Lipídicas/metabolismo , Gotas Lipídicas/patología , Gotas Lipídicas/virología , Hígado/metabolismo , Hígado/patología , Hígado/virología , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/virología , Polimorfismo de Nucleótido Simple/genética , Estudios RetrospectivosRESUMEN
Human umbilical cord blood (CB) has attracted much attention as a reservoir for functional hematopoietic stem and progenitor cells, and, recently, as a source of blood-borne fibroblasts (CB-BFs). Previously, we demonstrated that bone marrow stromal cell (BMSC) and CB-BF pellet cultures make cartilage in vitro Furthermore, upon in vivo transplantation, BMSC pellets remodelled into miniature bone/marrow organoids. Using this in vivo model, we asked whether CB-BF populations that express characteristics of the hematopoietic stem cell (HSC) niche contain precursors that reform the niche. CB ossicles were regularly observed upon transplantation. Compared with BM ossicles, CB ossicles showed a predominance of red marrow over yellow marrow, as demonstrated by histomorphological analyses and the number of hematopoietic cells isolated within ossicles. Marrow cavities from CB and BM ossicles included donor-derived CD146-expressing osteoprogenitors and host-derived mature hematopoietic cells, clonogenic lineage-committed progenitors and HSCs. Furthermore, human CD34+ cells transplanted into ossicle-bearing mice engrafted and maintained human HSCs in the niche. Our data indicate that CB-BFs are able to recapitulate the conditions by which the bone marrow microenvironment is formed and establish complete HSC niches, which are functionally supportive of hematopoietic tissue.
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Células de la Médula Ósea/citología , Sangre Fetal/citología , Fibroblastos/citología , Células Madre Hematopoyéticas/citología , Organoides/citología , Nicho de Células Madre , Adulto , Compartimento Celular , Niño , Fibroblastos/trasplante , Trasplante de Células Madre Hematopoyéticas , Homeostasis , Humanos , Nicho de Células Madre/genética , Células del Estroma/citologíaRESUMEN
Mucopolysaccharidosis type I (MPS-I), a lysosomal storage disorder caused by a deficiency of alpha-L-iduronidase enzyme, results in the progressive accumulation of glycosaminoglycans and consequent multiorgan dysfunction. Despite the effectiveness of hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) in correcting clinical manifestations related to visceral organs, complete improvement of musculoskeletal and neurocognitive defects remains an unmet challenge and provides an impact on patients' quality of life. We tested the therapeutic efficacy of combining HSCT and ERT in the neonatal period. Using a mouse model of MPS-I, we demonstrated that the combination therapy improved clinical manifestations in organs usually refractory to current treatment. Moreover, combination with HSCT prevented the production of anti-IDUA antibodies that negatively impact ERT efficacy. The added benefits of combining both treatments also resulted in a reduction of skeletal anomalies and a trend towards decreased neuroinflammation and metabolic abnormalities. As currently there are limited therapeutic options for MPS-I patients, our findings suggest that the combination of HSCT and ERT during the neonatal period may provide a further step forward in the treatment of this rare disease.
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Remodelación Ósea , Modelos Animales de Enfermedad , Terapia de Reemplazo Enzimático/métodos , Trasplante de Células Madre Hematopoyéticas/métodos , Iduronidasa/fisiología , Mucopolisacaridosis I/terapia , Animales , Animales Recién Nacidos , Terapia Combinada , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mucopolisacaridosis I/enzimología , Mucopolisacaridosis I/patologíaRESUMEN
We compared the effects of a nitrogen-containing bisphosphonate (N-BP), zoledronic acid (ZA), and an anti-mouse RANKL antibody (anti-mRANKL Ab) on the bone tissue pathology of a transgenic mouse model of human fibrous dysplasia (FD). For comparison, we also reviewed the histological samples of a child with McCune-Albright syndrome (MAS) treated with Pamidronate for 3 years. EF1α-GsαR201C mice with FD-like lesions in the tail vertebrae were treated with either 0.2 mg/kg of ZA at day 0, 7, and 14 or with 300 µg/mouse of anti-mRANKL Ab at day 0 and 21. All mice were monitored by Faxitron and histological analysis was performed at day 42. ZA did not affect the progression of the radiographic phenotype in EF1α-GsαR201C mice. FD-like lesions in the ZA group showed the persistence of osteoclasts, easily detectable osteoclast apoptotic activity and numerous "giant osteoclasts". In contrast, in the anti-mRANKL Ab-treated mice, osteoclasts were markedly reduced/absent, the radiographic phenotype reverted and the FD-like lesions were extensively replaced by newly formed bone. Numerous "giant osteoclasts" were also detected in the samples of the child with MAS. This study supports the hypothesis that osteoclasts per se, independently of their resorptive activity, are essential for development and expansion of FD lesions.
