MOLECULAR MECHANISMS OF ESTROGEN RECEPTOR BETA ACTION IN COLORECTAL CARCINOGENESIS

Colorectal cancer (CRC) is a major public health problem in the world population, which emphasizes the need to study novel molecular targets in order to develop alternative chemopreventive and chemotherapeutic strategies against it. Estrogens have been shown to exert a protective role against CRC and its actions seem to be mediated by estrogen receptor β (ERβ). However, further studies are required to elucidate the role of ERβ in the colon. To achieve this goal, we evaluated the effects of ERβ deficiency in sporadic CRC and colitis-associated CRC (CAC) by using two in vivo models. In addition, we stably transfected RKO colon cancer cells to overexpress ERβ and identify novel molecules regulated by ERβ signaling in vitro. In the sporadic CRC in vivo model, azoxymethane (AOM)-treated ERβ knockout (βERKO) mice showed a significantly higher incidence and multiplicity of colonic preneoplastic lesions compared to AOM-treated ERα knockout and wild-type (WT) mice. These results were associated with a loss of normal colonic crypt organization and a decrease in apoptosis rates suggesting that ERβ is the ER subtype with a protective role against sporadic CRC progression. Confirming this hypothesis, we observed that AOM-treated βERKO mice presented a significantly higher incidence of adenomas than WT mice. By real time-polymerase chain reaction and immunohistochemistry analyses, ERβ-deficient adenomas were shown to be more proliferative and less differentiated than adenomas in WT mice. Furthermore, in the CAC in vivo model, βERKO mice developed more severe clinical colitis compared to WT mice, as evidenced by significantly higher disease activity index, weight to length ratio of the colons, inflammation score, and grade of dysplasia. ERβ-deficient tumors were characterized by a significant increase in pro-inflammatory xv molecules, suggesting that ERβ might exert anti-inflammatory effects in CAC. Moreover, in vitro results revealed a novel molecular mechanism by which ERβ might drive differentiation of goblet cells in the colonic epithelium. Altogether these findings highlight the importance of ERβ in protection against colorectal carcinogenesis and provide a clinical and translational potential to use ERβ selective agonists in order to prevent and/or treat CRC.PH.D in Biology, July 201

Type I and II Interferons in the Anti-Tumor Immune Response

The interferons (IFNs) are essential components of the immune response against infections and malignancies. IFNs are potent promoters of the anti-tumor response, but there is also evidence that feedback mechanisms regulated by IFNs negatively control immune responses to avoid hyper-activation and limit inflammation. This balance of responses plays an important role in cancer surveillance, immunoediting and response to anticancer therapeutic approaches. Here we review the roles of both type I and type II IFNs on the control of the immune response against malignancies in the context of effects on both malignant cells and cells of the immune system in the tumor microenvironment

Global longitudinal strain in chronic asymptomatic aortic regurgitation: systematic review

Chronic aortic regurgitation (AR) patients typically remain asymptomatic for a long time. Left ventricular mechanics, namely global longitudinal strain (GLS), has been associated with outcomes in AR patients. The authors conducted a systematic review to summarize and appraise GLS impact on mortality, the need for aortic valve replacement (AVR) and disease progression in AR patients. A literature search was performed using these key terms 'aortic regurgitation' and 'longitudinal strain' looking at all randomized and nonrandomized studies conducted on chronic aortic regurgitation. The search yielded six observational studies published from 2011 and 2018 with a total of 1571 patients with moderate to severe chronic AR. Only two studies included all-cause mortality as their endpoint. The other studies looked at the association between GLS with AVR and disease progression. The mean follow-up period was 4.2 years. We noted a great variability of clinical, methodological and/or statistical origin. Thus, meta-analytic portion of our study was limited. Despite a relevant heterogeneity, an impaired GLS was associated with adverse cardiac outcomes. Left ventricular GLS may offer incremental value in risk stratification and decision-making

