The Werner Syndrome Protein Suppresses Telomeric Instability Caused by Chromium (VI) Induced DNA Replication Stress

Telomeres protect the chromosome ends and consist of guanine-rich repeats coated by specialized proteins. Critically short telomeres are associated with disease, aging and cancer. Defects in telomere replication can lead to telomere loss, which can be prevented by telomerase-mediated telomere elongation or activities of the Werner syndrome helicase/exonuclease protein (WRN). Both telomerase and WRN attenuate cytotoxicity induced by the environmental carcinogen hexavalent chromium (Cr(VI)), which promotes replication stress and DNA polymerase arrest. However, it is not known whether Cr(VI)-induced replication stress impacts telomere integrity. Here we report that Cr(VI) exposure of human fibroblasts induced telomeric damage as indicated by phosphorylated H2AX (γH2AX) at telomeric foci. The induced γH2AX foci occurred in S-phase cells, which is indicative of replication fork stalling or collapse. Telomere fluorescence in situ hybridization (FISH) of metaphase chromosomes revealed that Cr(VI) exposure induced an increase in telomere loss and sister chromatid fusions that were rescued by telomerase activity. Human cells depleted for WRN protein exhibited a delayed reduction in telomeric and non-telomeric damage, indicated by γH2AX foci, during recovery from Cr(VI) exposure, consistent with WRN roles in repairing damaged replication forks. Telomere FISH of chromosome spreads revealed that WRN protects against Cr(VI)-induced telomere loss and downstream chromosome fusions, but does not prevent chromosome fusions that retain telomere sequence at the fusion point. Our studies indicate that environmentally induced replication stress leads to telomere loss and aberrations that are suppressed by telomerase-mediated telomere elongation or WRN functions in replication fork restoration

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

Variações anatômicas e sinusopatias: estudo por tomografia computadorizada Anatomical variations and sinusitis: a computed tomographic study

Introdução: A tomografia computadorizada tem sido cada vez mais utilizada para a identificação e avaliação das variações anatômicas das cavidades nasais que podem levar às sinusites. Objetivo: Avaliar, por meio da tomografia computadorizada, a incidência de espessamento mucoso nos seios paranasais de pacientes com sintomas de sinusite e a correlação entre sinusopatias e presença de célula de Haller, concha média bolhosa e desvio de septo nasal localizado no meato médio. Forma de Estudo: Clínico retrospectivo. Material e Método: Foram avaliadas retrospectivamente 150 tomografias computadorizadas de seios paranasais de pacientes com idade igual ou superior a 13 anos, realizadas no Departamento de Diagnóstico por Imagem da Universidade Federal de São Paulo - Escola Paulista de Medicina, no período de julho de 1999 a outubro de 2001. Foram excluídos os exames de pacientes com pós-operatório de cirurgias de seios paranasais e de base de crânio, além dos portadores de lesões tumorais envolvendo estas regiões. Resultados: 70% dos pacientes apresentavam espessamento mucoso em pelo menos um dos seios paranasais. Observou-se a freqüência de 52,7% de sinusopatia maxilar, 28,0% de etmoidal, 13,0% de esfenoidal e 8,3% de frontal. Concha média bolhosa foi encontrada em 33,3% das cavidades nasais, desvio de septo nasal localizado no meato médio em 23,3% e célula de Haller em 9,3%. Conclusões: Os seios paranasais mais freqüentemente acometidos foram, em ordem decrescente: maxilar, etmoidal, esfenoidal e frontal. Não foi observado correlação entre sinusopatias e presença de célula de Haller, concha média bolhosa e desvio de septo nasal localizado no meato médio.<br>Introduction: Computed tomography has been increasingly used both to identify and to evaluate anatomy variations of nasal cavities that can lead to the development of sinusitis. Purpose: The purpose of the present study is to determine the incidence of mucosal abnormalities in paranasal sinuses found in CT scans of patients with symptons of sinusitis and analyze the correlation between sinusitis and presence of Haller's cell, concha bullosa and nasal septal deviation located in middle meatus. Study Design: Clinical retrospective. Material and Method: Paranasal sinus CT scans were obtained in 150 patients aged 13 years or more, from July 1999 to October 2001. The CT scans were performed in the Department of Radiology of Universidade Federal de São Paulo - Escola Paulista de Medicina. Patients with history of skull base or sinus surgery and tumor in these regions were excluded. Results: 70% of patients present mucosal abnormalities at least in one paranasal sinus. Maxillary sinusitis were observed in 52,7% of sinus, ethmoidal sinusitis in 28,0%, sphenoidal sinusitis in 13,0% and frontal sinusitis in 8,3%. Concha bullosa was observed in 33,3% of nasal cavities, nasal septal deviation (located in middle meatus) in 23,3% and Haller's cell in 9,3%. Conclusions: The most affected paranasal sinuses were: maxillary, ethmoid, sphenoid and frontal. Correlation between sinusitis and presence of Haller's cell, concha bullosa and nasal septal deviation (located in middle meatus) was not observed

Partial Mesenchymal to Epithelial Reverting Transition in Breast and Prostate Cancer Metastases

Epithelial to mesenchymal transition (EMT) is an oft-studied mechanism for the initiation of metastasis. We have recently shown that once cancer cells disseminate to a secondary organ, a mesenchymal to epithelial reverting transition (MErT) may occur, which we postulate is to enable metastatic colonization. Despite a wealth of in vitro and in vivo studies, evidence supportive of MErT in human specimens is rare and difficult to document because clinically detectable metastases are typically past the micrometastatic stage at which this transition is most likely evident. We obtained paired primary and metastatic tumors from breast and prostate cancer patients and evaluated expression of various epithelial and mesenchymal markers by immunohistochemistry. The metastases exhibited increased expression of membranous E-cadherin compared to primary tumors, consistent with EMT at the primary site and MErT at the metastatic site. However, the re-emergence of the epithelial phenotype was only partial or incomplete. Expression of epithelial markers connexins 26 and/or 43 was also increased on the majority of metastases, particularly those to the brain. Despite the upregulation of epithelial markers in metastases, expression of mesenchymal markers vimentin and FSP1 was mostly unchanged. We also examined prostate carcinoma metastases of varied sizes and found that while E-cadherin expression was increased compared to the primary lesion, the expression inversely correlated with size of the metastasis. This not only suggests that a second EMT may occur in the ectopic site for tumor growth or to seed further metastases, but also provides a basis for the failure to discern epithelial phenotypes in clinically examined macrometastases. In summary, we report increased expression of epithelial markers and persistence of mesenchymal markers consistent with a partial MErT that readily allows for a second EMT at the metastatic site. Our results suggest that cancer cells continue to display phenotypic plasticity beyond the EMT that initiates metastasis