Targeted proteomic quantitation of NRF2 signaling and predictive biomarkers in HNSCC

The NFE2L2 (NRF2) oncogene and transcription factor drives a gene expression program that promotes cancer progression, metabolic reprogramming, immune evasion, and chemoradiation resistance. Patient stratification by NRF2 activity may guide treatment decisions to improve outcome. Here, we developed a mass spectrometry-based targeted proteomics assay based on internal standard-triggered parallel reaction monitoring to quantify 69 NRF2 pathway components and targets, as well as 21 proteins of broad clinical significance in head and neck squamous cell carcinoma (HNSCC). We improved an existing internal standard-triggered parallel reaction monitoring acquisition algorithm, called SureQuant, to increase throughput, sensitivity, and precision. Testing the optimized platform on 27 lung and upper aerodigestive cancer cell models revealed 35 NRF2 responsive proteins. In formalin-fixed paraffin-embedded HNSCCs, NRF2 signaling intensity positively correlated with NRF2-activating mutations and with SOX2 protein expression. Protein markers of T-cell infiltration correlated positively with one another and with human papilloma virus infection status. CDKN2A (p16) protein expression positively correlated with the human papilloma virus oncogenic E7 protein and confirmed the presence of translationally active virus. This work establishes a clinically actionable HNSCC protein biomarker assay capable of quantifying over 600 peptides from frozen or formalin-fixed paraffin-embedded archived tissues in under 90 min

Effect of HPV on head and neck cancer patient survival, by region and tumor site: A comparison of 1362 cases across three continents

Objectives: To explore whether HPV-related biomarkers predict oropharyngeal squamous cell cancer (OPSCC) survival similarly across different global regions, and to explore their prognostic utility among non-oropharyngeal (non-OP) head and neck cancers. Methods: Data from 1362 head and neck SCC (HNSCC) diagnosed 2002–2011 was used from epidemiologic studies in: Brazil (GENCAPO study, n = 388), U.S. (CHANCE study, n = 472), and Europe (ARCAGE study, n = 502). Tumors were centrally tested for p16INK4a and HPV16 DNA (by PCR). Risk of mortality was examined using Cox proportional hazard models. Results: There were 517 OPSCC and 845 non-OP HNSCC. Cases were primarily male (81%), ever smokers (91%), with median age of 58 years and median follow-up of 3.1 years (IQR = 1.4–5.9). Among OPSCC, the risk of mortality was significantly lower among 184 HPV-related (i.e., p16+/HPV16+) compared to 333 HPV-unrelated (p16- and/or HPV16-) cases (HR = 0.25, 95%CI = 0.18–0.34). Mortality was reduced among HPV-related OPSCC cases from the U.S., Europe, and Brazil (each p ⩽ 0.01) and after adjustment, remained significantly reduced (aHR = 0.34, 95%CI = 0.24–0.49). Among non-OP HNSCC, neither p16 (aHR = 0.83, 95%CI = 0.60–1.14), HPV16 DNA (aHR = 1.20, 95%CI = 0.89–1.63), or p16+/HPV16+ (aHR = 0.59, 95%CI = 0.32–1.08) was a significantly predictor of mortality. When interaction was tested, the effect of HPV16/p16 was significantly different in OPSCC than non-OP HNSCC (p-interaction = 0.02). Conclusion: HPV-related OPSCCs had similar survival benefits across these three regions. Prognostic utility of HPV among non-OP HNSCC is limited so tumor HPV/p16 testing should not be routinely done among non-OP HNSCC

Local hydrological conditions influence tree diversity and composition across the Amazon basin

Tree diversity and composition in Amazonia are known to be strongly determined by the water supplied by precipitation. Nevertheless, within the same climatic regime, water availability is modulated by local topography and soil characteristics (hereafter referred to as local hydrological conditions), varying from saturated and poorly drained to well-drained and potentially dry areas. While these conditions may be expected to influence species distribution, the impacts of local hydrological conditions on tree diversity and composition remain poorly understood at the whole Amazon basin scale. Using a dataset of 443 1-ha non-flooded forest plots distributed across the basin, we investigate how local hydrological conditions influence 1) tree alpha diversity, 2) the community-weighted wood density mean (CWM-wd) – a proxy for hydraulic resistance and 3) tree species composition. We find that the effect of local hydrological conditions on tree diversity depends on climate, being more evident in wetter forests, where diversity increases towards locations with well-drained soils. CWM-wd increased towards better drained soils in Southern and Western Amazonia. Tree species composition changed along local soil hydrological gradients in Central-Eastern, Western and Southern Amazonia, and those changes were correlated with changes in the mean wood density of plots. Our results suggest that local hydrological gradients filter species, influencing the diversity and composition of Amazonian forests. Overall, this study shows that the effect of local hydrological conditions is pervasive, extending over wide Amazonian regions, and reinforces the importance of accounting for local topography and hydrology to better understand the likely response and resilience of forests to increased frequency of extreme climate events and rising temperatures

