Reg3A Overexpression Facilitates Hepatic Metastasis by Altering Cell Adhesion in LoVo Colon Cancer Cells.

Reg3A is upregulated in various cancers and considered a potential target for antitumor treatments. However, the effect of Reg3A in metastasis has been elusive. This study aims to disclose the role of Reg3A overexpression in hepatic metastasis of LoVo colon cancer cells. A stable cell line of LoVo cells overexpressing Reg3A (LoVo-luc-Reg3A), labeled with luc reporter gene, was constructed. Cell proliferation, apoptosis, migration, and invasion were determined using MTT, EdU, Hoechst's staining, flow cytometry, and transwell assays, respectively. Hepatic metastasis of LoVo-luc-Reg3A cells was investigated in BALB/c nude mice. Living bioluminescence imaging, histological examination, and mRNA sequencing (mRNA-seq) were performed to assess the metastatic efficiency and gene expression alteration. Reg3A content was determined by Western blotting and Enzyme-Linked Immunosorbent Assay. Cell attachment capacity was determined in the Matrigel culture. Reg3A overexpression did not promote LoVo cell proliferation or apoptosis, but facilitated cell migration and invasion. In the hepatic metastasis model, Reg3A overexpression increased the number of metastatic colonies. The result of mRNA-seq suggested 349 differentially expressed genes (DEGs) by Reg3A upregulation, many of which were related to colon adenocarcinoma tumorigenesis compared to normal colon tissue. Gene ontology enrichment assay indicated that the DEGs are mainly associated with cell adhesion, leukocyte regulation, extracellular matrix (ECM) remodeling, integrin binding, and STAT protein binding. Reg3A overexpression led to an enrichment of Reg3A protein in local tumor tissue of liver metastasis and ECM/intracellular space in ex vivo cultured cells. However, Reg3A concentration in serum and culture medium was relatively low. Reg3A overexpression also resulted in an increased number of cells that attach to Matrigel, which was attenuated by treatments of siRNA-Reg3A and single-chain variable fragment against Reg3A. Endogenous Reg3A overexpression facilitates hepatic metastasis of LoVo colon cancer cells. The prometastatic effect could be contributed by Reg3A enrichment in ECM, which alters the cell adhesion behavior.

Gasdermin B, an asthma-susceptibility gene, promotes MAVS-TBK1 signalling and airway inflammation.

RATIONALE: Respiratory virus-induced inflammation is the leading cause of asthma exacerbation, frequently accompanied by induction of interferon-stimulated genes (ISGs). How asthma-susceptibility genes modulate cellular response upon viral infection by fine-tuning ISG induction and subsequent airway inflammation in genetically susceptible asthma patients remains largely unknown. OBJECTIVES: To decipher the functions of gasdermin B (encoded by GSDMB) in respiratory virus-induced lung inflammation. METHODS: In two independent cohorts, we analysed expression correlation between GSDMB and ISG s. In human bronchial epithelial cell line or primary bronchial epithelial cells, we generated GSDMB-overexpressing and GSDMB-deficient cells. A series of quantitative PCR, ELISA and co-immunoprecipitation assays were performed to determine the function and mechanism of GSDMB for ISG induction. We also generated a novel transgenic mouse line with inducible expression of human unique GSDMB gene in airway epithelial cells and infected the mice with respiratory syncytial virus to determine the role of GSDMB in respiratory syncytial virus-induced lung inflammation in vivo. RESULTS: GSDMB is one of the most significant asthma-susceptibility genes at 17q21 and acts as a novel RNA sensor, promoting mitochondrial antiviral-signalling protein (MAVS)-TANK binding kinase 1 (TBK1) signalling and subsequent inflammation. In airway epithelium, GSDMB is induced by respiratory viral infections. Expression of GSDMB and ISGs significantly correlated in respiratory epithelium from two independent asthma cohorts. Notably, inducible expression of human GSDMB in mouse airway epithelium led to enhanced ISGs induction and increased airway inflammation with mucus hypersecretion upon respiratory syncytial virus infection. CONCLUSIONS: GSDMB promotes ISGs expression and airway inflammation upon respiratory virus infection, thereby conferring asthma risk in risk allele carriers.

Identification of a distal enhancer regulating hedgehog interacting protein gene in human lung epithelial cells.

