[Retracted] The AMPK­mTOR axis requires increased MALAT1 expression for promoting granulosa cell proliferation in endometriosis.

[This retracts the article DOI: 10.3892/etm.2020.9453.].

Superconductivity in Ca-intercalated bilayer graphene: C2CaC2.

The deposition and intercalation of metal atoms can induce superconductivity in monolayer and bilayer graphenes. For example, it has been experimentally proved that Li-deposited graphene is a superconductor with critical temperature Tc of 5.9 K, Ca-intercalated bilayer graphene C6CaC6 and K-intercalated epitaxial bilayer graphene C8KC8 are superconductors with Tc of 2-4 K and 3.6 K, respectively. However, the Tc of them are relatively low. To obtain higher Tc in graphene-based superconductors, here we predict a new Ca-intercalated bilayer graphene C2CaC2, which shows higher Ca concentration than the C6CaC6. It is proved to be thermodynamically and dynamically stable. The electronic structure, electron-phonon coupling (EPC) and superconductivity of C2CaC2 are investigated based on first-principles calculations. The EPC of C2CaC2 mainly comes from the coupling between the electrons of C-pz orbital and the high- and low-frequency vibration modes of C atoms. The calculated EPC constant λ of C2CaC2 is 0.75, and the superconducting Tc is 18.9 K, which is much higher than other metal-intercalated bilayer graphenes. By further applying -4% biaxial compressive strain to C2CaC2, the Tc can be boosted to 26.6 K. Thus, the predicted C2CaC2 provides a new platform for realizing superconductivity with the highest Tc in bilayer graphenes.

Role of reactive oxygen species in myelodysplastic syndromes.

Reactive oxygen species (ROS) serve as typical metabolic byproducts of aerobic life and play a pivotal role in redox reactions and signal transduction pathways. Contingent upon their concentration, ROS production not only initiates or stimulates tumorigenesis but also causes oxidative stress (OS) and triggers cellular apoptosis. Mounting literature supports the view that ROS are closely interwoven with the pathogenesis of a cluster of diseases, particularly those involving cell proliferation and differentiation, such as myelodysplastic syndromes (MDS) and chronic/acute myeloid leukemia (CML/AML). OS caused by excessive ROS at physiological levels is likely to affect the functions of hematopoietic stem cells, such as cell growth and self-renewal, which may contribute to defective hematopoiesis. We review herein the eminent role of ROS in the hematological niche and their profound influence on the progress of MDS. We also highlight that targeting ROS is a practical and reliable tactic for MDS therapy.

Platelet-derived TGF-ß1 induces functional reprogramming of myeloid-derived suppressor cells in immune thrombocytopenia.

Platelet α-granules are rich in TGF-ß1 which is associated with myeloid-derived suppressor cell (MDSC) biology. Responders to thrombopoietin receptor agonists (TPO-RAs) revealed a parallel increase in the number of both platelets and MDSCs. Here, anti-CD61 immune-sensitized splenocytes were transferred into severe combined immunodeficient mice to establish an active murine model of immune thrombocytopenia (ITP). Subsequently, we demonstrated that TPO-RAs augmented the inhibitory activities of MDSCs by arresting plasma cells differentiation, reducing Fas ligand expression on cytotoxic T cells, and re-balancing T cell subsets. Mechanistically, transcriptome analysis confirmed the participation of TGF-ß/Smad pathways in TPO-RA-corrected-MDSCs, which was offset by Smad2/3 knockdown. In platelet TGF-ß1-deficient mice, TPO-RA-induced amplification and enhanced suppressive capacity of MDSCs was waived. Furthermore, our retrospective data revealed that ITP patients achieving complete platelet response showed superior long-term outcomes compared with those who only reach partial response. In conclusion, we demonstrate that platelet TGF-ß1 induces the expansion and functional reprogramming of MDSCs via the TGF-ß/Smad pathway. These data indicate that platelet recovery not only serves as an endpoint of treatment response, but also paves the way for immune homeostasis in immune-mediated thrombocytopenia.

Evolving Therapeutic Landscape of Intracerebral Hemorrhage: Emerging Cutting-Edge Advancements in Surgical Robots, Regenerative Medicine, and Neurorehabilitation Techniques.