Da Amazônia ao Pacífico cruzando os Andes

A Área Amazônica (AA) é compartilhada por oito países sul-americanos independentes. Desde os tempos coloniais sentiu-se a necessidade da construção de uma via de união da AA com o Oceano Pacífico. Mas os Andes, em termos técnicos e econômicos, foram barreira insuperável até as últimas décadas do século XIX. Nos últimos anos, para o Brasil - país que tem perto de 60% da AA -, esta via vem se tornando cada vez mais importante em termos de exportação, especialmente para o mercado japonês, de grãos, madeira, polpa de madeira etc., ao mesmo tempo em que o Japão também deseja acesso direto à AA. Brasil e Peru, segundo país da AA, com a maior e mais ocidental costa no Pacífico, têm desenvolvido projetos para a construção de uma estrada, contando para isso com apoio financeiro oferecido pelo Japão em diversas oportunidades. Tais projetos tentam conciliar não apenas os interesses de Brasil e Peru, mas também os da Bolívia, país mediterrâneo que poderia finalmente ter acesso livre à costa do Pacífico. Os Estados Unidos, porém, opõem-se a construção da mencionada via e, o projeto está a espera de que o financiamento anteriormente aventado permita sua concretização. Parece que, na construção da projetada estrada, interesses estratégicos das grandes potências mundiais estão envolvidos.<br>The Amazon Area (AA) is shared by 8 independent south american countries. Since colonial times it was felt the need of a road linking the AA to the Pacific Ocean. Up to the last decades of the 19th Century the Andes were, in technical and economical terms, almost an insuperable challenge. In the last years for Brazil, the country that has about 60% of the AA, that road has become almost a need for exporting grains, timber, woodpulp etc. (mainly to Japan). And Japan also wants an acess to that area. So, Brasil, together with Peru - the second, after Brazil, AA country that has the largest and westernmost coast in the Pacific - have developed projects for building that highway counting with the financial support of Japan, who offered it in several occasions. Those projects are trying to conciliate mainly (not only) the interests of Brazil, Peru and also of Bolivia, a mediterranean country that, with the highway, could finally have a free access to the Pacific coast. But USA is oppossed to building this road because the financing of Japan. Then, all the projects are again in stand-still. It seems that in the construction of the mentioned road are directly involved strategic interests of the big world powers

Gender Associated with the Intention to Choose a Medical Specialty in Medical Students: A Cross-Sectional Study in 11 Countries in Latin America

INTRODUCTION:The selection of a medical specialty has been associated with multiple factors, such as personal preferences, academic exposure, motivational factors and sociodemographic factors, such as gender. The number of women in the medical field has increased in recent years. In Latin America, we have not found any studies that explore this relationship. OBJECTIVE:To determine whether there is an association between gender and the intention to choose a medical specialty in medical students from 11 countries in Latin America. METHODS:Secondary analysis of the Collaborative Working Group for the Research of Human Resources for Health (Red-LIRHUS) data; a multi-country project of students in their first year and fifth year of study, from 63 medical schools in 11 Latin American countries. All students who referred intention to choose a certain medical specialty were considered as participants. RESULTS:Of the 11073 surveyed students, 9235 indicated the name of a specific specialty. The specialties chosen most often in the fifth year were General Surgery (13.0%), Pediatrics (11.0%), Internal Medicine (10.3%) and Obstetrics/Gynecology (9.0%). For women, the top choices were Pediatrics (15.8%), Obstetrics/Gynecology (11.0%), Cardiology (8.7%), General Surgery (8.6%), and Oncology (6.4%). In the adjusted analysis, the female gender was associated with the choice of Obstetrics/Gynecology (RP: 2.75; IC95%: 2.24-3.39); Pediatric Surgery (RP: 2.19; IC95%: 1.19-4.00), Dermatology (RP: 1.91; IC95%:1.24-2.93), Pediatrics (RP: 1.83; IC95%: 1.56-2.17), and Oncology (RP: 1.37; IC95%: 1.10-1.71). CONCLUSIONS:There is an association between the female gender and the intention to choose Obstetrics/Gynecology, Pediatrics, Pediatric Surgery, Dermatology, and Oncology. We recommend conducting studies that consider other factors that can influence the choice of a medical specialty