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.
Solar energy, renewable energy, urban wind energy, environment, augmented wind turbine. Display omitted
► A system for on-site wind–solar hybrid power generation and rain water collection. ► The ...omni-direction-guide-vane (ODGV) overcomes the weak wind and turbulence conditions in urban areas. ► The ODGV improves the wind turbine performance by speeding-up and guiding the wind. ► The ODGV is designed to blend into the building architecture with safety enhancement. ► The wind tunnel test and CFD simulation results are presented.
A novel omni-direction-guide-vane (ODGV) that surrounds a vertical axis wind turbine (VAWT) is designed to improve the wind turbine performance. Wind tunnel testing was performed to evaluate the performance of a 5-bladed (Wortmann FX63-137 airfoil) H-rotor wind turbine, with and without the integration of the ODGV. The test was conducted using a scaled model turbine which was constructed to simulate the VAWT enclosed by the ODGV placed on a building. The VAWT shows an improvement on its self-starting behavior where the cut-in speed was reduced with the integration of the ODGV. Since the VAWT is able to self-start at a lower wind speed, the working hour of the wind turbine would increase. At a wind speed of 6m/s and under free-running condition (only rotor inertia and bearing friction were applied), the ODGV helps to increase the rotor rotational speed by 182%. With extra load application at the same wind speed (6m/s), the wind turbine power output was increased by 3.48 times at its peak torque with the aid of the ODGV. The working concept of the ODGV is to minimize the negative torque zone of a lift-type VAWT and to reduce turbulence and rotational speed fluctuation. It was verified by re-simulating the torque coefficient data of a single bladed (NACA 0015 airfoil) VAWT published by the Sandia National Laboratories. From the simulation results, with the presence of the ODGV, it was shown that the torque output of the NACA 0015 airfoil, single bladed VAWT has been increased by 58% and 39% at TSR=2.5 and TSR=5.1 respectively. The negative torque zone has been minimized thus the positive torque that provides higher power can be obtained. As a conclusion, the ODGV integrated wind power generation system improves the power output of a VAWT and it has great potential to be sited in urban areas for on-site and grid-connected power generation.
Conserving energy and reducing carbon emissions have become the common responsibility of the international community. During the year 2010, the Taiwan government planned a four-year project budgeted ...at 300 million US dollars, called “The Penghu Low Carbon Island Development Project.” The policy objective is to use Penghu Island (population 85,000) as a test platform to evaluate new ways to conserve energy and reduce carbon emissions before attempting to replicate the policies on Taiwan Island. For Taiwan, a zero carbon island green transportation policy will regulate the total number of electric scooters, the total number of gasoline motorcycles, influence government subsidy incentives, and create the need for new motorcycle license issuing and control. These factors interact with each other to form a complex and dynamic system that impacts policy as well as the current way of life. In this study, a system dynamics approach is designed to construct a model for evaluating the green transportation policy on Penghu Island. Simulations are conducted to model green transportation system behavior and related policy effects in a smaller, controlled environment before creating policies for Taiwan Island that will impact the lives of over 23 million people.
► Provides an overview of Taiwan's Penghu Low Carbon Island Development Project. ► Develops a systems dynamics approach for green transportation policy assessment. ► Provides causal analysis of social, economic, and environmental factors. ► Demonstrates that the proposed policy cannot meet the CO2 reduction goals. ► Alternative policies can be evaluated using the proposed approach.
Summary
Background
Deregulation of mammalian target of rapamycin (mTOR) signalling is common in human hepatocellular carcinoma (HCC).
Aim
To determine the maximum tolerated dose (MTD) of the oral ...mTOR inhibitor everolimus in advanced HCC patients.
Methods
Patients with locally advanced or metastatic HCC (Child‐Pugh class A or B) were enrolled in an open‐label phase 1 study and randomly assigned to daily (2.5–10 mg) or weekly (20–70 mg) everolimus in a standard 3 + 3 dose‐escalation design. MTD was based on the rate of dose‐limiting toxicities (DLTs). Secondary endpoints included safety, pharmacokinetics and tumour response. In a post hoc analysis, serum hepatitis B virus (HBV) DNA levels were quantified.
Results
Thirty‐nine patients were enrolled. DLTs occurred in five of 21 patients in the daily and two of 19 patients in the weekly cohort. Daily and weekly MTDs were 7.5 mg and 70 mg respectively. Grade 3/4 adverse events with a ≥10% incidence were thrombocytopenia, hypophosphataemia and alanine transaminase (ALT) elevation. In four hepatitis B surface antigen (HBsAg)‐seropositive patients, grade 3/4 ALT elevations were accompanied by significant (>1 log) increases in serum HBV levels. The incidence of hepatitis flare (defined as ALT increase >100 IU/mL from baseline) in HBsAg‐seropositive patients with and without detectable serum HBV DNA before treatment was 46.2% and 7.1% respectively (P < 0.01, Fisher exact test). Disease control rates in the daily and weekly cohorts were 71.4% and 44.4% respectively.
