Fast simulation for interacting four-level Rydberg atoms: electromagnetically induced transparency and Autler-Townes splitting.

Quantum sensing using Rydberg atoms is an emerging technology for precise measurement of electric fields. However, most existing computational methods are all based on a single-particle model and neglect Rydberg-Rydberg interaction between atoms. In this study, we introduce the interaction term into the conventional four-level optical Bloch equations. By incorporating fast iterations and solving for the steady-state solution efficiently, we avoid the computation of a massive 4N × 4N dimensional matrix. Additionally, we apply the Doppler frequency shift to each atom used in the calculation, eliminating the requirement for an additional Doppler iteration. These schemes allow for the calculation of the interaction between 7000 atoms around one minute. Based on the many-body model, we investigate the Rydberg-Rydberg interaction of Rydberg atoms under different atomic densities. Furthermore, we compare our results with the literature data of a three-level system and the experimental results of our own four-level system. The results demonstrate the validity of our model, with an effective error of 4.59% compared to the experimental data. Finally, we discover that the many-body model better predicts the linear range for measuring electric fields than the single-particle model, making it highly applicable in precise electric field measurements.

Low-dose pegylated recombinant human granulocyte-colony stimulating factor as hematopoietic support for adjuvant chemotherapy in Chinese patients with breast cancer: An open-label, randomized, non-inferiority trial.

AIMS: The recommended dosage of pegylated recombinant human granulocyte-colony stimulating factor (PEG-rhG-CSF) for Western chemotherapy patients is 6 mg per cycle. However, for Eastern Asians, the optimal dose remains unknown. METHODS: This open-label, randomized, non-inferiority trial (NCT05283616) enrolled Chinese female breast cancer patients receiving adjuvant chemotherapy. Participants were randomized to receive either 3 or 6 mg of PEG-rhG-CSF per cycle, stratified by body weight (BW; ≤60 kg vs. >60 kg). The primary endpoint was timely absolute neutrophil count (ANC) recovery before the second cycle of chemotherapy. RESULTS: A total of 122 patients were randomized and 116 were included for efficacy analyses. The timely ANC recovery rate in the 3 mg arm was 89.8%, compared to 93.0% in the 6 mg arm (one-sided 95% confidence interval [CI] lower limit for difference: -11.7%), meeting the prespecified non-inferiority margin of 15%. The rate was 93.3% with PEG-rhG-CSF 3 mg and 96.6% with 6 mg in patients with BW ≤ 60 kg, and 86.2% and 89.3%, respectively, in those with BW > 60 kg. Although the incidence of severe neutropenia was similar across arms, the occurrence of excessively high ANC and white blood cell counts was higher in the 6 mg arm. No grade ≥3 adverse events related to PEG-rhG-CSF occurred. CONCLUSION: Three milligrams of PEG-rhG-CSF per cycle provided non-inferior neutrophil protection and attenuated neutrophil overshoot compared to 6 mg doses. This low-dose regimen could be a new supportive care option for Chinese breast cancer patients receiving anthracycline-based adjuvant chemotherapy.

MOSP: A user-interface package for simulating metal nanoparticle's structure and reactivity under operando conditions.

The structures of metal nanoparticles (NPs) significantly influence their catalytic reactivities. Recent in situ experimental observations of dramatic structural changes in NPs underscore the need to establish a dynamic structure-property relationship that accounts for the reconstruction of NPs in reactive environments. Here, we present the MOSP, a free and open-source graphical user interface (GUI) package designed to simulate the structure and reactivity of metal NPs under operando conditions. MOSP integrates two models: the multiscale structure reconstruction model predicting equilibrium metal NP structures under specific reaction conditions and the kinetic Monte Carlo model simulating the reaction dynamics. This combination allows for the exploration of the dynamic structure-property relationships of NPs. MOSP enhances user accessibility through its intuitive GUI, facilitating easy input, post-processing, and visualization of simulation data. This article is the release note of MOSP, focusing on its implementation and functionality.

