MicroRNA-34a Attenuates Paclitaxel Resistance in Prostate Cancer Cells via Direct Suppression of JAG1/Notch1 Axis

Background/Aims: Treatment options for metastatic castrate-resistant prostate cancer (mCRPC) are limited and typically centered on paclitaxel-based chemotherapy. In this study, we aimed to evaluate whether miR-34a attenuates chemoresistance to paclitaxel by regulating target genes associated with drug resistance. Methods: We used data from The Cancer Genome Atlas to compare miR-34a expression levels in prostate cancer (PC) tissues with normal prostate tissues. The effects of miR-34a inhibition and overexpression on PC proliferation were evaluated in vitro via Cell Counting Kit-8 (CCK-8) proliferation, colony formation, apoptosis, and cell-cycle assays. A luciferase reporter assay was employed to identify the interactions between miR-34a and specific target genes. To determine the effects of up-regulation of miR-34a on tumor growth and chemo-resistance in vivo, we injected PC cells overexpressing miR-34a into nude mice subcutaneously and evaluated the rate of tumor growth during paclitaxel treatment. We examined changes in the expression levels of miR-34a target genes JAG1 and Notch1 and their downstream genes via miR-34a transfection by quantitative reverse transcription PCR (qRT-PCR) and western blot assay. Results: miR-34a served as an independent predictor of reduced patient survival. MiR-34a was down-regulated in PC-3PR cells compared with PC-3 cells. The CCK-8 assay showed that miR-34a overexpression resulted in increased sensitivity to paclitaxel while miR-34a down-regulation resulted in chemoresistance to paclitaxel in vitro. A study of gain and loss in a series of functional assays revealed that PC cells expressing miR-34a were chemosensitive. Furthermore, the overexpression of miR-34a increased the sensitivity of PC-3PR cells to chemotherapy in vivo. The luciferase reporter assay confirmed that JAG1 and Notch1 were directly targeted by miR-34a. Interestingly, western blot analysis and qRT-PCR confirmed that miR-34a inhibited the Notch1 signaling pathway. We found that miR-34a increased the chemosensitivity of PC-3PR cells by directly repressing the TCF1/ LEF1 axis. Conclusion: Our results showed that miR-34a is involved in the development of chemosensitivity to paclitaxel. By regulating the JAG1/Notch1 axis, miR-34a or its target genes JAG1 or Notch1 might serve as potential predictive biomarkers of response to paclitaxel-based chemotherapy and/or therapeutic targets that will help to overcome chemoresistance at the mCRPC stage

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

Effect of Cooling Rate on AlN Precipitation in FeCrAl Stainless Steel During Solidification

The effect of cooling rate on the evolution of AlN inclusions precipitated during solidification in FeCrAl stainless steel was investigated using an experimental study and thermodynamic and kinetic calculations. The number and size of AlN inclusions precipitated under different cooling rates were examined with the feature function of the field-emission scanning electron microscope. A model combining micro-segregation and the diffusion-controlled growth model was set up to determine the mechanism of AlN particle growth. The results showed that AlN precipitates in the mushy zone. The size of AlN particles decreases and the number of AlN particles increases with increasing cooling rate, whereas the volume fraction is essentially unchanged. The AlN particles grow during solidification after the content of solutes in molten steel has exceeded the concentration in equilibrium with AlN. The nitrogen content varies significantly with the cooling rate during solidification. Increasing the cooling rate and reducing the nitrogen content in the molten steel can reduce the AlN particle size in FeCrAl alloys as the growth time decreases

Electrochemiluminescent Detection of hNQO1 and Associated Drug Screening Enabled by Futile Redox Cycle Reaction

Human NAD(P)H: quinone oxidoreductase 1 (hNQO1), a proteinase that engages in detoxification of quinones and capable of activating anti-tumor drugs, has drawn increasing attention as tumor biomarker and drug target. To date, the detection of hNQO1 primarily uses stimulus-responsive probes, involving metabolization of synthetic quinone-functionalized substrates, which however, remain challenging to improve the sensing signal-to-noise ratio, and are lack of sufficient stability. Herein, we report a facile but general way for hNQO1 detection and associated drug screening as well by ECL sensing of the metabolic H2O2 enabled by futile redox cycle reaction. Taking advantage of the intrinsic circulatory amplification and the luminol-modified nickel foam electrode, the sensing system exhibited a record-level performance in electrochemiluminescent detection of hNQO1. The same strategy was also successfully applied to rapidly screening hNQO1-directed anti-tumor candidate drugs. The proposed new principle for hNQO1 detection would stimulate ECL as a promising tool that combines diagnostic and drug screening functions for the popularization of proteinases in cancer management

Facile Preparation of WO3-x Dots with Remarkably Low Toxicity and Uncompromised Activity as Coreactants for Clinic Electrochemiluminescent Diagnosis