BACKGROUND: An intergenic region at chromosome 4q31 is one of the most significant regions associated with COPD susceptibility and lung function in GWAS. In this region, the implicated causal gene HHIP has a unique epithelial expression pattern in adult human lungs, in contrast to dominant expression in fibroblasts in murine lungs. However, the mechanism underlying the species-dependent cell type-specific regulation of HHIP remains largely unknown. METHODS: We employed snATAC-seq analysis to identify open chromatin regions within the COPD GWAS region in various human lung cell types. ChIP-quantitative PCR, reporter assays, chromatin conformation capture assays and Hi-C assays were conducted to characterize the regulatory element in this region. CRISPR/Cas9-editing was performed in BEAS-2B cells to generate single colonies with stable knockout of the regulatory element. RT-PCR and Western blot assays were used to evaluate expression of HHIP and epithelial-mesenchymal transition (EMT)-related marker genes. FINDINGS: We identified a distal enhancer within the COPD 4q31 GWAS locus that regulates HHIP transcription at baseline and after TGFß treatment in a SMAD3-dependent, but Hedgehog-independent manner in human bronchial epithelial cells. The distal enhancer also maintains chromatin topological domains near 4q31 locus and HHIP gene. Reduced HHIP expression led to increased EMT induced by TGFß in human bronchial epithelial cells. INTERPRETATION: A distal enhancer regulates HHIP expression both under homeostatic condition and upon TGFß treatment in human bronchial epithelial cells. The interaction between HHIP and TGFß signalling possibly contributes to COPD pathogenesis. FUNDING: Supported by NIH grants R01HL127200, R01HL148667 and R01HL162783 (to X. Z).

Regulating protein corona on nanovesicles by glycosylated polyhydroxy polymer modification for efficient drug delivery.

The dynamic protein corona formed on nanocarriers has been revealed to strongly affect their in vivo behaviors. Precisely manipulating the formation of protein corona on nanocarriers may provide an alternative impetus for specific drug delivery. Herein, we explore the role of glycosylated polyhydroxy polymer-modified nanovesicles (CP-LVs) with different amino/hydroxyl ratios in protein corona formation and evolution. CP-LVs with an amino/hydroxyl ratio of approximately 0.4 (CP1-LVs) are found to efficiently suppress immunoglobulin adsorption in blood and livers, resulting in prolonged circulation. Moreover, CP1-LVs adsorb abundant tumor distinctive proteins, such as CD44 and osteopontin in tumor interstitial fluids, mediating selective tumor cell internalization. The proteins corona transformation specific to the environment appears to be affected by the electrostatic interaction between CP-LVs and proteins with diverse isoelectric points. Benefiting from surface modification-mediated protein corona regulation, paclitaxel-loaded CP1-LVs demonstrate superior antitumor efficacy to PEGylated liposomes. Our work offers a perspective on rational surface-design of nanocarriers to modulate the protein corona formation for efficient drug delivery.

Automatic Sleep Staging Based on Contextual Scalograms and Attention Convolution Neural Network Using Single-Channel EEG.

Single-channel EEG based sleep staging is of interest to researchers due to its broad application prospect in daily sleep monitoring recently. We proposed using contextual scalograms as input and developed a convolutional neural network with attention modules named Co-ScaleNet for sleep staging. The contextual scalograms were obtained by combining the same color channels of three original RGB scalograms from consecutive epochs, and a simple and efficient data augmentation was designed according to their various forms. The Co-ScaleNet consists of two main parts. Firstly, three parallel convolutional branches with attention modules correspondingly extract and fuse features from contextual scalograms at the top layers. The remaining part is a stack of lightweight blocks. We achieved an overall accuracy of 87.0% for healthy individuals, 84.7% for depressed patients. And we obtained comparable performance on the public Sleep-EDFx (82.8%), ISRUC (84.6%) and SHHS datasets (87.7%), including a high recall of N1. The contextual scalograms of R channel as input achieved the best performance, which conform to the features of interest in visual scoring. The attention modules improved the recall of N1 and N3. Overall, the contextual scalograms provided a novel scheme for both contextual information extraction and data augmentation. Our study successfully expanded its application to depression datasets, as well as patients with sleep apnea, demonstrating its wide applicability.

The level of life space mobility among community-dwelling elderly: A systematic review and meta-analysis.

