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1.
Am J Med Genet A ; 194(6): e63551, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38321651

RESUMEN

Capillary malformations (CMs) are the most common type of vascular anomalies, affecting around 0.3% of newborns. They are usually caused by somatic pathogenic variants in GNAQ or GNA11. PIK3CA and PIK3R1, part of the phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin pathway, are mutated in fainter CMs such as diffuse CM with overgrowth and megalencephaly CM. In this study, we present two young patients with a CM-like phenotype associated with cerebral anomalies and severe epilepsy. Pathogenic variants in PIK3CA and PIK3R1, as well as GNAQ and GNA11, were absent in affected cutaneous tissue biopsies. Instead, we identified two somatic pathogenic variants in the AKT3 gene. Subsequent analysis of the DNA obtained from surgically resected brain tissue of one of the two patients confirmed the presence of the AKT3 variant. Focal cortical dysplasia was also detected in this patient. Genetic analysis thus facilitated workup to reach a precise diagnosis for these patients, associating the vascular anomaly with the neurological symptoms. This study underscores the importance of searching for additional signs and symptoms to guide the diagnostic workup, especially in cases with atypical vascular malformations. In addition, it strongly emphasizes the significance of genotype-phenotype correlation studies in guiding clinicians' informed decision-making regarding patient care.


Asunto(s)
Capilares , Epilepsia , Proteínas Proto-Oncogénicas c-akt , Telangiectasia , Malformaciones Vasculares , Femenino , Humanos , Recién Nacido , Masculino , Capilares/anomalías , Capilares/patología , Epilepsia/genética , Epilepsia/patología , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Mosaicismo , Mutación/genética , Fenotipo , Proteínas Proto-Oncogénicas c-akt/genética , Telangiectasia/genética , Telangiectasia/patología , Telangiectasia/diagnóstico , Malformaciones Vasculares/genética , Malformaciones Vasculares/patología , Malformaciones Vasculares/diagnóstico , Malformaciones Vasculares/complicaciones , Adolescente
2.
Histochem Cell Biol ; 160(5): 377-389, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37523091

RESUMEN

X-ray phase contrast imaging (X-PCI) is a powerful technique for high-resolution, three-dimensional imaging of soft tissue samples in a non-destructive manner. In this technical report, we assess the quality of standard histopathological techniques performed on formalin-fixed, paraffin-embedded (FFPE) human tissue samples that have been irradiated with different doses of X-rays in the context of an X-PCI experiment. The data from this study demonstrate that routine histochemical and immunohistochemical staining quality as well as DNA and RNA analyses are not affected by previous X-PCI on human FFPE samples. From these data we conclude it is feasible and acceptable to perform X-PCI on FFPE human biopsies.


Asunto(s)
Intervención Coronaria Percutánea , Sincrotrones , Humanos , Rayos X , Estudios de Factibilidad , Imagenología Tridimensional , Adhesión en Parafina , Formaldehído , Fijación del Tejido
3.
Acta Neuropathol ; 145(6): 793-814, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37000196

RESUMEN

Neuronal TDP-43-positive inclusions are neuropathological hallmark lesions in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Pathogenic missense variants in TARDBP, the gene encoding TDP-43, can cause ALS and cluster in the C-terminal prion-like domain (PrLD), where they modulate the liquid condensation and aggregation properties of the protein. TDP-43-positive inclusions are also found in rimmed vacuole myopathies, including sporadic inclusion body myositis, but myopathy-causing TDP-43 variants have not been reported. Using genome-wide linkage analysis and whole exome sequencing in an extended five-generation family with an autosomal dominant rimmed vacuole myopathy, we identified a conclusively linked frameshift mutation in TDP-43 producing a C-terminally altered PrLD (TDP-43p.Trp385IlefsTer10) (maximum multipoint LOD-score 3.61). Patient-derived muscle biopsies showed TDP-43-positive sarcoplasmic inclusions, accumulation of autophagosomes and transcriptomes with abnormally spliced sarcomeric genes (including TTN and NEB) and increased expression of muscle regeneration genes. In vitro phase separation assays demonstrated that TDP-43Trp385IlefsTer10 does not form liquid-like condensates and readily forms solid-like fibrils indicating increased aggregation propensity compared to wild-type TDP-43. In Drosophila TDP-43p.Trp385IlefsTer10 behaved as a partial loss-of-function allele as it was able to rescue the TBPH (fly ortholog of TARDBP) neurodevelopmental lethal null phenotype while showing strongly reduced toxic gain-of-function properties upon overexpression. Accordingly, TDP-43p.Trp385IlefsTer10 showed reduced toxicity in a primary rat neuron disease model. Together, these genetic, pathological, in vitro and in vivo results demonstrate that TDP-43p.Trp385IlefsTer10 is an aggregation-prone partial loss-of-function variant that causes autosomal dominant vacuolar myopathy but not ALS/FTD. Our study genetically links TDP-43 proteinopathy to myodegeneration, and reveals a tissue-specific role of the PrLD in directing pathology.


