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Background Myocardial infarction (MI) is a severe ischemic disease responsible for heart failure and sudden death. Mature B lymphocytes have been shown to exacerbate tissue injury and deterioration of cardiac function after MI. However, the cellular and molecular mechanisms governing B cell deleterious effects in the ischemic milieu remain to be defined. Purpose In this study, we speculate that endogenous activation of the miR21/HIFα-related pathways mediates the effect of B lymphocytes on post-ischemic cardiac remodeling. Methods Acute MI was induced by permanent ligation of the left anterior descending artery in mice. Cardiac function and remodeling was determined by echocardiography and immunohistochemistry. Inflammatory cell number and phenotype were defined by FACS analysis. To evaluate the role of HIFα isoforms in B cells, we generated mice with B cell lineage specific (Cd79aCre/+) conditional deletion of HIF1α (HIF1αflox/flox), HIF2α (HIF2αflox/flox), or both isoforms (HIF1α-HIF2αflox/flox). Results Acute MI increased miR21 levels in B cells. miR21 deficient mice showed reduced B cell numbers in the spleen, blood and subsequently in the injured cardiac tissue. Transplantation of bone marrow derived cells isolated from miR21-deficient mice (miR21−/−) improved cardiac function and remodeling when compared to administration of wild-type (WT) bone marrow cells. Similarly, in Rag1−/− immunodeficient mice with acute MI, re-supplementation with miR21−/− B lymphocytes restored cardiac repair and function when compared to injection of WT B cells. miR21 abrogated PTEN contents and subsequently enhanced HIF1α levels in cultured B cells. B cell deletion of HIF1α, but not that of HIF2α, reduced B cell accumulation and improved cardiac function after MI. Mice, which were equally deficient in HIF1α and HIF2α, also exhibited abrogation of adverse ventricular remodeling and showed recovery of cardiac function after MI. Toll like receptor agonist, CpG, fostered the release of the monocyte chemo-attractant protein, Ccl7, in cultured WT B cells but not in miR21- or HIF1α- deficient B cells. Ccl7 circulating levels were also reduced in miR21−/− and Cd79aCre/+/HIF1α flox/flox animals after acute MI. Ccl7 down-regulation hampered Ly6Chigh monocyte infiltration in the ischemic myocardium, leading to decreased infarct size and interstitial fibrosis, supporting cardiac repair. Conclusion This work reveals a novel function for miR21/HIF1α related pathways in B lymphocyte dependent effect on cardiac function and remodeling in the setting of acute MI. more...

Objectives Endometrial cancer presents well-defined risk factors such as depth of myometrial invasion, histological subtype, tumour differentiation grade and lymphovascular space invasion (LVSI). The aim of this study was to investigate other clinical-pathological factors that might influence the recurrence of patients diagnosed with low and intermediate risk endometrial cancer. Methods Case-control study from a cohort retrospective of 196 patients diagnosed with low and intermediate risk endometrial cancer at a single institution between 2009 and 2014 was conducted. Medical records were reviewed to compare clinical (race, smoking, menopause, body mass index (BMI)) and pathological (histological subtype (endometrioid vs endometrioid with squamous differentiation), tumour differentiation grade, tumour localization, endocervical invasion, LVSI) carachteristics into patients with recurrence (case) and without recurrence (control) of disease. Three controls for each patient case was matched for age and staging. Results Twenty-one patients with recurrence was found (10.7%), of which 14 were stage IA and 7 were stage IB. We selected 63 patients without recurrence (controls). There were no significant differences in any clinical carachteristic between case and control patients. Among pathological variables, presence of squamous differentiation (28.6% vs. 4.8%, p=0.007), tumour differentiation grade 2 or 3 (57.1% vs. 30.2%, p=0.037) and presence of endocervical invasion (28.6% vs. 12.7%, p=0.103) were associated with disease recurrence from univariate analysis. On multivariable analysis, only squamous differentiation was a significant risk factor for recurrence (p=0.031). Conclusions Our data suggest that squamous differentiation may be a poor prognostic factor in patients with low and intermediate-risk endometrial carcinoma, had a 5.6 fold increased risk for recurrence. more...

