An Epstein-Barr virus–encoded microRNA targets PUMA to promote host cell survival

Epstein-Barr virus (EBV) is a herpesvirus associated with nasopharyngeal carcinoma (NPC), gastric carcinoma (GC), and other malignancies. EBV is the first human virus found to express microRNAs (miRNAs), the functions of which remain largely unknown. We report on the regulation of a cellular protein named p53 up-regulated modulator of apoptosis (PUMA) by an EBV miRNA known as miR-BART5, which is abundantly expressed in NPC and EBV-GC cells. Modulation of PUMA expression by miR-BART5 and anti–miR-BART5 oligonucleotide was demonstrated in EBV-positive cells. In addition, PUMA was found to be significantly underexpressed in ∼60% of human NPC tissues. Although expression of miR-BART5 rendered NPC and EBV-GC cells less sensitive to proapoptotic agents, apoptosis can be triggered by depleting miR-BART5 or inducing the expression of PUMA. Collectively, our findings suggest that EBV encodes an miRNA to facilitate the establishment of latent infection by promoting host cell survival

Efeitos do tratamento com captopril e losartan em ratos Wistar e ratos espontaneamente hipertensos submetidos a hipertensão arterial pulmonar com monocrotalina

A hipertensão arterial pulmonar (HAP) é uma doença que se inicia com o aumento da resistência das arteríolas pulmonares. Após a sua instalação, sucedem-se várias alterações sobre os sistemas cardiovascular, respiratório e autonômico. Apesar dos trabalhos disponíveis na literatura, o desenvolvimento desta doença em modelos experimentais de hipertensão arterial sistêmica permanece ainda por ser estudado, bem como os efeitos terapêuticos de bloqueadores do sistema renina-angiotensina na reversão desta doença. Os objetivos deste estudo foram avaliar os efeitos cardiovasculares, autonômicos e respiratórios promovidos pela HAP induzida pela monocrotalina (MCT) em ratos Wistar e SHR e os efeitos terapêuticos do tratamento crônico com captopril e losartan na reversão da HAP. Para tanto, foram utilizados ratos Wistar (150-180g) e SHR (150-180g), divididos nos seguintes grupos: Wistar controle tratado com salina ou MCT (WIS-CON-SAL e WIS-CON-MCT, respectivamente), SHR controle tratado com salina ou MCT (SHR-CON-SAL e SHR-CON-MCT, respectivamente), Wistar tratados com Captopril + salina ou MCT (WIS-CPT-SAL e WIS-CPT-MCT, respectivamente), SHR tratados com Captopril + salina ou MCT (SHR-CPT-SAL e SHR-MCT-CPT, respectivamente), Wistar tratados com Losartan + salina ou MCT (WIS-LOS-SAL e WIS-LOS-MCT, respectivamente), SHR tratados com Losartan + salina ou MCT (SHR-LOS-SAL e SHR-LOS-MCT, respectivamente). Os animais tratados com MCT receberam uma única injeção subcutânea (60 mg/Kg SC) e os controles receberam o mesmo volume de salina (~0,8 mL). Ao término da 3ª senama, quando os animais MCTs controle apresentaram HAP, foi feito o tratamento com captopril (100 mg/Kg/mL) ou losartan (30 mg/Kg/mL) na água de beber por 2 semanas no volume diário de 30 mL. Após o tratamento com captopril ou losartan, foram realizados os registros cardiovasculares, respiratórios, gasométricos e a histologia pulmonar. Os resultados mostraram um significativo aumento do Índice Pulmonar nos animais controles tratados com MCT (Wistar e SHR) quando comparados com seus respectivos controles. As pressões ventriculares (PSmáx, PDI e PDF) também foram significativamente aumentadas nos grupos MCTs, bem como os valores de pressão arterial sistólica and diastólica, frequência cardíaca, pressão de pulso e labilidade da pressão arterial média. O tratamento com captopril normalizou todos os parâmetros estudados, no entanto, o losartan se mostrou ineficiente em normalizar os parâmetros hemodinâmicos. As análises morfométricas mostraram um espessamento da camada média dos dos ramos distais da artéria pulmonar e uma diminuição do lúmen nos grupos tratados com MCT. O tratamento com captopril e losartan normalizou estes parâmetros, embora o grupo tratado com losartan tenha sido menos eficaz que o captopril, pois os tratamentos mostraram diferenças significativas entre si. Quanto a avaliação autonômica, os animais MCT mostraram aumento do tônus simpático cardíaco e redução do tônus parassimpático cardíaco. Novamente, o tratamento com captopril normalizou estes parâmetros, enquanto que o losartan foi ineficaz em normalizá-los. Quanto aos parâmetros respiratórios, observamos aumentos no volume corrente, na frequência respiratória, na ventilação minuto e na ventilação alveolar dos animais controles tratados com MCT. Apenas o tratamento com captopril normalizou estes parâmetros. A avaliação gasométrica mostrou que os grupos controles tratados com MCT apresentaram redução da pressão parcial de O2 (hipóxia), aumento da pressão parcial de CO2 (hipercapnia), queda da porcentagem de saturação da hemoglobina (% Hb), aumento do bicarbonato (HCO3-) e acidose. O tratamento com captopril normalizou todos os parâmetros gasométricos, enquanto que o mesmo não foi observado com o losartan para os animais SHR submetidos a HAP. Nossos resultados mostraram que a MCT induziu ao quadro de HAP nos animais Wistar e SHR, bem como importantes alterações cardiovasculares, autonômicas, respiratórias, gasométricas e morfológicas pulmonares. Os tratamentos com captopril e losartan foram capazes de reverter a HAP em animais Wistar e SHR, porém, o captopril se mostrou mais eficiente em normalizar esses parâmetros quando comparados ao losartan. Estes resultados sugerem que o uso de bloqueadores do sistema renina angiotensina pode ser uma opção terapêutica para o tratamento da HAP. Palavras chave: hipertensão arterial pulmonar; monocrotalina; SHR; captopril; losartan

