Inhibition of Tissue Factor Expression in Brain Microvascular Endothelial Cells by Nanoparticles Loading NF-κB Decoy Oligonucleotides

To investigate a nuclear factor-kappa B decoy oligonucleotides strategy on the inhibition of tissue factor (TF) expression in cultured rat brain microvascular endothelial cells (BMECs) by polylactic acid (PLA) nanoparticles delivery system and to evaluate this new vector for in vitro gene therapy. Nanoparticles were formulated using poly D,L-polylactic acid with surface modifying by polysorbates 80. 3-[4,5-Dimethylthiazol-2,5-diphenyl-2H-tetrazolium bromide] (MTT) assays showed that PLA nanoparticles were not toxic to the cultured BMECs.The decoy oligonuceotides (ODNs) loaded within nanoparticles was 6 μg/mg, encapsulation efficacy was (60.5±1.5)%. It was observed by flow cytometry that the cellular uptake of nanoparticles depended on the time of incubation and the concentration of nanoparticles in the medium. And confocal microscopy demonstrated that nanoparticles localized mostly in the BMECs cytoplasm. The released decoy oligonuceotides (ODNs) uptaked by BMECs retained their biologic activity and led to reduced level of tissue factor expression as compared to control cultures. These findings offer a potential therapeutic strategy in the control of TF expression in BMECs in vitro and suggest that PLA nanoparticles may be appropriate as delivery vehicles for decoy strategy in the gene therapy of cerebral thrombosis

Overall survival and cancer-specific survival were improved in local treatment of metastatic prostate cancer

BackgroundFor metastatic prostate cancer (mPCa), radical prostatectomy (RP) and radiation therapy (RT) may improve overall survival (OS) and cancer-specific survival (CSS). Compared with RT, RP shows significant advantages in improving patient outcomes. External beam radiation therapy (EBRT) even slightly elevates CSM with no statistical difference in OS compared with no local treatment (NLT).ObjectiveTo evaluate OS and CSS after local treatment (LT) (including RP and RT) versus NLT in mPCa.Design, setting, and participantsWithin the Surveillance, Epidemiology and End Results (SEER) database (2000-2018), 20098 patients with metastatic prostate cancer were selected in this study, of which 19433 patients had no local treatment, 377 patients with radical prostate treatment, and 288 patients with RT.Outcome measurements and statistical analysisMultivariable competing risks regression analysis after propensity score matching (PSM) was used to calculate CSM. Multivariable Cox regression analysis was used to identify the risk factors. Kaplan-Meier methods were used to calculate OS.Results and limitationsA total of 20098 patients were included: NLT (n = 19433), RP (n=377) and RT (n=288). In a competing risk regression analysis after PSM (ratio 1:1), RP resulted in a significantly lower CSM (hazard ratio [HR] 0.36, 95% confidence interval [CI] 0.29-0.45) than NLT, while RT showed a slightly lower CSM (HR 0.77, 95% CI 0.63-0.95). In a competing risk regression analysis after PSM (ratio 1:1), RP led to a lower CSM (HR 0.56, 95% CI 0.41-0.76) versus RT. As for all-cause mortality (ACM), RP (HR 0.37, 95% CI 0.31-0.45) and RT (HR 0.66, 95% CI 0.56-0.79). also showed a downward trend. In terms of OS, RP and RT significantly improved the survival probability compared with NLT, with the effect of RP being more pronounced. Obviously, older age, Gleason scores ≥8, AJCC T3-T4 stage, AJCC N1, AJCC M1b-M1c were all associated with higher CSM (P <0.05). The same results held true for ACM. The limitation of this article is that it is not possible to assess the effect of differences in systemic therapy on CSM in mPCa patients and clinical trials are needed to verify the results.ConclusionsFor patients with mPCa, both RP and RT are beneficial to patients, and the efficacy of RP is better than RT from the perspective of CSM and ACM. Older age, higher gleason scores and the more advanced AJCC TNM stage all put patients at higher risk of dying.Patient summaryA large population-based cancer database showed that in addition to first-line therapy (hormonal treatment), RP and radiotherapy can also benefit patients with mPCa

Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1

Monotherapy with Menin inhibitor (MI), e.g., SNDX-5613, induces clinical remissions in patients with relapsed/refractory AML harboring MLL1-r or mtNPM1, but most patients either fail to respond or eventually relapse. Utilizing single-cell RNA-Seq, ChiP-Seq, ATAC-Seq, RNA-Seq, RPPA, and mass cytometry (CyTOF) analyses, present pre-clinical studies elucidate gene-expression correlates of MI efficacy in AML cells harboring MLL1-r or mtNPM1. Notably, MI-mediated genome-wide, concordant, log2 fold-perturbations in ATAC-Seq and RNA-Seq peaks were observed at the loci of MLL-FP target genes, with upregulation of mRNAs associated with AML differentiation. MI treatment also reduced the number of AML cells expressing the stem/progenitor cell signature. A protein domain-focused CRISPR-Cas9 screen in MLL1-r AML cells identified targetable co-dependencies with MI treatment, including BRD4, EP300, MOZ and KDM1A. Consistent with this, in vitro co-treatment with MI and BET, MOZ, LSD1 or CBP/p300 inhibitor induced synergistic loss of viability of AML cells with MLL1-r or mtNPM1. Co-treatment with MI and BET or CBP/p300 inhibitor also exerted significantly superior in vivo efficacy in xenograft models of AML with MLL1-r. These findings highlight novel, MI-based combinations that could prevent escape of AML stem/progenitor cells following MI monotherapy, which is responsible for therapy-refractory AML relapse

Upregulation of MIAT Regulates LOXL2 Expression by Competitively Binding MiR-29c in Clear Cell Renal Cell Carcinoma

Background/Aims: MIAT is a long noncoding RNA (lncRNA) involved in cell proliferation and the development of tumor. However, the exact effects and molecular mechanisms of MIAT in clear cell renal cell carcinoma (ccRCC) progression are still unknown. Methods: We screened the lncRNAs’ profile of ccRCC in The Cancer Genome Atlas database, and then examined the expression levels of lncRNA MIAT in 45 paired ccRCC tissue specimens and in cell lines by q-RT-PCR. MTS, colony formation, EdU, and Transwell assays were performed to examine the effect of MIAT on proliferation and metastasis of ccRCC. Western blot and luciferase assays were performed to determine whether MIAT can regulate Loxl2 expression by competitively binding miR-29c in ccRCC. Results: MIAT was up-regulated in ccRCC tissues and cell lines. High MIAT expression correlated with worse clinicopathological features and shorter survival rate. Functional assays showed that knockdown of MIAT inhibited renal cancer cell proliferation and metastasis in vitro and in vivo. Luciferase and western blot assays further confirmed that miR-29c binds with MIAT. Additionally, the correlation of miR-29c with MIAT and Loxl2 was further verified in patients' samples. Conclusion: Our data indicated that MIAT might be an oncogenic lncRNA that promoted proliferation and metastasis of ccRCC, and could be a potential therapeutic target in human ccRCC

Potential of Core-Collapse Supernova Neutrino Detection at JUNO

JUNO is an underground neutrino observatory under construction in Jiangmen, China. It uses 20kton liquid scintillator as target, which enables it to detect supernova burst neutrinos of a large statistics for the next galactic core-collapse supernova (CCSN) and also pre-supernova neutrinos from the nearby CCSN progenitors. All flavors of supernova burst neutrinos can be detected by JUNO via several interaction channels, including inverse beta decay, elastic scattering on electron and proton, interactions on C12 nuclei, etc. This retains the possibility for JUNO to reconstruct the energy spectra of supernova burst neutrinos of all flavors. The real time monitoring systems based on FPGA and DAQ are under development in JUNO, which allow prompt alert and trigger-less data acquisition of CCSN events. The alert performances of both monitoring systems have been thoroughly studied using simulations. Moreover, once a CCSN is tagged, the system can give fast characterizations, such as directionality and light curve

Detection of the Diffuse Supernova Neutrino Background with JUNO

As an underground multi-purpose neutrino detector with 20 kton liquid scintillator, Jiangmen Underground Neutrino Observatory (JUNO) is competitive with and complementary to the water-Cherenkov detectors on the search for the diffuse supernova neutrino background (DSNB). Typical supernova models predict 2-4 events per year within the optimal observation window in the JUNO detector. The dominant background is from the neutral-current (NC) interaction of atmospheric neutrinos with 12C nuclei, which surpasses the DSNB by more than one order of magnitude. We evaluated the systematic uncertainty of NC background from the spread of a variety of data-driven models and further developed a method to determine NC background within 15\% with {\it{in}} {\it{situ}} measurements after ten years of running. Besides, the NC-like backgrounds can be effectively suppressed by the intrinsic pulse-shape discrimination (PSD) capabilities of liquid scintillators. In this talk, I will present in detail the improvements on NC background uncertainty evaluation, PSD discriminator development, and finally, the potential of DSNB sensitivity in JUNO

