RESUMEN
Chloride is a key anion involved in cellular physiology by regulating its homeostasis and rheostatic processes. Changes in cellular Cl- concentration result in differential regulation of cellular functions such as transcription and translation, post-translation modifications, cell cycle and proliferation, cell volume, and pH levels. In intracellular compartments, Cl- modulates the function of lysosomes, mitochondria, endosomes, phagosomes, the nucleus, and the endoplasmic reticulum. In extracellular fluid (ECF), Cl- is present in blood/plasma and interstitial fluid compartments. A reduction in Cl- levels in ECF can result in cell volume contraction. Cl- is the key physiological anion and is a principal compensatory ion for the movement of the major cations such as Na+, K+, and Ca2+. Over the past 25 years, we have increased our understanding of cellular signaling mediated by Cl-, which has helped in understanding the molecular and metabolic changes observed in pathologies with altered Cl- levels. Here, we review the concentration of Cl- in various organs and cellular compartments, ion channels responsible for its transportation, and recent information on its physiological roles.
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Cloruros , Humanos , Cloruros/metabolismo , Animales , Homeostasis , Canales de Cloruro/metabolismo , Canales de Cloruro/genética , Transducción de Señal , Líquido Extracelular/metabolismo , Transporte IónicoRESUMEN
Two new dactylogyrid species were found infecting the gill filaments of two freshwater fishes collected in the Amazon River basin around Madre de Dios, Peru, namely, Demidospermus wilveri n. sp. from Loricaria sp. (Siluriformes: Loricariidae), and Notozothecium agusti n. sp. from Brycon amazonicus (Spix & Agassiz) (Characiformes: Bryconidae). Demidospermus wilveri n. sp. is characterized by having the following combination of characteristics: (1) a male copulatory organ (MCO) with 1½ rings and a spoon-shaped distal end, (2) an accessory piece with expanded distal end, (3) dorsal and ventral bars with broadly V-shaped and expanded ends, and (4) hooks similar in size. Notozothecium agusti n. sp. differs from its ten congeners by the following combination of characteristics: (1) a coiled MCO with 1½ rings and a sinuous accessory piece with kidney-shaped distal end, (2) an rod-shaped and straight dorsal bar, (3) and anchors with robust superficial roots. Demidospermus wilveri n. sp. represents the thirty-second species in the genus, the eighth from Peru and the fifth parasitising a loricariid catfish from the Peruvian Amazon. Notozothecium agusti n. sp. is the second species of the genus described in Peru and the first species infecting a bryconid host.
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Bagres , Cefalosporinas , Characiformes , Trematodos , Masculino , Animales , Perú , Branquias , Especificidad de la EspecieRESUMEN
Chloride intracellular channels (CLICs) are a family of proteins that exist in soluble and transmembrane forms. The newest discovered member of the family CLIC6 is implicated in breast, ovarian, lung gastric, and pancreatic cancers and is also known to interact with dopamine-(D(2)-like) receptors. The soluble structure of the channel has been resolved, but the exact physiological role of CLIC6, biophysical characterization, and the membrane structure remain unknown. Here, we aimed to characterize the biophysical properties of this channel using a patch-clamp approach. To determine the biophysical properties of CLIC6, we expressed CLIC6 in HEK-293 cells. On ectopic expression, CLIC6 localizes to the plasma membrane of HEK-293 cells. We established the biophysical properties of CLIC6 by using electrophysiological approaches. Using various anions and potassium (K+) solutions, we determined that CLIC6 is more permeable to chloride-(Cl-) as compared to bromide-(Br-), fluoride-(F-), and K+ ions. In the whole-cell configuration, the CLIC6 currents were inhibited after the addition of 10 µM of IAA-94 (CLIC-specific blocker). CLIC6 was also found to be regulated by pH and redox potential. We demonstrate that the histidine residue at 648 (H648) in the C terminus and cysteine residue in the N terminus (C487) are directly involved in the pH-induced conformational change and redox regulation of CLIC6, respectively. Using qRT-PCR, we identified that CLIC6 is most abundant in the lung and brain, and we recorded the CLIC6 current in mouse lung epithelial cells. Overall, we have determined the biophysical properties of CLIC6 and established it as a Cl- channel.