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Displasia Fibrosa Ósea/tratamiento farmacológico , Células Gigantes , Osteoclastos , Ácido Zoledrónico/uso terapéutico , Animales , Difosfonatos , Modelos Animales de Enfermedad , Displasia Fibrosa Ósea/patología , Ratones , Ratones TransgénicosRESUMEN
The mechanisms whereby autoreactive T cells escape peripheral tolerance establishing thus autoimmune diseases in humans remain an unresolved question. Here, we demonstrate that autoreactive polyfunctional CD8+ T cells recognizing self-antigens (i.e., vimentin, actin cytoplasmic 1, or non-muscle myosin heavy chain 9 epitopes) with high avidity, counter-regulate Tregs by killing them, in a consistent percentage of rheumatoid arthritis (RA) patients. Indeed, these CD8+ T cells express a phenotype and gene profile of effector (eff) cells and, upon antigen-specific activation, kill Tregs indirectly in an NKG2D-dependent bystander fashion in vitro. This data provides a mechanistic basis for the finding showing that AE-specific (CD107a+) CD8+ T killer cells correlate, directly with the disease activity score, and inversely with the percentage of activated Tregs, in both steady state and follow-up studies in vivo. In addition, multiplex immunofluorescence imaging analyses of inflamed synovial tissues in vivo show that a remarkable number of CD8+ T cells express granzyme-B and selectively contact FOXP3+ Tregs, some of which are in an apoptotic state, validating hence the possibility that CD8+ Teff cells can counteract neighboring Tregs within inflamed tissues, by killing them. Alternatively, the disease activity score of a different subset of patients is correlated with the expansion of a peculiar subpopulation of autoreactive low avidity, partially-activated (pa)CD8+ T cells that, despite they conserve the conventional naïve (N) phenotype, produce high levels of tumor necrosis factor (TNF)-α and exhibit a gene expression signature of a progressive activation state. Tregs directly correlate with the expansion of this autoreactive (low avidity) paCD8+ TN cell subset in vivo, and efficiently control their differentiation rather their proliferation in vitro. Interestingly, autoreactive high avidity CD8+ Teff cells or low avidity paCD8+ TN cells are significantly expanded in RA patients who would become non-responders or patients who would become responders to TNF-α inhibitor therapy, respectively. These data provide evidence of a previously undescribed role of such mechanisms in the progression and therapy of RA.
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Artritis Reumatoide/inmunología , Autoinmunidad , Linfocitos T CD8-positivos/inmunología , Linfocitos T Reguladores/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/metabolismo , Biomarcadores , Linfocitos T CD8-positivos/metabolismo , Susceptibilidad a Enfermedades , Femenino , Antígenos de Histocompatibilidad Clase I/química , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Inmunomodulación , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Especificidad del Receptor de Antígeno de Linfocitos T , Linfocitos T Reguladores/metabolismoRESUMEN
Despite antiretroviral therapy, HIV+ individuals still have increased risk to develop lymphomas, including marginal zone lymphomas, suggesting that factors other than HIV-related immunosuppression are probably acting as lymphomagenic factors in the HIV setting. The possible pathogenic involvement of HIV p17 protein variants was investigated in a particularly informative case of HIV-related splenic marginal zone lymphoma, which was negative for oncogenic virus infections, thus allowing us to assess the possible direct contribution of these HIV-encoded proteins to lymphomagenesis. The presence of p17 protein was analyzed by immunohistochemistry in lymphoma tissue. Recombinant p17 protein derived from the dominant sequence detected in plasma and lymphoma biopsy was characterized for B-cell proliferation, clonogenicity in soft agar, in vitro tube formation and wound healing. Intracellular signaling was investigated by immunoblotting. HIV p17 protein was detected in reactive lymphoid follicles but not within lymphoma cells. An identical dominant variant p17 sequence, p17-Lyrm, carrying a 117 to 118 Ala-Ala insertion was detected in both plasma and lymphoma tissue. Recombinant p17-Lyrm enhanced B-cell proliferation and clonogenicity promoted the formation of capillary-like structures and enhanced endothelial cell migration. Unlike reference p17, the p17-Lyrm variant enhanced the activation of Akt and ERK, critical kinases in lymphomagenesis. p17-Lyrm clonogenic activity was dependent on the activation of Akt but not of ERK1/2. These results indicated that HIV p17 variants with distinct molecular signatures and functional properties may accumulate in lymphoid tissues of HIV-infected individuals where they may act as a local stimulus promoting the development of lymphomas.
