Changes in the secretory profile of NSCLC-associated fibroblasts after ablative radiotherapy: potential impact on angiogenesis and tumor growth

In the context of radiotherapy, collateral effects of ablative ionizing radiation (AIR) on stromal components of tumors remains understudied. In this work, cancer-associated fibroblasts (CAFs) isolated from freshly resected human lung tumors were exposed to AIR (1x18Gy) and analyzed for their release of paracrine factors. Inflammatory mediators and regulators of angiogenesis and tumor growth were analyzed by multiplex protein assays in conditioned medium (CM) from irradiated and non-irradiated CAFs. Additionally, the profile of secreted proteins was examined by proteomics. In functional assays, effects of CAF-CM on proliferative and migratory capacity of lung tumor cells (H-520/H-522) and endothelial cells (HUVECs), and on the tube-forming capacity of endothelial cells was assessed. Our data show that exposure of CAFs to ablative doses of ionizing radiation results in a) down-regulated release of angiogenic factors SDF-1, angiopoietin and thrombospondin-2; b) up-regulated release of growth factor bFGF from most donors, and c) unaffected expression-levels of HGF and inflammatory mediators IL-6, IL-8, IL-1ƒÒ and TNF-£. Conditioned medium from irradiated and control CAFs did not affect differently the proliferative or migratory capacity of tumor cells (H-520/H-522), whereas migratory capacity of endothelial HUVEC cells was partially reduced in the presence of irradiated CAF conditioned medium. Overall we conclude that AIR mediates a transformation on the secretory profile of CAFs that could influence the behavior of other cells in the tumor tissue and hence guide to some extent therapeutic outcomes. The downstream consequences of the changes observed in this study merits further investigations

Reproductive factors and risk of melanoma : a population-based cohort study

Background The association between reproductive factors and risk of cutaneous melanoma (CM) is unclear. We investigated this issue in the Norwegian Women and Cancer cohort study. Objectives To examine the association between the reproductive factors age at menarche, menstrual cycle length, parity, age at first and last birth, menopausal status, breastfeeding duration and length of ovulatory life, and CM risk, overall and by histological subtypes and anatomical site. Methods We followed 165 712 women aged 30-75 years at inclusion from 1991-2007 to the end of 2015. Multivariable Cox regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Results The mean age at cohort enrolment was 49 years. During a median follow-up of 18 years, 1347 cases of CM were identified. No reproductive factors were clearly associated with CM risk. When stratifying by histological subtype we observed significant heterogeneity (P = 0 center dot 01) in the effect of length of ovulatory life on the risk of superficial spreading melanoma (HR 1 center dot 02, 95% CI 1 center dot 01-1 center dot 04 per year increase) and nodular melanoma (HR 0 center dot 97, 95% CI 0 center dot 94-1 center dot 01 per year increase). When stratifying by anatomical site, menopausal status (HR 0 center dot 54, 95% CI 0 center dot 31-0 center dot 92, postmenopausal vs. premenopausal) and menstrual cycle length (HR 1 center dot 07, 95% CI 1 center dot 01-1 center dot 13, per day increase) were associated with CM of the trunk, and significant heterogeneity between anatomical sites was observed for menopausal status (P = 0 center dot 04). Conclusions In this large population-based Norwegian cohort study, we did not find convincing evidence of an association between reproductive factors and risk of CM.Peer reviewe

Alpha-2-adrenergic receptor agonists for the prevention of delirium and cognitive decline after open heart surgery (ALPHA2PREVENT): protocol for a multicentre randomised controlled trial

INTRODUCTION: Postoperative delirium is common in older cardiac surgery patients and associated with negative short-term and long-term outcomes. The alpha-2-adrenergic receptor agonist dexmedetomidine shows promise as prophylaxis and treatment for delirium in intensive care units (ICU) and postoperative settings. Clonidine has similar pharmacological properties and can be administered both parenterally and orally. We aim to study whether repurposing of clonidine can represent a novel treatment option for delirium, and the possible effects of dexmedetomidine and clonidine on long-term cognitive trajectories, motor activity patterns and biomarkers of neuronal injury, and whether these effects are associated with frailty status. METHODS AND ANALYSIS: This five-centre, double-blind randomised controlled trial will include 900 cardiac surgery patients aged 70+ years. Participants will be randomised 1:1:1 to dexmedetomidine or clonidine or placebo. The study drug will be given as a continuous intravenous infusion from the start of cardiopulmonary bypass, at a rate of 0.4 µg/kg/hour. The infusion rate will be decreased to 0.2 µg/kg/hour postoperatively and be continued until discharge from the ICU or 24 hours postoperatively, whichever happens first.Primary end point is the 7-day cumulative incidence of postoperative delirium (Diagnostic and Statistical Manual of Mental Disorders, fifth edition). Secondary end points include the composite end point of coma, delirium or death, in addition to delirium severity and motor activity patterns, levels of circulating biomarkers of neuronal injury, cognitive function and frailty status 1 and 6 months after surgery. ETHICS AND DISSEMINATION: This trial is approved by the Regional Committee for Ethics in Medical Research in Norway (South-East Norway) and by the Norwegian Medicines Agency. Dissemination plans include publication in peer-reviewed medical journals and presentation at scientific meetings. TRIAL REGISTRATION NUMBER: NCT05029050