Asunto(s)
Esclerosis Amiotrófica Lateral , Demencia Frontotemporal , Enfermedad de Pick , Animales , Ratas , Esclerosis Amiotrófica Lateral/patología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Mutación del Sistema de Lectura , Demencia Frontotemporal/genética , Demencia Frontotemporal/patología , Mutación , Humanos
4.
BMC Infect Dis ; 22(1): 676, 2022 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-35933382

RESUMEN

BACKGROUND: The incidence of high-risk human papillomavirus (hrHPV)-driven head and neck squamous cell carcinoma, in particular oropharyngeal cancers (OPC), is increasing in high-resource countries. Patients with HPV-induced cancer respond better to treatment and consequently have lower case-fatality rates than patients with HPV-unrelated OPC. These considerations highlight the importance of reliable and accurate markers to diagnose truly HPV-induced OPC. METHODS: The accuracy of three possible test strategies, i.e. (a) hrHPV DNA PCR (DNA), (b) p16(INK4a) immunohistochemistry (IHC) (p16), and (c) the combination of both tests (considering joint DNA and p16 positivity as positivity criterion), was analysed in tissue samples from 99 Belgian OPC patients enrolled in the HPV-AHEAD study. Presence of HPV E6*I mRNA (mRNA) was considered as the reference, indicating HPV etiology. RESULTS: Ninety-nine OPC patients were included, for which the positivity rates were 36.4%, 34.0% and 28.9% for DNA, p16 and mRNA, respectively. Ninety-five OPC patients had valid test results for all three tests (DNA, p16 and mRNA). Using mRNA status as the reference, DNA testing showed 100% (28/28) sensitivity, and 92.5% (62/67) specificity for the detection of HPV-driven cancer. p16 was 96.4% (27/28) sensitive and equally specific (92.5%; 62/67). The sensitivity and specificity of combined p16 + DNA testing was 96.4% (27/28) and 97.0% (65/67), respectively. In this series, p16 alone and combined p16 + DNA missed 1 in 28 HPV driven cancers, but p16 alone misclassified 5 in 67 non-HPV driven as positive, whereas combined testing would misclassify only 2 in 67. CONCLUSIONS: Single hrHPV DNA PCR and p16(INK4a) IHC are highly sensitive but less specific than using combined testing to diagnose HPV-driven OPC patients. Disease prognostication can be encouraged based on this combined test result.


Asunto(s)
Carcinoma de Células Escamosas , Neoplasias Orofaríngeas , Infecciones por Papillomavirus , Carcinoma de Células Escamosas/diagnóstico , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , ADN Viral/análisis , ADN Viral/genética , Humanos , Inmunohistoquímica , Neoplasias Orofaríngeas/diagnóstico , Neoplasias Orofaríngeas/patología , Papillomaviridae/genética , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/diagnóstico , Reacción en Cadena de la Polimerasa , ARN Mensajero/análisis
5.
J Med Genet ; 58(11): 778-782, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-32900841

RESUMEN

BACKGROUND: Although carpal tunnel syndrome (CTS) is the most common form of peripheral entrapment neuropathy, its pathogenesis remains largely unknown. An estimated heritability index of 0.46 and an increased familial occurrence indicate that genetic factors must play a role in the pathogenesis. METHODS AND RESULTS: We report on a family in which CTS occurred in subsequent generations at an unusually young age. Additional clinical features included brachydactyly and short Achilles tendons resulting in toe walking in childhood. Using exome sequencing, we identified a heterozygous variant (c.5009T>G; p.Phe1670Cys) in the fibrillin-2 (FBN2) gene that co-segregated with the phenotype in the family. Functional assays showed that the missense variant impaired integrin-mediated cell adhesion and migration. Moreover, we observed an increased transforming growth factor-ß signalling and fibrosis in the carpal tissues of affected individuals. A variant burden test in a large cohort of patients with CTS revealed a significantly increased frequency of rare (6.7% vs 2.5%-3.4%, p<0.001) and high-impact (6.9% vs 2.7%, p<0.001) FBN2 variants in patient alleles compared with controls. CONCLUSION: The identification of a novel FBN2 variant (p.Phe1670Cys) in a unique family with early onset CTS, together with the observed increased frequency of rare and high-impact FBN2 variants in patients with sporadic CTS, strongly suggest a role of FBN2 in the pathogenesis of CTS.