BACKGROUND: Multiple countries have conducted surveys on the level of life space mobility for community-dwelling elderly through the Life-Space Assessment, the results vary greatly, from 41.7 to 88.6. However, there is no meta-analysis on the current situation of community-dwelling elderly life space mobility. OBJECTIVE: To systematically assess the global level of life space mobility for community-dwelling elderly, to identify potential covariates such as geographical regions, survey years, gender, and age that contribute to the heterogeneity between the studies, and to identify the dynamic trend based on survey years. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Two reviewers searched the following 8 electronic bibliographic databases from inception until May 28, 2023: PubMed, The Cochrane Library, Web of Science, Embase, Chinese Biomedical Database, China Knowledge Resource Integrated Database, WanFang, and Weipu Database. REVIEW METHODS: This review was conducted using the Stata 14.1 and R 4.3.1. The Cochrane's Q statistical and I2 index were used to test for heterogenicity and assess the degree of heterogenicity, respectively. Studies were appraised using the Agency for Healthcare Research and Quality tool, the Newcastle-Ottawa Scale for the quality of cross-sectional studies, cohort studies, respectively. RESULTS: A total of 29 studies were selected from databases and reference lists. The pooled score of Life-Space Assessment was 66.84 (95% CI: 63.30-70.39) and the prevalence of restricted life space was 42% (95% CI: 0.27-0.57). The geographical regions, survey years, gender were found to be a significant covariate of the pooled score of life space mobility estimate in the subgroup analysis. The mean score of Life-Space Assessment gradually achieved stability after 2017. CONCLUSIONS: The life space mobility of community-dwelling elderly in the global is at a moderate level, with 42% of them experiencing restricted life space. South America, females and earlier survey years have a lower level of life space mobility. In the future, the government should identify vulnerable groups for targeted intervention to promote the level of LSM in the community-dwelling elderly. REGISTRATION: PROSPERO [CRD42023443054].

Artesunate attenuates serum amyloid A-induced M1 macrophage differentiation through the promotion of PHGDH.

Clinical studies indicated that Serum Amyloid A (SAA) might be a promising biomarker for forecasting the activity, severity, and adverse prognosis of systemic lupus erythematosus (SLE). Simultaneously, a positive correlation has been observed between macrophages, Th17 cells, and SLE disease activity, with both these immune cells being affected by SAA. Presently, the relationship between SAA and the aforementioned immune cell types in SLE remains to be elucidated. To discern the immune cell type most closely associated with SAA, we undertook a single-cell RNA sequencing data analysis via the GEO database. Subsequent results revealed a strong association between macrophages and SAA, a relationship further validated through flow cytometry of spleen macrophages in the MRL/lpr model. We discovered that SAA stimulate M1 macrophage differentiation along with the upregulation of pro-inflammatory cytokines such as IL-6 and IL-1ß. Our findings suggest that SAA may promote M1 macrophage differentiation via the downregulation of phosphoglycerate dehydrogenase (PHGDH). Artesunate (ART), primarily utilized for malaria treatment, was shown to inhibit M1 macrophage differentiation and pro-inflammatory cytokine levels via upregulating the PHGDH expression, thereby attenuating the disease activity in SLE.

Key Determinants of Immune-Mediated Adverse Reactions to Oncology Drugs.

To overcome the epidemiological severity of cancer, developing effective treatments is urgently required. In response, immune checkpoint inhibitors (ICIs) have been revealed as a promising resolution for treatment-resistant cancers across the world. Yet, they have both advantages and disadvantages, bringing therapeutic benefits while simultaneously inducing toxicity, and in particular, immune-mediated adverse drug reactions (imADRs), to the human body. These imADRs can be pathogenic and sometimes lethal, hampering health prediction and monitoring following the provision of ICI treatment. Therefore, it is necessary to collectively identify the determinant factors that contribute to these imADRs induced by ICIs. This article evaluated treatment-, tumor-, and patient-related determinants, and indicated a research gap for future investigations on the pathogenic mechanism of imADRs and translational conversion of determinants into clinical biomarkers to aid pharmacovigilance and cancer therapies.

Tumor-suppressive effect of Reg3A in COAD is mediated by T cell activation in nude mice.

