Fibromixoma plexiforme del antro gástrico: descripción de 2 casos y revisión de la literatura / Plexiform fibromyxoma of the gastric antrum: a report of 2 cases and a review of the literature

El tumor miofibroblástico angiomixoide plexiforme o fibromixoma plexiforme es una neoplasia mesenquimal benigna, rara, recientemente descrita, que afecta al antro gástrico. Histológicamente presenta crecimiento plexiforme y está compuesta por células fibro/miofibroblásticas en un estroma mixoide, variable, con marcada trama capilar. En el presente artículo llevamos a cabo una revisión de la literatura y aportamos 2 casos adicionales en pacientes jóvenes (36 y 46 años) que consultaron por molestias gástricas inespecíficas y hemorragia digestiva alta. Ambas lesiones estaban situadas en la submucosa y en la capa muscular propia y presentaban un patrón de crecimiento plexiforme. Las células tumorales eran fusiformes y se disponían en el seno de una matriz mixoide abundante. La vascularización estaba constituida por numerosos vasos de pared fina y pequeño calibre. Con las técnicas de inmunohistoquímica, las células tumorales fueron positivas para actina de músculo liso, vimentina, caldesmón y desmina (un caso) y negativas para CD117, DOG1, EMA, S100, Beta-catenina y CD34. El estudio molecular no detectó mutaciones en los genes KIT y PDGFRA, en ninguno de los 2 casos. Hasta la fecha (4 años y 8 meses), ninguno de los pacientes ha desarrollado recidivas ni metástasis. El diagnóstico diferencial incluye una gran variedad de lesiones mixoides que pueden asentar o invadir la pared del estómago (GIST, tumor desmoide intraabdominal, pólipo fibroide inflamatorio, leiomioma-leiomiosarcoma, perineuroma, schwannoma y neurofibroma), pero solo el neurofibroma plexiforme comparte su característico patrón de crecimiento. Aunque en la revisión de la literatura hemos encontrado un total de 23 casos bajo la denominación de tumor gástrico miofibroblástico angiomixoide plexiforme o fibromixoma plexiforme, también hemos advertido que antes de la introducción de estos términos se habían descrito lesiones gástricas mixoides semejantes, no muy bien caracterizadas, que comparten mayoritariamente la localización antral gástrica, por lo que cabría especular sobre la posible existencia de una misma entidad con variable grado de diferenciación fibro/miofibroblástica y de patrón plexiforme, desarrollada probablemente en una población celular limitada exclusivamente al estómago(AU)

Plexiform, angiomyxoid myofibrobastic tumour, or plexiform fibromyoma, is a rare, recently described, benign neoplasm that affects the gastric antrum. Histologically the tumour has a plexiform growth pattern and is composed of fibro/myofibroblastic cells in a variable mixed stroma with a prominent capillary network. We have reviewed the literature and present 2 further cases occurring in young patients (36 and 46 years of age) who presented with gastric discomfort and upper gastrointestinal bleeding. Both lesions were located in the submucosa and muscularis and showed a plexiform growth pattern. Fusiform cells were found in an abundant myxoid extracellular matrix. Numerous small fine-walled blood vessels were present. Immunohistochemistry revealed positivity for smooth muscle actin, vimentin, h-caldesmon and desmin (in one case) and negativity for CD117, DOG1, EMA, S100, Beta-catenin and CD34. Molecular studies showed no mutations in the KIT and PDGFRA genes in either case. To date, neither of the patients has recurrences or metastases, 4 years and 8 months after diagnosis. Differential diagnosis includes a wide variety of myxoid lesions that may arise in or invade the stomach wall (GIST, intraabdominal desmoid tumour, inflammatory fibroid polyp, leiomyoma-leiomyosarcoma, perineuroma, schwannoma and neurofibroma), among these, plexiform neurofibroma is the only one showing the characteristic growth pattern. In our review of the literature, we found 23 cases described as gastric plexiform angiomyxoid myofibroblastic tumour, or gastric plexiform fibromyxoma. However, before the introduction of these terms, similar, if not completely characterized, gastric myxoid lesions had been described in the gastric antrum, suggesting that a single entity with a variable degree of fibro/myofibroblastic differentiation and a plexiform growth pattern might exist, perhaps developing in cells found only in the stomach(AU)

Human microRNAs miR-22, miR-138-2, miR-148a, and miR-488 are associated with panic disorder and regulate several anxiety candidate genes and related pathways.