Asunto(s)
Síndrome del Túnel Carpiano/genética , Fibrilina-2/genética , Tendón Calcáneo/anomalías , Estatura/genética , Síndrome del Túnel Carpiano/diagnóstico por imagen , Síndrome del Túnel Carpiano/etiología , Humanos , Masculino , Mutación Missense , Linaje
6.
Nanomedicine ; 40: 102485, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34748959

RESUMEN

There is a continued need for effective hemostatic agents that are safe for neurosurgical use. Self-assembling peptide hydrogels have been suggested as novel hemostatic agents. They offer some advantages for neurosurgical hemostasis (e.g., transparency), but their efficacy and safety for neurosurgery have not been established. In this paper, the efficacy and safety of two self-assembling peptides, RADA16 and IEIK13, are explored for hemostasis of oozing bleeding on the rat cerebral cortex (n = 56). Chronic safety was evaluated by neuropathological evaluation at one, four, and twelve weeks after craniotomy (n = 32). An inactive control and oxidized cellulose served as comparators. Mean time-to-hemostasis was significantly shorter for RADA16 and IEIK13 compared to controls, while safety evaluation yielded similar results. Histopathological response consisted primarily of macrophage infiltration at the lesion site in all groups. This study confirms the hemostatic potential and safety of RADA16 and IEIK13 for hemostasis in the rat brain.


Asunto(s)
Hemostasis , Hemostáticos , Animales , Hemorragia , Hemostáticos/farmacología , Hidrogeles/farmacología , Péptidos/farmacología , Ratas
7.
Neuropathology ; 41(1): 3-20, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33599033

RESUMEN

Brain involvement in myotonic dystrophy type 1 (DM1) is characterized by heterogeneous cognitive, behavioral, and affective symptoms and imaging alterations indicative of widespread grey and white matter involvement. The aim of the present study was to systematically review the literature on brain pathology in DM1. We conducted a structured search in EMBASE (index period 1974-2017) and MEDLINE (index period 1887-2017) on December 11, 2017, using free text and index search terms related to myotonic dystrophy type 1 and brain structures or regions. Eligible studies were full-text studies reporting on microscopic brain pathology of DM1 patients without potentially interfering comorbidity. We discussed the findings based on the anatomical region and the nature of the anomaly. Neuropathological findings in DM1 can be classified as follows: (1) protein and nucleotide deposits; (2) changes in neurons and glial cells; and (3) white matter alterations. Most findings are unspecific to DM1 and may occur with physiological aging, albeit to a lesser degree. There are similarities and contrasts with Alzheimer's disease; both show the appearance of neurofibrillary tangles in the limbic system without plaque occurrence. Likewise, there is myelin loss and gliosis, and there are dilated perivascular spaces in the white matter resemblant of cerebral small vessel disease. However, we did not find evidence of lacunar infarction or microbleeding. The various neuropathological findings in DM1 are reflective of the heterogeneous clinical and neuroimaging features of the disease. The strength of conclusions from this study's findings is bounded by limited numbers of participants in studies, methodological constraints, and lack of assessed associations between histopathology and clinical or neuroimaging findings.


Asunto(s)
Encéfalo/patología , Sustancia Gris/patología , Distrofia Miotónica/patología , Sustancia Blanca/patología , Encéfalo/diagnóstico por imagen , Sustancia Gris/diagnóstico por imagen , Humanos , Cuerpos de Inclusión/patología , Distrofia Miotónica/diagnóstico por imagen , Ovillos Neurofibrilares/patología , Neuroimagen/métodos , Sustancia Blanca/diagnóstico por imagen
8.
PLoS Genet ; 14(12): e1007845, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30543681

RESUMEN

Nucleoporins build the nuclear pore complex (NPC), which, as sole gate for nuclear-cytoplasmic exchange, is of outmost importance for normal cell function. Defects in the process of nucleocytoplasmic transport or in its machinery have been frequently described in human diseases, such as cancer and neurodegenerative disorders, but only in a few cases of developmental disorders. Here we report biallelic mutations in the nucleoporin NUP88 as a novel cause of lethal fetal akinesia deformation sequence (FADS) in two families. FADS comprises a spectrum of clinically and genetically heterogeneous disorders with congenital malformations related to impaired fetal movement. We show that genetic disruption of nup88 in zebrafish results in pleiotropic developmental defects reminiscent of those seen in affected human fetuses, including locomotor defects as well as defects at neuromuscular junctions. Phenotypic alterations become visible at distinct developmental stages, both in affected human fetuses and in zebrafish, whereas early stages of development are apparently normal. The zebrafish phenotypes caused by nup88 deficiency are rescued by expressing wild-type Nup88 but not the disease-linked mutant forms of Nup88. Furthermore, using human and mouse cell lines as well as immunohistochemistry on fetal muscle tissue, we demonstrate that NUP88 depletion affects rapsyn, a key regulator of the muscle nicotinic acetylcholine receptor at the neuromuscular junction. Together, our studies provide the first characterization of NUP88 in vertebrate development, expand our understanding of the molecular events causing FADS, and suggest that variants in NUP88 should be investigated in cases of FADS.


