Long non-coding RNA SNHG7 serves as a diagnostic biomarker for acute coronary syndrome and its predictive value for the clinical outcome after percutaneous coronary intervention.

BACKGROUND: Acute coronary syndrome (ACS) is one of the common causes of cardiovascular death. The related lncRNAs were novel approaches for early diagnosis and intervention. This paper focused on the clinical function of SNHG7 for patients after PCI. METHODS: The expression of SNHG7 was assessed in ACS patients. The predictive roles of SNHG7 were unveiled by the ROC curve. The relationship between SNHG7 and Gensini scores was judged by Pearson analysis. One-year follow-up was conducted and all patients were catalogued into different groups based on the prognosis. The qRT-PCR, K-M curve, and Cox regression analysis were performed to document the prognostic significance of SNHG7. RESULTS: SNHG7 was highly expressed in ACS and its three subtypes. SNHG7 showed a certain value in predicting ACS, UA, NSTEMI, and STEMI. Gensini is a closely correlated indicator of SNHG7. The declined expression of SNHG7 was observed in the non-MACE and survival groups. The risk of MACE and death was increased in the group with high expression of SNHG7. SNHG7 was an independent biomarker in patients with ACS after PCI. CONCLUSIONS: SNHG7 might be a diagnostic and prognostic tool for ACS patients.

Anticancer effect of hUC-MSC-derived exosome-mediated delivery of PMO-miR-146b-5p in colorectal cancer.

Antisense oligonucleotide (ASO) is a novel therapeutic platform for targeted cancer therapy. Previously, we have demonstrated that miR-146b-5p plays an important role in colorectal cancer progression. However, a safe and effective strategy for delivery of an ASO to its targeted RNA remains as a major hurdle in translational advances. Human umbilical cord mesenchymal cell (hUC-MSC)-derived exosomes were used as vehicles to deliver an anti-miR-146b-5p ASO (PMO-146b). PMO-146b was assembled onto the surface of exosomes (e) through covalent conjugation to an anchor peptide CP05 (P) that recognized an exosomal surface marker, CD63, forming a complex named ePPMO-146b. After ePPMO-146b treatment, cell proliferation, uptake ability, and migration assays were performed, and epithelial-mesenchymal transition progression was evaluated in vitro. A mouse xenograft model was used to determine the antitumor effect and distribution of ePPMO-146b in vivo. ePPMO-146b was taken up by SW620 cells and effectively inhibited cell proliferation and migration. The conjugate also exerted antitumor efficacy in a xenograft mouse model of colon cancer by systematic administration, where PPMO-146b was enriched in tumor tissue. Our study highlights the potential of hUC-MSC-derived exosomes anchored with PPMO-146b as a novel safe and effective approach for PMO backboned ASO delivery.

Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial.

Importance: The effect of continued treatment with tirzepatide on maintaining initial weight reduction is unknown. Objective: To assess the effect of tirzepatide, with diet and physical activity, on the maintenance of weight reduction. Design, Setting, and Participants: This phase 3, randomized withdrawal clinical trial conducted at 70 sites in 4 countries with a 36-week, open-label tirzepatide lead-in period followed by a 52-week, double-blind, placebo-controlled period included adults with a body mass index greater than or equal to 30 or greater than or equal to 27 and a weight-related complication, excluding diabetes. Interventions: Participants (n = 783) enrolled in an open-label lead-in period received once-weekly subcutaneous maximum tolerated dose (10 or 15 mg) of tirzepatide for 36 weeks. At week 36, a total of 670 participants were randomized (1:1) to continue receiving tirzepatide (n = 335) or switch to placebo (n = 335) for 52 weeks. Main Outcomes and Measures: The primary end point was the mean percent change in weight from week 36 (randomization) to week 88. Key secondary end points included the proportion of participants at week 88 who maintained at least 80% of the weight loss during the lead-in period. Results: Participants (n = 670; mean age, 48 years; 473 [71%] women; mean weight, 107.3 kg) who completed the 36-week lead-in period experienced a mean weight reduction of 20.9%. The mean percent weight change from week 36 to week 88 was -5.5% with tirzepatide vs 14.0% with placebo (difference, -19.4% [95% CI, -21.2% to -17.7%]; P < .001). Overall, 300 participants (89.5%) receiving tirzepatide at 88 weeks maintained at least 80% of the weight loss during the lead-in period compared with 16.6% receiving placebo (P < .001). The overall mean weight reduction from week 0 to 88 was 25.3% for tirzepatide and 9.9% for placebo. The most common adverse events were mostly mild to moderate gastrointestinal events, which occurred more commonly with tirzepatide vs placebo. Conclusions and Relevance: In participants with obesity or overweight, withdrawing tirzepatide led to substantial regain of lost weight, whereas continued treatment maintained and augmented initial weight reduction. Trial Registration: ClinicalTrials.gov Identifier: NCT04660643.