A Novel Interpretable Radiomics Model to Distinguish Nodular Goiter From Malignant Thyroid Nodules.

OBJECTIVES: The purpose of this study is to inquire about the potential association between radiomics features and the pathological nature of thyroid nodules (TNs), and to propose an interpretable radiomics-based model for predicting the risk of malignant TN. METHODS: In this retrospective study, computed tomography (CT) imaging and pathological data from 141 patients with TN were collected. The data were randomly stratified into a training group (n = 112) and a validation group (n = 29) at a ratio of 4:1. A total of 1316 radiomics features were extracted by using the pyradiomics tool. The redundant features were removed through correlation testing, and the least absolute shrinkage and selection operator (LASSO) or the minimum redundancy maximum relevance standard was used to select features. Finally, 4 different machine learning models (RF Hybrid Feature, SVM Hybrid Feature, RF, and LASSO) were constructed. The performance of the 4 models was evaluated using the receiver operating characteristic curve. The calibration curve, decision curve analysis, and SHapley Additive exPlanations method were used to evaluate or explain the best radiomics machine learning model. RESULTS: The optimal radiomics model (RF Hybrid Feature model) demonstrated a relatively high degree of discrimination with an area under the receiver operating characteristic curve (AUC) of 0.87 (95% CI, 0.70-0.97; P < 0.001) for the validation cohort. Compared with the commonly used LASSO model (AUC, 0.78; 95% CI, 0.60-0.91; P < 0.01), there is a significant improvement in AUC in the validation set, net reclassification improvement, 0.79 (95% CI, 0.13-1.46; P < 0.05), and integrated discrimination improvement, 0. 20 (95% CI, 0.10-0.30; P < 0.001). CONCLUSION: The interpretable radiomics model based on CT performs well in predicting benign and malignant TNs by using quantitative radiomics features of the unilateral total thyroid. In addition, the data preprocessing method incorporating different layers of features has achieved excellent experimental results. CLINICAL RELEVANCE STATEMENT: As the detection rate of TNs continues to increase, so does the diagnostic burden on radiologists. This study establishes a noninvasive, interpretable and accurate machine learning model to rapidly identify the nature of TN found in CT.

Integrative analysis from multi-center studies identifies a weighted gene co-expression network analysis-based Tregs signature in ovarian cancer.

Ovarian cancer (OC) is a malignancy associated with poor prognosis and has been linked to regulatory T cells (Tregs) in the immune microenvironment. Nevertheless, the association between Tregs-related genes (TRGs) and OC prognosis remains incompletely understood. The xCell algorithm was used to analyze Tregs scores across multiple cohorts. Weighted gene co-expression network analysis (WGCNA) was utilized to identify potential TRGs and molecular subtypes. Furthermore, we used nine machine learning algorithms to create risk models with prognostic indicators for patients. Reverse transcription-quantitative polymerase chain reaction and immunofluorescence staining were used to demonstrate the immunosuppressive ability of Tregs and the expression of key TRGs in clinical samples. Our study found that higher Tregs scores were significantly correlated with poorer overall survival. Recurrent patients exhibited increased Tregs infiltration and reduced CD8+ T cell. Moreover, molecular subtyping using seven key TRGs revealed that subtype B exhibited higher enrichment of multiple oncogenic pathways and had a worse prognosis. Notably, subtype B exhibited high Tregs levels, suggesting immune suppression. In addition, we validated machine learning-derived prognostic models across multiple platform cohorts to better distinguish patient survival and predict immunotherapy efficacy. Finally, the differential expression of key TRGs was validated using clinical samples. Our study provides novel insights into the role of Tregs in the immune microenvironment of OC. We identified potential therapeutic targets derived from Tregs (CD24, FHL2, GPM6A, HOXD8, NAP1L5, REN, and TOX3) for personalized treatment and created a machining learning-based prognostic model for OC patients, which could be useful in clinical practice.