Report of a Study on IMRT Planning Strategies for Ethmoid Sinus Cancer

This communication reviews the planning strategies and dose statistics of nine IMRT plans generated for a complex head and neck case. Patient and Method: An ethmoid sinus cancer case was sent as an IMRT planning task to all participants of the ESTRO course on “IMRT and Other Conformal Techniques in Practice”, held in Amsterdam in June 2001. Results: Nine IMRT plans were generated for the case, the majority of the plans generated with commercial planning systems. The number of beam incidences ranged between four and eleven, while five of the nine beam setups were coplanar. The planning target volume dose homogeneity was inversely correlated with the degree of sparing of the surrounding organs at risk. Conclusion: IMRT strategies for complex head and neck cases, such as ethmoid sinus cancer, can be strikingly different in various aspects, such as beam setup, total number of segments, PTV dose coverage and dose statistics for organs at risks. Diese Kurzmitteilung beschreibt und vergleicht die Planungsstrategien und Dosisstatistiken von neun IMRT-Plänen für einen Nasennebenhöhlentumor.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42467/1/21780572.pd

Milk Consumption Across Life Periods in Relation to Lower Risk of Nasopharyngeal Carcinoma: A Multicentre Case-Control Study

Background: The much higher incidence of nasopharyngeal carcinoma (NPC) in men suggests sex hormones as a risk factor, and dairy products contain measurable amounts of steroid hormones. Milk consumption has greatly increased in endemic regions of NPC. We investigated the association between NPC and milk consumption across life periods in Hong Kong.Methods: A multicentre case-control study included 815 histologically confirmed NPC incident cases and 1,502 controls who were frequency-matched on age and sex at five major hospitals in Hong Kong in 2014–2017. Odds ratios (ORs) of NPC (cases vs. controls) for milk consumption at different life periods were estimated by unconditional logistic regression, adjusting for sex, age, socioeconomic status score, smoking and alcohol drinking status, exposure to occupational hazards, family history of cancer, IgA against Epstein-Barr virus viral capsid antigen, and total energy intake.Results: Compared with abstainers, lower risks of NPC were consistently observed in regular users (consuming ≥5 glasses of milk [fresh and powdered combined] per month) across four life periods of age 6–12 (adjusted OR 0.74, 95% CI 0.54–0.86), 13–18 (0.68, 0.55–0.84), 19–30 (0.68, 0.55–0.84), and 10 years before recruitment (0.72, 0.59–0.87). Long-term average milk consumption of ≤2.5, >2.5, and ≤12.5, >12.5 glasses per month yielded adjusted OR (95% CI) of 1.00 (0.80–1.26), 0.98 (0.81–1.18), 0.95 (0.76–1.18), and 0.55 (0.43–0.70), respectively (all P-values for trend < 0.05).Conclusion: Consumption of milk across life periods was associated with lower risks of NPC. If confirmed to be causal, this has important implications for dairy product consumption and prevention of NPC

MicroRNA profiling study reveals MIR-150 in association with metastasis in nasopharyngeal carcinoma

© 2017 The Author(s). MicroRNAs (miRNAs) are small non-coding RNAs that play a crucial role in pathogenesis of human cancers. Several miRNAs have been shown to involve in nasopharyngeal carcinoma (NPC) pathogenesis through alteration of gene networks. A global view of the miRNA expression profile of clinical specimens would be the best way to screen out the possible miRNA candidates that may be involved in disease pathogenesis. In this study, we investigated the expression profiles of miRNA in formalin-fixed paraffin-embedded tissues from patients with undifferentiated NPC versus non-NPC controls using a miRNA real-time PCR platform, which covered a total of 95 cancer-related miRNAs. Hierarchical cluster analysis revealed that NPC and non-NPC controls were clearly segregated. Promisingly, 10 miRNA candidates were differentially expressed. Among them, 9 miRNAs were significantly up-regulated of which miR-205 and miR-196a showed the most up-regulated in NPC with the highest incidence percentage of 94.1% and 88.2%, respectively, while the unique down-regulated miR-150 was further validated in patient sera. Finally, the in vitro gain-of-function and loss-of-function assays revealed that miR-150 can modulate the epithelial-mesenchymal-transition property in NPC/HK-1 cells and led to the cell motility and invasion. miR-150 may be a potential biomarker for NPC and plays a critical role in NPC tumourigenesis.Link_to_subscribed_fulltex