Intracerebral hemorrhage (ICH) is the most serious form of stroke and has limited available therapeutic options. As knowledge on ICH rapidly develops, cutting-edge techniques in the fields of surgical robots, regenerative medicine, and neurorehabilitation may revolutionize ICH treatment. However, these new advances still must be translated into clinical practice. In this review, we examined several emerging therapeutic strategies and their major challenges in managing ICH, with a particular focus on innovative therapies involving robot-assisted minimally invasive surgery, stem cell transplantation, in situ neuronal reprogramming, and brain-computer interfaces. Despite the limited expansion of the drug armamentarium for ICH over the past few decades, the judicious selection of more efficacious therapeutic modalities and the exploration of multimodal combination therapies represent opportunities to improve patient prognoses after ICH.

The effect of an extended culture period on birth weight among singletons born after single or double vitrified embryo transfer.

Aim: To evaluate the effect of an extended culture period on birth weight among singletons born after vitrified-warmed embryo transfer. Methods: A retrospective cohort study was performed among 12400 women who gave birth to 1015, 1027, 687, and 9671 singletons after single blastocyst transfer, single cleavage-stage embryo transfer, double blastocyst transfer, and double cleavage-stage embryo transfer, respectively. Results: The unadjusted birth weight of singletons born after vitrified blastocyst transfer were heavier than those born after cleavage-stage transfer (ß=30.28, SE=13.17, P=0.022), as were the adjusted birth weights (ß=0.09, SE=0.03, P=0.007). In addition, there was a 37% increased odd of having an infant with high birth weight after vitrified blastocyst transfer compared with vitrified cleavage stage transfer (OR=1.37, 95% CI:1.07-1.77). Conclusion: The unadjusted and adjusted birth weight and odds of having an infant with high birth weight significantly increased after blastocyst transfer compared with cleavage-stage embryo transfer in vitrified-warmed cycles.

Neuroimaging Marker-CT Perfusion of Early Neurological Deterioration in Patients with Minor Stroke and Large Vessel Occlusion after Intravenous Thrombolysis.

OBJECTIVE: Early Neurological Deterioration (END) is one of the complications in Acute ischemic stroke (AIS) and relates to prognosis. However, the reason why it occurs is still unclear. Our study is to investigate if CT perfusion (CTP) can predict END in patients with Minor Stroke and Large Vessel Occlusion after Intravenous Thrombolysis (IVT). METHODS: Patients who underwent IVT with Large Vessel Occlusion were enrolled continuously from January 2021 to August 2023. After evaluating the National Institutes of Health Stroke Scale (NIHSS) score, they were divided into the END group (n=21) and the Non-END group (n=20). Multivariate logistic regression analysis was performed to explore the factors of END. Receiver-operating characteristic (ROC) curve analysis was also used to assess the discriminative ability of CTP in predicting END. RESULTS: A total of 41 patients (mean age, 62.34 ± 10.82 years, 27 male) were finally included in the analysis; 21 patients had END, and 9 patients underwent Endovascular thrombectomy (EVT). Multivariate logistic regression analysis indicated that rCBV (OR=0.081, 95%CI=0.009- 0.721, p = 0.024) and admission-NIHSS (OR=1.990, 95%CI=1.049-3.772, p = 0.035) were significantly associated with END. The area under the curve (AUC) of rCBV and NIHSS to discriminate END were 0.708 and 0.758. We found patients with END had a higher modified Rankin Scale (mRS) in 3 months. CONCLUSIONS: The rCBV and NIHSS were associated with post-thrombolysis END and may become reliable markers to predicate END. END might predict a poor 3-month functional outcome.

Diffusion tensor imaging combined with chemical shift-encoded sequence to quantify the adaptive changes of calf muscles in amateur marathoners.