Effects of laparoscopic radical prostatectomy on wound infection of surgery in patients with prostate cancer: A meta-analysis.

This meta-analysis aims to comprehensively assess the impact of laparoscopic radical prostatectomy (LRP) on wound infection in patients with prostate cancer (PCa). A systematic search was conducted, from database inception to November 2023, in EMBASE, Google Scholar, Cochrane Library, PubMed, Wanfang and China National Knowledge Infrastructure databases for randomized controlled trials (RCTs) comparing LRP with open radical prostatectomy (ORP) in the treatment of PCa. Two researchers independently screened the literature, extracted data and conducted quality assessments based on pre-defined inclusion and exclusion criteria. Stata 17.0 software was employed for data analysis. Overall, 15 RCTs involving 1458 PCa patients were included. The analysis revealed the incidence of wound infection (odds ratio [OR] = 0.28, 95% confidence interval [CI] = 0.16-0.51, p < 0.001) and complications (OR = 0.27, 95% CI = 0.20-0.37, p < 0.001) was significantly lower in the LRP group compared to the ORP group. This study demonstrates that LRP in PCa patients can effectively reduce the incidence of wound infections and complications, indicating significant therapeutic efficacy and justifying its broader clinical application.

The roles of branched-chain amino acids metabolism in tumorigenesis and progression.

Branched-chain amino acids (BCAAs), including leucine, valine, and isoleucine, play crucial roles in regulating metabolic balance and maintaining physiological functions in the body. Extensive studies have been focused on their implications in obesity, diabetes, and cardiovascular diseases. Nevertheless, accumulating evidence suggests that BCAAs metabolism also plays significant roles in tumorigenesis and progression. In this review, we overview recent progress of the study on BCAAs metabolism including its relationship with epigenetic regulation. Particularly, we discuss the metabolic reprogramming and metabolic sensing of BCAAs and its intermediate metabolites in tumor cells and microenvironment to decipher their functions. An enhanced understanding of the roles and mechanism of BCAAs metabolism in tumorigenesis and progression will contribute to development of novel therapeutic strategies against tumor.

FGF21-Sirtuin 3 Axis Confers the Protective Effects of Exercise Against Diabetic Cardiomyopathy by Governing Mitochondrial Integrity.

BACKGROUND: Exercise is an effective nonpharmacological strategy to alleviate diabetic cardiomyopathy (DCM) through poorly defined mechanisms. FGF21 (fibroblast growth factor 21), a peptide hormone with pleiotropic benefits on cardiometabolic homeostasis, has been identified as an exercise responsive factor. This study aims to investigate whether FGF21 signaling mediates the benefits of exercise on DCM, and if so, to elucidate the underlying mechanisms. METHODS: The global or hepatocyte-specific FGF21 knockout mice, cardiomyocyte-selective ß-klotho (the obligatory co-receptor for FGF21) knockout mice, and their wild-type littermates were subjected to high-fat diet feeding and injection of streptozotocin to induce DCM, followed by a 6-week exercise intervention and assessment of cardiac functions. Cardiac mitochondrial structure and function were assessed by electron microscopy, enzymatic assays, and measurements of fatty acid oxidation and ATP production. Human induced pluripotent stem cell-derived cardiomyocytes were used to investigate the receptor and postreceptor signaling pathways conferring the protective effects of FGF21 against toxic lipids-induced mitochondrial dysfunction. RESULTS: Treadmill exercise markedly induced cardiac expression of ß-klotho and significantly attenuated diabetes-induced cardiac dysfunction in wild-type mice, accompanied by reduced mitochondrial damage and increased activities of mitochondrial enzymes in hearts. However, such cardioprotective benefits of exercise were largely abrogated in mice with global or hepatocyte-selective ablation of FGF21, or cardiomyocyte-specific deletion of ß-klotho. Mechanistically, exercise enhanced the cardiac actions of FGF21 to induce the expression of the mitochondrial deacetylase SIRT3 by AMPK-evoked phosphorylation of FOXO3, thereby reversing diabetes-induced hyperacetylation and functional impairments of a cluster of mitochondrial enzymes. FGF21 prevented toxic lipids-induced mitochondrial dysfunction and oxidative stress by induction of the AMPK/FOXO3/SIRT3 signaling axis in human induced pluripotent stem cell-derived cardiomyocytes. Adeno-associated virus-mediated restoration of cardiac SIRT3 expression was sufficient to restore the responsiveness of diabetic FGF21 knockout mice to exercise in amelioration of mitochondrial dysfunction and DCM. CONCLUSIONS: The FGF21-SIRT3 axis mediates the protective effects of exercise against DCM by preserving mitochondrial integrity and represents a potential therapeutic target for DCM. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03240978.