Biomimetic photosensitizer nanocrystals trigger enhanced ferroptosis for improving cancer treatment.

As a novel non-apoptotic cell death pathway, ferroptosis can effectively enhance the antitumor effects of photodynamic therapy (PDT) by disrupting intracellular redox homeostasis. However, the reported nanocomposites that combined the PDT and ferroptosis are cumbersome to prepare, and the unfavorable tumor microenvironment also severely interferes with their tumor suppressive effects. To address this inherent barrier, this study attempted to explore photosensitizers that could activate ferroptosis pathway and found that the photosensitizer aloe-emodin (AE) could induce cellular ferroptosis based on its specific inhibiting activity to Glutathione S-transferase P1(GSTP1), a key protein for ferroptosis. Herein, we prepared AE@RBC/Fe nanocrystals (NCs) with synergistic PDT and ferroptosis therapeutic effects by one-step emulsification to obtain AE NCs cores and further modification of red blood cells (RBC) membranes and ferritin. Benefiting from the involvement of ferritin, the prepared AE@RBC/Fe NCs provide not only sufficient oxygen for oxygen-dependent PDT, but also Fe3+ for iron-dependent ferroptosis in tumor cells. Furthermore, the biomimetic surface functionalization facilitated the prolonged circulation and cancer targeting of AE@RBC/Fe NCs in vivo. The in vitro and in vivo results demonstrate that AE@RBC/Fe NCs exhibit significantly enhanced therapeutic effects for the combined two antitumor mechanisms and provide a promising prospect for achieving PDT/ferroptosis synergistic therapy.

Mueller matrix imaging with a spatially modulated polarization light source.

In this paper, we present a Mueller matrix imaging system consisting of a spatially modulated polarization light source (SMPL) and a dual division-of-focal-plane (DoFP) polarimeters as the PSA and 2D detector. The system does not contain moving parts such as a rotating stage, which leads to more robust and reliable operations for applications in hostile settings. By taking Muller matrix images at variable distances between the SMPL and the target, we examine in details errors due to different spatial distributions in angle and intensity of different polarized lights. A calibration method is proposed to reduce such errors introduced by SMPL. The performances of the new imaging technique and the calibration method are tested in Mueller matrix imaging of different samples.

Serum exosomal and serum glypican-1 are associated with early recurrence of pancreatic ductal adenocarcinoma.

