ΔNp63-Senataxin circuit controls keratinocyte differentiation by promoting the transcriptional termination of epidermal genes.

SignificanceΔNp63 is a master regulator of skin homeostasis since it finely controls keratinocyte differentiation and proliferation. Here, we provide cellular and molecular evidence demonstrating the functional role of a ΔNp63 interactor, the R-loop-resolving enzyme Senataxin (SETX), in fine-tuning keratinocyte differentiation. We found that SETX physically binds the p63 DNA-binding motif present in two early epidermal differentiation genes, Keratin 1 (KRT1) and ZNF750, facilitating R-loop removal over their 3' ends and thus allowing efficient transcriptional termination and gene expression. These molecular events translate into the inability of SETX-depleted keratinocytes to undergo the correct epidermal differentiation program. Remarkably, SETX is dysregulated in cutaneous squamous cell carcinoma, suggesting its potential involvement in the pathogenesis of skin disorders.

Emerging roles of the HECT-type E3 ubiquitin ligases in hematological malignancies.

Ubiquitination-mediated proteolysis or regulation of proteins, ultimately executed by E3 ubiquitin ligases, control a wide array of cellular processes, including transcription, cell cycle, autophagy and apoptotic cell death. HECT-type E3 ubiquitin ligases can be distinguished from other subfamilies of E3 ubiquitin ligases because they have a C-terminal HECT domain that directly catalyzes the covalent attachment of ubiquitin to their substrate proteins. Deregulation of HECT-type E3-mediated ubiquitination plays a prominent role in cancer development and chemoresistance. Several members of this subfamily are indeed frequently deregulated in human cancers as a result of genetic mutations and altered expression or activity. HECT-type E3s contribute to tumorigenesis by regulating the ubiquitination rate of substrates that function as either tumour suppressors or oncogenes. While the pathological roles of the HECT family members in solid tumors are quite well established, their contribution to the pathogenesis of hematological malignancies has only recently emerged. This review aims to provide a comprehensive overview of the involvement of the HECT-type E3s in leukemogenesis.

p63 at the Crossroads between Stemness and Metastasis in Breast Cancer.

After lung cancer, breast cancer (BC) is the most frequent cause of cancer death among women, worldwide. Although advances in screening approaches and targeted therapeutic agents have decreased BC incidence and mortality, over the past five years, triple-negative breast cancer (TNBC) remains the breast cancer subtype that displays the worst prognosis, mainly due to the lack of clinically actionable targets. Genetic and molecular profiling has unveiled the high intrinsic heterogeneity of TNBC, with the basal-like molecular subtypes representing the most diffuse TNBC subtypes, characterized by the expression of basal epithelial markers, such as the transcription factor p63. In this review, we will provide a broad picture on the physiological role of p63, in maintaining the basal epithelial identity, as well as its involvement in breast cancer progression, emphasizing its relevance in tumor cell invasion and stemness.

ΔNp63 in squamous cell carcinoma: defining the oncogenic routes affecting epigenetic landscape and tumour microenvironment.

Squamous cell carcinoma (SCC) is a treatment-refractory tumour which arises from the epithelium of diverse anatomical sites such as oesophagus, head and neck, lung and skin. Accumulating evidence has revealed a number of genomic, clinical and molecular features commonly observed in SCC of distinct origins. Some of these genetic events culminate in fostering the activity of ΔNp63, a potent oncogene which exerts its pro-tumourigenic effects by regulating specific transcriptional programmes to sustain malignant cell proliferation and survival. In this review, we will describe the genetic and epigenetic determinants underlying ΔNp63 oncogenic activities in SCC, and discuss some relevant transcriptional effectors of ΔNp63, emphasizing their impact in modulating the crosstalk between tumour cells and tumour microenvironment (TME).

ΔNp63 promotes IGF1 signalling through IRS1 in squamous cell carcinoma.

Accumulating evidence has proved that deregulation of ΔNp63 expression plays an oncogenic role in head and neck squamous cell carcinomas (HNSCCs). Besides p63, the type 1-insulin-like growth factor (IGF) signalling pathway has been implicated in HNSCC development and progression. Most insulin/IGF1 signalling converges intracellularly onto the protein adaptor insulin receptor substrate-1 (IRS-1) that transmits signals from the receptor to downstream effectors, including the PI3K/AKT and the MAPK kinase pathways, which, ultimately, promote proliferation, invasion, and cell survival. Here we report that p63 directly controls IRS1 transcription and cellular abundance and fosters the PI3K/AKT and MAPK downstream signalling pathways. Inactivation of ΔNp63 expression indeed reduces tumour cell responsiveness to IGF1 stimulation, and inhibits the growth potential of HNSCC cells. In addition, a positive correlation was observed between p63 and IRS1 expression in human HNSCC tissue arrays and in publicly available gene expression data. Our findings indicate that aberrant expression of ΔNp63 in HNSSC may act as an oncogenic stimulus by altering the IGF signalling pathway.

