Regulatory effect of Ganoderma lucidum and its active components on gut flora in diseases.

Driven by the good developmental potential and favorable environment at this stage, Ganoderma lucidum is recognized as a precious large fungus with medicinal and nutritional health care values. Among them, polysaccharides, triterpenoids, oligosaccharides, trace elements, etc. are important bioactive components in G. lucidum. These bioactive components will have an impact on gut flora, thus alleviating diseases such as hyperglycemia, hyperlipidemia and obesity caused by gut flora disorder. While numerous studies have demonstrated the ability of G. lucidum and its active components to regulate gut flora, a systematic review of this mechanism is currently lacking. The purpose of this paper is to summarize the regulatory effects of G. lucidum and its active components on gut flora in cardiovascular, gastrointestinal and renal metabolic diseases, and summarize the research progress of G. lucidum active components in improving related diseases by regulating gut flora. Additionally, review delves into the principle by which G. lucidum and its active components can treat or assist treat diseases by regulating gut flora. The research progress of G. lucidum in intestinal tract and its potential in medicine, health food and clinical application were fully explored for researchers.

Effects of electroacupuncture on postoperative cognitive dysfunction and its underlying mechanisms: a literature review of rodent studies.

With the aging of the population, the health of the elderly has become increasingly important. Postoperative cognitive dysfunction (POCD) is a common neurological complication in elderly patients following general anesthesia or surgery. It is characterized by cognitive decline that may persist for weeks, months, or even longer. Electroacupuncture (EA), a novel therapy that combines physical nerve stimulation with acupuncture treatment from traditional Chinese medicine, holds potential as a therapeutic intervention for preventing and treating POCD, particularly in elderly patients. Although the beneficial effects of EA on POCD have been explored in preclinical and clinical studies, the reliability of EA is limited by methodological shortcomings, and the underlying mechanisms remain largely unexplored. Therefore, we have synthesized existing evidence and proposed potential biological mechanisms underlying the effects of EA on neuroinflammation, oxidative stress, autophagy, the microbiota-gut-brain axis, and epigenetic modification. This review summarizes recent advances in EA and POCD, provides a theoretical foundation, explores potential molecular mechanisms for the prevention and treatment of POCD, and offers a basis for conducting relevant clinical trials.

Structural heterogeneity in tetra-armed gels revealed by computer simulation: Evidence from a graph theory assisted characterization.

Designing homogeneous networks is considered one typical strategy for solving the problem of strength and toughness conflict of polymer network materials. Experimentalists have proposed the hypothesis of obtaining a structurally homogeneous hydrogel by crosslinking tetra-armed polymers, whose homogeneity was claimed to be verified by scattering characterization and other methods. Nevertheless, it is highly desirable to further evaluate this issue from other perspectives. In this study, a coarse-grained molecular dynamics simulation coupled with a stochastic reaction model is applied to reveal the topological structure of a polymer network synthesized by tetra-armed monomers as precursors. Two different scenarios, distinguished by whether internal cross-linking is allowed, are considered. We introduce the Dijkstra algorithm from graph theory to precisely characterize the network structure. The microscopic features of the network structure, e.g., loop size, dispersity, and size distribution, are obtained via the Dijkstra algorithm. By comparing the two reaction scenarios, Scenario II exhibits an overall more idealized structure. Our results demonstrate the feasibility of the Dijkstra algorithm for precisely characterizing the polymer network structure. We expect this work will provide a new insight for the evaluation and description of gel networks and further help to reveal the dynamic process of network formation.

Targeting the molecular chaperone CCT2 inhibits GBM progression by influencing KRAS stability.

