Dysregulation of cell surface proteolysis has been strongly implicated in tumorigenicity and metastasis. In this study, we delineated the role of hepatocyte growth factor activator inhibitor-2 ...(HAI-2) in prostate cancer (PCa) cell migration, invasion, tumorigenicity and metastasis using a human PCa progression model (103E, N1, and N2 cells) and xenograft models. N1 and N2 cells were established through serial intraprostatic propagation of 103E human PCa cells and isolation of the metastatic cells from nearby lymph nodes. The invasion capability of these cells was revealed to gradually increase throughout the serial isolations (103E<N1<N2). In this series of cells, the expression of HAI-2 but not HAI-1 was significantly decreased throughout the progression and occurred in parallel with increased activation of matriptase. The expression level and activity of matriptase increased whereas the HAI-2 protein level decreased over the course of orthotopic tumor growth in mice, which was consistent with the immunohistochemical profiles of matriptase and HAI-2 in archival PCa specimens. Knockdown of matriptase reduced the PCa cell invasion induced by HAI-2 knockdown. HAI-2 overexpression or matriptase silencing in N2 cells downregulated matriptase activity and significantly decreased tumorigenicity and metastatic capability in orthotopically xenografted mice. These results suggest that during the progression of human PCa, matriptase activity is primarily controlled by HAI-2 expression. The imbalance between HAI-2 and matriptase expression led to matriptase activation, thereby increasing cell migration, invasion, tumorigenicity and metastasis.
ABSTRACT
We present the Global Rapid Advanced Network Devoted to the Multi-messenger Addicts (GRANDMA). The network consists of 21 telescopes with both photometric and spectroscopic facilities. They ...are connected together thanks to a dedicated infrastructure. The network aims at coordinating the observations of large sky position estimates of transient events to enhance their follow-up and reduce the delay between the initial detection and optical confirmation. The GRANDMA programme mainly focuses on follow-up of gravitational-wave alerts to find and characterize the electromagnetic counterpart during the third observational campaign of the Advanced LIGO and Advanced Virgo detectors. But it allows for follow-up of any transient alerts involving neutrinos or gamma-ray bursts, even those with poor spatial localization. We present the different facilities, tools, and methods we developed for this network and show its efficiency using observations of LIGO/Virgo S190425z, a binary neutron star merger candidate. We furthermore report on all GRANDMA follow-up observations performed during the first six months of the LIGO–Virgo observational campaign, and we derive constraints on the kilonova properties assuming that the events’ locations were imaged by our telescopes.
We report the first genome-wide association study in 1000 bipolar I patients and 1000 controls, with a replication of the top hits in another 409 cases and 1000 controls in the Han Chinese ...population. Four regions with most strongly associated single-nucleotide polymorphisms (SNPs) were detected, of which three were not found in previous GWA studies in the Caucasian populations. Among them, SNPs close to specificity protein 8 (SP8) and ST8 α-N-acetyl- neuraminide α-2,8-sialyltransferase (ST8SIA2) are associated with Bipolar I, with P-values of 4.87 × 10(-7) (rs2709736) and 6.05 × 10(-6) (rs8040009), respectively. We have also identified SNPs in potassium channel tetramerization domain containing 12 gene (KCTD12) (rs2073831, P=9.74 × 10(-6)) and in CACNB2 (Calcium channel, voltage-dependent, β-2 subunit) gene (rs11013860, P=5.15 × 10(-5)), One SNP nearby the rs1938526 SNP of ANK3 gene and another SNP nearby the SNP rs11720452 in chromosome 3 reported in previous GWA studies also showed suggestive association in this study (P=6.55 × 10(-5) and P=1.48 × 10(-5), respectively). This may suggest that there are common and population-specific susceptibility genes for bipolar I disorder.
To validate and compare the definition of the Disease Activity Score 28 based on C-reactive protein (DAS28 (CRP)) to the definition based on erythrocyte sedimentation rate (ESR).