Asunto(s)
Artrogriposis/genética , Genes Letales , Mutación , Proteínas de Complejo Poro Nuclear/genética , Alelos , Secuencia de Aminoácidos , Animales , Animales Modificados Genéticamente , Artrogriposis/embriología , Artrogriposis/fisiopatología , Consanguinidad , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Modelos Moleculares , Proteínas Musculares/metabolismo , Unión Neuromuscular/fisiopatología , Proteínas de Complejo Poro Nuclear/química , Proteínas de Complejo Poro Nuclear/deficiencia , Linaje , Embarazo , Conformación Proteica , Receptores Nicotínicos/metabolismo , Homología de Secuencia de Aminoácido , Pez Cebra/anomalías , Pez Cebra/genética , Pez Cebra/fisiología , Proteínas de Pez Cebra/deficiencia , Proteínas de Pez Cebra/genética
9.
PLoS Genet ; 14(4): e1007321, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29621230

RESUMEN

Hyperostosis Cranialis Interna (HCI) is a rare bone disorder characterized by progressive intracranial bone overgrowth at the skull. Here we identified by whole-exome sequencing a dominant mutation (L441R) in SLC39A14 (ZIP14). We show that L441R ZIP14 is no longer trafficked towards the plasma membrane and excessively accumulates intracellular zinc, resulting in hyper-activation of cAMP-CREB and NFAT signaling. Conditional knock-in mice overexpressing L438R Zip14 in osteoblasts have a severe skeletal phenotype marked by a drastic increase in cortical thickness due to an enhanced endosteal bone formation, resembling the underlying pathology in HCI patients. Remarkably, L438R Zip14 also generates an osteoporotic trabecular bone phenotype. The effects of osteoblastic overexpression of L438R Zip14 therefore mimic the disparate actions of estrogen on cortical and trabecular bone through osteoblasts. Collectively, we reveal ZIP14 as a novel regulator of bone homeostasis, and that manipulating ZIP14 might be a therapeutic strategy for bone diseases.


Asunto(s)
Proteínas de Transporte de Catión/genética , Homeostasis/genética , Hiperostosis/genética , Mutación , Osteosclerosis/genética , Base del Cráneo/anomalías , Animales , Línea Celular , Células Cultivadas , Modelos Animales de Enfermedad , Células HEK293 , Humanos , Hiperostosis/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Osteoblastos/citología , Osteoblastos/metabolismo , Osteosclerosis/metabolismo , Transducción de Señal/genética , Base del Cráneo/metabolismo , Zinc/metabolismo
10.
Clin Genet ; 98(5): 423-432, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32333401

RESUMEN

Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (PVHH, OMIM 225790), also known as Fowler syndrome, is a rare autosomal recessive disorder of brain angiogenesis. PVHH has long been considered to be prenatally lethal. We evaluated the phenotypes of the first three siblings with survival into adulthood, performed a systematic review of the Fowler syndrome literature and delineated genotype-phenotype correlations using a scoring system to rate the severity of the disease. Thirty articles were included, describing 69 individual patients. To date, including our clinical reports, 72 patients have been described with Fowler syndrome. Only 6/72 (8%) survived beyond birth. Although our three patients carry the same mutations (c.327T>A-p.Asn109Lys and c.887C>T-p.Ser296Leu) in FLVCR2, only two of them presented with the same cerebral features, ventriculomegaly and cerebral calcifications, as affected fetuses. The third sibling has a surprisingly milder clinical and radiological phenotype, suggesting intrafamilial variability. Although no clear phenotype-genotype correlation exists, some variants appear to be associated with a less severe phenotype compatible with life. As such, it is important to consider Fowler syndrome in patients with gross ventriculomegaly, cortical malformations and/or cerebral calcifications on brain imaging.


Asunto(s)
Hidranencefalia/genética , Proteínas de Transporte de Membrana/genética , Neovascularización Patológica/genética , Receptores Virales/genética , Encéfalo/metabolismo , Encéfalo/patología , Estudios de Asociación Genética , Humanos , Hidranencefalia/patología , Mutación/genética , Neovascularización Patológica/patología , Fenotipo
11.
J Inherit Metab Dis ; 43(6): 1265-1278, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32557630

RESUMEN

Sjögren-Larsson syndrome (SLS) is a rare neurometabolic syndrome caused by deficient fatty aldehyde dehydrogenase. Patients exhibit intellectual disability, spastic paraplegia, and ichthyosis. The accumulation of fatty alcohols and fatty aldehydes has been demonstrated in plasma and skin but never in brain. Brain magnetic resonance imaging and spectroscopy studies, however, have shown an abundant lipid peak in the white matter of patients with SLS, suggesting lipid accumulation in the brain as well. Using histopathology, mass spectrometry imaging, and lipidomics, we studied the morphology and the lipidome of a postmortem brain of a 65-year-old female patient with genetically confirmed SLS and compared the results with a matched control brain. Histopathological analyses revealed structural white matter abnormalities with the presence of small lipid droplets, deficient myelin, and astrogliosis. Biochemically, severely disturbed lipid profiles were found in both white and gray matter of the SLS brain, with accumulation of fatty alcohols and ether lipids. Particularly, long-chain unsaturated ether lipid species accumulated, most prominently in white matter. Also, there was a striking accumulation of odd-chain fatty alcohols and odd-chain ether(phospho)lipids. Our results suggest that the central nervous system involvement in SLS is caused by the accumulation of fatty alcohols leading to a disbalance between ether lipid and glycero(phospho)lipid metabolism resulting in a profoundly disrupted brain lipidome. Our data show that SLS is not a pure leukoencephalopathy, but also a gray matter disease. Additionally, the histopathological abnormalities suggest that astrocytes and microglia might play a pivotal role in the underlying disease mechanism, possibly contributing to the impairment of myelin maintenance.