PURPOSE: Calf muscles play an important role in marathon race, and the incidence of injury is high in this process. This study prospectively quantified diffusion tensor metrics, muscle fat fraction (MFF) and cross-sectional area (CSA) of calf muscles induced by endurance exercise in amateur marathoners, and the potential mechanisms underlying the changes in these parameters were analyzed. METHOD: In this prospective study, 35 marathoners (27 males, 8 females; mean age (standard deviation, SD), 38.92 (4.83) years) and 26 controls (18 males, 8 females; mean age (SD), 38.35 (6.75) years) underwent magnetic resonance imaging (MRI) from September 2022 to March 2023. The diffusion tensor eigenvalues (λ1, λ2, λ3), radial diffusivity (RD), fractional anisotropy (FA), MFF and CSA of calf muscles were compared between marathoners and controls. A binary logistic regression model with gender correction was performed analyze the relationship between marathon exercise and DTI parameters, CSA and MFF of calf muscles. RESULTS: Interobserver agreement was good (κ = 0.71). The results of binary logistic regression model with gender correction showed that the regression coefficients of FA values in anterior group of calf (AC), soleus (SOL), medial gastrocnemius (MG) and lateral gastrocnemius (LG) were negative, and the odds ratios (OR) were 0.33, 0.45, 0.35, 0.05, respectively (P < 0.05). The OR of RD in SOL and λ2 in external group of calf (EC) were relatively higher, 3.74 and 3.26, respectively (P < 0.05). CSA was greater in SOL of marathoners, with an OR value of 1.00(P < 0.05). The MFF in AC and LG was lower in marathoners and OR of two indexes were -0.69 and -0.59, respectively (P < 0.05). CONCLUSIONS: Diffusion tensor imaging (DTI) combined with chemical shift-encoded sequence can noninvasively detect and quantify the adaptive changes of calf muscle morphology, microstructure and tissue composition induced by long-term running training in amateur marathoners.

Antibacterial, biocompatible, and mineralization-inducing properties of calcium silicate-based cements.

BACKGROUND: Different pulp capping materials have different origins and compositions, require different preparations, and may vary in their bioactive properties. AIM: The purpose of this study was to evaluate the antibacterial activity, biocompatibility, and mineralization-inducing potential of calcium silicate-based pulp capping materials. DESIGN: Six contemporary calcium silicate-based cements, ProRoot MTA, MTA Angelus, Biodentine, EndoSequence, NeoMTA 2, and NeoPutty, were evaluated. The antibacterial effects of these materials against Streptococcus mutans UA159 and Enterococcus faecalis ATCC 29212 were determined by the agar diffusion assay and the direct culture test. The biocompatibility and mineralization-inducing potential of these materials in preodontoblastic 17IIA11 cells were evaluated by the MTT assay and by Alizarin Red S staining, respectively. RESULTS AND CONCLUSION: In agar diffusion test, only Biodentine showed distinct antibacterial effects against S. mutans. All the tested materials, however, showed antibacterial effects against S. mutans and E. faecalis in the direct culture test, with Biodentine showing the strongest growth inhibition against both S. mutans and E. faecalis. All the tested materials showed acceptable biocompatibility and mineralization-supporting potential in our experimental conditions. In summary, ProRoot MTA, MTA Angelus, Biodentine, EndoSequence, NeoMTA 2, and NeoPutty demonstrated acceptable in vitro antimicrobial, biocompatible, and mineralization-supporting properties.

Functional Characterization of Sesquiterpene Synthases and P450 Enzymes in Flammulina velutipes for Biosynthesis of Spiro [4.5] Decane Terpene.

Flammulina velutipes, a popular edible mushroom, contains sesquiterpenes with potential health benefits. We characterized 12 sesquiterpene synthases and one P450 enzyme in F. velutipes using Aspergillus oryzae as a heterologous expression system, culminating in the biosynthesis of 16 distinct sesquiterpene compounds. An enzyme encoded by the axeB gene responsible for the synthesis of the spiro [4.5] decane compound axenol was discovered, and the mechanism of spirocycle formation was elucidated through quantum mechanical calculations. Furthermore, we delineated the role of a P450 enzyme colocated with AxeB in producing the novel compound 3-oxo-axenol. Our findings highlight the diverse array of sesquiterpene skeletons and functional groups biosynthesized by these enzymes in F. velutipes and underscore the effectiveness of the A. oryzae system as a heterologous host for expressing genes in the Basidiomycota genome. These insights into the biosynthesis of bioactive compounds in F. velutipes have significant implications for functional food and drug development.

