Suppression of uPA and uPAR Attenuates Angiogenin Mediated Angiogenesis in Endothelial and Glioblastoma Cell Lines

In our earlier reports, we showed that downregulation of uPA and uPAR inhibited glioma tumor angiogenesis in SNB19 cells, and intraperitoneal injection of a hairpin shRNA expressing plasmid targeting uPA and uPAR inhibited angiogenesis in nude mice. The exact mechanism by which inhibition of angiogenesis takes place is not clearly understood.In the present study, we have attempted to investigate the mechanism by which uPA/uPAR downregulation by shRNA inhibits angiogenesis in endothelial and glioblastoma cell lines. uPA/uPAR downregulation by shRNA in U87 MG and U87 SPARC co-cultures with endothelial cells inhibited angiogenesis as assessed by in vitro angiogenesis assay and in vivo dorsal skin-fold chamber model in nude mice. Protein antibody array analysis of co-cultures of U87 and U87 SPARC cells with endothelial cells treated with pU2 (shRNA against uPA and uPAR) showed decreased angiogenin secretion and angiopoietin-1 as well as several other pro-angiogenic molecules. Therefore, we investigated the role of angiogenin and found that nuclear translocation, ribonucleolytic and 45S rRNA synthesis, which are all critical for angiogenic function of angiogenin, were significantly inhibited in endothelial cells transfected with uPA, uPAR and uPA/uPAR when compared with controls. Moreover, uPA and uPAR downregulation significantly inhibited the phosphorylation of Tie-2 receptor and also down regulated FKHR activation in the nucleus of endothelial cells via the GRB2/AKT/BAD pathway. Treatment of endothelial cells with ruPA increased angiogenin secretion and angiogenin expression as determined by ELISA and western blotting in a dose-dependent manner. The amino terminal fragment of uPA down regulated ruPA-induced angiogenin in endothelial cells, thereby suggesting that uPA plays a critical role in positively regulating angiogenin in glioblastoma cells.Taken together, our results suggest that uPA/uPAR downregulation suppresses angiogenesis in endothelial cells induced by glioblastoma cell lines partially by downregulation of angiogenin and by inhibition of the angiopoietin-1/AKT/FKHR pathway

Influence of Adjuvant Therapy in Cancer Survivors on Endothelial Function and Skeletal Muscle Deoxygenation

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The descriptive epidemiology of female breast cancer: an international comparison of screening, incidence, survival and mortality

Background: This paper presents the latest international descriptive epidemiological data for invasive breast cancer amongst women, including incidence, survival and mortality, as well as information on mammographic screening programmes

Breast Cancer Incidence and Survival among Young Females in Queensland, Australia

Breast cancer is the most common cancer diagnosed among adolescent and young adult (AYA) females worldwide, but epidemiological patterns unique to this group are often obscured when results are combined with older patients. This study investigates breast cancer incidence and survival among AYA females, including differences by broad stage at diagnosis. Methods: A retrospective, population-based cohort study was conducted using de-identified data for females in Queensland, Australia, aged 15-39 diagnosed with a first primary breast cancer between 1997 and 2014 with follow-up to December 31, 2016. Incidence rate trends were examined with Joinpoint analysis. Cause-specific survival was calculated for key characteristics, and 5-year adjusted hazard ratios (HRs) were estimated from a multivariable flexible parametric model. Results: The study cohort comprised 2337 patients, of whom two-thirds (n = 1565, 67%) were diagnosed with advanced disease (tumor diameter >20 mm, lymph node involvement or presence of distant metastases at diagnosis). Incidence rates of localized tumors decreased by 1.9% per year (95% confidence interval [CI] -3.5% to -0.4%) over the study period, whereas the trend for advanced breast cancers remained stable. Five-year cause-specific survival increased from 85% to 92% for 2011-2014 compared to 1997-2001 (adjusted HR = 0.43, 95% CI = 0.29-0.65). Patients who were Indigenous from disadvantaged areas or diagnosed with advanced stage experienced significantly worse survival. Conclusion: The high proportion of younger females diagnosed with advanced breast cancer should be the focus of future campaigns to improve awareness and earlier detection. While survival has increased over time, further work is required to ensure that this progress is experienced equitably by all patients.</p

Prognostic significance of calcitonin immunoreactivity, amyloid staining, and flow cytometric DNA measurements in medullary thyroid carcinoma

The proven power of DNA ploidy to predict mortality risk in medullary thyroid carcinoma (MTC) may be weakened when analyzed in conjunction with calcitonin immunoreactivity (CI) and amyloid staining (AS) of tumors. In this study 12 prognostic variables, including DNA ploidy, CI, and AS, were studied in 65 patients with MTC (57 sporadic; mean age 51 years) treated during 1946 through 1970. Cause-specific mortality rates at 10 and 15 years were 15% and 26%, respectively. By univariate analysis, TNM stages III or IV (p < 0.0001), tumor unresectability (p < 0.0001), male sex (p = 0.019), negative AS (p = 0.032), and low CI (p = 0.033) were significant predictors of increased mortality rates. DNA ploidy (p = 0.058) and inheritance pattern (p = 0.25) were nonsignificant. By multivariate analysis, only TNM stage, tumor resectability, and AS were independently significant (p < 0.005). A prognostic model was created, based on presence or absence of these independent risk factors, and four risk groups were defined, capable of predictably defining mortality rates in MTC (p < 0.0001). The model requires validation in larger series and independent verification by others. However, we believe that a risk-group scheme for MTC based on AS, disease stage, and completeness of tumor resection may have wide applicability and prove relevant to clinicians treating this disease

Atypical Ductal Hyperplasia of the Breast in Young Women: Two Case Reports

Atypical ductal hyperplasia of the breast is a benign proliferative condition that is associated with an increased risk of development of breast cancer in either the ipsilateral or contralateral breast. Following diagnosis at biopsy, respective management options range from observation to chemoprophylaxis to prophylactic surgery. We present two cases in young women, facing prolonged follow-up, one managed with observation only, and the other managed with ipsilateral mastectomy and reconstruction

Surgical and physical stress increases circulating blood dendritic cell count independently of monocyte counts

Dendritic cells (DCs) are specialized antigen-presenting cells that have the unique ability to initiate a primary immune response. The effect of physiologic stress on circulating blood DCs has thus far not been studied. In this study, we applied a recently developed method of counting blood DCs to test the hypothesis that significant stress to the body such as surgery and exercise might induce measurable changes in the DC numbers, subsets, phenotype, and function. Twenty-six patients scheduled for elective laparoscopic cholecystectomy, 4 for elective hysterectomy,56 controls, and 5 volunteers who underwent a stress exercise test were enrolled in the study. Absolute DC counts increased acutely (71.7% +/- 11% [SEM], p = .0001) in response to the stress of surgery and dropped below preoperative levels (-25% +/- 14% [SEM], P = .05) on days 2-3, The perioperative DC subset balance remained constant. Interestingly, DC counts changed independently of monocyte counts. Exercise also induced a rise in DC counts but coincidentally with monocyte counts. Surprisingly, no phenotypic or functional activation of DCs was seen in either stress situations in vivo. DCs are rapidly mobilized into the circulation in response to surgical and exercise stress, which may serve to prepare the host's immune defenses against trauma. The independent regulation of the DC and monocyte counts reinforces the distinction between these 2 cell populations. (C) 2001 by The American Society of Hematology