SOX10-Internal Tandem Duplications and PLAG1 or HMGA2 Fusions Segregate Eccrine-Type and Apocrine-Type Cutaneous Mixed Tumors.

Cutaneous mixed tumors exhibit a wide morphologic diversity and are currently classified into apocrine and eccrine types based on their morphologic differentiation. Some cases of apocrine-type cutaneous mixed tumors (ACMT), namely, hyaline cell-rich apocrine cutaneous mixed tumors (HCR-ACMT) show a prominent or exclusive plasmacytoid myoepithelial component. Although recurrent fusions of PLAG1 have been observed in ACMT, the oncogenic driver of eccrine-type cutaneous mixed tumors (ECMT) is still unknown. The aim of the study was to provide a comprehensive morphologic, immunohistochemical, and molecular characterization of these tumors. Forty-one cases were included in this study: 28 cases of ACMT/HCR-ACMT and 13 cases of ECMT. After morphologic and immunohistochemical characterization, all specimens were analyzed by RNA sequencing. By immunohistochemistry, all cases showed expression of SOX10, but only ACMT/HCR-ACMT showed expression of PLAG1 and HMGA2. RNA sequencing confirmed the presence of recurrent fusion of PLAG1 or HMGA2 in all cases of ACMT/HCR-ACMT, with a perfect correlation with PLAG1/HMGA2 immunohistochemical status, and revealed internal tandem duplications of SOX10 (SOX10-ITD) in all cases of ECMT. Although TRPS1::PLAG1 was the most frequent fusion, HMGA2::WIF1 and HMGA2::NFIB were detected in ACMT cases. Clustering analysis based on gene expression profiling of 110 tumors, including numerous histotypes, showed that ECMT formed a distinct group compared with all other tumors. ACMT, HCR-ACMT, and salivary gland pleomorphic adenoma clustered together, whereas myoepithelioma with fusions of EWSR1, FUS, PBX1, PBX3, POU5F1, and KLF17 formed another cluster. Follow-up showed no evidence of disease in 23 cases across all 3 tumor types. In conclusion, our study demonstrated for the first time SOX10-ITD in ECMT and HMGA2 fusions in ACMT and further refined the prevalence of PLAG1 fusions in ACMT. Clustering analyses revealed the transcriptomic distance between these different tumors, especially in the heterogenous group of myoepitheliomas.

Recurrent PAK2 rearrangements in poroma with folliculo-sebaceous differentiation.

AIMS: Poroma is a benign adnexal neoplasm with differentiation towards the upper portion of the sweat gland apparatus. In 2019, Sekine et al. demonstrated recurrent YAP1::MAML2 and YAP1::NUTM1 fusion in poroma and porocarcinoma. Follicular, sebaceous and/or apocrine differentiation has been reported in rare cases of poroma and whether these tumours constitute a variant of poroma or represent a distinctive tumour is a matter to debate. Herein we describe the clinical, immunophenotypic, and molecular features of 13 cases of poroma with folliculo-sebaceous differentiation. METHODS AND RESULTS: Most of the tumours were located on the head and neck region (n = 7), and on the thigh (n = 3). All presented were adults with a slight male predilection. The median tumour size was 10 mm (range: 4-25). Microscopically, lesions displayed features of poroma with nodules of monotonous basophilic cells associated with a second population of larger eosinophilic cells. In all cases, ducts and scattered sebocytes were identified. Infundibular cysts were present in 10 cases. In two cases high mitotic activity was noted, and in three cases cytologic atypia and areas of necrosis were identified. Whole transcriptome RNA sequencing demonstrated in-frame fusion transcripts involving RNF13::PAK2 (n = 4), EPHB3::PAK2 (n = 2), DLG1::PAK2 (n = 2), LRIG1::PAK2 (n = 1), ATP1B3::PAK2 (n = 1), TM9SF4::PAK2 (n = 1), and CTNNA1::PAK2 (n = 1). Moreover, fluorescence in situ hybridisation (FISH) analysis revealed PAK2 rearrangement in an additional case. No YAP1::MAML2 or YAP1::NUTM1 fusion was detected. CONCLUSION: Recurrent fusions involving the PAK2 gene in all analysed poroma with folliculo-sebaceous differentiation in this study confirms that this neoplasm represents a separate tumour entity distinct from YAP1::MAML2 or YAP1::NUTM1 rearranged poromas.

Protective association exhibited by a single nucleotide polymorphism of the IFIH1 gene in patients with psoriasis: A case-control study. / Asociación protectora del polimorfismo de nucleótido único en IFIH1 en pacientes con psoriasis: estudio de casos y controles.