Can Arthrogenic Muscle Inhibition Exist in Peroneal Muscles Among People with Chronic Ankle Instability? A Cross-sectional Study.

BACKGROUND: Ankle sprains lead to an unexplained reduction of ankle eversion strength, and arthrogenic muscle inhibition (AMI) in peroneal muscles is considered one of the underlying causes. This study aimed to observe the presence of AMI in peroneal muscles among people with chronic ankle instability (CAI). METHODS: Sixty-three people with CAI and another sixty-three without CAI conducted maximal voluntary isometric contraction (MVIC) and superimposed burst (SIB) tests during ankle eversion, then fifteen people with CAI and fifteen without CAI were randomly invited to repeat the same tests to calculate the test-retest reliability. Electrical stimulation was applied to the peroneal muscles while the participants were performing MVIC, and the central activation ratio (CAR) was obtained by dividing MVIC torque by the sum of MVIC and SIB torques, representing the degree of AMI. RESULTS: The intra-class correlation coefficients were 0.77 (0.45-0.92) and 0.92 (0.79-0.97) for the affected and unaffected limbs among people with CAI, and 0.97 (0.91-0.99) and 0.93 (0.82-0.97) for the controlled affected and unaffected limbs among people without CAI; Significant group × limb interaction was detected in the peroneal CAR (p = 0.008). The CARs were lower among people with CAI in the affected and unaffected limbs, compared with those without CAI (affected limb = 82.54 ± 9.46%, controlled affected limb = 94.64 ± 6.37%, p < 0.001; unaffected limb = 89.21 ± 8.04%, controlled unaffected limb = 94.93 ± 6.01%, p = 0.016). The CARs in the affected limbs were lower than those in the unaffected limbs among people with CAI (p = 0.023). No differences between limbs were found for CAR in the people without CAI (p = 0.10). CONCLUSIONS: Bilateral AMI of peroneal muscles is observed among people with CAI. Their affected limbs have higher levels of AMI than the unaffected limbs.

Total ginsenosides decrease Aß production through activating PPARγ.

INTRODUCTION: Total ginsenosides (TG), the major active constituents of ginseng, have been proven to be beneficial in treatment of Alzheimer's disease (AD). However, the underlying mechanism of TG remains unclear. METHODS: APP/PS1 mice and N2a/APP695 cells were used as in vivo and in vitro model, respectively. Morris water maze (MWM) was used to investigate behavioral changes of mice; neuronal pathological changes were assessed by hematoxylin and eosin (H&E) and nissl staining; immunofluorescence staining was used to examine amyloid beta (Aß) deposition; Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were used to examine the expression of relative amyloidogenic genes and proteins. Moreover, the antagonist of PPARγ, GW9662, was used to determine whether the effects of TG on Aß production were associated with PPARγ activity. RESULTS: TG treatment increased the spatial learning and memory abilities of APP/PS1 mice while decreasing the Aß accumulation in the cortex and hippocampus. In N2a/APP695 cells, TG treatment attenuated the secretion of Aß1-40 and Aß1-42 acting as an PPARγ agonist by inhibiting the translocation of NF-κB p65. Additionally, TG treatment also decreased the expression of amyloidogenic pathway related gene BACE1, PS1 and PS2. CONCLUSIONS: TG treatment reduced the production of Aß both in vivo and in vitro. Activating PPARγ might be a potential therapeutic target of TG in facilitating Aß clearance and ameliorating cognitive deficiency in APP/PS1 mice.

Analysing influencing factors and correlation paths of learning burnout among secondary vocational students in the context of social media: An integrated ISM-MICMAC approach.