Data were analysed ...from two randomised, double-blind, placebo-controlled trials of abatacept of 6-month and 12-month duration in patients with rheumatoid arthritis. European League Against Rheumatism (EULAR) response criteria and the proportion of patients in remission (DAS28 <2.6) based on the two DAS28 definitions were examined. Trends in radiographic progression (erosion score, joint space narrowing score and total score) and physical function (Health Assessment Questionnaire Disability Index (HAQ-DI)) across the EULAR responder states (none, moderate and good) were analysed.
There was general agreement in determining the EULAR responder state using both DAS28 definitions (kappa = 0.80, 95% CI 0.76 to 0.83). Overall, there was 82.4% agreement on the EULAR response criteria; when disagreements occurred, the DAS28 (CRP) yielded a better EULAR response more often then DAS28 (ESR) (12.6% vs 4.9%, respectively). There was also agreement in determining remission: kappa = 0.69 (95% CI 0.60 to 0.78). Radiographic progression decreased in patients treated with abatacept across EULAR states (from none to moderate to good) based on both definitions. For patients treated with placebo, the trend was not as pronounced, with radiographic scores higher for moderate vs non-responders. For physical function, similar trends were observed across the EULAR states for both DAS28 definitions.
The DAS28 (CRP) has been validated against radiographic progression and physical function. While the DAS28 (CRP) yielded a better EULAR response more often than the DAS28 (ESR), the validation profile was similar to the DAS28 (ESR), indicating that both measures are useful for assessing disease activity in patients with rheumatoid arthritis.
Major causes of head and neck squamous cell carcinoma (HNSCC)-related deaths are cervical node and distant metastasis. We previously demonstrated that overexpression of the DNA double-strand break ...repair protein Nijmegen breakage syndrome 1 (NBS1) is a prognostic marker of advanced HNSCCs. Epithelial-mesenchymal transition (EMT) was demonstrated to be the major mechanism responsible for mediating invasiveness and metastasis of late-stage cancers. We therefore investigated the role of NBS1 overexpression in mediating EMT and metastasis. NBS1 overexpression was associated with metastasis of HNSCC patients using tissue microarray-immunohistochemistry approach. Induction of EMT was observed in an NBS1-overexpressing HNSCC cell line (FADUNBS), whereas short-interference RNA (siRNA)-mediated repression of endogenous NBS1 reversed the shift of EMT markers. Increased migration/invasiveness of FADUNBS was shown by in vitro and in vivo assays. NBS1 overexpression upregulated the expression of an EMT regulator Snail and its downstream target matrix metalloproteinase-2. EMT phenotypes and increased migration/invasiveness of FADUNBS cells were reversed by siRNA-mediated repression of Snail expression or a phosphatidylinositol 3-kinase-specific inhibitor. In HNSCC samples, co-expression of NBS1/Snail in primary tumors correlated with metastasis and the worst prognosis. These results indicate that NBS1 overexpression induces EMT through the upregulation of Snail expression, and co-expression of NBS1/Snail predicts metastasis in HNSCCs.
Background and purpose: The relationship between myasthenia gravis (MG) and extrathymic malignancies has not been determined. This study aimed to explore the risk of extrathymic malignancy in ...patients with MG based on a nationwide population‐based dataset.
Methods: We identified 2614 patients with MG from the Taiwan National Health Insurance database between 1997 and 2005 and compared the incidence rates of extrathymic malignancies with 15 684 randomly selected age‐, sex‐, and comorbidity‐matched subjects without MG. Both cohorts were followed until the end of 2009. Cox proportional hazard model was used to evaluate the predictors of extrathymic malignancy in the MG cohort, including age, sex, comorbidities, and prescription drugs.
Results: After an average follow‐up of 8 years, the MG cohort had a higher risk of extrathymic cancers with an incidence rate ratio (IRR) of 1.38 (95% CI 1.12–1.68, P = 0.002) than the control cohort. Although breast cancer was the most common cancer found, no statistically significant relationship between MG and any specific malignancy was observed. Cox multivariate proportional hazards analysis showed that only age (HR = 1.05, 95% CI 1.04–1.06, P < 0.001) and liver cirrhosis (IRR = 3.85, 95% CI 1.22–12.14, P = 0.021) were predictors of extrathymic cancers in the MG cohort.
Conclusions: Our study showed that patients with MG had an increased risk of extrathymic malignancy in a follow‐up of 8 years, but no specific susceptibility to certain malignancies was found.