ΔNp63 regulates the expression of hyaluronic acid-related genes in breast cancer cells.

Triple negative breast cancers (TNBC) represent the most aggressive and clinically relevant breast carcinomas. On the basis of specific molecular signature, the majority of TNBC can be classified as basal-like breast carcinoma. Here, we report data showing that in basal-like breast carcinoma cells ΔNp63 is capable of sustaining the production of the hyaluronic acid (HA), one of the major component of the extracellular matrix (ECM). At molecular level, we found that ΔNp63 regulates the expression of HA-related genes, such as the HA synthase HAS3, the hyaluronidase HYAL-1 and CD44, the major HA cell membrane receptor. By controlling this pathway, ∆Np63 contributes to maintain the self-renewal of breast cancer stem cells. Importantly, high HAS3 expression is a negative prognostic factor of TNBC patients. Our data suggest that in basal-type breast carcinoma ∆Np63 might favor a HA-rich microenviroment, which can sustain tumor proliferation and stemness.

ΔNp63-mediated regulation of hyaluronic acid metabolism and signaling supports HNSCC tumorigenesis.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and several molecular pathways that underlie the molecular tumorigenesis of HNSCC have been identified. Among them, amplification or overexpression of ΔNp63 isoforms is observed in the majority of HNSCCs. Here, we unveiled a ΔNp63-dependent transcriptional program able to regulate the metabolism and the signaling of hyaluronic acid (HA), the major component of the extracellular matrix (ECM). We found that ∆Np63 is capable of sustaining the production of HA levels in cell culture and in vivo by regulating the expression of the HA synthase HAS3 and two hyaluronidase genes, HYAL-1 and HYAL-3. In addition, ∆Np63 directly regulates the expression of CD44, the major HA cell membrane receptor. By controlling this transcriptional program, ∆Np63 sustains the epithelial growth factor receptor (EGF-R) activation and the expression of ABCC1 multidrug transporter gene, thus contributing to tumor cell proliferation and chemoresistance. Importantly, p63 expression is positively correlated with CD44, HAS3, and ABCC1 expression in squamous cell carcinoma datasets and p63-HA pathway is a negative prognostic factor of HNSCC patient survival. Altogether, our data shed light on a ∆Np63-dependent pathway functionally important to the regulation of HNSCC progression.

Aplicabilidad de la Predicción de Moyers 75% en pacientes Mapuche-Hulliche, Chile / Applicability of the Moyers prediction tables at 75% on Mapuche-Huilliche patients, Chile

Objetivo: determinar aplicabilidad del método Moyers 75% en población mapuche huilliche, Chile. Material y metodos: estudio descriptivo observacional se evaluó la predicción de Moyers nivel 75% en una población Mapuche Huilliche entre los 11 y 17 años de edad (25 hombres y 25 mujeres). Se determinó la suma de incisivos inferiores y la sumatoria de caninos y premolares de cada hemiarcada comparando con los valores predictivos. Resultados: Mayor número de casos en el rango 23.5 mm a 25.2 mm en la suma de incisivos inferiores, 60% de la muestra. La suma entre caninos y premolares presentó un promedio en el maxilar de 23.7 mm en hombres y 23.1 mm en mujeres y en la mandíbula un promedio de 22.9 mm en hombres y 22.1 mm en mujeres. Se encontró una discrepancia negativa de 60% en hombres y de un 40% en mujeres. En mujeres la discrepancia positiva superó a las negativas con porcentajes de 88% y 8%, significativamente. Conclusión:El método Moyers 75% es aplicable en hombres para ambos maxilares y parcialmente en mujeres huilliches.

Objective. To determine the applicability of the Moyers prediction tables at 75% on patients from the Mapuche-Huilliche population, Chile. Materials and Methods. A descriptive, observational study which evaluated the Moyers prediction tables at 75% in a Mapuche-Huilliche population aged between 11 and 17(25 men and 25 women). The sum of the lower incisors, and the sum of the canines and premolars of each quadrant was compared with each of the predictive values. Results. Increased number of cases in the range from 23.5 mm to 25.2 mm in the sum of lower incisors, which represent 60% of the sample. The sum of canines and premolars showed in maxilla a mean of 23.7 mm in men and 23.1 mm in women, and in mandiblea mean of 22.9 mm in men and 22.1 mm in women. A negative discrepancy of 60% was found in men and of 40% in women. For women, the positive discrepancysignificantly exceeded the negative discrepancies with percentages of 88% and 8%. Conclusions. The Moyers method at 75% was applicable in maxilla and mandible on Huilliche men, and partially applicable on women of the same ethnic group.