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Canales de Cloruro , Cloruros , Animales , Humanos , Ratones , Aniones/metabolismo , Canales de Cloruro/genética , Canales de Cloruro/metabolismo , Cloruros/metabolismo , Células Epiteliales/metabolismo , Células HEK293RESUMEN
OBJECTIVE: This study aimed to determine how metabolic syndrome is related to benign prostatic enlargement in males under 60 years old in a national military hospital in Peru. MATERIALS AND METHODS: We conducted a retrospective, quantitative, case-control study. By simple random sampling, 87 cases with benign prostatic enlargement and 174 controls were included, with a statistical power of 80%. The benign prostatic enlargement was evaluated by clinical picture and ultrasound and the metabolic syndrome was evaluated according to the Adult Treatment Panel III criteria. The statistical analysis was performed using the STATAv14 program, the chi-square statistical test was used and odds ratio was obtained, at a significance level of 5%. RESULTS: The mean age of the cases and controls was 55 (51-58) and 52 (46-57), respectively. By multivariate analysis, the factors related to benign prostatic enlargement were the presence of benign prostatic enlargement (adjusted odds ratio: 2.71, 95% CI: 1.27-5.80; P=.010), waist circumference ≥102 cm (adjusted odds ratio: 6.51, 95% CI: 3.09-13.71; P < .001), elevated fasting glucose (adjusted odds ratio: 1.38, 95% CI: 0.65-2.91; P=.399), high triglycerides (adjusted odds ratio: 5.29, 95%: CI 2.40-11.64; P < .001), and arterial hypertension (adjusted odds ratio: 4.67, 95% CI 2.19-9.95; P < .001). Elevated high-density lipoprotein cholesterol was a protective factor (adjusted odds ratio: 0.09, 95% CI: 0.04-0.20; P < .001). CONCLUSION: The present study showed that metabolic syndrome and its components (waist circumference, hypertension, triglycerides, and high-density lipoprotein cholesterol) are factors related to benign prostatic enlargement in patients under 60 years old in a military hospital in Peruvian population. Waist circumference as an indicator of overweight/obesity is a practical anthropometric marker of interest in public health.
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Posttransplant lymphoproliferative disorders (PTLDs) represent a broad spectrum of lymphoid proliferations, frequently associated with Epstein-Barr virus (EBV) infection. The molecular profile of pediatric monomorphic PTLDs (mPTLDs) has not been elucidated, and it is unknown whether they display similar genetic features as their counterpart in adult and immunocompetent (IMC) pediatric patients. In this study, we investigated 31 cases of pediatric mPTLD after solid organ transplantation, including 24 diffuse large B-cell lymphomas (DLBCLs), mostly classified as activated B cell, and 7 cases of Burkitt lymphoma (BL), 93% of which were EBV positive. We performed an integrated molecular approach, including fluorescence in situ hybridization, targeted gene sequencing, and copy number (CN) arrays. Overall, PTLD-BL carried mutations in MYC, ID3, DDX3X, ARID1A, or CCND3 resembling IMC-BL, higher mutational burden than PTLD-DLBCL, and lesser CN alterations than IMC-BL. PTLD-DLBCL showed a very heterogeneous genomic profile with fewer mutations and CN alterations than IMC-DLBCL. Epigenetic modifiers and genes of the Notch pathway were the most recurrently mutated in PTLD-DLBCL (both 28%). Mutations in cell cycle and Notch pathways correlated with a worse outcome. All 7 patients with PTLD-BL were alive after treatment with pediatric B-cell non-Hodgkin lymphoma protocols, whereas 54% of patients with DLBCL were cured with immunosuppression reduction, rituximab, and/or low-dose chemotherapy. These findings highlight the low complexity of pediatric PTLD-DLBCL, their good response to low-intensity treatment, and the shared pathogenesis between PTLD-BL and EBV-positive IMC-BL. We also suggest new potential parameters that could help in the diagnosis and the design of better therapeutic strategies for these patients.
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Linfoma de Burkitt , Infecciones por Virus de Epstein-Barr , Linfoma de Células B Grandes Difuso , Trastornos Linfoproliferativos , Trasplante de Órganos , Niño , Humanos , Linfoma de Burkitt/genética , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/genética , Herpesvirus Humano 4/genética , Hibridación Fluorescente in Situ , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/terapia , Trastornos Linfoproliferativos/genética , Trastornos Linfoproliferativos/patología , Trasplante de Órganos/efectos adversosRESUMEN
Introducció. La malaltia de Kikuchi-Fujimoto, o limfadenitisnecrosant histiocítica, és una malaltia rara i benigna quesol autolimitar-se.Cas clínic. Pacient de 12 anys amb febre de llarga duradadorigen desconegut i una adenopatia axil·lar. Lanàlisi desang no mostrava alteracions específiques de lorigen etiològic del quadre. Lecografia a la zona axil·lar va evidenciarun conglomerat adenopàtic de 5x7 cm amb signes inflamatoris. Es va fer una tomografia per emissió de positrons -tomografia computada (PET-TC) que mostrava adenopatiessupra- i infradiafragmàtiques hiperactives amb una taxametabòlica moderada-alta; ladenopatia axil·lar presentavaun centre no metabòlic, suggestiu de necrosi. El diagnòsticdefinitiu de malaltia de Kikuchi-Fujimoto es va establirmitjançant la biòpsia dun gangli limfàtic, que també vaconduir a la resolució clínica del quadre.Comentaris. Mitjançant aquest cas sespera poder millorarla pràctica clínica dels pediatres davant dun cas de febreamb una adenopatia, en què cal excloure causes més freqüents com malalties infeccioses, inflamatòries, autoimmunitàries o oncològiques, i facilitar-los la comprensió dela malaltia de Kikuchi-Fujimoto, ja que sovint no estan familiaritzats amb el diagnòstic daquesta entitat i això condueix a cursos inadequats dantibiòtics i a un augment deltemps fins al diagnòstic definitiu. Cal remarcar que lextirpació de ladenopatia sol establir el diagnòstic i resoldre la clínica. (AU)