BACKGROUND: The involvement of microRNAs (miRNAs) in neuronal differentiation and synaptic plasticity suggests a role for miRNAs in psychiatric disorders; association analyses and functional approaches were used to evaluate the implication of miRNAs in the susceptibility for panic disorder. METHODS: Case-control studies for 712 single-nucleotide polymorphisms (SNPs) tagging 325 human miRNA regions were performed in 203 Spanish patients with panic disorder and 341 control subjects. A sample of 321 anxiety patients and 642 control subjects from Finland and 102 panic disorder patients and 829 control subjects from Estonia was used as a replica. Reporter-gene assays and miRNA overexpression experiments in neuroblastoma cells were used to functionally evaluate the spectrum of genes regulated by the associated miRNAs. RESULTS: Two SNPs associated with panic disorder: rs6502892 tagging miR-22 (p < .0002), and rs11763020 tagging miR-339 (p < .00008). Other SNPs tagging miR-138-2, miR-488, miR-491, and miR-148a regions associated with different panic disorder phenotypes. Replication in the north-European sample supported several of these associations, although they did not pass correction for multiple testing. Functional studies revealed that miR-138-2, miR-148a, and miR-488 repress (30%-60%) several candidate genes for panic disorder--GABRA6, CCKBR and POMC, respectively--and that miR-22 regulates four other candidate genes: BDNF, HTR2C, MAOA, and RGS2. Transcriptome analysis of neuroblastoma cells transfected with miR-22 and miR-488 showed altered expression of a subset of predicted target genes for these miRNAs and of genes that might be affecting physiological pathways related to anxiety. CONCLUSIONS: This work represents the first report of a possible implication of miRNAs in the etiology of panic disorder.

Overexpression of miR-128 specifically inhibits the truncated isoform of NTRK3 and upregulates BCL2 in SH-SY5Y neuroblastoma cells.

BACKGROUND: Neurotrophins and their receptors are key molecules in the regulation of neuronal differentiation and survival. They mediate the survival of neurons during development and adulthood and are implicated in synaptic plasticity. The human neurotrophin-3 receptor gene NTRK3 yields two major isoforms, a full-length kinase-active form and a truncated non-catalytic form, which activates a specific pathway affecting membrane remodeling and cytoskeletal reorganization. The two variants present non-overlapping 3'UTRs, indicating that they might be differentially regulated at the post-transcriptional level. Here, we provide evidence that the two isoforms of NTRK3 are targeted by different sets of microRNAs, small non-coding RNAs that play an important regulatory role in the nervous system. RESULTS: We identify one microRNA (miR-151-3p) that represses the full-length isoform of NTRK3 and four microRNAs (miR-128, miR-485-3p, miR-765 and miR-768-5p) that repress the truncated isoform. In particular, we show that the overexpression of miR-128 - a brain enriched miRNA - causes morphological changes in SH-SY5Y neuroblastoma cells similar to those observed using an siRNA specifically directed against truncated NTRK3, as well as a significant increase in cell number. Accordingly, transcriptome analysis of cells transfected with miR-128 revealed an alteration of the expression of genes implicated in cytoskeletal organization as well as genes involved in apoptosis, cell survival and proliferation, including the anti-apoptotic factor BCL2. CONCLUSIONS: Our results show that the regulation of NTRK3 by microRNAs is isoform-specific and suggest that neurotrophin-mediated processes are strongly linked to microRNA-dependent mechanisms. In addition, these findings open new perspectives for the study of the physiological role of miR-128 and its possible involvement in cell death/survival processes.

Design and evaluation of a panel of single-nucleotide polymorphisms in microRNA genomic regions for association studies in human disease.