Conclusions
The recommended everolimus dosing schedule for future hepatocellular carcinoma studies is 7.5 mg daily. Prophylactic anti‐viral therapy should be mandatory for HBsAg‐seropositive patients (ClinicalTrials.gov NCT00390195).
Chronic inflammation plays an important role in cancer development and progression. Cyclooxygenases-2 (COX-2) is a key enzyme in generating prostaglandins causing inflammation, is often found to be ...overexpressed in prostate cancer (PCa) and is correlated with PCa cell invasion and metastasis. We aim to investigate the molecular mechanism of how COX-2 promotes PCa cell invasion and metastasis and to evaluate the effect of COX-2 inhibitors in a selected model of PCa progression. Our results showed that the expression of COX-2 and Interleukin 1β (IL-1β) was upregulated in highly invasive PCa cells and was correlated with the activated levels of membrane-anchored serine protease matriptase. The expression levels of COX-2 were increased and were correlated with matriptase levels in PCa specimens. Moreover, results showed that COX-2 overexpression or a COX-2 product Prostaglandin E
(PGE
) caused an increase in matriptase activation and PCa cell invasion, whereas COX-2 silencing antagonized matriptase activation and cell invasion. In addition, the inhibition of COX-2-mediated matriptase activation by Celebrex and sulindac sulfide suppressed the androgen-independent and COX2-overexpressing PCa PC-3 cell invasion, tumor growth and lung metastasis in an orthotopic xenograft model. Our results indicate that COX-2/matriptase signaling contributes to the invasion, tumor growth and metastasis of COX-2-overexpressing and androgen-independent PCa cells.
The associations between long-term risk of hepatocellular carcinoma (HCC) and spontaneous seroclearance of HBV e antigen (HBeAg), HBV DNA and HBV surface antigen (HBsAg) have never been examined by a ...prospective study using serially measured seromarkers. This study aimed to assess the importance of spontaneous HBeAg, HBV DNA and HBsAg seroclearance in the prediction of HCC risk.
This study included 2946 HBsAg seropositive individuals who were seronegative for antibodies against HCV and free of liver cirrhosis. Serial serum samples collected at study entry and follow-up health examinations were tested for HBeAg, HBV DNA and HBsAg. Cox proportional hazards models were used to calculate the HRs of developing HCC after seroclearance of HBV markers.
The HR (95% CI) of developing HCC after seroclearance of HBeAg, HBV DNA and HBsAg during follow-up was 0.63 (0.38 to 1.05), 0.24 (0.11 to 0.57) and 0.18 (0.09 to 0.38), respectively, after adjustment for age, gender and serum level of alanine aminotransferase at study entry. High HBV DNA levels at the seroclearance of HBeAg (mean±SD, 4.35±1.64 log10 IU/mL) may explain the non-significant association between HBeAg seroclearance and HCC risk. Among HBeAg seronegative participants with detectable serum HBV DNA at study entry, the lifetime (30-75-years-old) cumulative incidence of HCC was 4.0%, 6.6% and 14.2%, respectively, for those with seroclearance of both HBV DNA and HBsAg, seroclearance of HBV DNA only, and seroclearance of neither.
Spontaneous seroclearance of HBV DNA and HBsAg are important predictors of reduced HCC risk.
UX Orionis stars (UXors) are Herbig Ae/Be or T Tauri stars exhibiting sporadic occultation of stellar light by circumstellar dust. GM Cephei is such a UXor in the young (∼4 Myr) open cluster Trumpler ...37, showing prominent infrared excess, emission-line spectra, and flare activity. Our photometric monitoring (2008-2018) detects (1) an ∼3.43 day period, likely arising from rotational modulation by surface starspots, (2) sporadic brightening on timescales of days due to accretion, (3) irregular minor flux drops due to circumstellar dust extinction, and (4) major flux drops, each lasting for a couple of months with a recurrence time, though not exactly periodic, of about two years. The star experiences normal reddening by large grains, i.e., redder when dimmer, but exhibits an unusual "blueing" phenomenon in that the star turns blue near brightness minima. The maximum extinction during relatively short (lasting ≤50 days) events, is proportional to the duration, a consequence of varying clump sizes. For longer events, the extinction is independent of duration, suggestive of a transverse string distribution of clumps. Polarization monitoring indicates an optical polarization varying ∼3%-8%, with the level anticorrelated with the slow brightness change. Temporal variation of the unpolarized and polarized light sets constraints on the size and orbital distance of the circumstellar clumps in the interplay with the young star and scattering envelope. These transiting clumps are edge-on manifestations of the ring- or spiral-like structures found recently in young stars with imaging in infrared of scattered light, or in submillimeter of thermalized dust emission.