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Transformación Celular Viral , Antígenos VIH , Infecciones por VIH , VIH-1 , Linfoma de Células B de la Zona Marginal , Mutagénesis Insercional , Neoplasias del Bazo , Productos del Gen gag del Virus de la Inmunodeficiencia Humana , Femenino , Antígenos VIH/genética , Antígenos VIH/metabolismo , Infecciones por VIH/genética , Infecciones por VIH/metabolismo , Infecciones por VIH/patología , VIH-1/genética , VIH-1/metabolismo , Humanos , Linfoma de Células B de la Zona Marginal/genética , Linfoma de Células B de la Zona Marginal/metabolismo , Linfoma de Células B de la Zona Marginal/patología , Linfoma de Células B de la Zona Marginal/virología , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias del Bazo/genética , Neoplasias del Bazo/metabolismo , Neoplasias del Bazo/patología , Neoplasias del Bazo/virología , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/metabolismoRESUMEN
An accurate histological diagnosis may distinguish essential thrombocythaemia (ET) from early primary myelofibrosis (early-PMF), which is associated with worse outcome. Outcome of ET is also negatively affected by the presence of the JAK2V617F mutation. To investigate the impact of JAK2V617F mutation burden and histology on outcome, we collected 475 WHO-diagnosed ET (69.2%) or early-PMF JAK2V617F -positive patients followed in 4 Italian haematology centers. JAK2V617F allele burden was ≤50% in 90% and 87% of ET and early-PMF patients, respectively (P = .34). During follow-up, 32 (9.7%) ET and 18 (12.3%) early-PMF patients experienced 59 thrombotic events, and 27 patients (5.6%) and 6 (1.2%) patients evolved to myelofibrosis and acute leukemia, respectively. At last contact, 28 (5.8%) patients had died. In early-PMF compared to ET, the 10-year mortality rates (6.7% and 4.3%, P = .73), leukemic transformation rates (1.4% and 1.2%, P = .45), and thrombosis rates (16.7% and 12.2%, P = .12) were comparable. Only progression to overt myelofibrosis at 10 years was significantly worse (11.4% and 1.5%, P = .004). In multivariate analysis, a higher (>50%) JAK2V617F burden was significantly correlated with fibrotic progression and histology. Considering JAK2V617F -positive disease, a higher (>50%) JAK2V617F burden and histological classification are independent prognostic risk factors for disease progression. These findings reinforce the need for standardized detection of this mutation.
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Janus Quinasa 2/genética , Mielofibrosis Primaria/enzimología , Trombocitemia Esencial/enzimología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Mielofibrosis Primaria/genética , Mielofibrosis Primaria/mortalidad , Mielofibrosis Primaria/patología , Análisis de Supervivencia , Trombocitemia Esencial/genética , Trombocitemia Esencial/mortalidad , Trombocitemia Esencial/patología , Resultado del Tratamiento , Adulto JovenAsunto(s)
Adenoma Pleomórfico , Patología Clínica , Humanos , Patólogos , Estudios Retrospectivos , Glándulas SalivalesRESUMEN
Neonatal bone marrow transplantation (BMT) could offer a novel therapeutic opportunity for genetic disorders by providing sustainable levels of the missing protein at birth, thus preventing tissue damage. We tested this concept in mucopolysaccharidosis type I (MPS IH; Hurler syndrome), a lysosomal storage disorder caused by deficiency of α-l-iduronidase. MPS IH is characterized by a broad spectrum of clinical manifestations, including severe progressive skeletal abnormalities. Although BMT increases the life span of patients with MPS IH, musculoskeletal manifestations are only minimally responsive if the timing of BMT delays, suggesting already irreversible bone damage. In this study, we tested the hypothesis that transplanting normal BM into newborn MPS I mice soon after birth can prevent skeletal dysplasia. We observed that neonatal BMT was effective at restoring α-l-iduronidase activity and clearing elevated glycosaminoglycans in blood and multiple organs. At 37 weeks of age, we observed an almost complete normalization of all bone tissue parameters, using radiographic, microcomputed tomography, biochemical, and histological analyses. Overall, the magnitude of improvements correlated with the extent of hematopoietic engraftment. We conclude that BMT at a very early stage in life markedly reduces signs and symptoms of MPS I before they appear.