Regenerating family protein 3 A (Reg3A) is highly expressed in a variety of organs and inflammatory tissues, and is closely related to tumorigenesis and cancer progression. However, clinical statistics show that high expression of Reg3A is associated with better prognosis in colorectal cancer (CRC) patients, suggesting a tumor-suppressive effect. The precise action and underlying mechanism of Reg3A in CRC remain controversial. The present study sought to investigate the relationship among Reg3A expression, CRC development, and immune cell alteration in patients using the TCGA, GEPIA, PrognoScan, TIMER and TISIDB databases. Reg3A-overexpressing LoVo cell line (LoVo-Reg3A), a representative of colon adenocarcinoma (COAD), was constructed and the action of Reg3A was assessed in a xenograft nude mouse model. Our bioinformatical analyses revealed that Reg3A upregulation is highly associated with CRC, along with increased frequency of immune cell infiltration. In the xenograft nude mice, Reg3A overexpression offered a tumor-suppressive effect by inhibiting cell proliferation and promoting apoptosis. The result of RNA-seq suggested a positive regulation of leukocytes and an upregulation of T cells in LoVo-Reg3A tumor tissue. CD4+ and CD8+ T cells in tumors, splenic Reg3A-reactive IFN-γ+/CD4+ T cells, and serum TNF-α, IFN-γ and IL-17 were significantly increased by Reg3A overexpression. In the ex vivo co-culture experiment, elevated cytotoxic effect, increased proportion of CD3ε+ T cells, and upregulated expressions of TNF-α, IFN-γ and IL-17 were detected in the PBMCs isolated from LoVo-Reg3A cell-xenografted nude mice. In conclusion, high expression of Reg3A could activate and recruit T cells in COAD leading to the cytotoxic tumor-suppressive effect.

ß-Sitosterol Inhibits The Proliferation of Endometrial Cells via Regulating Smad7-Mediated TGF-ß/Smads Signaling Pathway.

OBJECTIVE: To investigate the effect of ß-sitosterol on endometrial cells to understand the underlying mechanism. MATERIALS AND METHODS: This is a laboratory-based experimental study conducted on animals and cells. Histological assays were performed to determine the effect of ß-sitosterol on endometrial cells. The CCK-8 assay was used to assess the inhibitory effect of ß-sitosterol on the proliferation of ectopic endometrial stromal cells (hEM15A). Flow cytometry was performed to evaluate the induction of apoptosis by ß-sitosterol in hEM15A cells. The transwell invasion assay was conducted to measure the suppression of hEM15A cell migration by ß-sitosterol. Western blot analyses were performed to analyze the effect of ß-sitosterol on the expression of Smad family member 7 (Smad7) and the activity of transforming growth factor-ß (TGF-ß1), as well as the phosphorylation of Smad2 and Smad3. RESULTS: Histological assays showed that ß-sitosterol regulates histopathology and induces apoptosis of endometrial cells in vivo. The CCK-8 assay revealed that ß-sitosterol could inhibit the proliferation of hEM15A in human endometriosis patients. Flow cytometry showed that apoptosis was triggered by ß-sitosterol in hEM15A. The transwell invasion assay indicated that the hEM15A migration under the ß-sitosterol treatment group was suppressed. Western blot analyses suggested that ß-sitosterol increased the expression of Smad7, decreased the activity of TGF-ß1, and reduced the phosphorylation of Smad2 and Smad3. The effect of ß-sitosterol was weakened by the silence of Smad7. CONCLUSION: The results suggest that ß-sitosterol can inhibit the proliferation of endometrial cells and relieve endometriosis by inhibiting TGF-ß-induced phosphorylation of Smads through regulation of Smad7.

Roles of FcRn in Antigen-Presenting Cells during Autoimmunity and a Clinical Evaluation of Efgartigimod as an FcRn Blocker.