Background. We examined whether viral dynamics in the genital tract during the natural history of acute human immunodeficiency virus type 1 (HIV-1) infection could explain efficient heterosexual ...transmission of HIV. Methods. We measured HIV-1 concentration in blood and semen samples from patients with acute and long-term HIV-1 infection. We explored the effect of changes in viral dynamics in semen on the probability of transmission per coital act, using a probabilistic model published elsewhere. Results. Considered over time from infection, semen HIV-1 concentrations, in men with acute infection, increase and decrease in approximate parallel with changes occurring in blood. Modeling suggests that these acute dynamics alone are sufficient to increase probability of heterosexual transmission by 8–10-fold between peak (day 20 after infection, based on the model) and virologic set points (day 54 and later after infection). Depending on the frequency of coitus, men with average semen HIV-1 loads and without sexually transmitted diseases (STDs) would be expected to infect 7%–24% of susceptible female sex partners during the first 2 months of infection. The predicted infection rate would be much higher when either partner has an STD. Conclusions. Empirical biological data strongly support the hypothesis that sexual transmission by acutely infected individuals has a disproportionate effect on the spread of HIV-1 infection. Acute hyperinfectiousness may, in part, explain the current pandemic in heterosexual individuals.
Secondary mutation of epidermal growth factor receptor (EGFR) resulting in drug resistance is one of the most critical issues in lung cancer therapy. Several drugs are being developed to overcome ...EGFR tyrosine kinase inhibitor (TKI) resistance. Here, we report that pyruvate kinase M2 (PKM2) stabilized mutant EGFR protein by direct interaction and sustained cell survival signaling in lung cancer cells. PKM2 silencing resulted in markedly reduced mutant EGFR expression in TKI-sensitive or -resistant human lung cancer cells, and in inhibition of tumor growth in their xenografts, concomitant with downregulation of EGFR-related signaling. Mechanistically, PKM2 directly interacted with mutant EGFR and heat-shock protein 90 (HSP90), and thus stabilized EGFR by maintaining its binding with HSP90 and co-chaperones. Stabilization of EGFR relied on dimeric PKM2, and the protein half-life of mutant EGFR decreased when PKM2 was forced into its tetramer form. Clinical levels of PKM2 positively correlated with mutant EGFR expression and with patient outcome. These results reveal a previously undescribed non-glycolysis function of PKM2 in the cytoplasm, which contribute to EGFR-dependent tumorigenesis and provide a novel strategy to overcome drug resistance to EGFR TKIs.
ABSTRACT We report the All-Sky Automated Survey for SuperNovae discovery of the tidal disruption event (TDE) ASASSN-23bd (AT 2023clx) in NGC 3799, a LINER galaxy with no evidence of strong active ...galactic nucleus (AGN) activity over the past decade. With a redshift of z = 0.01107 and a peak ultraviolet (UV)/optical luminosity of (5.4 ± 0.4) × 1042 erg s−1, ASASSN-23bd is the lowest-redshift and least-luminous TDE discovered to date. Spectroscopically, ASASSN-23bd shows H α and He i emission throughout its spectral time series, there are no coronal lines in its near-infrared spectrum, and the UV spectrum shows nitrogen lines without the strong carbon and magnesium lines typically seen for AGN. Fits to the rising ASAS-SN light curve show that ASASSN-23bd started to brighten on MJD 59988$^{+1}_{-1}$, ∼9 d before discovery, with a nearly linear rise in flux, peaking in the g band on MJD $60 \, 000^{+3}_{-3}$. Scaling relations and TDE light curve modelling find a black hole mass of ∼106 M⊙, which is on the lower end of supermassive black hole masses. ASASSN-23bd is a dim X-ray source, with an upper limit of $L_{0.3-10\, \mathrm{keV}} \lt 1.0\times 10^{40}$ erg s−1 from stacking all Swift observations prior to MJD 60061, but with soft (∼0.1 keV) thermal emission with a luminosity of $L_{0.3-2 \, \mathrm{keV}}\sim 4\times 10^{39}$ erg s−1 in XMM-Newton observations on MJD 60095. The rapid (t < 15 d) light curve rise, low UV/optical luminosity, and a luminosity decline over 40 d of ΔL40 ≈ −0.7 dex make ASASSN-23bd one of the dimmest TDEs to date and a member of the growing ‘Low Luminosity and Fast’ class of TDEs.
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