The exceptional nature of WO3-x dots has inspired widespread interests (Science, 2017, 358, 1192; Adv. Mater., 2016, 28, 10518), but it is still a major challenge to synthesize high-quality WO3-x dots without using unstable reactants, expensive equipment, and complex synthetic processes. Chemical tailoring of nanosheets is an essential way for the synthesis of nanodots, however it is NOT applicable to exfoliate bulk WO3 due to its covalently-bound layers. As such, most of the synthesis rely on a bottom-up method by using WCl6 as a typical precursor but water-free conditions are usually required due to the highly hydrolytic property of WCl6 (J. Am. Chem. Soc. 2005, 127, 15595). In addition, to diminish the anisotropic growth during the synthesis, the surface of the WO3-x dots is usually anchored with aliphatic amines or oleic acid as surfactant/template, which leads to SLOW Faradic electrochemistry (Adv. Mater. 2014, 26, 4260). Along these lines, it is of both fundamental and technical importance to overcome these deficiencies in the synthesis of high-quality WO3-x dots. In this work, we report the synthesis of WO3-x dots by a facile exfoliation of bulk WS2 instead of bulk WO3 followed by a mild chemical conversion. The WO3-x dots were not only ligand-FREE and highly water-dispersible but also had tunable oxygen-vacancies, ready for a varity of high-demanding applications. As an example, the WO3-x dots were emerged as a new generation of coreactants for the electrochemiluminescence (ECL) of Ru(bpy)32+ with a tremendous enhancement factor up to 500-fold, owing to the unique electrochemical and catalytic properties. More importantly, compared to the commonly used tripropylamine (TPA) coreactant in the clinics, the WO3-x dots displayed a factor of ca. 300 less ANIMAL toxicity. Along these lines, the enormous potential of WO3-x dots as ECL coreactants in replacing TPA for clinic diagnosis was further exemplified by cytosensing circulating tumor cells with a uncompromised performance. This work would not only open a new way to synthesize WO3-x dots with superior properties but also stimulate an emerging application in clinic ECL diagnosis as coreactants with uncompromised high performance and unprecedented low toxicity.</p

Identifying tumor cell-released extracellular vesicles as biomarkers for breast cancer diagnosis by a three-dimensional hydrogel-based electrochemical immunosensor

Abstract Tumor cell-released LC3+ extracellular vesicles (LC3+ EVs) participate in immunosuppression during autophagy and contribute to the occurrence and development of breast cancer. In view of the strong association between the LC3+ EVs and breast cancer, developing an effective strategy for the quantitative detection of LC3+ EVs levels with high sensitivity to identify LC3+ EVs as new biomarkers for accurate diagnosis of breast cancer is crucial, but yet not been reported. Herein, an ultrasensitive electrochemical immunosensor is presented for the quantitative determination of LC3+ EVs using a three-dimensional graphene oxide hydrogel-methylene blue composite as a redox probe, showing a low detection limit and a wide linear range. With this immunosensor, the expression levels of LC3+ EVs in various practical sample groups including different cancer cell lines, the peripheral blood of tumor-bearing mice before and after immunotherapy, and the peripheral blood from breast cancer patients with different subtypes and stages were clearly distinguished. This study demonstrated that LC3+ EVs were superior as biomarkers for the accurate diagnosis of breast cancer compared to traditional biomarkers, particularly for cancer subtype discrimination. This work would provide a new noninvasive detection tool for the early diagnosis and prognosis assessment of breast cancer in clinics

Further Optimized Design of a Nested Rotate Sextupole Permanent Magnet Lens for the Focusing of Pulsed Neutrons

A compact nested rotate sextupole permanent magnet (Nest-Rot-SPM) lens was designed for the focusing of pulsed neutrons. It is based on the working conditions of the Very Small Angle Neutron Scattering (VSANS) instrument at the China Spallation Neutron Source (CSNS), and is expected to focus a neutron pulse from 6 &Aring; to 10.5 &Aring;, without chromatic aberration. Three hurdles must be addressed, i.e., the tremendous torque, the heat deposition, and the synchronization with the neutron pulse, respectively. The bore diameter and segment length of the lens are optimized using a formula analysis of the key parameters and model simulations of the torque and heat deposition. A twin torque canceling design is used to reduce the torque to one-third of its original value, or even lower. The goal of this project is to take the device into practical use in the VSANS at the CSNS

Further Optimized Design of a Nested Rotate Sextupole Permanent Magnet Lens for the Focusing of Pulsed Neutrons

A compact nested rotate sextupole permanent magnet (Nest-Rot-SPM) lens was designed for the focusing of pulsed neutrons. It is based on the working conditions of the Very Small Angle Neutron Scattering (VSANS) instrument at the China Spallation Neutron Source (CSNS), and is expected to focus a neutron pulse from 6 Å to 10.5 Å, without chromatic aberration. Three hurdles must be addressed, i.e., the tremendous torque, the heat deposition, and the synchronization with the neutron pulse, respectively. The bore diameter and segment length of the lens are optimized using a formula analysis of the key parameters and model simulations of the torque and heat deposition. A twin torque canceling design is used to reduce the torque to one-third of its original value, or even lower. The goal of this project is to take the device into practical use in the VSANS at the CSNS