Impact of systemic hypoxemia on cancer aggressiveness and circulating vascular endothelial growth factors A and C in gastroesophaeal cancer patients with chronic respiratory insufficiency

Aim: Due to the common etiologic factor, a considerable number of esophagogastric cancer patients suffer from respiratory insufficiency in course of chronic obstructive pulmonary disease, primary to cancer. Systemic hypoxemia may account for poor oxygenation of tumor tissue-a main driving force of tumor neoangiogenesis. We hypothesized that in cancer patients with respiratory insufficiency, systemic hypoxemia may be related to enhanced aggressiveness of cancer on one side and to the elevation of angiogenic factors on the other. Methods: The levels of vascular endothelial growth factors A and C were determined with immunoenzymatic methods in patients diagnosed with esophagogastric cancer with or without co-existing respiratory insufficiency in course of chronic obstructive pulmonary disease and in healthy controls. Blood gasometry and hemoglobin levels of cancer patients were related to cancer histology and TNM status, and to circulating vascular endothelial growth factors A and C. Results: Patients with systemic hypoxemia had higher incidence rates of locally advanced tumors. Partial oxygen pressure and blood oxygen saturation were significantly lowered in patients with T4 cancers as compared to less advanced onces. Circulating vascular endothelial growth factor A, but not C, was more elevated in esophagogastric cancer patients with co-existing respiratory insufficiency, as compared to those without respiratory insufficiency. Vascular endothelial growth factor A was also strongly related to the extension of primary tumor. Conclusion: Our results show that systemic hypoxemia in esophagogastric cancer patients is associated with the extension of primary tumor and that this effect might be mediated by the up-regulation of circulating vascular endothelial growth factor A.Цель: в связи с общим этиологическим фактором заболевания , значительное количество больных гастроэзофагальным раком страдает от респираторной недостаточности в процессе хронического обструктивного легочного заболевания, кото- рое предшествует раку. Системная гип оксемия может влиять на пониженн ую оксигена цию опухолево й ткани — основной источник опухолевого неоангиогенеза. Авторы предп оложили , что у больных онкологического п рофиля с респираторно й недостаточностью системная гипоксемия может быть связана с повышенной агрессивностью опухолевого процесса, с одной стороны, и повышенным уровнем ангиогенных факторов — с другой. Методы: сод ержание факторов роста эндо- телия сосудов A и C ( VEGF ) опред еляли имму ноферментными мето дами у пациентов с гастроэзофагальным раком на фоне респираторной недостаточности в процессе хронического обструктивного заболевания легких или в отсутствие такового, а также у здоровых доноров. Анализировали д анные газометрии и сод ержания гемоглобина в зависимости от гистологии новообразования, статуса TNM и уровня VEGF A и C. Результаты: у больных с системно й гипоксемие й частота появления новообразований была выше. Парциальное давление кислоро да и насыщение крови кислоро д ом значительно снижено у пациентов с категорией T4. Повышение сод ержания циркулирующего VEGF A, но не C, более выражено у больных с респи- раторной недостаточностью, чем без нее. Содержание VEGF коррелировало с объемом первично й опухоли . Выводы: на результаты показывают, что системная гипоксемия у пациентов с гастроэзофагальным раком связана с увеличением объема первичной опухоли, и такой эффект может быть опосредован повышением содержания циркулирующего VEGF

Even a mild anemia is related to tumor aggressiveness mediated by angiogenic factors

Esophagogastric cancers have high recurrence rates with lymph nodes being a common pattern. Pre-treatment anemia has been reported an independent prognostic factor of treatment failure regardless of treatment strategy, particularly associated with poor locoregional control. A causative relationship between anemia — tumor hypoxia — tumor aggressiveness mediated by angiogenesis up-regulation is advocated, yet remains controversial. Aim: To determine whether and how the pre-treatment anemia is associated with various aspects of disease aggressiveness and to evaluate the possible involvement of angiogenesis mediators. Methods: In 111 esophagogastric cancer patients we investigated the association of pre-treatment hemoglobin concentration and anemia presence with cancer-related, patients-related features and laboratory parameters including angiogenic factors: vascular endothelial growth factors A and C, interleukin-8 and midkine. Serum levels of angiogenic factors were assessed with immunoenzymatic tests. Results: Histology, disease stage, regional metastasis and dissemination in general, malnutrition and angiogenesis represented by midkine were found to correlate with anemia presence and hemoglobin concentration, while tumor extension, patient’s age and sex accounted only for anemia presence. A tendency towards hemoglobin correlation with VEGF-A and Il-8 was also observed. Midkine, tumor histology and malnutrition were found to exert an independent effect on pre-treatment hemoglobin concentration and anemia presence in esophagogastric cancer patients. Hemoglobin level of 12 g/dL was found an optimal cut-off value for discrimination between localized and disseminated cancers. Conclusions: Even a mild pre-treatment anemia is associated with cancers metastasizing especially to regional lymph nodes, which seems to be mediated by some of studied angiogenic factors

Translational control of cardiac fibrosis

Background Fibrosis is a common pathology in many cardiac disorders and is driven by the activation of resident fibroblasts. The global post-transcriptional mechanisms underlying fibroblast-to-myofibroblast conversion in the heart have not been explored. Methods Genome-wide changes of RNA transcription and translation during human cardiac fibroblast activation were monitored with RNA sequencing and ribosome profiling. We then used miRNA-and RNA-binding protein-based analyses to identify translational regulators of fibrogenic genes. To reveal post-transcriptional mechanisms in the human fibrotic heart, we then integrated our findings with cardiac ribosome occupancy levels of 30 dilated cardiomyopathy patients. Results We generated nucleotide-resolution translatome data during the TGFβ1-driven cellular transition of human cardiac fibroblasts to myofibroblasts. This identified dynamic changes of RNA transcription and translation at several time points during the fibrotic response, revealing transient and early-responder genes. Remarkably, about one-third of all changes in gene expression in activated fibroblasts are subject to translational regulation and dynamic variation in ribosome occupancy affects protein abundance independent of RNA levels. Targets of RNA-binding proteins were strongly enriched in post-transcriptionally regulated genes, suggesting genes such as MBNL2 can act as translational activators or repressors. Ribosome occupancy in the hearts of patients with dilated cardiomyopathy suggested an extensive post-transcriptional regulatory network underlying cardiac fibrosis. Key network hubs include RNA-binding proteins such as PUM2 and QKI that work in concert to regulate the translation of target transcripts in human diseased hearts. Conclusions We reveal widespread translational effects of TGFβ1 and define novel post-transcriptional events that control the fibroblast-to-myofibroblast transition. Regulatory networks that affect ribosome occupancy in fibroblasts are paralleled in human heart disease. Our findings show the central importance of translational control in fibrosis and highlight novel pathogenic mechanisms in heart failure

Seizure prediction : ready for a new era

Acknowledgements: The authors acknowledge colleagues in the international seizure prediction group for valuable discussions. L.K. acknowledges funding support from the National Health and Medical Research Council (APP1130468) and the James S. McDonnell Foundation (220020419) and acknowledges the contribution of Dean R. Freestone at the University of Melbourne, Australia, to the creation of Fig. 3.Peer reviewedPostprin