By analysing the factors influencing secondary vocational students' learning burnout in the context of social media, this study unearthed the underlying causes of learning burnout. It also determined the correlation paths among the factors influencing learning burnout, providing references for educational and pedagogical improvement. This contributes to preventing secondary vocational students' learning burnout and enhancing learning efficiency in secondary vocational schools. Combined with previous research results and a theoretical basis, this study identifies 10 influencing factors employing the Delphi method, and uses Interpretative Structural Modelling (ISM) and Matrice d' Impacts Croisés Multiplication Appliqués à un Classement (MICMAC) to elucidate the relationship between influencing factors of learning burnout among secondary vocational students in the context of social media. This study also constructs a corresponding mechanism model and subsequently proposes prevention and improvement strategies. The results show that the overdevelopment of social media, as driving factors, has the greatest impact on secondary vocational students' learning burnout. Simultaneously, it takes the lead in addressing cognitive bias among students, decreased self-control, and low learning efficiency, factors that contribute to learning burnout. This is particularly beneficial in alleviating the degree of learning burnout among secondary vocational students in the context of social media and improves overall learning outcomes for these students. The hierarchical structure and correlation paths identified in this study offer robust invaluable guidance for developing a scientific program to address the problem of learning burnout among this demographic. This includes implementing related educational practises, thereby reducing the unpredictability of the practical applications.

Mgp High-Expressing MSCs Orchestrate the Osteoimmune Microenvironment of Collagen/Nanohydroxyapatite-Mediated Bone Regeneration.

Activating autologous stem cells after the implantation of biomaterials is an important process to initiate bone regeneration. Although several studies have demonstrated the mechanism of biomaterial-mediated bone regeneration, a comprehensive single-cell level transcriptomic map revealing the influence of biomaterials on regulating the temporal and spatial expression patterns of mesenchymal stem cells (MSCs) is still lacking. Herein, the osteoimmune microenvironment is depicted around the classical collagen/nanohydroxyapatite-based bone repair materials via combining analysis of single-cell RNA sequencing and spatial transcriptomics. A group of functional MSCs with high expression of matrix Gla protein (Mgp) is identified, which may serve as a pioneer subpopulation involved in bone repair. Remarkably, these Mgp high-expressing MSCs (MgphiMSCs) exhibit efficient osteogenic differentiation potential and orchestrate the osteoimmune microenvironment around implanted biomaterials, rewiring the polarization and osteoclastic differentiation of macrophages through the Mdk/Lrp1 ligand-receptor pair. The inhibition of Mdk/Lrp1 activates the pro-inflammatory programs of macrophages and osteoclastogenesis. Meanwhile, multiple immune-cell subsets also exhibit close crosstalk between MgphiMSCs via the secreted phosphoprotein 1 (SPP1) signaling pathway. These cellular profiles and interactions characterized in this study can broaden the understanding of the functional MSC subpopulations at the early stage of biomaterial-mediated bone regeneration and provide the basis for materials-designed strategies that target osteoimmune modulation.

Alkaline sphingomyelinase deficiency impairs intestinal mucosal barrier integrity and reduces antioxidant capacity in dextran sulfate sodium-induced colitis.

BACKGROUND: Ulcerative colitis is a chronic inflammatory disease of the colon with an unknown etiology. Alkaline sphingomyelinase (alk-SMase) is specifically expressed by intestinal epithelial cells, and has been reported to play an anti-inflammatory role. However, the underlying mechanism is still unclear. AIM: To explore the mechanism of alk-SMase anti-inflammatory effects on intestinal barrier function and oxidative stress in dextran sulfate sodium (DSS)-induced colitis. METHODS: Mice were administered 3% DSS drinking water, and disease activity index was determined to evaluate the status of colitis. Intestinal permeability was evaluated by gavage administration of fluorescein isothiocyanate dextran, and bacterial translocation was evaluated by measuring serum lipopolysaccharide. Intestinal epithelial cell ultrastructure was observed by electron microscopy. Western blotting and quantitative real-time reverse transcription-polymerase chain reaction were used to detect the expression of intestinal barrier proteins and mRNA, respectively. Serum oxidant and antioxidant marker levels were analyzed using commercial kits to assess oxidative stress levels. RESULTS: Compared to wild-type (WT) mice, inflammation and intestinal permeability in alk-SMase knockout (KO) mice were more severe beginning 4 d after DSS induction. The mRNA and protein levels of intestinal barrier proteins, including zonula occludens-1, occludin, claudin-3, claudin-5, claudin-8, mucin 2, and secretory immunoglobulin A, were significantly reduced on 4 d after DSS treatment. Ultrastructural observations revealed progressive damage to the tight junctions of intestinal epithelial cells. Furthermore, by day 4, mitochondria appeared swollen and degenerated. Additionally, compared to WT mice, serum malondialdehyde levels in KO mice were higher, and the antioxidant capacity was significantly lower. The expression of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in the colonic mucosal tissue of KO mice was significantly decreased after DSS treatment. mRNA levels of Nrf2-regulated downstream antioxidant enzymes were also decreased. Finally, colitis in KO mice could be effectively relieved by the injection of tertiary butylhydroquinone, which is an Nrf2 activator. CONCLUSION: Alk-SMase regulates the stability of the intestinal mucosal barrier and enhances antioxidant activity through the Nrf2 signaling pathway.