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Enfermedades del Desarrollo Óseo/prevención & control , Trasplante de Médula Ósea/métodos , Mucopolisacaridosis I/patología , Mucopolisacaridosis I/terapia , Factores de Edad , Animales , Animales Recién Nacidos , Enfermedades del Desarrollo Óseo/metabolismo , Enfermedades del Desarrollo Óseo/patología , Huesos/metabolismo , Huesos/patología , Modelos Animales de Enfermedad , Femenino , Glicosaminoglicanos/sangre , Glicosaminoglicanos/metabolismo , Humanos , Iduronidasa/genética , Iduronidasa/metabolismo , Recién Nacido , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mucopolisacaridosis I/genéticaRESUMEN
Although infectious complications represent a relevant cause of morbidity and mortality in patients with myelofibrosis (MF), little is known about their incidence, outcome and risk factors. We retrospectively evaluated a cohort of 507 MF patients, diagnosed between 1980 and 2014 in five Italian hematology centers, to define the epidemiology of infections and describe the impact of ruxolitinib (RUX) treatment. Overall, 112 patients (22%) experienced 160 infectious events (grade 3-4, 45%) for an incidence rate of 3.9% per patient-year. Infections were mainly bacterial (78%) and involving the respiratory tract (52% of cases). Also, viral (11%) and fungal infections (2%) were recorded. Overall, infections were fatal in 9% of the cases. Among baseline features, high/intermediate-2 IPSS category (HR 1.8, 95%CI:1.2-2.7; P = 0.02) and spleen length ≥10 cm below left costal margin (HR 1.6, 95%CI:1.1-2.5; P = 0.04) were associated with higher infectious risk in multivariate analysis. Overall, the rate of infections was higher in the cohort of 128 RUX-treated patients (44% vs. 20%, P < 0.001). In conclusion, IPSS-category and splenomegaly, emerged as the main risk factors for infections in MF. RUX-treated patients experienced significantly more infection episodes; however, future prospective studies are needed to isolate the confounding contribution of other risk factors such as disease stage. Am. J. Hematol. 92:37-41, 2017. © 2016 Wiley Periodicals, Inc.
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Enfermedades Transmisibles/etiología , Mielofibrosis Primaria/tratamiento farmacológico , Pirazoles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Enfermedades Transmisibles/epidemiología , Enfermedades Transmisibles/inmunología , Femenino , Humanos , Incidencia , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/genética , Masculino , Persona de Mediana Edad , Nitrilos , Mielofibrosis Primaria/complicaciones , Mielofibrosis Primaria/epidemiología , Mielofibrosis Primaria/inmunología , Pirazoles/administración & dosificación , Pirazoles/efectos adversos , Pirimidinas , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Osteonecrosis of the jaw (ONJ) is a well known complication in patients treated with bisphosphonates (BPs) for skeletal metastasis and multiple myeloma (MM). Few oncologic patients under treatment with BPs and with ONJ and metastasis or MM at the same site of the jaw have been described. We report here on a 54-year old white female who was treated with intra-venous zoledronic acid for skeletal metastasis of breast cancer who developed ONJ. Because of a fracture at the site of ONJ, resection of the affected segment was performed. Although metastasis was not suspected by pre-operative image analysis, histological examination revealed syncronous osteonecrosis and breast cancer metastasis in the resected mandibular segment. This case highlights that, in oncologic patients treated with BPs, ONJ may hide malignancy and that histology is the unique tool by which the diagnosis of either osteonecrosis or malignancy or both can be made definitely.
Asunto(s)
Osteonecrosis de los Maxilares Asociada a Difosfonatos/diagnóstico , Osteonecrosis de los Maxilares Asociada a Difosfonatos/patología , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Difosfonatos/efectos adversos , Difosfonatos/uso terapéutico , Imidazoles/efectos adversos , Imidazoles/uso terapéutico , Neoplasias Mandibulares/diagnóstico , Neoplasias Mandibulares/patología , Neoplasias Primarias Múltiples/diagnóstico , Neoplasias Primarias Múltiples/patología , Neoplasias Óseas/patología , Diagnóstico Diferencial , Resultado Fatal , Femenino , Fracturas Espontáneas/diagnóstico , Fracturas Espontáneas/patología , Humanos , Infusiones Intravenosas , Mandíbula/patología , Persona de Mediana Edad , Radiografía Panorámica , Tomografía Computarizada por Rayos X , Ácido ZoledrónicoRESUMEN
Multiple non-ossifying fibromas (MNOFs) occur either isolated or in association with other anomalies, are usually localized in the long bones of the lower limbs, may be radiographically confused with other skeletal lesions, and tend to heal spontaneously with the completion of the skeletal growth. Segmental distribution, either monomelic or polymelic and ipsilateral, is rare and commonly observed in the context of developmental diseases known as "RASopathies", which are caused by mutations in genes that encode components or regulators within the Ras/mitogen-activated protein kinase signaling pathway. We describe here the radiographic and pathologic features of an 18-year-old Caucasian boy, whose clinical history started at the age of 3 when the diagnosis of aneurysmal bone cyst was made on a lytic lesion of his left clavicle. Over the following 2 years, the patient developed polyostotic and monomelic lesions within the left humerus, radius, and ulna. No other skeletal and extra-skeletal anomalies were clinically detected. The lesions were interpreted as consistent with polyostotic fibrous dysplasia and MNOFs and showed an unusually aggressive clinical course with progressive increase in size and coalescence. The definitive diagnosis of MNOFs was made after the exclusion of fibrous dysplasia by molecular analysis. The polyostotic and monomelic distribution of the lesions and the unusually aggressive clinical course contribute to make this case of MNOFs unique.