Dysregulation of iron homeostasis by TfR-1 renders EZH2 wild type diffuse large B-cell lymphoma resistance to EZH2 inhibition.

EZH2 has been regarded as an efficient target for diffuse large B-cell lymphoma (DLBCL), but the clinical benefits of EZH2 inhibitors (EZH2i) are limited. To date, only EPZ-6438 has been approved by FDA for the treatment of follicular lymphoma and epithelioid sarcoma. We have discovered a novel EZH1/2 inhibitor HH2853 with a better antitumor effect than EPZ-6438 in preclinical studies. In this study we explored the molecular mechanism underlying the primary resistance to EZH2 inhibitors and sought for combination therapy strategy to overcome it. By analyzing EPZ-6438 and HH2853 response profiling, we found that EZH2 inhibition increased intracellular iron through upregulation of transferrin receptor 1 (TfR-1), ultimately triggered resistance to EZH2i in DLBCL cells. We demonstrated that H3K27ac gain by EZH2i enhanced c-Myc transcription, which contributed to TfR-1 overexpression in insensitive U-2932 and WILL-2 cells. On the other hand, EZH2i impaired the occurrence of ferroptosis by upregulating the heat shock protein family A (Hsp70) member 5 (HSPA5) and stabilizing glutathione peroxidase 4 (GPX4), a ferroptosis suppressor; co-treatment with ferroptosis inducer erastin effectively overrode the resistance of DLBCL to EZH2i in vitro and in vivo. Altogether, this study reveals iron-dependent resistance evoked by EZH2i in DLBCL cells, and suggests that combination with ferroptosis inducer may be a promising therapeutic strategy.

Curtailing FGF19's mitogenicity by suppressing its receptor dimerization ability.

As a physiological regulator of bile acid homeostasis, FGF19 is also a potent insulin sensitizer capable of normalizing plasma glucose concentration, improving lipid profile, ameliorating fatty liver disease, and causing weight loss in both diabetic and diet-induced obesity mice. There is therefore a major interest in developing FGF19 as a therapeutic agent for treating type 2 diabetes and cholestatic liver disease. However, the known tumorigenic risk associated with prolonged FGF19 administration is a major hurdle in realizing its clinical potential. Here, we show that nonmitogenic FGF19 variants that retain the full beneficial glucose-lowering and bile acid regulatory activities of WT FGF19 (FGF19WT) can be engineered by diminishing FGF19's ability to induce dimerization of its cognate FGF receptors (FGFR). As proof of principle, we generated three such variants, each with a partial defect in binding affinity to FGFR (FGF19ΔFGFR) and its coreceptors, i.e., ßklotho (FGF19ΔKLB) or heparan sulfate (FGF19ΔHBS). Pharmacological assays in WT and db/db mice confirmed that these variants incur a dramatic loss in mitogenic activity, yet are indistinguishable from FGF19WT in eliciting glycemic control and regulating bile acid synthesis. This approach provides a robust framework for the development of safer and more efficacious FGF19 analogs.