Asunto(s)
Encéfalo/metabolismo , Éteres/metabolismo , Alcoholes Grasos/metabolismo , Metabolismo de los Lípidos/fisiología , Síndrome de Sjögren-Larsson/metabolismo , Anciano , Encéfalo/patología , Femenino , Humanos , Imagen por Resonancia Magnética , Síndrome de Sjögren-Larsson/patología
12.
Cancer Immunol Immunother ; 68(10): 1573-1583, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31511925

RESUMEN

Desmoid tumors (DTs) are local aggressive neoplasms, whose therapeutic approach has remained so far unsolved and in many instances controversial. Nowadays, immunotherapy appears to play a leading role in the treatment of various tumor types. Characterization of the tumor immune microenvironment (TME) and immune checkpoints can possibly help identify new immunotherapeutic targets for DTs. We performed immunohistochemistry (IHC) on 33 formalin-fixed paraffin-embedded (FFPE) tissue sections from DT samples to characterize the TME and the immune checkpoint expression profile. We stained for CD3, CD4, CD8, CD20, FoxP3, CD45RO, CD56, CD68, NKp46, granzyme B, CD27, CD70, PD1 and PD-L1. We investigated the expression of the markers in the tumoral stroma, as well as at the periphery of the tumor. We found that most of the tumors showed organization of lymphocytes into lymphoid aggregates at the periphery of the tumor, strongly resembling tertiary lymphoid organs (TLOs). The tumor expressed a significant number of memory T cells, both at the periphery and in the tumoral stroma. In the lymphoid aggregates, we also recognized a significant proportion of regulatory T cells. The immune checkpoint ligand PD-L1 was negative on the tumor cells in almost all samples. On the other hand, PD1 was partially expressed in lymphocytes at the periphery of the tumor. To conclude, we are the first to show that DTs display a strong immune infiltration at the tumor margins, with formation of lymphoid aggregates. Moreover, we demonstrated that there is no PD-L1-driven immune suppression present in the tumor cells.


Asunto(s)
Antígeno B7-H1/fisiología , Fibromatosis Agresiva/inmunología , Tolerancia Inmunológica , Adolescente , Adulto , Anciano , Antígenos CD20/análisis , Ligando CD27/análisis , Femenino , Fibromatosis Agresiva/patología , Humanos , Antígenos Comunes de Leucocito/análisis , Masculino , Persona de Mediana Edad , Microambiente Tumoral , Adulto Joven
13.
Blood ; 130(15): 1713-1721, 2017 10 12.
Artículo en Inglés | MEDLINE | ID: mdl-28830889

RESUMEN

Relapse is a major problem in acute myeloid leukemia (AML) and adversely affects survival. In this phase 2 study, we investigated the effect of vaccination with dendritic cells (DCs) electroporated with Wilms' tumor 1 (WT1) messenger RNA (mRNA) as postremission treatment in 30 patients with AML at very high risk of relapse. There was a demonstrable antileukemic response in 13 patients. Nine patients achieved molecular remission as demonstrated by normalization of WT1 transcript levels, 5 of which were sustained after a median follow-up of 109.4 months. Disease stabilization was achieved in 4 other patients. Five-year overall survival (OS) was higher in responders than in nonresponders (53.8% vs 25.0%; P = .01). In patients receiving DCs in first complete remission (CR1), there was a vaccine-induced relapse reduction rate of 25%, and 5-year relapse-free survival was higher in responders than in nonresponders (50% vs 7.7%; P < .0001). In patients age ≤65 and >65 years who received DCs in CR1, 5-year OS was 69.2% and 30.8% respectively, as compared with 51.7% and 18% in the Swedish Acute Leukemia Registry. Long-term clinical response was correlated with increased circulating frequencies of polyepitope WT1-specific CD8+ T cells. Long-term OS was correlated with interferon-γ+ and tumor necrosis factor-α+ WT1-specific responses in delayed-type hypersensitivity-infiltrating CD8+ T lymphocytes. In conclusion, vaccination of patients with AML with WT1 mRNA-electroporated DCs can be an effective strategy to prevent or delay relapse after standard chemotherapy, translating into improved OS rates, which are correlated with the induction of WT1-specific CD8+ T-cell response. This trial was registered at www.clinicaltrials.gov as #NCT00965224.