Introducción. La enfermedad de Kikuchi-Fujimoto, o linfadenitisnecrotizante histiocítica, es una enfermedad rara y benigna quesuele autolimitarse.Caso clínico. Niño de 12 años con fiebre de larga duración deorigen desconocido y una adenopatía axilar. El análisis de sangreno mostraba alteraciones específicas del origen etiológico delcuadro. La ecografía a nivel axilar evidenció un conglomeradoadenopático de 5x7 cm con signos inflamatorios. Se realizó unatomografía de positrones - tomografía computarizada (PET-TC)que mostraba adenopatías supra e infradiafragmáticas vas con una tasa metabólica moderada-alta; la adenopatía axilarpresentaba un centro no metabólico, sugestivo de necrosis. Eldiagnóstico definitivo de enfermedad de Kikuchi-Fujimoto se estableció mediante la biopsia de un ganglio linfático, que tambiéncondujo a la resolución clínica del cuadro.Comentarios. Mediante este caso, se espera poder mejorar la práctica clínica de los pediatras frente a un caso de fiebre con unaadenopatía, donde se tienen que excluir causas más frecuentescomo enfermedades infecciosas, inflamatorias, autoinmunes u oncológicas, y facilitarles comprensión de la enfermedad de KikuchiFujimoto, ya que a menudo no están familiarizado con el diagnóstico de esta entidad y ello conduce a cursos inadecuados deantibióticos y un aumento del tiempo hasta el diagnóstico definitivo. Remarcar que la extirpación de la adenopatía suele establecerel diagnóstico y resuelve la clínica. (AU)
Introduction. Kikuchi-Fujimoto disease, or histiocytic necrotizinglymphadenitis, is a rare and benign self-limited disease.Case report. 12-year-old child with long-lasting fever of unknownorigin and one axillary adenopathy. The blood tests failed to identify the etiological origin of the condition. Axillary ultrasoundshowed a 5x7 cm adenopathy conglomerate with inflammatorysigns. A PET-CT was performed reporting hyperactive supra andinfradiaphragmatic adenopathies with a moderate-high metabolicrate; the axillary adenopathy presented a non-metabolic center,suggestive of necrosis. The definitive diagnosis of Kikuchi-Fujimoto disease was established by biopsy of a lymph node, whichalso led to the clinical resolution of the condition.Comments. Through this case, we aimed at improving the clinicalpractice of pediatricians in the presence of a case of fever with anadenopathy, where more frequent causes such as infectious, inflammatory, autoimmune, or oncologic diseases should be excluded; and to provide a better understanding of Kikuchi-Fujimotodisease, as the diagnosis of this entity is often unfamiliar, whichleads to inappropriate courses of antibiotics and increased timebefore final diagnosis. The excision of the adenopathy usually establishes the diagnosis and resolves the symptoms. (AU)
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Humanos , Masculino , Niño , Linfadenitis Necrotizante Histiocítica/diagnóstico , Linfadenitis Necrotizante Histiocítica/terapia , Fiebre , Linfadenopatía , LinfadenitisRESUMEN
BACKGROUND: T-cell lymphoblastic lymphoma (T-LBL) is an aggressive neoplasm closely related to T-cell acute lymphoblastic leukaemia (T-ALL). Despite their similarities, and contrary to T-ALL, studies on paediatric T-LBL are scarce and, therefore, its molecular landscape has not yet been fully elucidated. Thus, the aims of this study were to characterize the genetic and molecular heterogeneity of paediatric T-LBL and to evaluate novel molecular markers differentiating this entity from T-ALL. PROCEDURE: Thirty-three paediatric T-LBL patients were analyzed using an integrated approach, including targeted next-generation sequencing, RNA-sequencing transcriptome analysis and copy-number arrays. RESULTS: Copy number and mutational analyses allowed the detection of recurrent homozygous deletions of 9p/CDKN2A (78%), trisomy 20 (19%) and gains of 17q24-q25 (16%), as well as frequent mutations of NOTCH1 (62%), followed by the BCL11B (23%), WT1 (19%) and FBXW7, PHF6 and RPL10 genes (15%, respectively). This genetic profile did not differ from that described in T-ALL in terms of mutation incidence and global genomic complexity level, but unveiled virtually exclusive 17q25 gains and trisomy 20 in T-LBL. Additionally, we identified novel gene fusions in paediatric T-LBL, including NOTCH1-IKZF2, RNGTT-SNAP91 and DDX3X-MLLT10, the last being the only one previously described in T-ALL. Moreover, clinical correlations highlighted the presence of Notch pathway alterations as a factor related to favourable outcome. CONCLUSIONS: In summary, the genomic landscape of paediatric T-LBL is similar to that observed in T-ALL, and Notch signaling pathway deregulation remains the cornerstone in its pathogenesis, including not only mutations but fusion genes targeting NOTCH1.
