EGFR inhibitors identified as a potential treatment for chordoma in a focused compound screen.

Chordoma is a rare malignant bone tumour with a poor prognosis and limited therapeutic options. We undertook a focused compound screen (FCS) against 1097 compounds on three well-characterized chordoma cell lines; 154 compounds were selected from the single concentration screen (1 µm), based on their growth-inhibitory effect. Their half-maximal effective concentration (EC50 ) values were determined in chordoma cells and normal fibroblasts. Twenty-seven of these compounds displayed chordoma selective cell kill and 21/27 (78%) were found to be EGFR/ERBB family inhibitors. EGFR inhibitors in clinical development were then studied on an extended cell line panel of seven chordoma cell lines, four of which were sensitive to EGFR inhibition. Sapitinib (AstraZeneca) emerged as the lead compound, followed by gefitinib (AstraZeneca) and erlotinib (Roche/Genentech). The compounds were shown to induce apoptosis in the sensitive cell lines and suppressed phospho-EGFR and its downstream pathways in a dose-dependent manner. Analysis of substituent patterns suggested that EGFR-inhibitors with small aniline substituents in the 4-position of the quinazoline ring were more effective than inhibitors with large substituents in that position. Sapitinib showed significantly reduced tumour growth in two xenograft mouse models (U-CH1 xenograft and a patient-derived xenograft, SF8894). One of the resistant cell lines (U-CH2) was shown to express high levels of phospho-MET, a known bypass signalling pathway to EGFR. Neither amplifications (EGFR, ERBB2, MET) nor mutations in EGFR, ERBB2, ERBB4, PIK3CA, BRAF, NRAS, KRAS, PTEN, MET or other cancer gene hotspots were detected in the cell lines. Our findings are consistent with the reported (p-)EGFR expression in the majority of clinical samples, and provide evidence for exploring the efficacy of EGFR inhibitors in the treatment of patients with chordoma and studying possible resistance mechanisms to these compounds in vitro and in vivo. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Association between blood pressure and angiotensin-converting enzymes activity in prepubertal children ∗.

OBJECTIVES: Angiotensin-converting enzymes' (ACEs) relationship with blood pressure (BP) during childhood has not been clearly established. We aimed to compare ACE and ACE2 activities between BMI groups in a sample of prepubertal children, and to characterize the association between these enzymes' activities and BP. METHODS: Cross-sectional study of 313 children aged 8-9 years old, included in the birth cohort Generation XXI (Portugal). Anthropometric measurements and 24-h ambulatory BP monitoring were performed. ACE and ACE2 activities were quantified by fluorometric methods. RESULTS: Overweight/obese children demonstrated significantly higher ACE and ACE2 activities, when compared to their normal weight counterparts [median (P25-P75), ACE: 39.48 (30.52-48.97) vs. 42.90 (35.62-47.18) vs. 43.38 (33.49-49.89) mU/ml, P for trend = 0.009; ACE2: 10.41 (7.58-15.47) vs. 21.56 (13.34-29.09) vs. 29.00 (22.91-34.32) pM/min per ml, P for trend < 0.001, in normal weight, overweight and obese children, respectively]. In girls, night-time systolic BP (SBP) and diastolic BP (DBP) increased across tertiles of ACE activity ( P < 0.001 and P  = 0.002, respectively). ACE2 activity was associated with higher night-time SBP and DBP in overweight/obese girls ( P  = 0.037 and P  = 0.048, respectively) and night-time DBP in the BMI z-score girl adjusted model ( P  = 0.018). Median ACE2 levels were significantly higher among nondipper girls (16.7 vs. 11.6 pM/min per ml, P  = 0.009). CONCLUSIONS: Our work shows that obesity is associated with activation of the renin-angiotensin-aldosterone system, with significant increase of ACE and ACE2 activities already in childhood. Also, we report sex differences in the association of ACE and ACE2 activities with BP.

Pervasive transcription read-through promotes aberrant expression of oncogenes and RNA chimeras in renal carcinoma.

Aberrant expression of cancer genes and non-canonical RNA species is a hallmark of cancer. However, the mechanisms driving such atypical gene expression programs are incompletely understood. Here, our transcriptional profiling of a cohort of 50 primary clear cell renal cell carcinoma (ccRCC) samples from The Cancer Genome Atlas (TCGA) reveals that transcription read-through beyond the termination site is a source of transcriptome diversity in cancer cells. Amongst the genes most frequently mutated in ccRCC, we identified SETD2 inactivation as a potent enhancer of transcription read-through. We further show that invasion of neighbouring genes and generation of RNA chimeras are functional outcomes of transcription read-through. We identified the BCL2 oncogene as one of such invaded genes and detected a novel chimera, the CTSC-RAB38, in 20% of ccRCC samples. Collectively, our data highlight a novel link between transcription read-through and aberrant expression of oncogenes and chimeric transcripts that is prevalent in cancer.