Asunto(s)
Vacunas contra el Cáncer/inmunología , Células Dendríticas/inmunología , Leucemia Mieloide Aguda/prevención & control , Leucemia Mieloide Aguda/terapia , Vacunación , Anciano , Biomarcadores de Tumor/metabolismo , Citocinas/metabolismo , Supervivencia sin Enfermedad , Electroporación , Femenino , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/inmunología , Masculino , ARN Mensajero/genética , ARN Mensajero/metabolismo , Recurrencia , Inducción de Remisión , Resultado del Tratamiento , Proteínas WT1/genética , Proteínas WT1/metabolismo
14.
Int J Mol Sci ; 20(9)2019 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-31052546

RESUMEN

RANK ligand (RANKL) is a member of the tumor necrosis factor alpha superfamily of cytokines. It is the only known ligand binding to a membrane receptor named receptor activator of nuclear factor-kappa B (RANK), thereby triggering recruitment of tumor necrosis factor (TNF) receptor associated factor (TRAF) adaptor proteins and activation of downstream pathways. RANK/RANKL signaling is controlled by a decoy receptor called osteoprotegerin (OPG), but also has additional more complex levels of regulation. The existing literature on RANK/RANKL signaling in cervical cancer was reviewed, particularly focusing on the effects on the microenvironment. RANKL and RANK are frequently co-expressed in cervical cancer cells lines and in carcinoma of the uterine cervix. RANKL and OPG expression strongly increases during cervical cancer progression. RANKL is directly secreted by cervical cancer cells, which may be a mechanism they use to create an immune suppressive environment. RANKL induces expression of multiple activating cytokines by dendritic cells. High RANK mRNA levels and high immunohistochemical OPG expression are significantly correlated with high clinical stage, tumor grade, presence of lymph node metastases, and poor overall survival. Inhibition of RANKL signaling has a direct effect on tumor cell proliferation and behavior, but also alters the microenvironment. Abundant circumstantial evidence suggests that RANKL inhibition may (partially) reverse an immunosuppressive status. The use of denosumab, a monoclonal antibody directed to RANKL, as an immunomodulatory strategy is an attractive concept which should be further explored in combination with immune therapy in patients with cervical cancer.


Asunto(s)
Ligando RANK/inmunología , Receptor Activador del Factor Nuclear kappa-B/inmunología , Neoplasias del Cuello Uterino/inmunología , Animales , Cuello del Útero/inmunología , Cuello del Útero/patología , Femenino , Humanos , Inmunoterapia/métodos , Ligando RANK/análisis , Receptor Activador del Factor Nuclear kappa-B/análisis , Transducción de Señal , Microambiente Tumoral , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/terapia
15.
N Engl J Med ; 370(6): 533-42, 2014 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-24499211

RESUMEN

BACKGROUND: Congenital disorders of glycosylation are genetic syndromes that result in impaired glycoprotein production. We evaluated patients who had a novel recessive disorder of glycosylation, with a range of clinical manifestations that included hepatopathy, bifid uvula, malignant hyperthermia, hypogonadotropic hypogonadism, growth retardation, hypoglycemia, myopathy, dilated cardiomyopathy, and cardiac arrest. METHODS: Homozygosity mapping followed by whole-exome sequencing was used to identify a mutation in the gene for phosphoglucomutase 1 (PGM1) in two siblings. Sequencing identified additional mutations in 15 other families. Phosphoglucomutase 1 enzyme activity was assayed on cell extracts. Analyses of glycosylation efficiency and quantitative studies of sugar metabolites were performed. Galactose supplementation in fibroblast cultures and dietary supplementation in the patients were studied to determine the effect on glycosylation. RESULTS: Phosphoglucomutase 1 enzyme activity was markedly diminished in all patients. Mass spectrometry of transferrin showed a loss of complete N-glycans and the presence of truncated glycans lacking galactose. Fibroblasts supplemented with galactose showed restoration of protein glycosylation and no evidence of glycogen accumulation. Dietary supplementation with galactose in six patients resulted in changes suggestive of clinical improvement. A new screening test showed good discrimination between patients and controls. CONCLUSIONS: Phosphoglucomutase 1 deficiency, previously identified as a glycogenosis, is also a congenital disorder of glycosylation. Supplementation with galactose leads to biochemical improvement in indexes of glycosylation in cells and patients, and supplementation with complex carbohydrates stabilizes blood glucose. A new screening test has been developed but has not yet been validated. (Funded by the Netherlands Organization for Scientific Research and others.).