The immune system is a complex network of multiple cells, tissues, and organs that protects the body against foreign pathogenic invaders. However, the immune system may mistakenly attack healthy cells and tissues due to the cross-reactivity of anti-pathogen immunity, leading to autoimmunity by autoreactive T cells and/or autoantibody-secreting B cells. Autoantibodies can accumulate, resulting in tissue or organ damage. The neonatal crystallizable fragment receptor (FcRn) is an important factor in immune regulation through controlling the trafficking and recycling of immunoglobulin G (IgG) molecules, the most abundant antibody in humoral immunity. In addition to its role in IgG trafficking and recycling, FcRn is also involved in antigen presentation, which is a crucial step in the activation of the adaptive immune response via directing the internalization and trafficking of antigen-bound IgG immune complexes into compartments of degradation and presentation in antigen-presenting cells. Efgartigimod, an FcRn inhibitor, has shown promise in reducing the levels of autoantibodies and alleviating the autoimmune severity of myasthenia gravis, primary immune thrombocytopenia, and pemphigus vulgaris/foliaceus. This article aims to provide an overview of the importance of FcRn in antigen-presenting cells and its potential as a therapeutic target in autoimmune diseases, using efgartigimod as an example.

Investigating the influence of an adjustable zoned air mattress on sleep: a multinight polysomnography study.

Introduction: A comfortable mattress should improve sleep quality. In this study, we sought to investigate the specific sleep parameters that could be affected by a mattress and explore any potential differences between the effects felt by each sex. Methods: A total of 20 healthy young adults (10 females and 20 males; 22.10 ± 1.25 years) participated in the experiments. A smart adjustable zoned air mattress was designed to maintain comfortable support, and an ordinary mattress was used for comparison. The participants individually spent four nights on these two mattresses in four orders for polysomnography (PSG) scoring. Sleep architecture, electroencephalogram (EEG) spectrum, and heart rate variability (HRV), which reflect the central and autonomic nervous activities, were used to compare the difference between the two mattresses. Results: An individual difference exited in sleep performance. The modes of influence of the mattresses were different between the sexes. The adjustable air mattress and the increase in experimental nights improved female participants' sleep efficiency, while male participants exhibited a smaller response to different mattresses. With an increasing number of experiment nights, both sexes showed increased REM and decreased N2 proportions; the N3 sleep proportion decreased in the male participants, and the heart rate decreased in both sexes. The performance of the EEG spectrum supports the above results. In addition, the adjustable air mattress weakened automatic nerve activity during N3 sleep in most participants. The female participants appeared to be more sensitive to mattresses. Experiment night was associated with psychological factors. There were differences in the results for this influence between the sexes. Conclusion: This study may shed some light on the differences between the ideal sleep environment of each sex.

HER2/neu-based vaccination with li-Key hybrid, GM-CSF immunoadjuvant and trastuzumab as a potent triple-negative breast cancer treatment.

PURPOSE: Constituting 15 to 20% of breast cancer cases, the triple-negative subtype lacks effective treatments as being less responsive to hormone-associated therapies. Alternatively, a more powerful immunotherapeutic vaccination can trigger immune recognition and destruction against breast cancer by incorporating oncological antigens such as human epidermal growth factor receptor 2 (HER2/neu). Currently, HER2/neu-based vaccines have finished three phases with breast cancer patients, in conjunction with granulocyte-macrophage colony-stimulating factor (GM-CSF) that was proven to be a promising vaccine adjuvant in other cancer trials previously. METHODS: Completed HER2/neu-based vaccine trials with GM-CSF immunoadjuvants for breast cancer were summarised, and additionally, the article discussed prominent findings of vaccine effectiveness in triple-negative breast cancer, regarding li-Key hybrid in vaccine design and co-administration of anti-HER2/neu trastuzumab. RESULTS: Nine clinical trials of three HER2/neu epitopes, one with li-Key hybrid, were analysed with or without the presence of trastuzumab. Immunological responses and minimal toxicities were observed in these epitopes, and disease-free survival was especially improved in the triple-negative population. CONCLUSION: HER2/neu-based peptide vaccine is a safe and effective approach against breast cancer, and its benefits can be potentially furthered by combining the li-Key hybrid vaccine with targeted drugs and adjuvants selected to enhance cross-presentation for exogenous vaccine antigens. Graphical abstract was created with Biorender.com (license number: HA24UHRBV4 and FP24UHRGDD).

Metformin confers longitudinal cardiac protection by preserving mitochondrial homeostasis following myocardial ischemia/reperfusion injury.