Caracterização dos hábitos e sintomas vocais de locutores de rádio / Characterization of habits and vocal symptoms of radio presenters / Caracterización de los hábitos y síntomas vocales de presentadores de radiodifución

Objetivo: caracterizar os hábitos e sintomas vocais de locutores de rádio. Método: estudo observacional, descritivo e transversal, cuja população foi constituída por 31 locutores, de ambos os sexos, sendo 28 homens e três mulheres, que pertenciam a seis emissoras de rádio com modo de transmissão AM e FM, localizadas em uma cidade do interior do Paraná. Todos os participantes responderam a um questionário composto por 30 perguntas objetivas sobre hábitos saudáveis e deletérios e sintomas vocais. Resultados: a quantidade média de sintomas foi de 2,13. O hábito vocal saudável de maior ocorrência foi ?ingestão de água em temperatura ambiente? (n=25; 80,60%) e os deletérios foram ?tosse ou pigarro? (n=11; 35,5%) e ?fala em forte intensidade? (n=11; 35,5%). A maioria dos locutores não pratica esportes (p<0,001), não teve necessidade de modificar o padrão vocal para atuar na área (p<0,001), não possuí problemas respiratórios (p<0,001) e não teve problemas vocais diagnosticados (p<0,001). À medida que a quantidade de hábitos deletérios aumenta, maior também é a quantidade de sintomas (p=0,001). Observou-se, também, que locutores que tiveram formação profissional específica possuem maior quantidade de hábitos saudáveis (p=0,021). Os indivíduos que precisaram modificar o padrão vocal para poder trabalhar com locução estão na profissão há mais tempo que os sujeitos que não precisaram modificá-lo (p=0,047). Conclusão: a média de sintomas referida por locutores de rádio é baixa. Apesar disso, a adoção de hábitos deletérios pode desencadear alterações vocais, tornando-se importante o trabalho de promoção da saúde vocal junto a essa população.

Objective: characterize the vocal habits and symptoms of radio broadcasters. Methods: observational, descriptive, cross-sectional sample which comprised 31 speakers, of both sexes, with 28 men and three women, belonging to six radio transmission mode with AM and FM, in a city located in the interior of Paraná . All participants answered a questionnaire composed of 30 objective questions about habits, healthy and harmful, and vocal symptoms. Results: the average number of symptoms was 2,13. The highest occurrence of healthy habits was that of ?drinking room temperature water? (n=25;80,60%) and the deleterious were ?cough or phlegm? (n=11;35,5%) and ?speaks in strong intensity ?(n=11;35,5%). Most radio broadcasters do not practice sports (p<0,001), had no need to modify the standard for vocal work in the area (p=<0,001), did not present breathing problems (p=<0,001) and did not have vocal problems diagnosed (p=<0,001). As the amount of harmful habits increases, the number of symptoms also is increased (p=0,001). We also noticed that radio broadcasters who have had specific training have a higher amount of healthy habits (p=0,021). Individuals who changed the voice to be able to work with voiceover are in the profession for longer time than the subjects who did not modify the vocal pattern (p=0,047). Conclusion: the average of symptoms reported by radio broadcasters is low. Nevertheless, the adoption of harmful habits can trigger vocal alterations, making it important the work of vocal health promotion with this population.

Objetivo: Caracterizar los hábitos y síntomas vocales de locutores de radiodifusión. Método: estudio observacional, descriptivo, de corte transversal cuya populación fue de 31 locutores, de ambos sexos, 28 hombres y tres mujeres pertenecientes a seis estaciones de radio con modo de transmisión AM y FM, ubicada en una ciudad del interior Paraná. Todos los participantes respondieron un cuestionario compuesto por 30 preguntas objetivas sobre hábitos saludables y prejudiciales, y síntomas vocales. Resultados: El promedio de los síntomas fue de 2,13. El hábito vocal saludable de mayor ocurrencia fue ?beber agua a temperatura ambiente? (n=25; 80,60%) y los prejudiciales fueron ?la tos o flema? (n=11; 35,5%) y ?habla con fuerte intensidad? (n=11; 35,5%). La mayoría de los locutores no practica deporte (p<0,001), no tubo necesidad de modificar el patron vocal para el trabajo (p<0,001), no tenía problemas respiratorios (p<0,001) y no tubo problemas vocales diagnosticados (p<0,001). Cuanto mas aumentan los hábitos nocivos, también aumenta el número de síntomas (p=0,001). También se observó que locutores que tuvieron una formación profesional específica tenian mayor cantidad de hábitos sanos (p=0,021). Las personas que tuvieron que cambiar el patron vocal para poder trabajar con locución se encuentran en la profesión hace mas tiempo que los sujetos que no necesitaron cambiarlo (p=0,047). Conclusión: La media de los síntomas reportados por locutores de radio es baja. Sin embargo, la adopción de hábitos nocivos pueden desencadenar trastornos vocales, por lo que es importante para la labor el trabajo de promoción de la salud vocal con esta población.