Protein Z and Protein Z-dependent protease inhibitor in patients with acute ischemic stroke: A prospective mechanistic study.

OBJECTIVES: Protein Z (PZ) /Protein Z-dependent protease inhibitor (ZPI) (PZ/ZPI) system is a new anticoagulant system discovered in recent years, which plays an important role in many diseases. We aimed to compare the plasma PZ/ZPI levels of acute ischemic stroke (AIS) patients and non-stroke control participants and the role of PZ/ZPI in the development of stroke was preliminarily analyzed. MATERIALS AND METHODS: Enzyme linked immunosorbent assay (ELISA) was used to detect and compare plasma PZ levels of 86 patients with acute AIS and 85 non-stroke control patients. Multivariable Logistic regression was used to analyze whether PZ was an independent risk factor for AIS. RESULTS: In the present study, plasma PZ is closely related to inflammatory response, coagulation process and platelet activation, and may participate in the development of AIS by inducing inflammatory responses and interfering with the coagulation process. CONCLUSIONS: Our results suggested that plasma PZ level is one of the independent risk factors of AIS, and plasma ZPI was closely related to coagulation and platelet parameter and may play a role in the coagulation process during AIS.

Chinese Consensus Report on Family-Based Helicobacter pylori Infection Control and Management (2021 Edition).

OBJECTIVE: Helicobacter pylori infection is mostly a family-based infectious disease. To facilitate its prevention and management, a national consensus meeting was held to review current evidence and propose strategies for population-wide and family-based H. pylori infection control and management to reduce the related disease burden. METHODS: Fifty-seven experts from 41 major universities and institutions in 20 provinces/regions of mainland China were invited to review evidence and modify statements using Delphi process and grading of recommendations assessment, development and evaluation system. The consensus level was defined as ≥80% for agreement on the proposed statements. RESULTS: Experts discussed and modified the original 23 statements on family-based H. pylori infection transmission, control and management, and reached consensus on 16 statements. The final report consists of three parts: (1) H. pylori infection and transmission among family members, (2) prevention and management of H. pylori infection in children and elderly people within households, and (3) strategies for prevention and management of H. pylori infection for family members. In addition to the 'test-and-treat' and 'screen-and-treat' strategies, this consensus also introduced a novel third 'family-based H. pylori infection control and management' strategy to prevent its intrafamilial transmission and development of related diseases. CONCLUSION: H. pylori is transmissible from person to person, and among family members. A family-based H. pylori prevention and eradication strategy would be a suitable approach to prevent its intra-familial transmission and related diseases. The notion and practice would be beneficial not only for Chinese residents but also valuable as a reference for other highly infected areas.

Dual-wavelength switching in InGaN quantum dot micro-cavity light-emitting diodes.

Dual-wavelength switchable emission has been demonstrated in InGaN quantum dot (QD) micro-cavity light-emitting diodes (MCLEDs). By simply modulating the injected current levels, the output of the device can be dynamically tuned between the two distinct cavity modes at 498.5 and 541.7 nm, exhibiting deterministic mode switching in the green spectral range. Owing to the microcavity effect, high spectral purity with a narrow linewidth of 0.21 nm was obtained. According to the experimental and theoretical results, it can be concluded that the dual-wavelength switching for the investigated MCLEDs is ascribed to the broad and tunable gain of a thin InGaN QD active region, together with the mode selection and enhancement effect of the cavity. To provide additional guidelines for controllable dual-wavelength switchable operation in nitride-based light-emitting devices, detailed design and fabrication strategies are discussed. This work presents an effective method to achieve mode switching for practical applications such as multi-wavelength optical recording, frequency mixing, flip-flop and optical switches.

Integrative analyses of genes related to liver ischemia reperfusion injury.