Proper protein folding relies on the assistance of molecular chaperones post-translation. Dysfunctions in chaperones can cause diseases associated with protein misfolding, including cancer. While previous studies have identified CCT2 as a chaperone subunit and an autophagy receptor, its specific involvement in glioblastoma remains unknown. Here, we identified CCT2 promote glioblastoma progression. Using approaches of coimmunoprecipitation, mass spectrometry and surface plasmon resonance, we found CCT2 directly bound to KRAS leading to increased stability and upregulated downstream signaling of KRAS. Interestingly, we found that dihydroartemisinin, a derivative of artemisinin, exhibited therapeutic effects in a glioblastoma animal model. We further demonstrated direct binding between dihydroartemisinin and CCT2. Treatment with dihydroartemisinin resulted in decreased KRAS expression and downstream signaling. Highlighting the significance of CCT2, CCT2 overexpression rescued the inhibitory effect of dihydroartemisinin on glioblastoma. In conclusion, the study demonstrates that CCT2 promotes glioblastoma progression by directly binding to and enhancing the stability of the KRAS protein. Additionally, dihydroartemisinin inhibits glioblastoma by targeting the CCT2 and the following KRAS signaling. Our findings overcome the challenge posed by the undruggable nature of KRAS and offer potential therapeutic strategies for glioblastoma treatment.

Effects of Tirofiban on Neurological Deterioration in Patients With Acute Ischemic Stroke: A Randomized Clinical Trial.

Importance: Evidence supports using antiplatelet therapy in patients with acute ischemic stroke. However, neurological deterioration remains common under the currently recommended antiplatelet regimen, leading to poor clinical outcomes. Objective: To determine whether intravenous tirofiban administered within 24 hours of stroke onset prevents early neurological deterioration in patients with acute noncardioembolic stroke compared with oral aspirin. Design, Setting, and Participants: This investigator-initiated, multicenter, open-label, randomized clinical trial with blinded end-point assessment was conducted at 10 comprehensive stroke centers in China between September 2020 and March 2023. Eligible patients were aged 18 to 80 years with acute noncardioembolic stroke within 24 hours of onset and had a National Institutes of Health Stroke Scale (NIHSS) score of 4 to 20. Intervention: Patients were assigned randomly (1:1) to receive intravenous tirofiban or oral aspirin for 72 hours using a central, web-based, computer-generated randomization schedule; all patients then received oral aspirin. Main Outcome: The primary efficacy outcome was early neurological deterioration (increase in NIHSS score ≥4 points) within 72 hours after randomization. The primary safety outcome was symptomatic intracerebral hemorrhage within 72 hours after randomization. Results: A total of 425 patients were included in the intravenous tirofiban (n = 213) or oral aspirin (n = 212) groups. Median (IQR) age was 64.0 years (56.0-71.0); 124 patients (29.2%) were female, and 301 (70.8%) were male. Early neurological deterioration occurred in 9 patients (4.2%) in the tirofiban group and 28 patients (13.2%) in the aspirin group (adjusted relative risk, 0.32; 95% CI, 0.16-0.65; P = .002). No patients in the tirofiban group experienced intracerebral hemorrhage. At 90-day follow-up, 3 patients (1.3%) in the tirofiban group and 3 (1.5%) in the aspirin group died (adjusted RR, 1.15; 95% CI, 0.27-8.54; P = .63), and the median (IQR) modified Rankin scale scores were 1.0 (0-1.25) and 1.0 (0-2), respectively (adjusted odds ratio, 1.28; 95% CI, 0.90-1.83; P = .17). Conclusions and Relevance: In patients with noncardioembolic stroke who were seen within 24 hours of symptom onset, tirofiban decreased the risk of early neurological deterioration but did not increase the risk of symptomatic intracerebral hemorrhage or systematic bleeding. Trial Registration: ClinicalTrials.gov Identifier: NCT04491695.

Compromised dynamic cerebral autoregulation is a hemodynamic marker for predicting poor prognosis even with good recanalization after endovascular thrombectomy.