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Linfoma de Células T , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Niño , Cromosomas Humanos Par 20 , Proteína 7 que Contiene Repeticiones F-Box-WD/genética , Humanos , Linfoma de Células T/genética , Mosaicismo , Mutación , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , ARN , Receptor Notch1/genética , Transducción de Señal/genética , Linfocitos T/patología , Factores de Transcripción/genética , Trisomía , Proteínas Supresoras de Tumor/genéticaRESUMEN
Peru hosts extremely diverse ecosystems which can be broadly classified into the following three major ecoregions: the Pacific desert coast, the Andean highlands, and the Amazon rainforest. Since its initial peopling approximately 12,000 years ago, the populations inhabiting such ecoregions might have differentially adapted to their contrasting environmental pressures. Previous studies have described several candidate genes underlying adaptation to hypobaric hypoxia among Andean highlanders. However, the adaptive genetic diversity of coastal and rainforest populations has been less studied. Here, we gathered genome-wide single-nucleotide polymorphism-array data from 286 Peruvians living across the three ecoregions and analyzed signals of recent positive selection through population differentiation and haplotype-based selection scans. Among highland populations, we identify candidate genes related to cardiovascular function (TLL1, DUSP27, TBX5, PLXNA4, SGCD), to the Hypoxia-Inducible Factor pathway (TGFA, APIP), to skin pigmentation (MITF), as well as to glucose (GLIS3) and glycogen metabolism (PPP1R3C, GANC). In contrast, most signatures of adaptation in coastal and rainforest populations comprise candidate genes related to the immune system (including SIGLEC8, TRIM21, CD44, and ICAM1 in the coast; CBLB and PRDM1 in the rainforest; and BRD2, HLA-DOA, HLA-DPA1 regions in both), possibly as a result of strong pathogen-driven selection. This study identifies candidate genes related to human adaptation to the diverse environments of South America.
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Altitud , Ecosistema , Adaptación Fisiológica/genética , Humanos , Hipoxia/genética , Perú , Polimorfismo de Nucleótido Simple , Selección Genética , Metaloproteinasas Similares a Tolloid/genéticaRESUMEN
Low-flow vascular malformations are congenital overgrowths composed of abnormal blood vessels potentially causing pain, bleeding and obstruction of different organs. These diseases are caused by oncogenic mutations in the endothelium, which result in overactivation of the PI3K/AKT pathway. Lack of robust in vivo preclinical data has prevented the development and translation into clinical trials of specific molecular therapies for these diseases. Here, we demonstrate that the Pik3caH1047R activating mutation in endothelial cells triggers a transcriptome rewiring that leads to enhanced cell proliferation. We describe a new reproducible preclinical in vivo model of PI3K-driven vascular malformations using the postnatal mouse retina. We show that active angiogenesis is required for the pathogenesis of vascular malformations caused by activating Pik3ca mutations. Using this model, we demonstrate that the AKT inhibitor miransertib both prevents and induces the regression of PI3K-driven vascular malformations. We confirmed the efficacy of miransertib in isolated human endothelial cells with genotypes spanning most of human low-flow vascular malformations.
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Fosfatidilinositol 3-Quinasas , Malformaciones Vasculares , Aminopiridinas , Animales , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Células Endoteliales/metabolismo , Imidazoles , Ratones , Mutación , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Malformaciones Vasculares/genética , Malformaciones Vasculares/metabolismo , Malformaciones Vasculares/patologíaRESUMEN
Extensive lymphatic malformations (LMs) of the head and neck region may require tracheostomy to secure the airway. Treatment of these life-threatening LMs is usually multimodal and includes sclerotherapy and surgery, among others. Recently, systemic therapy with sirolimus has been introduced as an effective treatment for venous and lymphatic malformations; its efficacy and safety profile in patients with extensive LM requiring tracheostomy are, however, as yet not fully known. We performed a retrospective, multicenter review and identified 13 patients with an extensive LM of the head and neck region, who previously underwent placement of tracheostomy and subsequently received sirolimus treatment with the aim to improve the local respiratory situation and remove the tracheostomy. Under sirolimus therapy, tracheostomy could be reversed in 8/13 (62%) patients, a further 2/13 (15%) patients improved markedly, and removal of the tracheostomy was planned at the time of writing, while 3/13 (23%) patients showed insufficient or absent response to sirolimus, rendering tracheostomy reversal not feasible. The median duration of sirolimus treatment until removal of tracheostomy was 18 months (range, 8 months to 5.6 years). Adverse events of sirolimus therapy were common [10/13 (77%) patients], yet the majority of these were mild [9/10 (90%) patients] and only one severe adverse event was recorded, with ulceration and necrosis at a catheter insertion site. In conclusion, sirolimus can be considered an effective and safe salvage treatment in patients with extensive LM even after placement of a tracheostomy, as closure of the latter was possible in the majority of patients (62%) of our retrospective cohort. A better understanding of when to start sirolimus therapy, of the duration of treatment, and of factors allowing the prediction of treatment response will require further investigation.
