Endoglin Is Essential for the Maintenance of Self-Renewal and Chemoresistance in Renal Cancer Stem Cells.

Renal cell carcinoma (RCC) is a deadly malignancy due to its tendency to metastasize and resistance to chemotherapy. Stem-like tumor cells often confer these aggressive behaviors. We discovered an endoglin (CD105)-expressing subpopulation in human RCC xenografts and patient samples with a greater capability to form spheres in vitro and tumors in mice at low dilutions than parental cells. Knockdown of CD105 by short hairpin RNA and CRISPR/cas9 reduced stemness markers and sphere-formation ability while accelerating senescence in vitro. Importantly, downregulation of CD105 significantly decreased the tumorigenicity and gemcitabine resistance. This loss of stem-like properties can be rescued by CDA, MYC, or NANOG, and CDA might act as a demethylase maintaining MYC and NANOG. In this study, we showed that Endoglin (CD105) expression not only demarcates a cancer stem cell subpopulation but also confers self-renewal ability and contributes to chemoresistance in RCC

Kansas City Cardiomyopathy Questionnaire Utility in Prediction of 30-Day Readmission Rate in Patients with Chronic Heart Failure

Background. Heart failure (HF) is one of the most common diagnoses associated with hospital readmission. We designed this prospective study to evaluate whether Kansas City Cardiomyopathy Questionnaire (KCCQ) score is associated with 30-day readmission in patients hospitalized with decompensated HF. Methods and Results. We enrolled 240 patients who met the study criteria. Forty-eight (20%) patients were readmitted for decompensated HF within thirty days of hospital discharge, and 192 (80%) patients were not readmitted. Compared to readmitted patients, nonreadmitted patients had a higher average KCCQ score (40.8 versus 32.6, P = 0.019) before discharge. Multivariate analyses showed that a high KCCQ score was associated with low HF readmission rate (adjusted OR = 0.566, P = 0.022). The c-statistic for the base model (age + gender) was 0.617. The combination of home medication and lab tests on the base model resulted in an integrated discrimination improvement (IDI) increase of 3.9%. On that basis, the KCQQ further increased IDI of 2.7%. Conclusions. The KCCQ score determined before hospital discharge was significantly associated with 30-day readmission rate in patients with HF, which may provide a clinically useful measure and could significantly improve readmission prediction reliability when combined with other clinical components

Impact of alirocumab/evolocumab on lipoprotein (a) concentrations in patients with familial hypercholesterolaemia: a systematic review and meta-analysis of randomized controlled trials

Introduction: Familial hypercholesterolaemia (FH) is a common hereditary genetic disorder, characterized by elevated circulating low-density lipoprotein cholesterol (LDL-C) and lipoprotein (a) [Lp(a)] concentrations, leading to atherosclerotic cardiovascular disease (ASCVD). Two types of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors — alirocumab and evolocumab — are efficient drugs in the treatment of FH, which can effectively reduce Lp(a) levels. Material and methods: Embase, MEDLINE, and PubMed up to November 2022 were searched for randomized clinical trials (RCTs) evaluating the effect of alirocumab/evolocumab and placebo treatment on plasma Lp(a) levels in FH. Statistics were analysed by Review Manager (RevMan 5.3) and Stata 15.1. Results: Eleven RCTs involved a total of 2408 participants. Alirocumab/evolocumab showed a significant efficacy in reducing Lp(a) [weighted mean difference (WMD): –20.10%, 95% confidence interval (CI): –25.59% to –14.61%] compared with placebo. In the drug type subgroup analyses, although the efficacy of evolocumab was slightly low (WMD: –19.98%, 95% CI: –25.23% to –14.73%), there was no difference with alirocumab (WMD: –20.54%, 95% CI: –30.07% to –11.02%). In the treatment duration subgroup analyses, the efficacy of the 12-week duration group (WMD: –17.61%, 95% CI: –23.84% to –11.38%) was lower than in the group of ≥ 24 weeks’ duration (WMD: –22.81%, 95% CI: –31.56% to –14.07%). In the participants’ characteristics subgroup analyses, the results showed that no differential effect of alirocumab/evolocumab therapy on plasma Lp(a) concentrations was observed (heterozygous FH [HeFH] WMD: –20.07%, 95% CI: –26.07% to –14.08%; homozygous FH [HoFH] WMD: –20.04%, 95% CI: –36.31% to –3.77%). Evaluation of all-cause adverse events (AEs) between alirocumab/evolocumab groups and placebo groups [relative risk (RR): 1.05, 95% CI: 0.98–1.12] implied no obvious difference between the 2 groups. Conclusions: Anti-PCSK9 drugs (alirocumab and evolocumab) may be effective as therapy for reducing serum Lp(a) levels in FH, and no differences were observed in treatment durations, participant characteristics, and other aspects of the 2 types of PCSk9 inhibitors. However, further experimental studies and RCTs are warranted to clarify the mechanism of PSCK9 inhibitors to lowering Lp(a) concentrations in FH