PURPOSE: In patients undergoing endovascular thrombectomy (EVT) with acute ischemic stroke (AIS), dynamic cerebral autoregulation (dCA) may minimize neurological injury from blood pressure fluctuations. This study set out to investigate the function of dCA in predicting clinical outcomes following EVT. METHODS: 43 AIS of the middle cerebral or internal carotid artery patients underwent with EVT, and 43 healthy individuals (controls) were enrolled in this case control research. The dCA was evaluated using transcranial Doppler 12 h and five days after EVT. The transfer function analysis was used to derive the dCA parameters, such as phase, gain, and coherence. The modified Rankin scale (mRS) at 3 months after EVT was used to assess the clinical outcomes. Thefavorable outcome group was defined with mRS ≤2 and the unfavorable outcome group was defined with mRS score of 3-6. Logistic regression analysis was performed to determine the risk factors of clinical outcomes. RESULTS: A significant impairment in dCA was observed on the ipsilateral side after EVT, particularly in patients with unfavorable outcomes. After 5 days, the ipsilateral phase was associated with poor functional outcomes (adjusted odds ratio [OR] = 0.911, 95% confidence interval [CI]: 0.854-0.972; P = 0.005) and the area under the curve (AUC) (AUC, 0.878, [95% CI: 0.756-1.000] P < 0.001) (optimal cutoff, 35.0°). Phase change was an independent predictor of clinical outcomes from 12 h to 5 days after EVT (adjusted OR = 1.061, 95% CI: 1.016-1.109, P = 0.008). CONCLUSIONS: dCA is impaired in patients with AIS after EVT. Change in dCA could be an independent factor related to the clinical outcomes.

Evaluation of stress and displacement of maxillary canine during the single canine retraction in the maxillary first premolar extraction cases- A finite element study.

OBJECTIVES: This finite element study aimed to simulate maxillary canine movement during anterior teeth retraction. MATERIALS AND METHODS: Three methods of maxillary canine movement including miniscrew sliding with high hooks (MSH), miniscrew sliding with low hooks (MSL), and the traditional sliding method (TS) without using miniscrews were simulated using three-dimensional finite element analysis. The initial displacement of the maxillary canine, the maximum principal stress of the periodontal ligament and the Von Mises stress were calculated. RESULTS: The distolingual tipping movements of the canine were shown in three movement modes. MSH showed a small tendency to lingual tipping movement and a extrusion movement while MSL had the largest lingual inclination. TS demonstrated a tendency toward distolingual torsion displacement. Compressive stress values were mainly concentrated in the range - 0.003 to -0.006 MPa. For tensile stress, the distribution of MSH and MSL was concentrated in the range 0.005 to 0.009 MPa, TS was mainly distributed about 0.003 MPa. Von Mises equivalent stress distribution showed no significant difference. CONCLUSIONS: The loss of tooth torque was inevitable, irrespective of which method was used to close the extraction space. However, miniscrew application and higher hooks reduced the loss of torque and avoided lingual rotation. CLINICAL RELEVANCE: This study shows that miniscrew implants with different hooks can better control the movement of the maxillary canines. The non-invasive nature of the finite element analysis and its good simulation of dental stress and instantaneous motion trend have a clinical advantage in the analysis of tooth movement.

Long term for patients with futile endovascular reperfusion after stroke.

AIMS: With the progress of thrombectomy technology, the vascular recanalization rate of patients with stroke has been continuously improved, but the proportion of futile recanalization (FR) is still quite a few. The long-term prognosis and survival of patients with FR and its influencing factors remain unclear. METHODS: Consecutive patients who received endovascular treatment (EVT) for ischemic stroke were enrolled between 2013 and 2021 from a single-center prospectively registry study. We evaluated the long-term outcome of these patients by Kaplan-Meier survival analysis, and the multivariable logistic regression curve was performed to analyze influencing factors. RESULTS: Among 458 patients with FR, 56.4% of patients survived at 1 year, and 50.4% at 2 years. In the multivariate regression analysis, age, premorbid modified Rankin Scale (mRS), National Institutes of Health Stroke Scale (NIHSS), posterior circulation infarct, general anesthesia, symptomatic intracerebral hemorrhage (sICH), and decompressive craniectomy were found to be related to unfavorable outcomes in long-term. Age, premorbid mRS, NIHSS, general anesthesia, and sICH were predictors of long-term mortality. CONCLUSIONS: Futile recanalization accounts for a large proportion of stroke patients after thrombectomy. This study on the long-term prognosis of such patients is beneficial to the formulation of treatment plans and the prediction of therapeutic effects.

Remote ischemic conditioning improves cerebral hemodynamics in symptomatic intracranial atherosclerosis: A PET/CT-guided randomized controlled study.