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Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory disorder. HLH can be considered as a threshold disease depending on the trigger and the residual NK-cell cytotoxicity. In this study, we analyzed the molecular and functional impact of a novel monoallelic mutation found in a patient with two episodes of HLH. A 9-month-old child was diagnosed at 2 months of age with cutaneous Langerhans cell histiocytosis (LCH). After successful treatment, the patient developed an HLH episode. At 16 month of age, the patient went through an HSCT losing the engraftment 5 months later concomitant with an HLH relapse. The genetic study revealed a monoallelic mutation in the STXBP2 gene (.pArg190Cys). We transfected COS7 cells to analyze the STXBP2-R190C expression and to test the interaction with STX11. We used the RBL-2H3 cell line expressing STXBP2-WT-EGFP or R190C-EGFP for degranulation assays. Mutation STXBP2-R190C did not affect protein expression or interaction with syntaxin-11. However, we have demonstrated that STXBP2-R190C mutation diminishes degranulation in the RBL-2H3 cell line compared with the RBL-2H3 cell line transfected with STXBP2-WT or nontransfected. These results suggest that STXBP2-R190C mutation acts as a modifier of the degranulation process producing a decrease in degranulation. Therefore, under homeostatic conditions, the presence of one copy of STXBP2-R190 could generate sufficient degranulation capacity. However, it is likely that early in life when adaptive immune system functions are not sufficiently developed, an infection may not be resolved with this genetic background, leading to a hyperinflammation syndrome and eventually develop HLH. This analysis highlights the need for functional testing of new mutations to validate their role in genetic susceptibility and to establish the best possible treatment for these patients.
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Histiocitosis de Células de Langerhans/diagnóstico , Histiocitosis de Células de Langerhans/genética , Linfohistiocitosis Hemofagocítica/diagnóstico , Linfohistiocitosis Hemofagocítica/genética , Proteínas Munc18/genética , Citotoxicidad Inmunológica , Predisposición Genética a la Enfermedad , Histiocitosis de Células de Langerhans/complicaciones , Humanos , Lactante , Linfohistiocitosis Hemofagocítica/complicaciones , Masculino , MutaciónRESUMEN
Sea urchin sperm swimming is regulated by speract, a decapeptide released from egg jelly that induces chemotaxis and triggers membrane potential (Em) changes, intracellular increases in cyclic nucleotides (cGMP, cAMP), pH (pHi) and calcium concentration ([Ca2+]i). The identity of the ionic transporters associated with the [Ca2+]i changes required for chemotaxis is not fully known. CatSper, a sperm exclusive Ca2+ channel has been detected by proteomic analysis and immunofluorescence in sea urchin sperm and there is evidence for its involvement in chemotaxis. This work presents an electrophysiological characterization of a CatSper channel in sea urchin sperm. By swelling sperm suspending them in 10-fold diluted artificial sea water (ASW) we achieve on-cell patch-clamp recordings that document a mildly voltage and pHi dependent Na+ permeable channel (in absence of divalent ions in the pipette), sensitive to speract, and blocked by Mibefradil (Mibe), NNC55-0396 (NNC) and RU1968 (RU) resembling CatSper. We also recorded a voltage dependent Cl- channel inhibited by Niflumic Acid and the TMEM16A blocker.
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Proteómica , Motilidad Espermática , Animales , Calcio/metabolismo , Canales de Calcio , Masculino , Erizos de Mar/metabolismo , Espermatozoides/metabolismoRESUMEN
The goals of this work were to identify factors favoring patient-derived xenograft (PDX) engraftment and study the association between PDX engraftment and prognosis in pediatric patients with Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma. We used immunodeficient mice to establish 30 subcutaneous PDX from patient tumor biopsies, with a successful engraftment rate of 44%. Age greater than 12 years and relapsed disease were patient factors associated with higher engraftment rate. Tumor type and biopsy location did not associate with engraftment. PDX models retained histology markers and most chromosomal aberrations of patient samples during successive passages in mice. Model treatment with irinotecan resulted in significant activity in 20 of the PDXs and replicated the response of rhabdomyosarcoma patients. Successive generations of PDXs responded similarly to irinotecan, demonstrating functional stability of these models. Importantly, out of 68 tumor samples from 51 patients with a median follow-up of 21.2 months, PDX engraftment from newly diagnosed patients was a prognostic factor significantly associated with poor outcome (p = 0.040). This association was not significant for relapsed patients. In the subgroup of patients with newly diagnosed Ewing sarcoma classified as standard risk, we found higher risk of relapse or refractory disease associated with those samples that produced stable PDX models (p = 0.0357). Overall, our study shows that PDX engraftment predicts worse outcome in newly diagnosed pediatric sarcoma patients.