Introduction Cardiovascular disease (CVD) is the main cause of death in non-communicable diseases. In response to myocardial infarction (MI), extracellular vesicles (EVs) including large (lEVs) and small (sEVs), are released within and from the heart to facilitate intercellular communication and maintaining cardiac homeostasis. Objective As diabetes increases the risk of CVD, the purpose of the study was to investigate how diabetes influences the release of intracardiac EVs after MI. Method C57BL/6 J male mice were fed normal chow diet or high-fat diet (HFD) for 3 months. HFD fed mice were glucose intolerant as attested by the measure of GTT above 200 mg/mL. Mice were subjected to MI by permanent ligation of the left anterior descending artery and sham animals underwent similar surgical procedure without ligation. Left ventricles from sham or MI mice were then harvested at either 15, 24, 48 or 72 hours after surgery (N = 5 per group at each time point) and processed for EV extraction by differential centrifugation. EVs were quantified and analyzed via Tunable Resistive Pulse Sensing Technology (TRPS), flow cytometry and Western blot. Results In chow diet fed mice, release of both lEVs and sEVs was increased at 24 h post-MI when compared to shams. These findings were in agreement with previous data obtained in younger control animals. In diabetic mice, lEVs peaked at 24 h post-MI and this increase was slightly greater than that observed in chow diet fed mice. However, there were no differences in sEV release between sham and MI diabetic mice. TRPS analysis revealed that diabetes does not change EV size and population. Furthermore, both control and diabetic derived EVs harboured cardiomyocyte marker (Troponin T) as revealed by Western blot. Conclusion Our results show that diabetes modulates the release of both intracardiac sEVs and lEVs after MI. Further work will be needed to fully investigate the functional impact of cardiac EVs in the diabetic heart after MI. more...

Introduction The chemokine CXCL12 is essential for cardiovascular system development and plays a major role in physio-pathological processes such as inflammation, angiogenesis but also tissue remodeling after an ischemic insult. In addition to the binding to its receptors, CXCR4 and CXCR7, CXCL12 interaction with heparan-sulfates (HS) commands its biological activity. Studies in experimental models of myocardial infarction (MI) revealed a protective role for CXCL12α. However, in mice, three CXCL12 isoforms (α, β and γ) have been identified and the CXCL12γ isoform shows an unchallenged ability to cooperate with HS, suggesting a pivotal role in tissue repair. Objective The aim of the study is to analyze the role of CXCL12γ isoform and the importance of CXCL12/HS interactions in post-ischemic cardiac remodeling in an acute model of MI. Method MI are induced in mice carrying a Cxcl12 gene mutation that precludes interactions with HS (Cxcl12Gagtm) and in Cxcl12γ knock-in animals (Cxcl12γ-KI), harboring CXCL12γ deficiency. Alternatively, the impact of CXCL12γ overexpression is also evaluated in wild-type (WT) mice receiving transcutaneous echo-guided injections of adenovirus encoding Cxcl12γ in cardiac tissue. Cardiac function and remodeling have been assessed through echocardiography analysis and evaluation of infarct size, interstitial fibrosis, capillary and arteriole densities and as well as inflammatory cell infiltration. Results After MI, Cxcl12Gagtm and Cxcl12γ-KI animals exhibit reduction in cardiac function and adverse left ventricular remodeling when compared to their respective WT littermates. Interestingly, overexpression of CXCL12γ in WT mice normalizes cardiac function by reducing the size of the infarcted area, interstitial fibrosis and promoting vascular growth. Conclusion We show that CXCL12γ isoform plays an important role in the regulation of cardiac function after MI and that its interactions with HS seems essential for adequate cardiac repair. more...

Objective To evaluate the impact of surgical resection and adjuvant treatment on the course of patients after malignant progression of previously treated isocitrate dehydrogenase 1 (IDH1)–mutated World Health Organization (WHO) grade II astrocytoma. Methods This retrospective study explored 56 patients undergoing tumor resection for malignant progression after previously treated IDH1-mutated WHO grade II astrocytoma. We analyzed survival after malignant progression, analyzed overall survival (OS), and identified prognostic factors using Kaplan-Meier estimates and log-rank test. Results By the time of malignant transformation, median age was 44 years, and median Karnofsky Performance Status (KPS) score was 90. Complete resection of contrast-enhancing tissue was achieved in 18 (32.1%) patients. Median survival after re-resection was 33 months (95% confidence interval [CI], 20–46); median OS was 123 months (95% CI, 77–170). Gross total tumor resection, postoperative KPS score ≥80, adjuvant radiochemotherapy, and prior radiotherapy significantly correlated with post-malignant progression survival. Conclusions Patients in good clinical condition with malignant progression of previously treated low-grade gliomas should receive aggressive treatment, including re-resection. more...