INTRODUCTION: Psoriasis is a chronic inflammatory dermatosis, a with variable clinical presentation and whose multifactorial etiology carries an essential genetic component. Multiple genetic variations associated with psoriasis have been described around the world. However, these variants are unknown among the Colombian population. This study aimed to evaluate the single nucleotide polymorphism rs10930046 (His460Arg) in the IFIH1 gene and its ssociation with the development of psoriasis in a Colombian population. METHODS: An observational, unmatched, case-control study was performed, including 51 patients with psoriasis and 151 population controls, all with self-reported Paisa ancestry (from the Antioquia region). All individuals were genotyped for the single nucleotide polymorphism rs10930046 (His460Arg) in the IFIH1 gene, and its association with psoriasis was pursued. Both groups were demographically characterized, and cases were also assessed for clinical variables. RESULTS: Through the allelic association analysis, cases were found to have a lower frequency of the single nucleotide polymorphism rs10930046 (His460Arg) in the IFIH1 gene than controls; 5% versus 22.67%, respectively. There were no significant differences in age or sex. We also found that psoriasis vulgaris was the most common variant (78%), that about half of the cases had nail psoriasis (56%), 19.6% had psoriatic arthritis, and that 45% had some comorbidity. CONCLUSIONS: The results obtained from this study confirm that carriers of the single nucleotide polymorphism rs10930046 (His460Arg) in the IFIH1 gene have a decreased risk of developing psoriasis.

INTRODUCCIÓN: La psoriasis es una dermatosis inflamatoria crónica, con presentación clínica variable y cuya etiología involucra un componente genético importante. Alrededor del mundo se han descrito múltiples variaciones genéticas asociadas a la enfermedad. Sin embargo, en población colombiana se desconocen estas variantes. En este estudio se evalúa el polimorfismo de nucleótido único rs10930046 (His460Arg) en el gen IFIH1 y su asociación con el desarrollo de psoriasis en población colombiana. Además, se caracteriza a los individuos demográfica y clínicamente. MÉTODOS: Se realizó un estudio observacional de casos y controles, no pareado, que incluyó 51 individuos con psoriasis y 151 controles poblacionales, todos de ancestría paisa (proveniente de la región de Antioquia) auto reportada. A todos los individuos se les realizó genotipificación del polimorfismo de nucleótido único rs10930046 (His460Arg) en el gen IFIH1 y se les determinó la asociación con la enfermedad. Se caracterizaron demográficamente ambos grupos y los casos clínicamente. RESULTADOS: Se encontró que los casos presentaron una menor frecuencia del polimorfismo de nucleótido único rs10930046 (His460Arg) en el gen IFIH1 en relación a los controles, 5 versus 22,67% respectivamente, con un análisis de asociación alélico. No hubo diferencias significativas en edad ni en sexo. La psoriasis vulgar fue la variante de presentación más común (78%). Alrededor de la mitad de los casos presentaron psoriasis ungular (56%), en menor frecuencia artritis psoriásica (19,6%) y el 45% de los casos tuvo alguna comorbilidad. CONCLUSIONES: Los resultados obtenidos confirman que los portadores del polimorfismo de nucleótido único rs10930046 (His460Arg) en el gen IFIH1, presentan un riesgo disminuido de desarrollar psoriasis.

Systemic delivery of TNF-armed myxoma virus plus immune checkpoint inhibitor eliminates lung metastatic mouse osteosarcoma.

Solid cancers that metastasize to the lungs represent a major therapeutic challenge. Current treatment paradigms for lung metastases consist of radiation therapy, chemotherapies, and surgical resection, but there is no single treatment or combination that is effective for all tumor types. To address this, oncolytic myxoma virus (MYXV) engineered to express human tumor necrosis factor (vMyx-hTNF) was tested after systemic administration in an immunocompetent mouse K7M2-Luc lung metastatic osteosarcoma model. Virus therapy efficacy against pre-seeded lung metastases was assessed after systemic infusion of either naked virus or ex vivo-loaded autologous bone marrow leukocytes or peripheral blood mononuclear cells (PBMCs). Results of this study showed that the PBMC pre-loaded strategy was the most effective at reducing tumor burden and increasing median survival time, but sequential intravenous multi-dosing with naked virus was comparably effective to a single infusion of PBMC-loaded virus. PBMC-loaded vMyx-hTNF also potentially synergized very effectively with immune checkpoint inhibitors anti-PD-1, anti-PD-L1, and anti-cytotoxic T lymphocyte associated protein 4 (CTLA-4). Finally, in addition to the pro-immune stimulation caused by unarmed MYXV, the TNF transgene of vMyx-hTNF further induced the unique expression of numerous additional cytokines associated with the innate and adaptive immune responses in this model. We conclude that systemic ex vivo virotherapy with TNF-α-armed MYXV represents a new potential strategy against lung metastatic cancers like osteosarcoma and can potentially act synergistically with established checkpoint immunotherapies.

Changes in Serotonin Modulation of Glutamate Currents in Pyramidal Offspring Cells of Rats Treated With 5-MT during Gestation.