Asunto(s)
Glucofosfatos/genética , Enfermedad del Almacenamiento de Glucógeno/genética , Fenotipo , Fosfoglucomutasa/genética , Galactosa/uso terapéutico , Genes Recesivos , Glucosa/metabolismo , Glucofosfatos/metabolismo , Enfermedad del Almacenamiento de Glucógeno/dietoterapia , Enfermedad del Almacenamiento de Glucógeno/metabolismo , Glicoproteínas/biosíntesis , Glicosilación , Humanos , Masculino , Mutación , Fosfoglucomutasa/metabolismo , ARN Mensajero/análisis
16.
Genet Med ; 19(4): 386-395, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-27632686

RESUMEN

PURPOSE: Thoracic aortic aneurysm and dissection (TAAD) is typically inherited in an autosomal dominant manner, but rare X-linked families have been described. So far, the only known X-linked gene is FLNA, which is associated with the periventricular nodular heterotopia type of Ehlers-Danlos syndrome. However, mutations in this gene explain only a small number of X-linked TAAD families. METHODS: We performed targeted resequencing of 368 candidate genes in a cohort of 11 molecularly unexplained Marfan probands. Subsequently, Sanger sequencing of BGN in 360 male and 155 female molecularly unexplained TAAD probands was performed. RESULTS: We found five individuals with loss-of-function mutations in BGN encoding the small leucine-rich proteoglycan biglycan. The clinical phenotype is characterized by early-onset aortic aneurysm and dissection. Other recurrent findings include hypertelorism, pectus deformity, joint hypermobility, contractures, and mild skeletal dysplasia. Fluorescent staining revealed an increase in TGF-ß signaling, evidenced by an increase in nuclear pSMAD2 in the aortic wall. Our results are in line with those of prior reports demonstrating that Bgn-deficient male BALB/cA mice die from aortic rupture. CONCLUSION: In conclusion, BGN gene defects in humans cause an X-linked syndromic form of severe TAAD that is associated with preservation of elastic fibers and increased TGF-ß signaling.Genet Med 19 4, 386-395.


Asunto(s)
Aneurisma de la Aorta Torácica/genética , Disección Aórtica/genética , Biglicano/genética , Mutación , Disección Aórtica/metabolismo , Aneurisma de la Aorta Torácica/metabolismo , Biglicano/metabolismo , Células Cultivadas , Femenino , Genes Ligados a X , Predisposición Genética a la Enfermedad , Humanos , Masculino , Linaje , Análisis de Secuencia de ADN/métodos , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo
17.
BMC Cancer ; 17(1): 586, 2017 Aug 29.
Artículo en Inglés | MEDLINE | ID: mdl-28851379

RESUMEN

BACKGROUND: The FOLFOX regimen, i.e., folinic acid (FOL), fluorouracil (F) and oxaliplatin (OX), is a drug cocktail that is used to treat gastric and colorectal cancers. Despite the concomitant improvements in response rate, duration of response and patient survival, reports of serious toxic pulmonary side effects have progressively emerged. CASE PRESENTATION: We describe a patient who was treated with FOLFOX as an adjuvant to a rectosigmoidal resection of a rectosigmoidal carcinoma and who developed respiratory insufficiency requiring mechanical ventilation. Computed tomography (CT) imaging and open lung biopsy findings were compatible with interstitial pneumonia (IP). She received multimodal combination treatment (acetylcysteine, corticosteroids, immune globulins and cyclophosphamide) and survived. We performed a systematic literature search and reviewed all 45 reported cases of FOLFOX-related lung toxicity and/or pulmonary fibrosis for their clinical characteristics and their outcomes related to therapy. CONCLUSIONS: We found that for the 45 cases with available data, the median age was 70 years, and the male-female ratio was 3.5: 1. In the patients exhibiting only mild respiratory symptoms, discontinuation of the culprit drug (oxaliplatin) resulted in a 100% regression of the symptoms. However the prognosis of the respiratory insufficient patient proved to be grim: death occurred in 76.9% of the cases despite conventional treatment with corticosteroids. We therefore urge oncologists and critical care specialists not to limit their interventions to the discontinuation of chemotherapy, artificial ventilation, corticosteroids and glutathione replenishment and to consider the gradual introduction of additional immune-modulating agents whenever life-threatening respiratory symptoms in oxaliplatin-treated patients do not subside; all the more so considering the fact that our analysis showed that every patient who survived intubation and mechanical ventilation experienced a full clinical recovery.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Terapia Combinada/métodos , Enfermedades Pulmonares Intersticiales/terapia , Neoplasias del Colon Sigmoide/tratamiento farmacológico , Corticoesteroides/administración & dosificación , Corticoesteroides/uso terapéutico , Anciano , Neoplasias Colorrectales/cirugía , Ciclofosfamida/administración & dosificación , Ciclofosfamida/uso terapéutico , Femenino , Fluorouracilo/efectos adversos , Humanos , Inmunoterapia , Leucovorina/efectos adversos , Enfermedades Pulmonares Intersticiales/inducido químicamente , Enfermedades Pulmonares Intersticiales/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/efectos adversos , Pronóstico , Respiración Artificial , Neoplasias del Colon Sigmoide/cirugía , Resultado del Tratamiento
19.
Am J Hum Genet ; 93(1): 6-18, 2013 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-23746549