Data concerning treatment of secondary glioblastoma evolving from previously treated WHO II or III grade tumors are very scarce. The aim of this study was to evaluate the impact of surgical resection and adjuvant treatment on survival in patients with secondary glioblastoma. Thirty-nine patients with secondary glioblastoma evolving from previously treated lower grade gliomas between 2004 and 2015 were included. We evaluated the extent of resection, pathological parameters, adjuvant treatment, as well as survival after malignant transformation. The primary tumor grade was WHO II in 16 (41.0%) and WHO III in 23 (59.0%) patients. Median age was 43 years (range 23–67). Median KPS was 80 (range 60–100) before surgery, and 70 (range 50–100) after surgery. Gross total resection (GTR) of contrast-enhancing disease was achieved in 19 (48.7%) patients. Adjuvant treatment was radio-chemotherapy in 23 (59.0%), radiotherapy in three (7.7%), chemotherapy in five (12.8%) and none in eight (20.5%) patients. Median survival was 11 months (range 1–35) in the entire group. Time since initial diagnosis and previous treatment did not correlate with survival after glioblastoma. Failed GTR, poor KPS after surgery, and no adjuvant treatment were prognostic factors for shorter survival in univariate analysis (p more...

Background: The PI3K pathway plays a major role in cancer cell growth and survival and is the most frequently altered pathway in cancer. BEZ235 is a potent and highly specific oral PI3K/mTOR inhibitor. Administered as hard-gelatine capsule, BEZ235 was well tolerated with a favorable safety profile. Available data showed that BEZ235 led to PRs (1 patient (pt) with NSCLC [PTENnull], 1 pt with ER+ breast cancer [mutation unknown]) and prolonged disease stabilization (4 to >24 months) in pts with PI3K pathway dysregulated tumors (N=9/51), 5/9 with ER+, 1/9 with HER2+ breast cancer. Here, we present data from patients (pts) receiving treatment with a special drug delivery system of BEZ235 (SDS) with improved PK properties (Cao SABCS 2010). Results: 22 pts have been treated with BEZ235 SDS capsule at 3 dose levels (qd): 400 mg (5); 800 mg (6), 1000 mg (11). Median age was 56 years. The most common tumor types among pts enrolled were: breast cancer (4), CRC (4) and NSCLC (3). 2/22 pts were treated for >3 cycles, 16/22 pts progressed within the first three cycles of treatment. The maximum tolerated dose (MTD) is 1000 mg/d. Dose-limiting toxicities (DLTs) included: 2 Grade (G)3 fatigue (800 mg and 1000 mg) and 1 G3 skin rash (at 1000 mg). The most common treatment-related AEs included: fatigue, diarrhea, nausea, vomiting (G1-3). Preliminary PK data showed a slow absorption rate, Cmax at ∼6 h post-dose (range 2-8 h). The elimination halflife is ∼6 h across doses and visits. Steady state was reached after 8 days of treatment; the mean (SD) exposures at steady state (AUC, rss) for the dose of 400, 800, and 1000 mg/d were 8864 (12210), 19060 (19860), 46010 (36150) ng*h/mL, respectively. The exposure across dose levels (AUC0- 24, SS) was above the exposure required for tumor stasis in PI3K pathway dysregulated tumors, estimated based on CT measurements in patients(Bottino SABCS 2010). Currently, the efficacy of BEZ235 SDS, alone and in combination with trastuzumab, in patients with PIK3CA mutated breast cancer is investigated. As of today 1 clinical PR was observed with BEZ235+trastuzumab in a patient with breast cancer (HER2+, PIK3CA mutated, trastuzumab refractory) with brain and peripheral metastases. Conclusions: BEZ235 SDS treatment is well tolerated. The MTD is 1000 mg/d. Available PD and efficacy data show that BEZ235 is active in breast cancer (especially PI3K pathway dysregulated tumors). Phase II studies in breast cancer combining BEZ235 SDS with other agents will start soon. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-07. more...