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Pronóstico , Sarcoma de Ewing/tratamiento farmacológico , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Adolescente , Animales , Niño , Preescolar , Modelos Animales de Enfermedad , Femenino , Xenoinjertos/efectos de los fármacos , Humanos , Irinotecán/farmacología , Irinotecán/uso terapéutico , Masculino , Ratones , Osteosarcoma/tratamiento farmacológico , Rabdomiosarcoma/tratamiento farmacológico , Sarcoma/tratamiento farmacológico , Resultado del TratamientoRESUMEN
OBJECTIVES: Clinical studies have shown low toxicity and a favorable safety profile for sirolimus in vascular anomalies. Here, we describe severe adverse events (SAEs) observed during "off-label use" for vascular anomalies. METHODS: We performed a retrospective, multicenter chart review for SAEs during "off-label" sirolimus therapy for vascular anomalies and analyzed these cases by a predesigned workflow. RESULTS: We identified 17 SAEs in 14 patients diagnosed with generalized lymphatic anomaly (n = 4), Gorham-Stout disease (n = 2), central conducting lymphatic anomaly (n = 1), lymphatic malformation (n = 4), tufted angioma (n = 1), kaposiform hemangioendothelioma (n = 1), and venous malformation in a patient with CLOVES syndrome (n = 1). Three patients presented two SAEs each. The age at initiation of sirolimus therapy was under 2 years (n = 5), 2-6 years (n = 5), and older than 12 years (n = 4). SAEs occurred during the first 3 months of sirolimus therapy (n = 7), between 3 and 12 months (n = 7) and after 1 year of therapy (n = 3). The most frequent SAE was viral pneumonia (n = 8) resulting in one death due to a metapneumovirus infection in a 3 months old and a generalized adenovirus infection in a 28-month-old child. Sirolimus blood level at the time of SAEs ranged between 2.7 and 21 ng/L. Five patients were on antibiotic prophylaxis. CONCLUSIONS: Most SAEs are observed in the first year of sirolimus therapy; however, SAEs can also occur after a longer treatment period. SAEs are potentially life threatening, especially in early infancy. Presence of other risk factors, that is, underlying vascular anomaly or immune status, may contribute to the risk of SAEs. Sirolimus is an important therapeutic option for vascular anomalies, but patients and physicians need to be aware that adequate monitoring is necessary, especially in patients with complex lymphatic anomalies that are overrepresented in our cohort of SAEs.
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Malformaciones Vasculares , Preescolar , Hemangioendotelioma , Humanos , Lactante , Síndrome de Kasabach-Merritt/tratamiento farmacológico , Anomalías Linfáticas/tratamiento farmacológico , Uso Fuera de lo Indicado , Estudios Retrospectivos , Sirolimus/efectos adversos , Malformaciones Vasculares/tratamiento farmacológicoRESUMEN
BACKGROUND: Li-Fraumeni Syndrome (LFS) is a cancer predisposition syndrome characterized by the early-onset of multiple primary cancers which can occur at different moments (metachronous onset) or, more rarely, coincidentally (synchronous onset). Here we describe a previously unreported patient with presentation of synchronous Wilms tumor and Choroid plexus papilloma, leading to the diagnosis of a Li-Fraumeni Syndrome (LFS). CASE PRESENTATION: A 6-year-old girl without previous complains presented with abdominal pain. Abdominal US and MRI showed a left renal tumor with subcapsular hematoma. Due to mild headaches, the diagnostic workup included a brain MRI that unexpectedly identified a large left parietal lobe tumor. Histopathological analysis determined the diagnosis of classic Wilms tumor and choroid-plexus papilloma (CPP), respectively. Both neoplasms showed intense nuclear p53 immunostaining associated with the pathogenic TP53 mutation c.844C > T (p.Arg282Trp). Our patient and her father shared the same heterozygous germline TP53 mutation, confirming the diagnosis of familiar Li-Fraumeni syndrome in the girl. The treatment was tailored to simultaneous tumor presentations. CONCLUSIONS: LFS has been associated with Choroid plexus carcinoma (CPC), but rarely with CPP as in our patient. That suggests that it may be advisable to consider the possibility of analyzing TP53 mutation, not only in all patients with CPC, but also in some patients with CPP, especially when histological or clinical evidences point out to perform this study. The dissimilar presentation of LFS among our patient's father, not having so far any neoplasia diagnosed, while her daughter presented precociously with two simultaneous different tumors, could be related to possible effects of modifier genes on the underlying mutant p53 genotype.