Patients with symptomatic intracranial arterial stenosis (sICAS) suffer embarrassed hemodynamic status and acute ischemic stroke (AIS) recurrence. We aimed to assess the efficacy of remote ischemic conditioning (RIC) on improving this status by evaluating cerebral blood flow (CBF) and cerebral glucose metabolism (CGM) via PET/CT. Adult patients with unilateral sICAS in middle cerebral artery and/or intracranial segment of internal carotid artery-related AIS or transient ischemic attack within 6 months prior to randomization were enrolled. Individuals who received intravenous thrombolysis or endovascular treatment, or sICAS caused by cardiac embolism, small vessel occlusion, or other determined causes were excluded. Twenty-three eligible patients were randomly assigned to standard medical treatment (SMT) (n = 10) or RIC group (n = 13). The RIC protocol consisted of 5 cycles, each for 5-min bilateral upper limb ischemia and 5-min reperfusion period, twice a day, with a total duration of 3 months. Ten healthy volunteers were enrolled as healthy control group. We tested CBF and CGM at the rest stage and the methazolamide-induced stress stage. All patients received PET/CT at baseline and three-month followup. Both CBF and CGM in ipsilateral hemisphere of sICAS patients were significantly decreased at the rest stage and the stress stage (p < .05), which were improved by three-month RIC (p < .05). The lesions decreased notably in RIC group compared to SMT group (p < .05). RIC ameliorated the hemodynamic status and glucose metabolism in regions at high risk of infarction, which might improve the resistance capacity towards ischemic load in sICAS patients.

Characteristics of bacterial community structure in the sediment of Chishui River (China) and the response to environmental factors.

Sediment microorganisms performed an essential function in the biogeochemical cycle of aquatic ecosystems, and their structural composition was closely related to environmental carrying capacity and water quality. In this study, the Chishui River (Renhuai section) was selected as the research area, and the concentrations of environmental factors in the water and sediment were detected. High⁃throughput sequencing was adopted to reveal the characteristics of bacterial community structures in the sediment. In addition, the response of bacteria to environmental factors was explored statistically. Meanwhile, the functional characteristics of bacterial were also analyzed based on the KEGG database. The results showed that the concentration of environmental factors in the water and sediment displayed spatial differences, with the overall trend of midstream > downstream > upstream, which was related to the wastewater discharge from the Moutai town in the midstream directly. Proteobacteria was the most dominant phylum in the sediment, with the relative abundance ranged from 52.06% to 70.53%. The distribution of genus-level bacteria with different metabolic activities varied in the sediment. Upstream was dominated by Massilia, Acinetobacter, and Thermomonas. In the midstream, Acinetobacter, Cloacibacterium and Comamonas were the main genus. Nevertheless, the abundance of Lysobacter, Arenimonas and Thermomonas was higher in the downstream. Redundancy analysis (RDA) showed that total nitrogen (TN) and total phosphorus (TP) were the main environmental factors which affected the structure of bacterial communities in sediment, while total organic carbon (TOC) was the secondary. The bacterial community was primarily associated with six biological pathway categories such as metabolism. Carbohydrate metabolism and amino acid metabolism were the most active functions in the 31 subfunctions. This study could contribute to the understanding of the structural composition and driving forces of bacteria in the sediment, which might benefit for the ecological protection of Chishui River.

HTRA1 promotes EMT through the HDAC6/Ac-α-tubulin pathway in human GBM cells.

BACKGROUND: The infiltrative nature of human gliomas renders complete surgical removal of tumors futile. Thus, illuminating mechanisms of their infiltrative properties may improve therapies and outcomes of glioma patients. METHODS: Comprehensive bioinformatic analyses of PRSS family were undertaken. Transfection of HTRA1 siRNAs was used to suppress HTRA1 expression. CCK-8, EdU, and colony formation assay were employed to assess cell viability, and cell migration/invasion was detected by transwell, wound healing, and 3D tumor spheroid invasion assays. Immunoprecipitation was applied to study the mechanism that HTRA1 affected cell migration. In addition, in situ xenograft tumor model was employed to explore the role of HTRA1 in glioma growth in vivo. RESULTS: HTRA1 knockdown could lead to suppression of cell viability, migration and invasion, as well as increased apoptosis. Immunoprecipitation results indicates HTRA1 might facilitate combination between HDAC6 and α-tubulin to enhance cell migration by decreasing α-tubulin acetylation. Besides, HTRA1 knockdown inhibited the growth of xenografts derived from orthotopic implantation of GBM cells and prolonged the survival time of tumor-bearing mice. CONCLUSION: Our results indicate that HTRA1 promotes the proliferation and migration of GBM cells in vitro and in vivo, and thus may be a potential target for treatment in gliomas.