Evaluación de anchos intercaninos e intermolares en escolares con dentición mixta, Comuna de Contulmo, Chile / Evaluation of intercanine and intermolar widths in students with mixed dentition, Contulmo Commune, Chile

Introducción: El éxito del tratamiento ortodóncico temprano se fundamenta en el conocimiento del desarrollo de la dentición, por lo cual la medición de susdimensiones en los diferentes estadios de desarrollo se considera como un factor predictor para el tratamiento y rehabilitación de la población. Objetivo: Conocer y evaluar las características cuantitativas de los anchos intercaninos e intermolares según sexo en la población de niños de 6 a 8 años de la Escuela Artística San Luis de Contulmo.Metodología: Estudio cuantitativo, no experimental, de corte transversal, descriptivo y correlacional. La población de estudio correspondió a 48 alumnos de 6 a 8 años seleccionados por muestreo por conveniencia, a los cuales se les tomó modelos de estudio, midiendo y comparando los anchos intercaninos e intermolares. Resultados: Los promedios resultantes de las mediciones efectuadas fueron: distancia intercanina maxilar 33,2 +/-2,6 mm en hombres y 32,2 +/-2,3 mm en mujeres, respectivamente la distancia intercanina mandibular 27,1 +/-2,3 mm y 26, 6 +/-1,9 mm, la distancia intermolar maxilar 51,9 +/-3,1 y 51,2 +/-3,0 mm y la distancia intermolar mandibular 46 +/-2,6 y 44,8 +/-3,0 mm. Conclusión: Las diferencias entre los anchos intercaninos e intermolares según sexo no son significativas, en cuanto a la edad se observan diferencias significativas entre los 6 y 8 años en el sexo masculino, no así en el femenino. Este estudio representa un interesante punto de partida para el análisis y discusión de futuras investigaciones.

Introduction: The early orthodontic treatment success is based on knowledge the development of the dentition, so measuring their dimensions at different stages of development is considered as a predictor for treatment and rehabilitation of the population. Objective: To explore and evaluate the quantitative characteristics of intercanine and intermolar widths by sex in the population of children of 6-8 years of the Escuela Artistica San Luis de Contulmo. Methodology: quantitative study, non-experimental, cross-sectional, descriptive and correlational. The study population corresponded to 48 students from 6 to 8 years selected by probabilistic sampling, unintentional and opportunistic, to which took study models, measuring and comparing intercanine and intermolar widths. Results: The resulting averages of measurements were: maxillary intercanine 33.2 +/-2.6 mm in men and 32.2 +/-2.3 mm in women, mandibular intercanine distances respectively 27.1 +/- 2.3 mm and 26 6 +/-1.9 mm, the distance intermolar maxillary 51.9 +/-3.1 and 51.2 +/-3.0 mm and the distance mandibular intermolar 46 +/-2.6 and 44.8 +/-3.0 mm. Conclusion: In relation to the difference between intercanine and intermolar widths by sex are not significant, in terms of age significant differences between 6 and 8 males but not in females. This study represents an interesting starting point for the analysis and discussion of future research.

Enfisema bilobar congénito: Una presentación poco común y revisión de la literatura / Congenital bilobar emphysema: An unusual presentation and literature review

Introducción: El enfisema bilobar congénito es una malformación poco frecuente, que puede ser causa de insuficiencia respiratoria en el niño. Las manifestaciones son producto de la sobreexpansión de un lóbulo pulmonar con comprensión del parénquima del pulmón sano con desplazamiento del mediastino. La lesión bilobar es extremadamente rara. El propósito del presente trabajo es presentar un caso tratado quirúrgicamente por el grupo, teniendo una buena evolución. Reporte de caso: Paciente masculino de 4 meses de edad obtenido a término por cesárea; el paciente inició manifestaciones pulmonares con taquipnea. La radiografía de tórax demostró atrapamiento de aire de hemitórax izquierdo con desplazamiento del hemitórax. La biopsia demostró enfisema lobar congénito y se le realizó una lobectomía. El paciente tuvo un seguimiento de más de dos años y su evolución fue satisfactoria. Discusión: El enfisema bilobar congénito es una condición poco frecuente. El diagnóstico de enfisema bilobar puede ser difícil. La cirugía debe ser guiada con bases clínicas y radiológicas; sin embargo, el manejo en los casos de lesión bilobar suele ser controversial.

Introduction: Congenital bilobar emphysema is an infrequent congenital malformation which may be the cause of respiratory insufficiency in the smaller suckling child. It is produced by the overexpansion of one lung lobe with compression of the normal lung parenchyma and displacement of the mediastinum bilobar or multifocal involvement is extremely rare. Our purpose is to present one cases of this illness which were surgically treated by our team. Case presented: A male infant developed respiratory distress at 4 months of age. He was born at term by abdominal delivery. The patient was hemodynamically stable, tachypneic, but with no abnormal lung sounds. Chest radiography demonstrated a hyperinflated left hemithorax with mediastinal shift to the right and mediastinal hernia. Surgery and histology examination demonstrated distended alveoli. He has been followed for 2 years and no complications have occurred since. Discussion: Congenital bilobar emphysema is a rare condition. Diagnosis of bilobar involvement may be difficult. Congenital bilobar emphysema may be managed by simultaneous or sequential bilobectomies. Surgical management should be guided by clinical and radiologic findings and evaluated peroperatively and postoperatively. Surgical management of bilobar emphysema is controversial.