RESUMEN
Pediatric large B-cell lymphomas (LBCLs) share morphological and phenotypic features with adult types but have better prognosis. The higher frequency of some subtypes such as LBCL with IRF4 rearrangement (LBCL-IRF4) in children suggests that some age-related biological differences may exist. To characterize the genetic and molecular heterogeneity of these tumors, we studied 31 diffuse LBCLs (DLBCLs), not otherwise specified (NOS); 20 LBCL-IRF4 cases; and 12 cases of high-grade B-cell lymphoma (HGBCL), NOS in patients ≤25 years using an integrated approach, including targeted gene sequencing, copy-number arrays, and gene expression profiling. Each subgroup displayed different molecular profiles. LBCL-IRF4 had frequent mutations in IRF4 and NF-κB pathway genes (CARD11, CD79B, and MYD88), losses of 17p13 and gains of chromosome 7, 11q12.3-q25, whereas DLBCL, NOS was predominantly of germinal center B-cell (GCB) subtype and carried gene mutations similar to the adult counterpart (eg, SOCS1 and KMT2D), gains of 2p16/REL, and losses of 19p13/CD70. A subset of HGBCL, NOS displayed recurrent alterations of Burkitt lymphoma-related genes such as MYC, ID3, and DDX3X and homozygous deletions of 9p21/CDKN2A, whereas other cases were genetically closer to GCB DLBCL. Factors related to unfavorable outcome were age >18 years; activated B-cell (ABC) DLBCL profile, HGBCL, NOS, high genetic complexity, 1q21-q44 gains, 2p16/REL gains/amplifications, 19p13/CD70 homozygous deletions, and TP53 and MYC mutations. In conclusion, these findings further unravel the molecular heterogeneity of pediatric and young adult LBCL, improve the classification of this group of tumors, and provide new parameters for risk stratification.
Asunto(s)
Factores Reguladores del Interferón/genética , Linfoma de Células B Grandes Difuso/genética , Mutación , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/patología , Masculino , Pronóstico , Transcriptoma , Adulto JovenRESUMEN
Burkitt-like lymphoma with 11q aberration is characterized by pathological features and gene expression profile resembling those of Burkitt lymphoma but lacks the MYC rearrangement and carries an 11q-arm aberration with proximal gains and telomeric losses. Whether this lymphoma is a distinct category or a particular variant of other recognized entities is controversial. To improve the understanding of Burkitt-like lymphoma with 11q aberration we performed an analysis of copy number alterations and targeted sequencing of a large panel of B-cell lymphoma-related genes in 11 cases. Most patients had localized nodal disease and a favorable outcome after therapy. Histologically, they were high grade B-cell lymphoma, not otherwise specified (8 cases), diffuse large B-cell lymphoma (2 cases) and only one was considered as atypical Burkitt lymphoma. All cases had a germinal center B-cell signature and phenotype with frequent LMO2 expression. The patients with Burkitt-like lymphoma with 11q aberration had frequent gains of 12q12-q21.1 and losses of 6q12.1-q21, and lacked common Burkitt lymphoma or diffuse large B-cell lymphoma alterations. Potential driver mutations were found in 27 genes, particularly involving BTG2, DDX3X, ETS1, EP300, and GNA13 However, ID3, TCF3, or CCND3 mutations were absent in all cases. These results suggest that Burkitt-like lymphoma with 11q aberration is a germinal center-derived lymphoma closer to high-grade B-cell lymphoma or diffuse large B-cell lymphoma than to Burkitt lymphoma.
Asunto(s)
Linfoma de Burkitt/genética , Aberraciones Cromosómicas , Cromosomas Humanos Par 11/genética , Centro Germinal/patología , Linfoma de Células B Grandes Difuso/genética , Adolescente , Adulto , Niño , ADN/análisis , Análisis Mutacional de ADN , Femenino , Dosificación de Gen , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Masculino , Fenotipo , Análisis de Secuencia de ADN , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: One of the most frequent non-infectious complications of humoral immunodeficiencies with a CVID-like pattern is a particular form of inflammatory lung disease which is called granulomatous-lymphocytic interstitial lung disease (GLILD). Its development worsens patient prognosis, with a significant decrease in survival. Currently, there are no unified guidelines regarding its management, and different combinations of immunosuppressants have been used with variable success. METHODS: Clinical and radiological data were collected from patient's medical charts. Flow cytometry was performed to characterize the immunological features with special focus in regulatory T cells (Tregs). RESULTS: A 16-year-old girl with Kabuki syndrome and a 12-year-old boy, both with a CVID-like humoral immunodeficiency on immunoglobulin replacement treatment, developed during follow-up an inflammatory complication radiologically, clinically, and histologically compatible with GLILD. They required treatment, and sirolimus was started, with very good response and no serious side effects. CONCLUSIONS: These 2 cases provide insight into the underlying local and systemic immune anomalies involved in the development of GLILD, including the possible role of Tregs. Combined chemotherapy is commonly used as treatment for GLILD when steroids fail, but there have been some reports of successful monotherapy. As far as we know, these are the first 2 GLILD patients treated successfully with sirolimus, suggesting the advisability of further study of mTOR inhibitors as a more targeted treatment for GLILD, if impairment in Tregs is demonstrated.