No-reflow after stroke reperfusion therapy: An emerging phenomenon to be explored.

In the field of stroke thrombectomy, ineffective clinical and angiographic reperfusion after successful recanalization has drawn attention. Partial or complete microcirculatory reperfusion failure after the achievement of full patency of a former obstructed large vessel, known as the "no-reflow phenomenon" or "microvascular obstruction," was first reported in the 1960s and was later detected in both experimental models and patients with stroke. The no-reflow phenomenon (NRP) was reported to result from intraluminal occlusions formed by blood components and extraluminal constriction exerted by the surrounding structures of the vessel wall. More recently, an emerging number of clinical studies have estimated the prevalence of the NRP in stroke patients following reperfusion therapy, ranging from 3.3% to 63% depending on its evaluation methods or study population. Studies also demonstrated its detrimental effects on infarction progress and neurological outcomes. In this review, we discuss the research advances, underlying pathogenesis, diagnostic techniques, and management approaches concerning the no-reflow phenomenon in the stroke population to provide a comprehensive understanding of this phenomenon and offer references for future investigations.

Night shift work was associated with functional outcomes in acute ischemic stroke patients treated with endovascular thrombectomy.

Objective: This study aimed to explore the impact of late night shift work on the functional outcomes of patients with acute ischemic stroke (AIS) treated with endovascular thrombectomy (EVT). Methods: Consecutive AIS patients who underwent EVT between June 2019 and June 2021 were enrolled and divided into non-night shift work and night shift work groups based on their occupational histories. The primary outcome was the modified Rankin Scale score defined 3-month functional outcome. The secondary outcomes were 3-month mortality, symptomatic intracerebral hemorrhage (sICH), ICH and early recanalization. Results: A total of 285 patients were enrolled, 35 patients (12.3%) were night shift workers, who were younger (P < 0.001) and had a significantly higher prevalence of smoking (P < 0.001), hyperlipidemia (P = 0.002), coronary heart disease (P = 0.031), and atrial fibrillation (P < 0.001). The 3-month favorable outcomes were achieved in 44.8% and 25.7% of patients in the non-night shift work and night shift work groups, respectively (adjusted odds ratio [OR]: 0.24, 95% CI: 0.10-0.57; adjusted P = 0.001). No difference was found in 3-month mortality (adjusted OR: 0.43; 95% CI: 0.14-1.25, adjusted P = 0.121), rates of ICH (adjusted OR: 0.73; 95% CI: 0.33-1.60; adjusted P = 0.430), sICH (adjusted OR: 0.75; 95% CI: 0.34-1.67; adjusted P = 0.487), or early successful recanalization (adjusted OR: 0.42; 95% CI: 0.12-1.56; adjusted P = 0.197). These results were consistent after PSM analysis. Conclusion: Our findings suggest that late night shift work is significantly associated with unfavorable outcomes in patients with AIS after EVT.

Olympic gels formed through catenation of dsDNA rings regulated by topoisomerase II: A coarse-grained model.

Topological regulation of DNA by topoisomerases in cells is very crucial for life. We propose a coarse-grained model to study the catenation process of double-stranded DNA (dsDNA) rings regulated by topoisomerase II (TOP2) and provide a computational method to characterize the topological structures of the Olympic gels obtained. The function of TOP2 in the catenation of dsDNA rings is implicitly fulfilled by operating the length of a stretchable catch bond in the dsDNA ring. After the catenation reaction of initially noncatenated dsDNA rings in the solution, the Olympic gel is obtained and the interlocked topology of the dsDNA rings can be characterized by a computational method derived from the HOMFLY polynomial, based on which the catenation degree and the complexity of catenation are quantified. Detailed dependence of the catenation degree and the complexity of the catenated topology on key parameters, including the size of the transient broken gap and the duration time of the break on the dsDNA ring during operation by TOP2, the initial molar ratio of TOP2 to the dsDNA rings, and the reaction temperature, has been investigated.