Bilateral hyperkeratosis of the nipples and areolae with linear nevus and acanthosis nigricans: A rare case report.

Hyperkeratosis of the nipples and areolae (HNA) is an uncommon skin disorder with no definite aetiology. We report a case of a 16-year-old boy, who presented with bilateral pigmentation and thickening of the nipples and areolae, accompanied with linear brown protrusions on the anterior neck and a velvet like appearance with pigmentation on the axillary bilaterlly. Based on clinical and histopathological, and dermatoscopic findings, the diagnosis of bilateral HNA accompanied by linear nevus and acanthosis nigricans was made. The skin lesions were improved by treatment with topical calcipotriol gel.

Addition of ruxolitinib to standard graft-versus-host disease prophylaxis for allogeneic stem cell transplantation in aplastic anemia patients.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers rapid hematopoietic and immune reconstitution for aplastic anemia (AA). As a non-malignant disorder, attenuation of GVHD remains a clinical priority in AA patients. Our study sought to investigate the safety and efficacy of the prophylactic use of ruxolitinib in allogeneic HSCT. A total of 35 AA patients were retrospectively consecutively treated with allo-HSCT whereby ruxolitinib was added to the standard GVHD prophylaxis regimen (rux group). The addition of peri-transplant ruxolitinib did not impact the engraftment and graft function, while better recovery of CD4+ Tregs in the rux group was observed. Interestingly, the rux group demonstrated significantly lower incidence of bacterial/fungal infections (17.14% vs 45.71%). Compared to the control group, the rux group exhibited significantly lower incidence of moderate to severe aGVHD (17.1% vs 48.6%) with a trend toward lower severe aGVHD (8.6% vs 20%) and cGVHD (26.2 vs 38.3). The rux group also demonstrated a trend toward higher GVHD and failure-free survival (GFFS: 85.7% vs 68.6%) and lower TRM (2.9% vs 14.3%). Addition of ruxolitinib to standard GVHD prophylaxis regimen, thus, represents a safe and highly efficient method for the attenuation of GVHD with better outcome of allo-HSCT.

IL-6-mediated endothelial injury impairs antiviral humoral immunity after bone marrow transplantation.

Endothelial function and integrity are compromised after allogeneic bone marrow transplantation (BMT), but how this affects immune responses broadly remains unknown. Using a preclinical model of CMV reactivation after BMT, we found compromised antiviral humoral responses induced by IL-6 signaling. IL-6 signaling in T cells maintained Th1 cells, resulting in sustained IFN-γ secretion, which promoted endothelial cell (EC) injury, loss of the neonatal Fc receptor (FcRn) responsible for IgG recycling, and rapid IgG loss. T cell-specific deletion of IL-6R led to persistence of recipient-derived, CMV-specific IgG and inhibited CMV reactivation. Deletion of IFN-γ in donor T cells also eliminated EC injury and FcRn loss. In a phase III clinical trial, blockade of IL-6R with tocilizumab promoted CMV-specific IgG persistence and significantly attenuated early HCMV reactivation. In sum, IL-6 invoked IFN-γ-dependent EC injury and consequent IgG loss, leading to CMV reactivation. Hence, cytokine inhibition represents a logical strategy to prevent endothelial injury, thereby preserving humoral immunity after immunotherapy.