PURPOSE: Myocardial ischemia-reperfusion (I/R) injury is associated with systemic oxidative stress, cardiac mitochondrial homeostasis, and cardiomyocyte apoptosis. Metformin has been recognized to attenuate cardiomyocyte apoptosis. However, the longitudinal effects and pathomechanism of metformin on the regulation of myocardial mitohormesis following I/R treatment remain unclear. This study aimed to investigate the longitudinal effects and mechanism of metformin in regulating cardiac mitochondrial homeostasis by serial imaging with the 18-kDa translocator protein (TSPO)-targeted positron emission tomography (PET) tracer 18F-FDPA. METHODS: Myocardial I/R injury was established in Sprague-Dawley rats, which were treated with or without metformin (150 mg/kg per day). Serial gated 18F-FDG and 18F-FDPA PET imaging were performed at 1, 4, and 8 weeks after surgery, followed by analysis of ventricular remodelling and cardiac mitochondrial homeostasis. The correlation between Hsp60 and 18F-FDPA uptake was analyzed. After PET imaging, the activity of antioxidant enzymes, immunostaining, and western blot analysis were performed to analyze the spatio-temporal effects and pathomechanism of metformin for cardiac protection after myocardial I/R injury. RESULTS: Oxidative stress and apoptosis increased 1 week after myocardial I/R injury (before significant progression of ventricular remodelling). TSPO expression was correlated with Hsp60 expression and was co-localized with inflammatory CD68+ macrophages in the infarct area, and TSPO uptake was associated with an upregulation of AMPK-p/AMPK and a downregulation of Bcl-2/Bax. However, these effects were reversed with metformin treatment. Eight weeks after myocardial I/R injury (representing the advanced stage of heart failure), 18F-FDPA uptake in myocardial cells in the distal non-infarct area increased without CD68+ expression, whereas the activity decreased with metformin treatment. CONCLUSION: Taken together, these results show that a prolonged metformin treatment has pleiotropic protective effects against myocardial I/R injury associated with a regional and temporal dynamic balance between mitochondrial homeostasis and cardiac outcome, which were assessed by TSPO-targeted imaging during cardiac remodelling.

The second randomized controlled ENhanced Control of Hypertension ANd Thrombectomy strokE stuDy (ENCHANTED2): Protocol and progress.

BACKGROUND: Uncertainty exists over the optimal level of blood pressure (BP) after mechanical thrombectomy (MT) for acute ischemic stroke (AIS). OBJECTIVES: We aim to determine the effectiveness and safety of intensive BP-lowering following MT reperfusion of large-vessel occlusion (LVO)-related AIS. DESIGN: The second ENhanced Control of Hypertension ANd Thrombolysis strokE stuDy (ENCHANTED2) is an investigator-initiated, multicenter, prospective, randomized, open, blinded-endpoint (PROBE) trial of intensive systolic BP (SBP) control in reperfused (extended treatment in cerebral infarction (eTICI) classification 2b/2c/3) LVO-AIS patients with persistent hypertension (SBP ⩾ 140 mmHg) at 60+ sites in China, and Australia and the United Kingdom. Eligible patients are centrally randomly allocated to more- (target SBP ⩽ 120 mmHg within 1 h) or less-intensive (target SBP 140-180 mmHg) BP management, to be maintained for 72 h. Primary outcome is an ordinal shift analysis of scores on the modified Rankin scale (mRS) at 90 days. Sample size of 2257 patients provides 90% power to detect a 6.5% absolute reduction in poor outcome from more-intensive BP-lowering using ordinal logistic regression. PROGRESS: Recruitment started in China in July 2020. At a meeting of the independent Data and Safety Monitoring Board in March 2022 to review primary outcome data available for 347 patients, they recommended suspension of recruitment due to safety concerns in the more-intensive group; which was implemented by the Trial Steering Committee (TSC) with 817 randomized patients only in China. The TSC then stopped recruitment after the safety concerns persisted on further review of the data in June 2022. The TSC will make a decision on restarting the trial with modification of the protocol when the results are made public. DISCUSSION: ENCHANTED2 will provide further randomized evidence on the role of intensive BP-lowering after reperfusion in MT-treated AIS patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT04140110; registered 25 October 2019.

Intensive blood pressure control after endovascular thrombectomy for acute ischaemic stroke (ENCHANTED2/MT): a multicentre, open-label, blinded-endpoint, randomised controlled trial.