Clinical implications and predictive value of the creatinine­cystatin C ratio in patients with multiple myeloma and renal impairment.

The creatinine (Cr)-cystatin C ratio (CCR) at the time of cancer diagnosis is associated with survival; however, to the best of our knowledge, the association between this ratio and mortality in patients with multiple myeloma and renal impairment (RI) is unclear. Therefore, the present study aimed to assess this association, as well as disease prognosis and the clinical significance of the CCR in patients with multiple myeloma and RI. The present retrospective study included 191 patients diagnosed with multiple myeloma and RI between 2012 and 2022. The predictive value of the CCR was evaluated using area under the receiver operating characteristic curve (AUC) values. The factors affecting overall survival (OS) were assessed using uni- and multivariate logistic regression analyses. The effect of the CCR on survival was evaluated using a Cox regression model and the Kaplan-Meier method. There was a significant association between low CCR and poor progression-free survival (PFS) and overall survival (OS). The 1-, 2- and 3-year PFS and OS rates in patients with a low CCR were significantly lower than those in patients with a high CCR. The 1-, 2- and 3-year AUC values of the CCR were 0.712, 0.764 and 0.746 respectively. Multivariate analysis revealed sex, age, Cr levels, CCR and C-reactive protein levels as independent prognostic factors affecting OS rates. The CCR is a potential prognostic indicator in patients with multiple myeloma with RI and is associated with clinical stages.

Engineering Sizable and Broad-Spectrum Antibacterial Fabrics through Hydrogen Bonding Interaction and Electrostatic Interaction.

Long-lasting and highly efficient antibacterial fabrics play a key role in public health occurrences caused by bacterial and viral infections. However, the production of antibacterial fabrics with a large size, highly efficient, and broad-spectrum antibacterial performance remains a great challenge due to the complex processes. Herein, we demonstrate sizable and highly efficient antibacterial fabrics through hydrogen bonding interaction and electrostatic interaction between surface groups of ZnO nanoparticles and fabric fibers. The production process can be carried out at room temperature and achieve a production rate of 300 × 1 m2 within 1 h. Under both visible light and dark conditions, the bactericidal rate against Gram-positive (S. aureus), Gram-negative (E. coli), and multidrug-resistant (MRSA) bacteria can reach an impressive 99.99%. Furthermore, the fabricated ZnO nanoparticle-decorated antibacterial fabrics (ZnO@fabric) show high stability and long-lasting antibacterial performance, making them easy to develop into variable antibacterial blocks for protection suits.

Bio-Inspired Trace Hydroxyl-Rich Electrolyte Additives for High-Rate and Stable Zn-Ion Batteries at Low Temperatures.

High-rate and stable Zn-ion batteries working at low temperatures are highly desirable for practical applications, but are challenged by sluggish kinetics and severe corrosion. Herein, inspired by frost-resistant plants, we report trace hydroxyl-rich electrolyte additives that implement a dual remodeling effect for high-performance low-temperature Zn-ion batteries. The additive with high Zn absorbability not only remodels Zn2+ primary solvent shell by alternating H2 O molecules, but also forms a shielding layer thus remodeling the Zn surface, which effectively enhances fast Zn2+ de-solvation reaction kinetics and prohibits Zn anode corrosion. Taking trace α-D-glucose (αDG) as a demonstration, the electrolyte obtains a low freezing point of -55.3 °C, and the Zn//Zn cell can stably cycle for 2000 h at 5 mA cm-2 under -25 °C, with a high cumulative capacity of 5000 mAh cm-2 . A full battery that stably operates for 10000 cycles at -50 °C is also demonstrated.

Remote ischemic conditioning reduces adverse events in patients with acute ischemic stroke complicating acute myocardial infarction: a randomized controlled trial.