Real-time Monitoring for the Next Core-Collapse Supernova in JUNO

Core-collapse supernova (CCSN) is one of the most energetic astrophysical events in the Universe. The early and prompt detection of neutrinos before (pre-SN) and during the SN burst is a unique opportunity to realize the multi-messenger observation of the CCSN events. In this work, we describe the monitoring concept and present the sensitivity of the system to the pre-SN and SN neutrinos at the Jiangmen Underground Neutrino Observatory (JUNO), which is a 20 kton liquid scintillator detector under construction in South China. The real-time monitoring system is designed with both the prompt monitors on the electronic board and online monitors at the data acquisition stage, in order to ensure both the alert speed and alert coverage of progenitor stars. By assuming a false alert rate of 1 per year, this monitoring system can be sensitive to the pre-SN neutrinos up to the distance of about 1.6 (0.9) kpc and SN neutrinos up to about 370 (360) kpc for a progenitor mass of 30$M_{\odot}$ for the case of normal (inverted) mass ordering. The pointing ability of the CCSN is evaluated by using the accumulated event anisotropy of the inverse beta decay interactions from pre-SN or SN neutrinos, which, along with the early alert, can play important roles for the followup multi-messenger observations of the next Galactic or nearby extragalactic CCSN.Comment: 24 pages, 9 figure

Methylprednisolone as Adjunct to Endovascular Thrombectomy for Large-Vessel Occlusion Stroke

Importance It is uncertain whether intravenous methylprednisolone improves outcomes for patients with acute ischemic stroke due to large-vessel occlusion (LVO) undergoing endovascular thrombectomy. Objective To assess the efficacy and adverse events of adjunctive intravenous low-dose methylprednisolone to endovascular thrombectomy for acute ischemic stroke secondary to LVO. Design, Setting, and Participants This investigator-initiated, randomized, double-blind, placebo-controlled trial was implemented at 82 hospitals in China, enrolling 1680 patients with stroke and proximal intracranial LVO presenting within 24 hours of time last known to be well. Recruitment took place between February 9, 2022, and June 30, 2023, with a final follow-up on September 30, 2023.InterventionsEligible patients were randomly assigned to intravenous methylprednisolone (n = 839) at 2 mg/kg/d or placebo (n = 841) for 3 days adjunctive to endovascular thrombectomy. Main Outcomes and Measures The primary efficacy outcome was disability level at 90 days as measured by the overall distribution of the modified Rankin Scale scores (range, 0 [no symptoms] to 6 [death]). The primary safety outcomes included mortality at 90 days and the incidence of symptomatic intracranial hemorrhage within 48 hours. Results Among 1680 patients randomized (median age, 69 years; 727 female [43.3%]), 1673 (99.6%) completed the trial. The median 90-day modified Rankin Scale score was 3 (IQR, 1-5) in the methylprednisolone group vs 3 (IQR, 1-6) in the placebo group (adjusted generalized odds ratio for a lower level of disability, 1.10 [95% CI, 0.96-1.25]; P = .17). In the methylprednisolone group, there was a lower mortality rate (23.2% vs 28.5%; adjusted risk ratio, 0.84 [95% CI, 0.71-0.98]; P = .03) and a lower rate of symptomatic intracranial hemorrhage (8.6% vs 11.7%; adjusted risk ratio, 0.74 [95% CI, 0.55-0.99]; P = .04) compared with placebo. Conclusions and Relevance Among patients with acute ischemic stroke due to LVO undergoing endovascular thrombectomy, adjunctive methylprednisolone added to endovascular thrombectomy did not significantly improve the degree of overall disability.Trial RegistrationChiCTR.org.cn Identifier: ChiCTR210005172

Monocular Visual-Inertial State Estimation for Micro Aerial Vehicles

Autonomous micro aerial vehicles (MAVs) equipped with onboard sensors, are idea platforms for missions in complex and confined environments for its low cost, small size and agile maneuver. Due to the size, power, weight and computation constraints inherent in the filed of MAVs, monocular visual-inertial system that consist of one camera and an inertial measurement (IMU) are the most suitable sensor suit for MAVs. In this paper, we proposed a monocular visual-inertial algorithm for estimating the state of a MAV. Firstly, the Semi-Direct Visual Odometry (SVO) algorithm used as the vision front-end of our framework was modified so that it can be used for forward-looking camera case. Second, an Error-state Kalman Filter was designed so that it can fuse the output of the SVO and IMU data to estimate the full state of the MAVs. We evaluated the proposed method with EuRoc Dataset and compare the results to the state-of-the-art visual-inertial algorithm, VINS-Mono. Experiments show that our estimator can achieve comparable accurate results