A Palette of Cytokines to Measure Anti-Tumor Efficacy of T Cell-Based Therapeutics

Cytokines are key molecules within the tumor microenvironment (TME) that can be used as biomarkers to predict the magnitude of anti-tumor immune responses. During immune monitoring, it has been customary to predict outcomes based on the abundance of a single cytokine, in particular IFN-γ or TGF-β, as a readout of ongoing anti-cancer immunity. However, individual cytokines within the TME can exhibit dual opposing roles. For example, both IFN-γ and TGF-β have been associated with pro- and anti-tumor functions. Moreover, cytokines originating from different cellular sources influence the crosstalk between CD4+ and CD8+ T cells, while the array of cytokines expressed by T cells is also instrumental in defining the mechanisms of action and efficacy of treatments. Thus, it becomes increasingly clear that a reliable readout of ongoing immunity within the TME will have to include more than the measurement of a single cytokine. This review focuses on defining a panel of cytokines that could help to reliably predict and analyze the outcomes of T cell-based anti-tumor therapies

Glycoprotein IIb/IIIa inhibitors for cardiogenic shock complicating acute myocardial infarction: a systematic review, meta-analysis, and meta-regression

Background: Cardiogenic shock complicates 5–10% of myocardial infarction (MI) cases. Data about the benefit of glycoprotein IIb/IIIa inhibitors (GPI) in these patients is sparse and conflicting. Methods: We performed a systematic review, meta-analysis, and meta-regression of studies assessing the impact of GPI use in the setting of MI complicated cardiogenic shock on mortality, angiographic success, and bleeding events. We systematically searched for studies comparing GPI use as adjunctive treatment versus standard care in this setting. Random-effects meta-analysis and meta-regression were performed. Results: Seven studies with a total of 1216 patients (GPI group, 720 patients; standard care group, 496 patients) were included. GPI were associated with a 45% relative reduction in the odds of death at 30 days (pooled OR 0.55; 95% CI 0.35–0.85; I2 = 57%; P = 0.007) and a 49% reduction in the odds of death at 1 year (pooled OR 0.51; 95% CI 0.32–0.82; I2 = 58%; P = 0.005). Reduction in short-term mortality seemed to be more important before 2000, as this benefit disappears if only the more recent studies are analyzed. GPI were associated with a 2-fold increase in the probability of achieving TIMI 3 flow (pooled OR, 2.05; 95% CI 1.37–3.05; I2 = 37%, P = 0.0004). Major bleeding events were not increased with GPI therapy (pooled OR, 1.0; 95% CI 0.55–1.83; I2 = 1%, P = 0.99). Meta-regression identified that patients not receiving an intra-aortic balloon pump seemed to benefit the most from GPI use (Z = − 1.57, P = 0.005). Conclusion: GPI therapy as an adjunct to standard treatment in cardiogenic shock was associated with better outcomes, including both short- and long-term survival, without increasing the risk of bleeding

Central Role of ULK1 in Type I Interferon Signaling

We provide evidence that the Unc-51-like kinase 1 (ULK1) is activated during engagement of the type I interferon (IFN) receptor (IFNR). Our studies demonstrate that the function of ULK1 is required for gene transcription mediated via IFN-stimulated response elements (ISRE) and IFNγ activation site (GAS) elements and controls expression of key IFN-stimulated genes (ISGs). We identify ULK1 as an upstream regulator of p38α mitogen-activated protein kinase (MAPK) and establish that the regulatory effects of ULK1 on ISG expression are mediated possibly by engagement of the p38 MAPK pathway. Importantly, we demonstrate that ULK1 is essential for antiproliferative responses and type I IFN-induced antineoplastic effects against malignant erythroid precursors from patients with myeloproliferative neoplasms. Together, these data reveal a role for ULK1 as a key mediator of type I IFNR-generated signals that control gene transcription and induction of antineoplastic responses