Background: The diagnostic performance and prognostic value of serum exosomal glypican 1 (GPC-1) in pancreatic ductal adenocarcinoma (PDAC) remain controversial. In this study, we detected serum exosomal GPC-1 using enzyme-linked immunosorbent assay (ELISA) and determined whether it serves as a predictor of diagnosis and recurrence for early-stage PDAC. Methods: Serum samples were obtained from patients with 50 PDAC, 6 benign pancreatic tumor (BPT), or 9 chronic pancreatitis (CP) and 50 healthy controls (HCs). Serum exosomes were isolated using an exosome isolation kit. Exosomal and serum GPC-1 levels were measured using ELISA. The freeze-thaw process was carried out to analyze the stability of GPC-1. Receiver operating characteristic (ROC) analysis was employed to assess the diagnostic value of GPC-1. Kaplan-Meier and multivariate Cox analyses were used to evaluate the prognostic value of GPC-1. Results: The average concentrations of serum exosomal and serum GPC-1 were 1.5 and 0.8 ng/ml, respectively. GPC-1 expression levels were stable under repeated freezing and thawing (d1-5 freeze-thaw cycles vs. d0 P > 0.05). Serum exosomal and serum GPC-1 were significantly elevated in patients with PDAC compared with HCs (P < 0.0001) but were slightly higher compared with that in patients with CP and BPT (P > 0.05). The expression levels of exosomal and serum GPC-1 were elevated 5 days after surgery in patients with PDAC, CP, and BPT (P < 0.05). Patients with high levels of exosomal and serum GPC-1 had a shorter relapse-free survival (RFS) (P = 0.006, and P = 0.010). Multivariate analyses showed that serum exosomal and serum GPC-1 were independent prognostic indicators for early RFS (P = 0.008, and P = 0.041). Conclusion: ELISA is an effective and sensitive method to detect exosomal and serum GPC-1. The detection of GPC-1 was stable under repeated freezing and thawing cycles and could distinguish early-stage PDAC from HCs but not CP and BPT. Exosomal and serum GPC-1 may be good independent predictors of early recurrence in early-stage PDAC.

MicroRNA-375 is a therapeutic target for castration-resistant prostate cancer through the PTPN4/STAT3 axis.

The functional role of microRNA-375 (miR-375) in the development of prostate cancer (PCa) remains controversial. Previously, we found that plasma exosomal miR-375 is significantly elevated in castration-resistant PCa (CRPC) patients compared with castration-sensitive PCa patients. Here, we aimed to determine how miR-375 modulates CRPC progression and thereafter to evaluate the therapeutic potential of human umbilical cord mesenchymal stem cell (hucMSC)-derived exosomes loaded with miR-375 antisense oligonucleotides (e-375i). We used miRNA in situ hybridization technique to evaluate miR-375 expression in PCa tissues, gain- and loss-of-function experiments to determine miR-375 function, and bioinformatic methods, dual-luciferase reporter assay, qPCR, IHC and western blotting to determine and validate the target as well as the effects of miR-375 at the molecular level. Then, e-375i complexes were assessed for their antagonizing effects against miR-375. We found that the expression of miR-375 was elevated in PCa tissues and cancer exosomes, correlating with the Gleason score. Forced expression of miR-375 enhanced the expression of EMT markers and AR but suppressed apoptosis markers, leading to enhanced proliferation, migration, invasion, and enzalutamide resistance and decreased apoptosis of PCa cells. These effects could be reversed by miR-375 silencing. Mechanistically, miR-375 directly interfered with the expression of phosphatase nonreceptor type 4 (PTPN4), which in turn stabilized phosphorylated STAT3. Application of e-375i could inhibit miR-375, upregulate PTPN4 and downregulate p-STAT3, eventually repressing the growth of PCa. Collectively, we identified a novel miR-375 target, PTPN4, that functions upstream of STAT3, and targeting miR-375 may be an alternative therapeutic for PCa, especially for CRPC with high AR levels.

MuellerNet: a hybrid 3D-2D CNN for cell classification with Mueller matrix images.

Different from conventional microimaging techniques, polarization imaging can generate multiple polarization images in a single perspective by changing the polarization angle. However, how to efficiently fuse the information in these multiple polarization images by a convolutional neural network (CNN) is still a challenging problem. In this paper, we propose a hybrid 3D-2D convolutional neural network called MuellerNet, to classify biological cells with Mueller matrix images (MMIs). The MuellerNet includes a normal stream and a polarimetric stream, in which the first Mueller matrix image is taken as the input of normal stream, and the rest MMIs are stacked to form the input of a polarimetric stream. The normal stream is mainly constructed with a backbone network and, in the polarimetric stream, the attention mechanism is used to adaptively assign weights to different convolutional maps. To improve the network's discrimination, a loss function is introduced to simultaneously optimize parameters of the two streams. Two Mueller matrix image datasets are built, which include four types of breast cancer cells and three types of algal cells, respectively. Experiments are conducted on these two datasets with many well-known and recent networks. Results show that the proposed network efficiently improves the classification accuracy and helps to find discriminative features in MMIs.

Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial.

BACKGROUND: Baricitinib is an oral selective Janus kinase 1/2 inhibitor with known anti-inflammatory properties. This study evaluates the efficacy and safety of baricitinib in combination with standard of care for the treatment of hospitalised adults with COVID-19. METHODS: In this phase 3, double-blind, randomised, placebo-controlled trial, participants were enrolled from 101 centres across 12 countries in Asia, Europe, North America, and South America. Hospitalised adults with COVID-19 receiving standard of care were randomly assigned (1:1) to receive once-daily baricitinib (4 mg) or matched placebo for up to 14 days. Standard of care included systemic corticosteroids, such as dexamethasone, and antivirals, including remdesivir. The composite primary endpoint was the proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28, assessed in the intention-to-treat population. All-cause mortality by day 28 was a key secondary endpoint, and all-cause mortality by day 60 was an exploratory endpoint; both were assessed in the intention-to-treat population. Safety analyses were done in the safety population defined as all randomly allocated participants who received at least one dose of study drug and who were not lost to follow-up before the first post-baseline visit. This study is registered with ClinicalTrials.gov, NCT04421027. FINDINGS: Between June 11, 2020, and Jan 15, 2021, 1525 participants were randomly assigned to the baricitinib group (n=764) or the placebo group (n=761). 1204 (79·3%) of 1518 participants with available data were receiving systemic corticosteroids at baseline, of whom 1099 (91·3%) were on dexamethasone; 287 (18·9%) participants were receiving remdesivir. Overall, 27·8% of participants receiving baricitinib and 30·5% receiving placebo progressed to meet the primary endpoint (odds ratio 0·85 [95% CI 0·67 to 1·08], p=0·18), with an absolute risk difference of -2·7 percentage points (95% CI -7·3 to 1·9). The 28-day all-cause mortality was 8% (n=62) for baricitinib and 13% (n=100) for placebo (hazard ratio [HR] 0·57 [95% CI 0·41-0·78]; nominal p=0·0018), a 38·2% relative reduction in mortality; one additional death was prevented per 20 baricitinib-treated participants. The 60-day all-cause mortality was 10% (n=79) for baricitinib and 15% (n=116) for placebo (HR 0·62 [95% CI 0·47-0·83]; p=0·0050). The frequencies of serious adverse events (110 [15%] of 750 in the baricitinib group vs 135 [18%] of 752 in the placebo group), serious infections (64 [9%] vs 74 [10%]), and venous thromboembolic events (20 [3%] vs 19 [3%]) were similar between the two groups. INTERPRETATION: Although there was no significant reduction in the frequency of disease progression overall, treatment with baricitinib in addition to standard of care (including dexamethasone) had a similar safety profile to that of standard of care alone, and was associated with reduced mortality in hospitalised adults with COVID-19. FUNDING: Eli Lilly and Company. TRANSLATIONS: For the French, Japanese, Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.

Probing the Cyanobacterial Microcystis Gas Vesicles after Static Pressure Treatment: A Potential In Situ Rapid Method.

The vertical migration trend of cyanobacterial cells with gas vesicles in water ecosystems can reflect the changes in the natural environment, such as temperature, nutrients, light conditions, etc. The static pressure treatment is one of the most important approaches to study the properties of the cyanobacterial cell and its gas vesicles. In this paper, a polarized light scattering method is used to probe the collapse and regeneration of the cyanobacterial gas vesicles exposed to different static pressures. During the course, both the axenic and wild type strain of cyanobacterial Microcystis were first treated with different static pressures and then recovered on the normal light conditions. Combining the observation of transmission electron microscopy and floating-sinking photos, the results showed that the collapse and regeneration of the cyanobacterial gas vesicles exposed to different static pressures can be characterized by the polarization parameters. The turbidity as a traditional indicator of gas vesicles but subjected to the concentration of the sample was also measured and found to be correlated with the polarization parameters. More analysis indicated that the polarization parameters are more sensitive and characteristic. The polarized light scattering method can be used to probe the cyanobacterial gas vesicles exposed to different static pressures, which has the potential to provide an in situ rapid and damage-free monitoring tool for observing the vertical migration of cyanobacterial cells and forecasting cyanobacterial blooms.