4.5 years multi-wavelength observations of Mrk 421 during the ARGO-YBJ and Fermi common operation time

We report on the extensive multi-wavelength observations of the blazar Markarian 421 (Mrk 421) covering radio to gamma-rays, during the 4.5 year period of ARGO-YBJ and Fermi common operation time, from August 2008 to February 2013. In particular, thanks to the ARGO-YBJ and Fermi data, the whole energy range from 100 MeV to 10 TeV is covered without any gap. In the observation period, Mrk 421 showed both low and high activity states at all wavebands. The correlations among flux variations in different wavebands were analyzed. Seven large flares, including five X-ray flares and two GeV gamma-ray flares with variable durations (3-58 days), and one X-ray outburst phase were identified and used to investigate the variation of the spectral energy distribution with respect to a relative quiescent phase. During the outburst phase and the seven flaring episodes, the peak energy in X-rays is observed to increase from sub-keV to few keV. The TeV gamma-ray flux increases up to 0.9-7.2 times the flux of the Crab Nebula. The behavior of GeV gamma-rays is found to vary depending on the flare, a feature that leads us to classify flares into three groups according to the GeV flux variation. Finally, the one-zone synchrotron self-Compton model was adopted to describe the emission spectra. Two out of three groups can be satisfactorily described using injected electrons with a power-law spectral index around 2.2, as expected from relativistic diffuse shock acceleration, whereas the remaining group requires a harder injected spectrum. The underlying physical mechanisms responsible for different groups may be related to the acceleration process or to the environment properties.Comment: 17 pages, 9 figures, 5 tables, Accepted for publication in ApJ

The cosmic ray proton plus helium energy spectrum measured by the ARGO-YBJ experiment in the energy range 3-300 TeV

The ARGO-YBJ experiment is a full-coverage air shower detector located at the Yangbajing Cosmic Ray Observatory (Tibet, People's Republic of China, 4300 m a.s.l.). The high altitude, combined with the full-coverage technique, allows the detection of extensive air showers in a wide energy range and offer the possibility of measuring the cosmic ray proton plus helium spectrum down to the TeV region, where direct balloon/space-borne measurements are available. The detector has been in stable data taking in its full configuration from November 2007 to February 2013. In this paper the measurement of the cosmic ray proton plus helium energy spectrum is presented in the region 3-300 TeV by analyzing the full collected data sample. The resulting spectral index is $\gamma = -2.64 \pm 0.01$. These results demonstrate the possibility of performing an accurate measurement of the spectrum of light elements with a ground based air shower detector.Comment: 18 pages, 8 figures, preprint submitted to Phys. Rev.