RESUMEN

Nemaline myopathy (NEM) is a common congenital myopathy. At the very severe end of the NEM clinical spectrum are genetically unresolved cases of autosomal-recessive fetal akinesia sequence. We studied a multinational cohort of 143 severe-NEM-affected families lacking genetic diagnosis. We performed whole-exome sequencing of six families and targeted gene sequencing of additional families. We identified 19 mutations in KLHL40 (kelch-like family member 40) in 28 apparently unrelated NEM kindreds of various ethnicities. Accounting for up to 28% of the tested individuals in the Japanese cohort, KLHL40 mutations were found to be the most common cause of this severe form of NEM. Clinical features of affected individuals were severe and distinctive and included fetal akinesia or hypokinesia and contractures, fractures, respiratory failure, and swallowing difficulties at birth. Molecular modeling suggested that the missense substitutions would destabilize the protein. Protein studies showed that KLHL40 is a striated-muscle-specific protein that is absent in KLHL40-associated NEM skeletal muscle. In zebrafish, klhl40a and klhl40b expression is largely confined to the myotome and skeletal muscle, and knockdown of these isoforms results in disruption of muscle structure and loss of movement. We identified KLHL40 mutations as a frequent cause of severe autosomal-recessive NEM and showed that it plays a key role in muscle development and function. Screening of KLHL40 should be a priority in individuals who are affected by autosomal-recessive NEM and who present with prenatal symptoms and/or contractures and in all Japanese individuals with severe NEM.


Asunto(s)
Proteínas Musculares/metabolismo , Músculo Esquelético/patología , Mutación Missense , Miopatías Nemalínicas/genética , Sustitución de Aminoácidos , Animales , Pueblo Asiatico/genética , Estudios de Cohortes , Mutación del Sistema de Lectura , Genes Recesivos , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Proteínas Musculares/genética , Miopatías Nemalínicas/etnología , Miopatías Nemalínicas/patología , Linaje , Polimorfismo de Nucleótido Simple , Índice de Severidad de la Enfermedad , Pez Cebra/genética
20.
J Neuroinflammation ; 13: 29, 2016 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-26842664

RESUMEN

BACKGROUND: Intra-amniotic Candida albicans (C. Albicans) infection is associated with preterm birth and high morbidity and mortality rates. Survivors are prone to adverse neurodevelopmental outcomes. The mechanisms leading to these adverse neonatal brain outcomes remain largely unknown. To better understand the mechanisms underlying C. albicans-induced fetal brain injury, we studied immunological responses and structural changes of the fetal brain in a well-established translational ovine model of intra-amniotic C. albicans infection. In addition, we tested whether these potential adverse outcomes of the fetal brain were improved in utero by antifungal treatment with fluconazole. METHODS: Pregnant ewes received an intra-amniotic injection of 10(7) colony-forming units C. albicans or saline (controls) at 3 or 5 days before preterm delivery at 0.8 of gestation (term ~ 150 days). Fetal intra-amniotic/intra-peritoneal injections of fluconazole or saline (controls) were administered 2 days after C. albicans exposure. Post mortem analyses for fungal burden, peripheral immune activation, neuroinflammation, and white matter/neuronal injury were performed to determine the effects of intra-amniotic C. albicans and fluconazole treatment. RESULTS: Intra-amniotic exposure to C. albicans caused a severe systemic inflammatory response, illustrated by a robust increase of plasma interleukin-6 concentrations. Cerebrospinal fluid cultures were positive for C. albicans in the majority of the 3-day C. albicans-exposed animals whereas no positive cultures were present in the 5-day C. albicans-exposed and fluconazole-treated animals. Although C. albicans was not detected in the brain parenchyma, a neuroinflammatory response in the hippocampus and white matter was seen which was characterized by increased microglial and astrocyte activation. These neuroinflammatory changes were accompanied by structural white matter injury. Intra-amniotic fluconazole reduced fetal mortality but did not attenuate neuroinflammation and white matter injury. CONCLUSIONS: Intra-amniotic C. albicans exposure provoked acute systemic and neuroinflammatory responses with concomitant white matter injury. Fluconazole treatment prevented systemic inflammation without attenuating cerebral inflammation and injury.


Asunto(s)
Lesiones Encefálicas/etiología , Candida albicans/patogenicidad , Candidiasis/complicaciones , Encefalitis/etiología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Animales , Lesiones Encefálicas/microbiología , Lesiones Encefálicas/patología , Proteínas de Unión al Calcio , Caspasa 3/metabolismo , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Encefalitis/microbiología , Encefalitis/patología , Ensayo de Inmunoadsorción Enzimática , Femenino , Fluoresceínas/metabolismo , Factor Estimulante de Colonias de Granulocitos/metabolismo , Interleucina-3/metabolismo , Interleucina-6/metabolismo , Antígeno Ki-67/metabolismo , Masculino , Proteínas de Microfilamentos , Proteína Básica de Mielina/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Embarazo , Proteínas Recombinantes de Fusión/metabolismo , Ovinos
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