Asunto(s)
Síndromes de Inmunodeficiencia/complicaciones , Inmunosupresores/uso terapéutico , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Sirolimus/uso terapéutico , Linfocitos T Reguladores/metabolismo , Anomalías Múltiples/inmunología , Adolescente , Biomarcadores/metabolismo , Niño , Cara/anomalías , Femenino , Enfermedades Hematológicas/complicaciones , Enfermedades Hematológicas/inmunología , Humanos , Síndromes de Inmunodeficiencia/inmunología , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/inmunología , Masculino , Enfermedades Vestibulares/complicaciones , Enfermedades Vestibulares/inmunologíaRESUMEN
To assess the physiological state of an animal, analysis and diagnostic tests comparable with defined reference values are necessary. These values are influenced by various factors and their definition should be based on the characteristics of each population. In the Veterinary Hospital of the University of Antioquia, universal reference values for hemogram are normally used. This represents a problem at the time of interpretation of results, due to local environmental factors that differ from the international ones, in which the reference values were originally defined. Objective: to determine reference limits of hemogram in clinically healthy dogs between 1 and 6 years of age, in the city of Medellín. Methods: retrospective study. In this study, medical records of healthy dogs attending the Veterinary Hospital of the Faculty of Agricultural Sciences of the University of Antioquia for ambulatory surgery, clinical examination, vaccination, and annual monitoring between 2002 and 2009 were analyzed. Information contained in medical records was collected using a questionnaire. The statistical analysis of the information was carried out using parametric and nonparametric methods. Results: reference limits were established. Significant statistically differences in some parameters of the hemogram in relation to variables such as age and breed of dogs were established. Conclusions: parameters of hemogram in evaluated dogs are related to physiological conditions such as age and race, as well as to environmental and nutritional conditions. Therefore, it is necessary to have reference values that match the characteristics of animals and the environment.
Para la determinación del estado fisiológico de un animal son necesarios análisis y pruebas diagnósticas comparables con valores de referencia definidos; estos valores se encuentran influenciados por diversos factores, y se establecen con base en las características propias de cada población. En el Hospital Veterinario de la Universidad de Antioquia se emplean valores de referencia universales para el hemograma, lo cual constituye un problema al momento de su interpretación, ya que los factores ambientales locales difieren de los internacionales donde los valores de referencia se definieron originalmente. Objetivo: determinar los límites de referencia del hemograma en perros entre 1 y 6 años de edad, clínicamente sanos de la ciudad de Medellín. Métodos: se diseñó un estudio retrospectivo para en el cual se analizaron historias clínicas de perros sanos que fueron llevados al Hospital Veterinario de la Facultad de Ciencias Agrarias de la Universidad de Antioquia a para cirugía ambulatoria, revisión general, vacunación, y control anual, entre los años 2002 y 2009. La información contenida en las historias clínicas se recopiló mediante el uso de una encuesta, y para su análisis se utilizó estadística paramétrica y no paramétrica. Resultados: se establecieron límites de referencia y se encontraron diferencias estadísticamente significativas en algunos parámetros del hemograma en relación con variables como edad y raza de los perros. Conclusión: los parámetros del hemograma en los perros evaluados se encuentran relacionados con condiciones fisiológicas como edad y raza, así como por condiciones medioambientales y de nutrición, por lo que es necesario tener límites de referencia que concuerden con las características propias de los animales y del medio.
O estado fisiológico de um animal é avaliado a partir de análises e provas diagnósticas comparáveis com valores de referência definidos. Esses valores estão influenciados por diversos fatores e são definidos com base nas características próprias de cada população. No Hospital Veterinário da Universidade de Antióquia são empregados limites de referência universais para o hemograma. Este é um problema no momento da interpretação, devido a que fatores ambientais locais são diferentes dos internacionais. Objetivo: o objetivo desta pesquisa foi determinar os limites de referência do hemograma em cães entre 1 e 6 anos de idade, clinicamente sadios, procedentes da cidade de Medellín. Métodos: foi desenhado um estudo retrospectivo no qual analisaram-se os prontuarios de cães sadios que foram submetidos a cirurgia ambulatória, revisão geral, vacinação e controle anual no Hospital Veterinário da Faculdade de Ciências Agrárias da Universidade de Antióquia entre os anos 2002 e 2009. A informação contida nos prontuarios foi recopilada mediante o uso de uma enquete e para sua análise utilizou-se estatística paramétrica e não paramétrica. Resultados: estabeleceram-se limites de referência e foram encontradas diferenças estatisticamente significativas em alguns parâmetros do hemograma como a idade e a raça dos cães. Conclusões: os parâmetros do hemograma nos cães avaliados estão relacionados com condições fisiológicas como idade e raça, assim como também por condições medioambientais e de nutrição. Por esta razão, é necessário ter limites de referência que estejam de acordo com as características próprias dos animais e do médio.