BACKGROUND: Liver ischemia reperfusion injury (LIRI) is not only a common injury during liver transplantation and major hepatic surgery, but also one of the primary factors that affect the outcome of postoperative diseases. However, there are still no reliable ways to tackle the problem. Our study aimed to find some characteristic genes associated with immune infiltration that affect LIRI, which can provide some insights for future research in the future. Therefore, it is essential for the treatment of LIRI, the elucidation of the mechanisms of LIRI, and exploring the potential biomarkers. Efficient microarray and bioinformatics analyses can promote the understanding of the molecular mechanisms of disease occurrence and development. METHOD: Data from GSE151648 were downloaded from GEO data sets, and we performed a comprehensive analysis of the differential expression, biological functions and interactions of LIRI-associated genes. Then we performed Gene ontology (GO) analysis and Kyotoencydlopedia of genes and genomes (KEGG) enrichment analysis of DEGs. At last, we performed a protein-protein interaction network to screen out hub genes. RESULTS: A total of 161 differentially expressed genes (DEGs) were identified. GO analysis results revealed that the changes in the modules were mostly enriched in the neutrophil degranulation, neutrophil activation involved in immune response, and neutrophil mediated immunity. KEGG enrichment analysis of DEGs demonstrated that LIRI mainly involved the cytokine-cytokine receptor interaction. Our data indicated that macrophages and neutrophils are closely related to LIRI. 9 hub genes were screened out in the protein-protein interaction network. CONCLUSIONS: In summary, our data indicated that neutrophil degranulation, neutrophil activation involved in immune response, neutrophil mediated immunity and cytokine-cytokine receptor interaction may play a key role in LIRI, HRH1, LRP2, P2RY6, PKD1L1, SLC8A3 and TNFRSF8, which were identified as potential biomarkers in the occurrence and development of LIRI. However, further studies are needed to validate these findings and explore the molecular mechanism of these biomarkers in LIRI.

SAF-189s, a potent new-generation ROS1 inhibitor, is active against crizotinib-resistant ROS1 mutant-driven tumors.

The ROS1 fusion kinase is an attractive antitumor target. Though with significant clinical efficacy, the well-known first-generation ROS1 inhibitor (ROS1i) crizotinib inevitably developed acquired resistance due to secondary point mutations in the ROS1 kinase. Novel ROS1is effective against mutations conferring secondary crizotinib resistance, especially G2032R, are urgently needed. In the present study, we evaluated the antitumor efficacy of SAF-189s, the new-generation ROS1/ALK inhibitor, against ROS1 fusion wild-type and crizotinib-resistant mutants. We showed that SAF-189s potently inhibited ROS1 kinase and its known acquired clinically resistant mutants, including the highly resistant G2032R mutant. SAF-189s displayed subnanomolar to nanomolar IC50 values against ROS1 wild-type and mutant kinase activity and a selectivity vs. other 288 protein kinases tested. SAF-189s blocked cellular ROS1 signaling, and in turn potently inhibited the cell proliferation in HCC78 cells and BaF3 cells expressing ROS1 fusion wild-type and resistance mutants. In nude mice bearing BaF3/CD74-ROS1 or BaF3/CD74-ROS1G2032R xenografts, oral administration of SAF-189s dose dependently suppressed the growth of both ROS1 wild-type- and G2032R mutant-driven tumors. In a patient-derived xenograft model of SDC4-ROS1 fusion NSCLC, oral administration of SAF-189s (20 mg/kg every day) induced tumor regression and exhibited notable prolonged and durable efficacy. In addition, SAF-189s was more potent than crizotinib and comparable to lorlatinib, the most advanced ROS1i known against the ROS1G2032R. Collectively, these results suggest the promising potential of SAF-189s for the treatment of patients with the ROS1 fusion G2032R mutation who relapse on crizotinib. It is now recruiting both crizotinib-relapsed and naive ROS1-positive NSCLC patients in a multicenter phase II trial (ClinicalTrials.gov Identifier: NCT04237805).