BACKGROUND: The optimum systolic blood pressure after endovascular thrombectomy for acute ischaemic stroke is uncertain. We aimed to compare the safety and efficacy of blood pressure lowering treatment according to more intensive versus less intensive treatment targets in patients with elevated blood pressure after reperfusion with endovascular treatment. METHODS: We conducted an open-label, blinded-endpoint, randomised controlled trial at 44 tertiary-level hospitals in China. Eligible patients (aged ≥18 years) had persistently elevated systolic blood pressure (≥140 mm Hg for >10 min) following successful reperfusion with endovascular thrombectomy for acute ischaemic stroke from any intracranial large-vessel occlusion. Patients were randomly assigned (1:1, by a central, web-based program with a minimisation algorithm) to more intensive treatment (systolic blood pressure target <120 mm Hg) or less intensive treatment (target 140-180 mm Hg) to be achieved within 1 h and sustained for 72 h. The primary efficacy outcome was functional recovery, assessed according to the distribution in scores on the modified Rankin scale (range 0 [no symptoms] to 6 [death]) at 90 days. Analyses were done according to the modified intention-to-treat principle. Efficacy analyses were performed with proportional odds logistic regression with adjustment for treatment allocation as a fixed effect, site as a random effect, and baseline prognostic factors, and included all randomly assigned patients who provided consent and had available data for the primary outcome. The safety analysis included all randomly assigned patients. The treatment effects were expressed as odds ratios (ORs). This trial is registered at ClinicalTrials.gov, NCT04140110, and the Chinese Clinical Trial Registry, 1900027785; recruitment has stopped at all participating centres. FINDINGS: Between July 20, 2020, and March 7, 2022, 821 patients were randomly assigned. The trial was stopped after review of the outcome data on June 22, 2022, due to persistent efficacy and safety concerns. 407 participants were assigned to the more intensive treatment group and 409 to the less intensive treatment group, of whom 404 patients in the more intensive treatment group and 406 patients in the less intensive treatment group had primary outcome data available. The likelihood of poor functional outcome was greater in the more intensive treatment group than the less intensive treatment group (common OR 1·37 [95% CI 1·07-1·76]). Compared with the less intensive treatment group, the more intensive treatment group had more early neurological deterioration (common OR 1·53 [95% 1·18-1·97]) and major disability at 90 days (OR 2·07 [95% CI 1·47-2·93]) but there were no significant differences in symptomatic intracerebral haemorrhage. There were no significant differences in serious adverse events or mortality between groups. INTERPRETATION: Intensive control of systolic blood pressure to lower than 120 mm Hg should be avoided to prevent compromising the functional recovery of patients who have received endovascular thrombectomy for acute ischaemic stroke due to intracranial large-vessel occlusion. FUNDING: The Shanghai Hospital Development Center; National Health and Medical Research Council of Australia; Medical Research Futures Fund of Australia; China Stroke Prevention; Shanghai Changhai Hospital, Science and Technology Commission of Shanghai Municipality; Takeda China; Hasten Biopharmaceutic; Genesis Medtech; Penumbra.

AKG Attenuates Cerebral Ischemia-Reperfusion Injury through c-Fos/IL-10/Stat3 Signaling Pathway.

Inflammation is dominant in the pathogenesis of ischemic stroke (IS). Alpha-ketoglutarate (AKG), according to previous studies, has demonstrated a variety of pharmacological effects such as antioxidation and inhibitive inflammation activities. However, whether AKG ameliorates cerebral ischemic injury, as well as the underlying molecular events, is still unclear. Therefore, the effect and underlying mechanisms of AKG on ischemic brain injury should be identified. The study established a cerebral ischemia-reperfusion (I/R) model in mice as well as an oxygen-glucose deprivation/reperfusion (OGD/R) model in SH-SY5Y cells, respectively. It was observed that AKG markedly suppressed infarction volume and neuronal injuries and improved the neurological score in vivo. Moreover, AKG reduced the inflammatory response and lowered the expression of proinflammatory cytokines. In vitro, AKG treatment strongly inhibited OGD/R-induced neuronal injury and the proinflammatory factors. It was also found that the increased SOD and GSH levels, as well as the lower ROS levels, showed that AKG reduced oxidative stress in OGD/R-treated SY-SY5Y cells. Mechanistically, AKG largely promoted IL-10 expression in ischemic brain injury and OGD/R-induced neuronal injury. Furthermore, IL-10 silencing neutralized the protective effect of AKG on inflammation. Notably, it was discovered that AKG could upregulate IL-10 expression by promoting the translocation of c-Fos from the cytoplasm to the nucleus. The results indicated that AKG demonstrated neuroprotection on cerebral ischemia while inhibiting inflammation through c-Fos/IL-10/stat3 pathway.