Quantitative data from DSA have become important tools for understanding hemodynamic changes of intracranial lesions. In this study, we evaluated 8 hemodynamic parameters in patients before and after ...carotid artery angioplasty.
DSA images of 34 patients with carotid stenosis who underwent angioplasty and stent placement were retrospectively analyzed. Eleven ROIs (M1, M2, A1, A2, the parietal vein, superior sagittal sinus, internal jugular vein, and 4 in the ICA) were selected on color-coded DSA. Eight hemodynamic parameters (bolus arrival time, TTP, relative TTP, full width at half maximum, wash-in slope, washout slope, maximum enhancement, and area under the curve) were measured from the time-concentration curves of these ROIs. The dependent
test for paired samples was applied to these parameters before and after stent placement.
We found that the treatment significantly reduced TTP, relative TTP, bolus arrival time, and washout slope at all arterial ROIs and full width at half maximum and area under the curve at some arterial ROIs. Bolus arrival time was significantly reduced after treatment for all arterial ROIs, the parietal vein, and the superior sagittal sinus. The maximum enhancement and wash-in slope did not show significant changes after treatment. After treatment, the relative TTP from the ICA to M1, M2, and the parietal vein returned to normal values.
In addition to TTP and relative TTP, other parameters can be used to evaluate peritherapeutic cerebral hemodynamic changes. Bolus arrival time has the potential to evaluate brain circulation at arterial and venous sites, especially when TTP cannot be measured because of an incomplete time-concentration curve.
Summary
Haemostasis is associated with the development and dissemination of cancer. Whether cancer incidence is increased in haemophiliacs remains uncertain; thus, we aimed to further examine this ...issue. By using data from the National Health Insurance Research Database in Taiwan, we obtained a cohort of 683 patients with haemophilia A, and compared the incidence rate ratio (IRR) of cancer in this cohort with an age‐ and sex‐matched control of 6830 patients. The log‐rank test was used to compare Kaplan–Meier curve of the cumulative cancer incidence between two cohorts. Cox regressions were used to identify independent risk factors of cancer in the study patients. The cancer incidence of patients with haemophilia A was significantly higher compared to the control group (IRR 1.95, 95% CI 1.18–3.09, P = 0.008) during the 14‐year follow‐up period. The non‐lymphoma and non‐liver cancer incidence in the haemophilia A cohort remained higher than that of the matched control (P = 0.050 by the log‐rank test). The multivariate Cox proportional hazards analysis indicated that age (per year, HR 1.09, 95% CI 1.06–1.12, P < 0.001) was the only significant risk factor for cancer development in haemophilia patients. Patients with haemophilia A had higher cancer incidence than the age‐ and sex‐matched patients, especially for the elderly. With increasing life expectancy for haemophiliacs, physicians should be aware of their cancer development.
A numerical simulation has been performed to investigate the effect of a cusp magnetic field on the melt flow, thermal field and oxygen concentration during the Czochralski silicon crystal growth ...process. The results show a decrease in the oxygen concentration due to the reduction in size of the secondary flow cell that formed between the Taylor–Proudman vortex and the buoyancy-driven one. There is a significant reduction in the size of the secondary flow cell when the magnetic field is applied. As a consequence of the higher strength of the magnetic field there is a significant decrease in the oxygen concentration along the melt-crystal surface. The oxygen concentration is also very sensitive to the crucible rotation rate. There is an optimum crucible rotation rate for obtaining the lowest oxygen concentration. The oxygen concentration is lower for higher argon flow rate. The oxygen concentration decreases as the zero-Gauss plane (ZGP) moves from the free surface towards crucible bottom. When the ZGP is far from the free surface, the secondary flow cell appears and then the oxygen concentration increases. There is an optimum position of the ZGP to obtain the lowest the oxygen concentration.
•Oxygen concentration is decreased by the size reduction of the secondary flow cell.•The secondary flow cell is significantly reduced when the magnetic field is applied.•There is an optimum crucible rotation rate for obtaining the lowest oxygen.•The oxygen concentration is lower for higher argon flow rate.•There is an optimum position of the ZGP for getting the lowest the oxygen.
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