Advances in treatment for nasopharyngeal carcinoma

published_or_final_versionabstractMedicineMasterDoctor of Medicin

Effects of Calcium Phosphate Nanocrystals on Osseointegration of Titanium Implant in Irradiated Bone

Radiotherapy may compromise the integration of implant and cause implant loss. Implant surface modifications have the possibility of promoting cell attachment, cell growth, and bone formation which ultimately enhance the osseointegration process. The present study aimed to investigate the effects of calcium phosphate nanocrystals on implant osseointegration in irradiated bone. Sixteen rabbits were randomly assigned into control and nano-CaP groups, receiving implants with dual acid-etched surface or dual acid-etched surface discretely deposited of nanoscale calcium-phosphate crystals, respectively. The left leg of all the rabbits received 15 Gy radiation, followed by implants placement one week after. Four animals in each group were sacrificed after 4 and 12 weeks, respectively. Implant stability quotient (ISQ), ratio of bone volume to total volume (BV/TV), bone growth rate, and bone-to-implant contact (BIC) were evaluated. The nano-CaP group showed significantly higher ISQ (week 12, P=0.031) and bone growth rate (week 6, P=0.021; week 9, P=0.001) than that in control group. No significant differences in BV/TV and BIC were found between two groups. Titanium implant surface modified with CaP nanocrystals provides a potential alternative to improve bone healing around implant in irradiated bone

Unfolding the Complexity of Exosome–Cellular Interactions on Tumour Immunity and Their Clinical Prospects in Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy situated in the posterolateral nasopharynx. NPC poses grave concerns in Southeast Asia due to its late diagnosis. Together with resistance to standard treatment combining chemo- and radiotherapy, NPC presents high metastatic rates and common recurrence. Despite advancements in immune-checkpoint inhibitors (ICIs) and cytotoxic-T-lymphocytes (CTLs)-based cellular therapy, the exhaustive T cell profile and other signs of immunosuppression within the NPC tumour microenvironment (TME) remain as concerns to immunotherapy response. Exosomes, extracellular vesicles of 30–150 nm in diameter, are increasingly studied and linked to tumourigenesis in oncology. These bilipid-membrane-bound vesicles are packaged with a variety of signalling molecules, mediating cell–cell communications. Within the TME, exosomes can originate from tumour, immune, or stromal cells. Although there are studies on tumour-derived exosomes (TEX) in NPC and their effects on tumour processes like angiogenesis, metastasis, therapeutic resistance, there is a lack of research on their involvement in immune evasion. In this review, we aim to enhance the comprehension of how NPC TEX contribute to cellular immunosuppression. Furthermore, considering the detectability of TEX in bodily fluids, we will also discuss the potential development of TEX-related biomarkers for liquid biopsy in NPC as this could facilitate early diagnosis and prognostication of the disease

Effect of Fluoride-Modified Titanium Surface on Early Adhesion of Irradiated Osteoblasts

Objective. The present study aimed to investigate the effect of fluoride-modified titanium surface on adhesion of irradiated osteoblasts. Materials and Methods. Fluoride-modified surface was obtained and the morphology, roughness, and chemical composition of the surface were evaluated by scanning electron microscopy, atomic force microscopy, and X-ray photoelectron spectroscopy, respectively. The adhesion of irradiated osteoblast-like cells, in terms of number, area, and fluorescence intensity on the titanium surface, was evaluated using immunofluorescence staining. Results. Numerous nanosize pits were seen only in the F-TiO surface. The pits were more remarkable and uniform on F-TiO surface than on TiO surface; however, the amplitude of peaks and bottoms on F-TiO surface appeared to be smaller than on TiO surface. The Sa value and Sdr percentage of TiO surfaces were significantly higher than those of F-TiO surface. The concentrations of main elements such as titanium, oxygen, and carbon were similar on both surfaces. The number of irradiated osteoblasts adhered on the control surface was larger than on fluoride-modified surface. Meanwhile, the cells on the fluoride-modified surface formed more actin filaments. Conclusions. The fluoride-modified titanium surface alters the adhesion of irradiated osteoblasts. Further studies are needed to investigate the proliferation, differentiation, maturation, gene expression, and cytokine production of irradiated osteoblasts on fluoride-modified titanium surface