MicroRNAs (miRNA) are recognized posttranscriptional gene repressors involved in the control of almost every biological process. Allelic variants in these regions may be an important source of phenotypic diversity and contribute to disease susceptibility. We analyzed the genomic organization of 325 human miRNAs (release 7.1, miRBase) to construct a panel of 768 single-nucleotide polymorphisms (SNPs) covering approximately 1 Mb of genomic DNA, including 131 isolated miRNAs (40%) and 194 miRNAs arranged in 48 miRNA clusters, as well as their 5-kb flanking regions. Of these miRNAs, 37% were inside known protein-coding genes, which were significantly associated with biological functions regarding neurological, psychological or nutritional disorders. SNP coverage analysis revealed a lower SNP density in miRNAs compared with the average of the genome, with only 24 SNPs located in the 325 miRNAs studied. Further genotyping of 340 unrelated Spanish individuals showed that more than half of the SNPs in miRNAs were either rare or monomorphic, in agreement with the reported selective constraint on human miRNAs. A comparison of the minor allele frequencies between Spanish and HapMap population samples confirmed the applicability of this SNP panel to the study of complex disorders among the Spanish population, and revealed two miRNA regions, hsa-mir-26a-2 in the CTDSP2 gene and hsa-mir-128-1 in the R3HDM1 gene, showing geographical allelic frequency variation among the four HapMap populations, probably because of differences in natural selection. The designed miRNA SNP panel could help to identify still hidden links between miRNAs and human disease.

Allele variants in functional MicroRNA target sites of the neurotrophin-3 receptor gene (NTRK3) as susceptibility factors for anxiety disorders.

Genetic and functional data indicate that variation in the expression of the neurotrophin-3 receptor gene (NTRK3) may have an impact on neuronal plasticity, suggesting a role for NTRK3 in the pathophysiology of anxiety disorders. MicroRNA (miRNA) posttranscriptional gene regulators act by base-pairing to specific sequence sites, usually at the 3'UTR of the target mRNA. Variants at these sites might result in gene expression changes contributing to disease susceptibility. We investigated genetic variation in two different isoforms of NTRK3 as candidate susceptibility factors for anxiety by resequencing their 3'UTRs in patients with panic disorder (PD), obsessive-compulsive disorder (OCD), and in controls. We have found the C allele of rs28521337, located in a functional target site for miR-485-3p in the truncated isoform of NTRK3, to be significantly associated with the hoarding phenotype of OCD. We have also identified two new rare variants in the 3'UTR of NTRK3, ss102661458 and ss102661460, each present only in one chromosome of a patient with PD. The ss102661458 variant is located in a functional target site for miR-765, and the ss102661460 in functional target sites for two miRNAs, miR-509 and miR-128, the latter being a brain-enriched miRNA involved in neuronal differentiation and synaptic processing. Interestingly, these two variants significantly alter the miRNA-mediated regulation of NTRK3, resulting in recovery of gene expression. These data implicate miRNAs as key posttranscriptional regulators of NTRK3 and provide a framework for allele-specific miRNA regulation of NTRK3 in anxiety disorders.

Nódulo en extremidad inferior / Nevus on lower extremity

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Detección de papilomavirus humano (HPV) en carcinoma epidermoide de paladar en paciente HIV positivo / Human Papíllomavírus (HPV) Detectíon in Squamous Carcinoma of the Palate in a Patient wíth AIDS

Los virus del papiloma humano son virus DNA epitel¡otro picos implicados en carcinogénesis cervical , evaluándose en la actualidad su papel en carcinogénesis oral. El aumento de la incidencia de cáncer epidermoide de cérvix uterino en pacientes con SIDA plantea la posible inte-racción HPV - HIV en su desarrollo y, por extensión, en el de carcinoma epidermoide de otras localizaciones extragenitales. Presentamos un caso de carcinoma escamoso de paladar en paciente joven con síndrome de i'nmunodeficiencia adquirida, en el que se demuestra la pre-sencia de- HPV en las células neoplásicas mediante hibridación in situ -utilizando una sonda genérica. Posteriormente , con técnica de PCR, se detectó HPV 18 (de alto riesgo oncogénico). Pensamos que la posible interacción oncogénica HPV HIV puede darse en otras localizaciones aparte de -la- genital. (AU)