Cell fusions in mammals

Cell fusions are important to fertilization, placentation, development of skeletal muscle and bone, calcium homeostasis and the immune defense system. Additionally, cell fusions participate in tissue repair and may be important to cancer development and progression. A large number of factors appear to regulate cell fusions, including receptors and ligands, membrane domain organizing proteins, proteases, signaling molecules and fusogenic proteins forming alpha-helical bundles that bring membranes close together. The syncytin family of proteins represent true fusogens and the founding member, syncytin-1, has been documented to be involved in fusions between placental trophoblasts, between cancer cells and between cancer cells and host cells. We review the literature with emphasis on the syncytin family and propose that syncytins may represent universal fusogens in primates and rodents, which work together with a number of other proteins to regulate the cell fusion machinery

Loss of PTEN expression is associated with IGFBP2 expression, younger age, and late stage in triple-negative breast cancer

© American Society for Clinical Pathology. Objectives: To investigate the association between PTEN loss and IGFBP2 expression in a series of triple-negative breast cancers and to relate this expression to basal cytokeratin expression and clinicopathologic features. Methods: One hundred and one formalin-fixed and paraffin-processed triple-negative breast cancer cases from the University of Malaya Medical Centre were tested immunohistochemically for cytokeratins 5/6 and 14, PTEN, and IGFBP2. The resulting slides were scored for proportion and intensity of staining. Results: Loss of tumor nuclear and cytoplasmic staining for PTEN occurred in 48.3% of cases and was significantly associated with younger age at diagnosis (47 years compared with 57 years in those without PTEN loss; P = .005). Independent predictors of PTEN loss were late stage at presentation ( P = .026), cytokeratin 5/6 positivity ( P = .028), and IGFBP2 expression ( P = .042). High levels of IGFBP2 expression were seen in 32% of cases; an independent predictor of high levels was cytokeratin 14 negativity ( P = .005). PTEN loss and high levels of IGFBP2 expression were associated with poorer survival, but neither of these trends was significant. Conclusions: PTEN loss is a frequent event in triple-negative breast cancers and is significantly associated with younger age at onset of breast cancer, late stage, and IGFBP2 expression

The emerging role of insulin-like growth factor 1 receptor (IGF1r) in gastrointestinal stromal tumors (GISTs)

Recent years have seen a growing interest in insulin-like growth factor 1 receptor (IGF1R) in medical oncology. Interesting data have been reported also on IGF1r in gastrointestinal stromal tumors (GISTs) especially in children and in young adult patients whose disease does not harbour mutations on KIT and PDGFRA and are poorly responsive to conventional therapies. However, it is too early to reach conclusions on IGF1R as a novel therapeutic target in GIST because the receptor's biological role is still to be defined and the clinical significance in patients needs to be studied in larger studies. We update and comment the current literature on IGF1R in GISTs and discuss the future perspectives in this promising field

A four-surface schematic eye of macaque monkey obtained by an optical method

AbstractSchematic eyes for four Macaca fascicularis monkeys were constructed from measurements of the positions and curvatures of the anterior and posterior surfaces of the cornea and lens. All of these measurements were obtained from Scheimpflug photography through the use of a ray-tracing analysis. Some of these measurements were also checked (and confirmed) by keratometry and ultrasound. Gaussian lens equations were applied to the measured dimensions of each individual eye in order to construct schematic eyes. The mean total power predicted by the schematic eyes agreed closely with independent measurements based on retinoscopy and ultrasound results, 74.2 ± 1.3 (SEM) vs 74.7 ± 0.3 (SEM) diopters. The predicted magnification of 202 μm/deg in one eye was confirmed by direct measurement of 205 μm/deg for a foveal laser lesion. The mean foveal retinal magnification calculated for our eight schematic eyes was 211 ± (SEM) μm/deg, slightly less than the value obtained by application of the method of Rolls and Cowey [Experimental Brain Research, 10, 298–310 (1970)] to our eight eyes but just 4% more than the value obtained by application of the method of Perry and Cowey [Vision Research, 12, 1795–1810 (1985)]

Mechanisms of metastasis

Metastasis is an enormously complex process that remains to be a major problem in the management of cancer. The fact that cancer patients might develop metastasis after years or even decades from diagnosis of the primary tumor makes the metastatic process even more complex. Over the years many hypotheses were developed to try to explain the inefficiency of the metastatic process, but none of these theories completely explains the current biological and clinical observations. In this review we summarize some of the proposed models that were developed in attempt to understand the mechanisms of tumor dissemination and colonization as well as metastatic progression