Transient cardioprotective effects of remote ischemic postconditioning on non-reperfused myocardial infarction: longitudinal evaluation study in pigs.

BACKGROUND: Remote ischemic postconditioning (RIPostC) has recently emerged as a potential novel therapeutic strategy to achieve protection against acute myocardial infarction (AMI) injury. We aimed to evaluate the longitudinal cardioprotective effects of RIPostC on AMI using 99mTc-MIBI SPECT myocardial perfusion imaging (MPI) and gated 18F-FDG PET (GPET) in pigs. METHODS: MI was induced in 12 Chinese pigs. RIPostC was conducted by four 5 min cycles of blood pressure cuff inflation applied to the lower limb immediately after AMI. MPI and GPET were performed longitudinally at baseline, 3rd, 14th, 28th, and 56th days after AMI. Total perfusion defect (TPD), hibernating myocardium (HM), scar, left ventricular (LV) remodeling (End diastolic volume, EDV), and bone marrow (BM) metabolic activity were analyzed, and inflammation biomarkers were measured. RESULTS: In outcome evaluation, there was a significant attenuation in TPD (Δ value, at 14th, 28th and 56th days), HM (Δ value, at 14th, 56th days) and Scar (Δ value, at 14th, 28th days) in the RIPostC group compared with the control group (P < 0.05). Additionally, RIPostC attenuated LV enlargement (ΔEDV, at 14th day) (P < 0.05) in comparison to controls. BM 18F-FDG uptake activity in the RIPostC group was lower than the control group (P < 0.05) at the 3rd day after AMI. There was a non-statistically significant trend of decreased MMP-2 levels in the RIPostC group post-AMI (P > 0.05). CONCLUSIONS: RIPostC presented the longitudinal cardioprotective effects by preserving myocardial viability, reducing infarct size, attenuating LV remodeling at early stage post-AMI, and may also have an anti-inflammatory effect at the acute phase.

Influence of ultrasound and microwave treatments on the structural and thermal properties of normal maize starch and potato starch: A comparative study.

The effects of ultrasound and microwave on the physicochemical properties of normal maize and potato starches were compared. The cavitation effect of ultrasound loosened the internal space and destroyed the structure of starch granules, increased the damaged starch content, which was consistent with the decrease in relative crystallinity and the number and brightness of Maltese crosses, and the increase in D(0.5) and D(4,3) values. Microwave vibrated the molecules inside the granules and generated heat to destroy the structure of starch. The content of damaged starch was significantly lower in microwave-treated starch compared with ultrasound-treated starch. Microwave treatment promoted the formation of amylose-lipid complex, with the larger peak area at 20°(2θ) than that of the ultrasound-treated starch. The type of starch and the treatment sequence showed a significant effect. The results might help understand the mechanism of ultrasound and microwave treatments influencing the structural properties of starches.

Recent Research for Unobtrusive Atrial Fibrillation Detection Methods Based on Cardiac Dynamics Signals: A Survey.

Atrial fibrillation (AF) is the most common cardiac arrhythmia. It tends to cause multiple cardiac conditions, such as cerebral artery blockage, stroke, and heart failure. The morbidity and mortality of AF have been progressively increasing over the past few decades, which has raised widespread concern about unobtrusive AF detection in routine life. The up-to-date non-invasive AF detection methods include electrocardiogram (ECG) signals and cardiac dynamics signals, such as the ballistocardiogram (BCG) signal, the seismocardiogram (SCG) signal and the photoplethysmogram (PPG) signal. Cardiac dynamics signals can be collected by cushions, mattresses, fabrics, or even cameras, which is more suitable for long-term monitoring. Therefore, methods for AF detection by cardiac dynamics signals bring about extensive attention for recent research. This paper reviews the current unobtrusive AF detection methods based on the three cardiac dynamics signals, summarized as data acquisition and preprocessing, feature extraction and selection, classification and diagnosis. In addition, the drawbacks and limitations of the existing methods are analyzed, and the challenges in future work are discussed.