Extended Clopidogrel Monotherapy vs DAPT in Patients With Acute Coronary Syndromes at High Ischemic and Bleeding Risk: The OPT-BIRISK Randomized Clinical Trial.

Importance: Purinergic receptor P2Y12 (P2Y12) inhibitor monotherapy after a certain period of dual antiplatelet therapy (DAPT) may be an attractive option of maintenance antiplatelet treatment for patients undergoing percutaneous coronary intervention (PCI) who are at both high bleeding and ischemic risk (birisk). Objective: To determine if extended P2Y12 inhibitor monotherapy with clopidogrel is superior to ongoing DAPT with aspirin and clopidogrel after 9 to 12 months of DAPT after PCI in birisk patients with acute coronary syndromes (ACS). Design, Setting, and Participants: This was a multicenter, double-blind, placebo-controlled, randomized clinical trial including birisk patients with ACS who had completed 9 to 12 months of DAPT after drug-eluting stent implantation and were free from adverse events for at least 6 months at 101 China centers between February 2018 and December 2020. Study data were analyzed from April 2023 to May 2023. Interventions: Patients were randomized either to clopidogrel plus placebo or clopidogrel plus aspirin for an additional 9 months. Main Outcomes and Measures: The primary end point was Bleeding Academic Research Consortium (BARC) types 2, 3, or 5 bleeding 9 months after randomization. The key secondary end point was major adverse cardiac and cerebral events (MACCE; the composite of all-cause death, myocardial infarction, stroke or clinically driven revascularization). The primary end point was tested for superiority, and the MACCE end point was tested for sequential noninferiority and superiority. Results: A total of 7758 patients (mean [SD] age, 64.8 [9.0] years; 4575 male [59.0%]) were included in this study. The primary end point of BARC types 2, 3, or 5 bleeding occurred in 95 of 3873 patients (2.5%) assigned to clopidogrel plus placebo and 127 of 3885 patients (3.3%) assigned to clopidogrel plus aspirin (hazard ratio [HR], 0.75; 95% CI, 0.57-0.97; difference, -0.8%; 95% CI, -1.6% to -0.1%; P = .03). The incidence of MACCE was 2.6% (101 of 3873 patients) in the clopidogrel plus placebo group and 3.5% (136 of 3885 patients) in the clopidogrel plus aspirin group (HR, 0.74; 95% CI, 0.57-0.96; difference, -0.9%; 95% CI, -1.7% to -0.1%; P < .001 for noninferiority; P = .02 for superiority). Conclusions and Relevance: Among birisk patients with ACS who completed 9 to 12 months of DAPT after drug-eluting stent implantation and were free from adverse events for at least 6 months before randomization, an extended 9-month clopidogrel monotherapy regimen was superior to continuing DAPT with clopidogrel in reducing clinically relevant bleeding without increasing ischemic events. Trial Registration: ClinicalTrials.gov Identifier: NCT03431142.

TIM-3+ CD8 T cells with a terminally exhausted phenotype retain functional capacity in hematological malignancies.

Chronic antigen stimulation is thought to generate dysfunctional CD8 T cells. Here, we identify a CD8 T cell subset in the bone marrow tumor microenvironment that, despite an apparent terminally exhausted phenotype (TPHEX), expressed granzymes, perforin, and IFN-γ. Concurrent gene expression and DNA accessibility revealed that genes encoding these functional proteins correlated with BATF expression and motif accessibility. IFN-γ+ TPHEX effectively killed myeloma with comparable efficacy to transitory effectors, and disease progression correlated with numerical deficits in IFN-γ+ TPHEX. We also observed IFN-γ+ TPHEX within CD19-targeted chimeric antigen receptor T cells, which killed CD19+ leukemia cells. An IFN-γ+ TPHEX gene signature was recapitulated in TEX cells from human cancers, including myeloma and lymphoma. Here, we characterize a TEX subset in hematological malignancies that paradoxically retains function and is distinct from dysfunctional TEX found in chronic viral infections. Thus, IFN-γ+ TPHEX represent a potential target for immunotherapy of blood cancers.