Evaluation of hepatitis B virus in clinical trials of baricitinib in rheumatoid arthritis.

BACKGROUND: Reactivation of hepatitis B virus (HBV) replication is a well-recognised complication in patients receiving disease-modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis (RA). Limited data exist on HBV reactivation among patients with RA treated with janus kinase (JAK) inhibitors. The objective of the current study was to assess HBV reactivation in clinical trials of baricitinib, an oral selective JAK1 and JAK2 inhibitor in RA. METHODS: Data were integrated from four completed Phase 3 trials and one ongoing long-term extension (data up to 1 April 2017) in patients naïve to DMARDs or who had inadequate response (IR) to DMARDs including methotrexate (MTX)-IR and/or other conventional synthetic DMARD (csDMARD)-IR, or tumour necrosis factor inhibitors-IR. Within the clinical programme, baricitinib-treated patients may have received concomitant csDMARDs including MTX, or previous treatment with active comparators including MTX or adalimumab + MTX. At screening, all patients were tested for HBV surface antigen (HBsAg), core antibody (HBcAb) and surface antibody (HBsAb). Patients were excluded if they had (1) HBsAg+, (2) HBcAb+/HBsAb- (in Japan, could enrol if HBV DNA-) or (3) HBsAb+ and HBV DNA+. HBV DNA monitoring, following randomisation in the originating Phase 3 studies, was performed in Japan for patients with HBcAb+ and/or HBsAb+ at screening, and was later instituted globally for HBcAb+ patients in accordance with evolving guidance for HBV monitoring and management with immunomodulatory therapy. RESULTS: In total, 2890 patients received at least one dose of baricitinib in Phase 3 (6993 patient-years exposure). Of 215 patients with baseline serology suggestive of prior HBV infection (HbcAb+) who received a post-baseline DNA test, 32 (14.9%) were HBV DNA+ at some point following treatment initiation; 8 of 215 patients (3.7%) had a single quantifiable result (≥29 IU/mL). Of these eight patients, four met the definition of reactivation of HBV (HBV DNA level ≥100 IU/mL); baricitinib was permanently discontinued in four patients, and temporarily interrupted in two patients. No patient developed clinical evidence of hepatitis and in five of eight patients, antiviral therapy was not used. CONCLUSION: HBV reactivation can occur among RA patients treated with DMARDs, including baricitinib, with prior HBV exposure. Our data suggest that such patients should be monitored for HBV DNA during treatment and might be treated safely with the use of antiviral therapy as needed. The risk of HBV reactivation in patients with HBsAg treated with baricitinib is unknown.

Enhancing thermal radiation by graphene-assisted hBN/SiO2 hybrid structures at the nanoscale.

A graphene-assisted hBN/SiO2 hybrid structure is proposed and demonstrated to enhance near-field thermal radiation (NFTR). Due to the complementarity between the hyperbolic phonon polaritons of hBN and the surface phonon polaritons of SiO2 at mid-infrared frequencies, coupling modes can remarkably improve the photon tunneling probability over a broad frequency band, especially when assisted by the surface plasmon polaritons of graphene sheets. Thus, the heat flux can exceed the blackbody limit by 4 orders of magnitude at a separation distance of 10 nm and reach 97% of the infinite limit of graphene-hBN multilayers using only two layers with a thickness of 20 nm each. The first graphene layer controls most of the heat flux, while the other layers can be used to regulate and optimize. The dynamic relationship between the chemical potential µ and the gap distance d are thoroughly discussed. Optimal heat flux of our graphene-assisted hBN/SiO2 hybrid structure with proper choices of (µ1, µ2, µ3) for different d (from 10 nm to 1000 nm) is further increased by 28.2% on average in comparison with the existing graphene-hBN triple-layer structure.