BACKGROUND: Acute ischemic stroke (AIS) complicating an acute myocardial infarction (AMI) is not uncommon, but can severely worsen the clinical prognosis. This study aimed to investigate whether remote ischemic conditioning (RIC) could provide clinical benefits to patients with AIS complicating AMI. METHODS: Subjects with AIS complicating AMI were recruited in this double-blind, randomized, controlled trial; assigned to the RIC and sham groups; and respectively underwent twice daily RIC and sham RIC for 2 weeks. All subjects received standard medical therapy. The primary endpoint was the rate of major adverse cardiac and cerebrovascular events (MACCEs) within 3 months after enrollment. MACCEs comprise of death from all causes, unstable anginas, AMI, acute ischemic strokes, and transient ischemic attacks. RESULTS: Eighty subjects were randomly assigned; 37 patients in the RIC group and 40 patients in the sham-RIC group completed the 3-month follow-up and were included in the final analysis. Both RIC and sham RIC procedures were well tolerated. At 3-month follow-up, 11 subjects (29.7%) in the RIC group experienced MACCEs compared to 21 (52.5%) in the sham group (hazard ratio [HR], 0.396; 95% confidence interval, 0.187-0.838; adjusted p < 0.05). Six subjects (16.2%) in the RIC group had died at the 3-month follow up, significantly lower than the 15 (37.5%) deaths in the sham group (adjusted HR 0.333; 95% CI 0.126-0.881; p = 0.027). Seventeen subjects (45.9%) in the RIC group and 6 subjects (15.0%) in the sham group achieved functional independence (mRS score ≤ 2) at 3-month follow-up (adjusted OR 12.75; 95% CI 2.104-77.21; p = 0.006). CONCLUSIONS: Among patients with acute ischemic stroke complicating acute myocardial infarction, treatment with remote ischemic conditioning decreased the major adverse cardiac and cerebrovascular events and improved functional outcomes at 90 days. TRIAL REGISTRATION: URL: www. CLINICALTRIALS: gov . Unique identifier: NCT03868007. Registered 8 March 2019.

The dopamine receptor D1 inhibitor, SKF83566, suppresses GBM stemness and invasion through the DRD1-c-Myc-UHRF1 interactions.

BACKGROUND: Extensive local invasion of glioblastoma (GBM) cells within the central nervous system (CNS) is one factor that severely limits current treatments. The aim of this study was to uncover genes involved in the invasion process, which could also serve as therapeutic targets. For the isolation of invasive GBM cells from non-invasive cells, we used a three-dimensional organotypic co-culture system where glioma stem cell (GSC) spheres were confronted with brain organoids (BOs). Using ultra-low input RNA sequencing (ui-RNA Seq), an invasive gene signature was obtained that was exploited in a therapeutic context. METHODS: GFP-labeled tumor cells were sorted from invasive and non-invasive regions within co-cultures. Ui-RNA sequencing analysis was performed to find a gene cluster up-regulated in the invasive compartment. This gene cluster was further analyzed using the Connectivity MAP (CMap) database. This led to the identification of SKF83566, an antagonist of the D1 dopamine receptor (DRD1), as a candidate therapeutic molecule. Knockdown and overexpression experiments were performed to find molecular pathways responsible for the therapeutic effects of SKF83566. Finally, the effects of SKF83566 were validated in orthotopic xenograft models in vivo. RESULTS: Ui-RNA seq analysis of three GSC cell models (P3, BG5 and BG7) yielded a set of 27 differentially expressed genes between invasive and non-invasive cells. Using CMap analysis, SKF83566 was identified as a selective inhibitor targeting both DRD1 and DRD5. In vitro studies demonstrated that SKF83566 inhibited tumor cell proliferation, GSC sphere formation, and invasion. RNA sequencing analysis of SKF83566-treated P3, BG5, BG7, and control cell populations yielded a total of 32 differentially expressed genes, that were predicted to be regulated by c-Myc. Of these, the UHRF1 gene emerged as the most downregulated gene following treatment, and ChIP experiments revealed that c-Myc binds to its promoter region. Finally, SKF83566, or stable DRD1 knockdown, inhibited the growth of orthotopic GSC (BG5) derived xenografts in nude mice. CONCLUSIONS: DRD1 contributes to GBM invasion and progression by regulating c-Myc entry into the nucleus that affects the transcription of the UHRF1 gene. SKF83566 inhibits the transmembrane protein DRD1, and as such represents a candidate small therapeutic molecule for GBMs.