Changes in stimuli and feeding in pregnant mothers alter the behavior of offspring. Since behavior is mediated by brain activity, it is expected that postnatal changes occur at the level of currents, receptors or soma and dendrites structure and modulation. In this work, we explore at the mechanism level the effects on Sprague-Dawley rat offspring following the administration of serotonin (5-HT) agonist 5-methoxytryptamine (5-MT). We analyzed whether 5-HT affects the glutamate-activated (IGlut) and N-methyl-D-aspartate (NMDA)-activated currents (IGlut, INMDA) in dissociated pyramidal neurons from the prefrontal cortex (PFC). For this purpose, we performed voltage-clamp experiments on pyramidal neurons from layers V-VI of the PFC of 40-day-old offspring born from 5-MT-treated mothers at the gestational days (GD) 11 to 21. We found that the pyramidal-neurons from the PFC of offspring of mothers treated with 5-MT exhibit a significant increased reduction in both the IGlut and INMDA when 5-HT was administered. Our results suggest that the concentration increase of a neuromodulator during the gestation induces changes in its modulatory action over the offspring ionic currents during the adulthood thus contributing to possible psychiatric disorders.

Striatal Neurodegeneration that Mimics Huntington's Disease Modifies GABA-induced Currents.

Huntington's Disease (HD) is a degenerative disease which produces cognitive and motor disturbances. Treatment with GABAergic agonists improves the behavior and activity of mitochondrial complexes in rodents treated with 3-nitropropionic acid to mimic HD symptomatology. Apparently, GABA receptors activity may protect striatal medium spiny neurons (MSNs) from excitotoxic damage. This study evaluates whether mitochondrial inhibition with 3-NP that mimics the early stages of HD, modifies the kinetics and pharmacology of GABA receptors in patch clamp recorded dissociated MSNs cells. The results show that MSNs from mice treated with 3-NP exhibited differences in GABA-induced dose-response currents and pharmacological responses that suggests the presence of GABAC receptors in MSNs. Furthermore, there was a reduction in the effect of the GABAC antagonist that demonstrates a lessening of this GABA receptor subtype activity as a result of mitochondria inhibition.

Factores asociados a los niveles de depresión situacional en pacientes oncológicas / Factors associated with levels of situational depression in cancer patients

Objetivo: la investigación tuvo como objetivo identificar los factores asociados a la depresión en pacientes oncológicos. Material y métodos: estudio cuantitativo, descriptivo y de corte transversal realizado en el servicio de oncología del Hospital Edgardo Rebagliati Martins de Lima durante los meses de mayo a junio 2010. La muestra estuvo conformada por 44 pacientes hospitalizados que cumplieron con los criterios de inclusión. El instrumento utilizado para medir el nivel de depresión fue el inventario de depresión de Beck, para identificar los factores asociados se utilizó un cuestionario de preguntas cerradas elaborado por las investigadoras y validado a través de juicio de expertos y prueba piloto. Resultado: muestran que el factor sociocultural sentimiento ante el diagnóstico (p=0,002). con estos datos se concluye que la depresión en pacientes oncológicos se ve influenciada por factores socioculturales y propios de la enfermedad.

Objective: The research had as an objective to identify the factors related to depression on oncological patients. Material and Methods: ItÆs a quantitative, descriptive and cross sectional study made at the Oncology Service at Edgardo Rebagliati Mastins Hospital-Lima during the months of may û june of 2010. The sample was conformed by 44 patients hospitalized who fulfilled inclusion criteria. The tool used to measure the depression level was the BeckÆs depression Inventory, and, to identify the associated factors, a closed question questionnaire was used, elaborated by investigators and validated by expertsÆ there was just an association between the patientsÆ satisfaction level about their disease and treatment (p=0.002). With these information itÆs concluded that depression on oncological patients is more influenced by sociocultural and diseaseÆs own factors, than personal factors.

A primary health care curriculum in action: the lived experience of primary health care nurses in a school of nursing in the Philippines: a phenomenological study.

Primary health care (PHC) nursing is widely practiced in the Philippines yet little is published about the nurses working in this field nor by these nurses. This paper describes a PHC nursing curriculum conducted in an island in the south of the Philippines and examines the experience of nurses working as faculty and simultaneously providing service to the local community. Data were collected from a convenience sample of faculty by interview and analysed using Huserrlian (descriptive) phenomenology and Colaizzi's method of data analysis. From 102 formulated meanings emerged four theme clusters: teaching PHC; external influences; the working reality and practicing PHC, and these are presented with exemplars from the interviews. The data gives a clear impression of the experience of implementing PHC and working with small communities and highlights the educational and clinical issues inherent in this unique model. The insights gained from the analysis of the interviews are contrasted with current literature and recommendations for future research are made.