Division of focal plane polarimeter-based 3 × 4 Mueller matrix microscope: a potential tool for quick diagnosis of human carcinoma tissues.

A polarization microscope is a useful tool to reveal the optical anisotropic nature of a specimen and can provide abundant microstructural information about samples. We present a division of focal plane (DoFP) polarimeter-based polarization microscope capable of simultaneously measuring both the Stokes vector and the 3×4 Mueller matrix with an optimal polarization illumination scheme. The Mueller matrix images of unstained human carcinoma tissue slices show that the m24 and m34 elements can provide important information for pathological observations. The characteristic features of the m24 and m34 elements can be enhanced by polarization staining under illumination by a circularly polarized light. Hence, combined with a graphics processing unit acceleration algorithm, the DoFP polarization microscope is capable of real-time polarization imaging for potential quick clinical diagnoses of both standard and frozen slices of human carcinoma tissues.

Effects of siRNA Livin on EJ human bladder cancer cells treated with mitomycin-C.

The aim of this study was to observe the inhibitory and therapeutic effects of small interfering RNA (siRNA) targeting Livin in EJ human bladder cancer cells. Specific siRNA targeting Livin was synthesized and transfected into EJ human bladder cancer cells treated or not treated with mitomycin-C (MMC). Livin mRNA and protein, as well as proliferation and apoptosis of EJ cells was examined with reverse transcription-polymerase chain reaction, western blotting, Cell Counting Kit-8 assay and flow cytometry, respectively. The results indicated that the expression of Livin mRNA and protein in EJ cells was significantly decreased by siRNA Livin. The proliferation of EJ cells was significantly inhibited by treatment with MMC and transfection of siRNA Livin. The inhibition of cell proliferation by treatment with MMC was further enhanced by transfection of siRNA Livin. The apoptotic rate of cells transfected with siRNA Livin and treated with MMC was significantly higher than those cells receiving a single transfection of siRNA Livin and single treatment of MMC. In conclusion, the present study demonstrates that transfection of siRNA Livin induces growth suppression and apoptosis in EJ human bladder cancer cells, and increases the chemotherapeutic sensitivity of cells to MMC.

Penetration depth of linear polarization imaging for two-layer anisotropic samples.

Polarization techniques can suppress multiply scattering light and have been demonstrated as an effective tool to improve image quality of superficial tissues where many cancers start to develop. Learning the penetration depth behavior of different polarization imaging techniques is important for their clinical applications in diagnosis of skin abnormalities. In the present paper, we construct a two-layer sample consisting of isotropic and anisotropic media and examine quantitatively using both experiments and Monte Carlo simulations the penetration depths of three different polarization imaging methods, i.e., linear differential polarization imaging (LDPI), degree of linear polarization imaging (DOLPI), and rotating linear polarization imaging (RLPI). The results show that the contrast curves of the three techniques are distinctively different, but their characteristic depths are all of the order of the transport mean free path length of the top layer. Penetration depths of LDPI and DOLPI depend on the incident polarization angle. The characteristic depth of DOLPI, and approximately of LDPI at small g, scales with the transport mean free path length. The characteristic depth of RLPI is almost twice as big as that of DOLPI and LDPI, and increases significantly as g increases.

Implantable radio frequency identification sensors: wireless power and communication.

There are significant technical challenges in the development of a fully implantable wirelessly powered neural interface. Challenges include wireless transmission of sufficient power to the implanted device to ensure reliable operation for decades without replacement, minimizing tissue heating, and adequate reliable communications bandwidth. Overcoming these challenges is essential for the development of implantable closed loop system for the treatment of disorders ranging from epilepsy, incontinence, stroke and spinal cord injury. We discuss the development of the wireless power, communication and control for a Radio-Frequency Identification Sensor (RFIDS) system with targeted power range for a 700 mV, 30 to 40 uA load attained at -2 dBm.