Study of the diffuse gamma-ray emission from the Galactic plane with ARGO-YBJ

The events recorded by ARGO-YBJ in more than five years of data collection have been analyzed to determine the diffuse gamma-ray emission in the Galactic plane at Galactic longitudes 25{\deg} < l < 100{\deg} and Galactic latitudes . The energy range covered by this analysis, from ~350 GeV to ~2 TeV, allows the connection of the region explored by Fermi with the multi-TeV measurements carried out by Milagro. Our analysis has been focused on two selected regions of the Galactic plane, i.e., 40{\deg} < l < 100{\deg} and 65{\deg} < l < 85{\deg} (the Cygnus region), where Milagro observed an excess with respect to the predictions of current models. Great care has been taken in order to mask the most intense gamma-ray sources, including the TeV counterpart of the Cygnus cocoon recently identified by ARGO-YBJ, and to remove residual contributions. The ARGO-YBJ results do not show any excess at sub-TeV energies corresponding to the excess found by Milagro, and are consistent with the predictions of the Fermi model for the diffuse Galactic emission. From the measured energy distribution we derive spectral indices and the differential flux at 1 TeV of the diffuse gamma-ray emission in the sky regions investigated.Comment: 11 pages, 6 figures, published in AP

EAS age determination from the study of the lateral distribution of charged particles near the shower axis with the ARGO-YBJ experiment

The ARGO-YBJ experiment, a full coverage extensive air shower (EAS) detector located at high altitude (4300 m a.s.l.) in Tibet, China, has smoothly taken data, with very high stability, since November 2007 to the beginning of 2013. The array consisted of a carpet of about 7000 m$^2$ Resistive Plate Chambers (RPCs) operated in streamer mode and equipped with both digital and analog readout, providing the measurement of particle densities up to few particles per cm$^2$. The unique detector features (full coverage, readout granularity, wide dynamic range, etc) and location (very high altitude) allowed a detailed study of the lateral density profile of charged particles at ground very close to the shower axis and its description by a proper lateral distribution function (LDF). In particular, the information collected in the first 10 m from the shower axis have been shown to provide a very effective tool for the determination of the shower development stage ("age") in the energy range 50 TeV - 10 PeV. The sensitivity of the age parameter to the mass composition of primary Cosmic Rays is also discussed

The ARGO-YBJ Experiment Progresses and Future Extension

Gamma ray source detection above 30TeV is an encouraging approach for finding galactic cosmic ray origins. All sky survey for gamma ray sources using wide field of view detector is essential for population accumulation for various types of sources above 100GeV. To target the goals, the ARGO-YBJ experiment has been established. Significant progresses have been made in the experiment. A large air shower detector array in an area of 1km2 is proposed to boost the sensitivity. Hybrid detection with multi-techniques will allow a good discrimination between different types of primary particles, including photons and protons, thus enable an energy spectrum measurement for individual specie. Fluorescence light detector array will extend the spectrum measurement above 100PeV where the second knee is located. An energy scale determined by balloon experiments at 10TeV will be propagated to ultra high energy cosmic ray experiments

High Altitude test of RPCs for the ARGO-YBJ experiment

A 50 m**2 RPC carpet was operated at the YangBaJing Cosmic Ray Laboratory (Tibet) located 4300 m a.s.l. The performance of RPCs in detecting Extensive Air Showers was studied. Efficiency and time resolution measurements at the pressure and temperature conditions typical of high mountain laboratories, are reported.Comment: 16 pages, 10 figures, submitted to Nucl. Instr. Met

Observation of TeV gamma rays from the Cygnus region with the ARGO-YBJ experiment

We report the observation of TeV gamma-rays from the Cygnus region using the ARGO-YBJ data collected from 2007 November to 2011 August. Several TeV sources are located in this region including the two bright extended MGRO J2019+37 and MGRO J2031+41. According to the Milagro data set, at 20 TeV MGRO J2019+37 is the most significant source apart from the Crab Nebula. No signal from MGRO J2019+37 is detected by the ARGO-YBJ experiment, and the derived flux upper limits at 90% confidence level for all the events above 600 GeV with medium energy of 3 TeV are lower than the Milagro flux, implying that the source might be variable and hard to be identified as a pulsar wind nebula. The only statistically significant (6.4 standard deviations) gamma-ray signal is found from MGRO J2031+41, with a flux consistent with the measurement by Milagro.Comment: 14 pages, 4 figure