The value of serum procalcitonin in the anti-infection therapy of acute stroke patients.

OBJECTIVES: To investigate the value of dynamic monitoring of serum procalcitonin (PCT) in anti-infective therapy of patients with acute stroke. METHODS: This is a case control retrospective study of acute stroke patients conducted from July 2016 to October 2018, in the Department of Neurology, Affiliated Hospital of Hebei University, who who reached within twenty four hours. They, were selected as the study subjects who were divided into infection group and non-infection group according to the inclusion and exclusion criteria. The serum PCT and CRP levels were compared between the two groups at 24 hours, 48 hours and 72 hours. In order to judge the changes of PCT level and the infection of stroke patients, different kinds of antibiotics were used for corresponding treatment. Retrospective analysis of the cases that did not monitor PCT anti infective treatment before July 2016 were compared with the cases that monitored PCT to guide anti infective treatment after July 2016, and compared the efficacy of antibiotics. RESULTS: The serum PCT level of patients in the infection group was significantly higher than that of patients in the noninfection group (P<0.001). For the patients whose PCT<0.5 ng/ml within 72 hour, anti-infective therapy was not administered. However, for those patients whose PCT<0.5 ng/ml and CRP rose significantly, WBC, body temperature and chest CT were closely monitored. For the patients whose PCT increased slightly (0.5 ng/mlPCT>2 ng/ml), mezlocillin/ sulbactam or ceftriaxone/ tazobactam was administered. For patients whose PCT increased significantly (PCT>5 ng/ml), carbapenem antibiotic or a combination of two antibiotics was administered. CONCLUSION: Dynamic detection of serum PCT concentration can make accurate judgment on the severity of bacterial infection in patients with acute stroke and guide the rational application of antibiotics.

PDE1 or PDE5 inhibition augments NO-dependent hypoxic constriction of porcine coronary artery via elevating inosine 3',5'-cyclic monophosphate level.

Hypoxic coronary vasospasm may lead to myocardial ischaemia and cardiac dysfunction. Inosine 3',5'-cyclic monophosphate (cIMP) is a putative second messenger to mediate this pathological process. Nevertheless, it remains unclear as to whether levels of cIMP can be regulated in living tissue such as coronary artery and if so, what is the consequence of this regulation on hypoxia-induced vasoconstriction. In the present study, we found that cIMP was a key determinant of hypoxia-induced constriction but not that of the subsequent relaxation response in porcine coronary arteries. Subsequently, coronary arteries were treated with various phosphodiesterase (PDE) inhibitors to identify PDE types that are capable of regulating cIMP levels. We found that inhibition of PDE1 and PDE5 substantially elevated cIMP content in endothelium-denuded coronary artery supplemented with exogenous purified cIMP. However, cGMP levels were far lower than their levels in intact coronary arteries and lower than cIMP levels measured in endothelium-denuded coronary arteries supplemented with exogenous cIMP. The increased cIMP levels induced by PDE1 or PDE5 inhibition further led to augmented hypoxic constriction without apparently affecting the relaxation response. In intact coronary artery, PDE1 or PDE5 inhibition up-regulated cIMP levels under hypoxic condition. Concomitantly, cGMP level increased to a comparable level. Nevertheless, the hypoxia-mediated constriction was enhanced in this situation that was largely compromised by an even stronger inhibition of PDEs. Taken together, these data suggest that cIMP levels in coronary arteries are regulated by PDE1 and PDE5, whose inhibition at a certain level leads to increased cIMP content and enhanced hypoxic constriction.

EZH2 inhibitors abrogate upregulation of trimethylation of H3K27 by CDK9 inhibitors and potentiate its activity against diffuse large B-cell lymphoma.

Aberrant expression of CDK9/cyclin T1 has been found in diffuse large B-cell lymphoma (DLBCL), and suggests that CDK9 is a potential therapeutic target for DLBCL. Here, we firstly demonstrated that CDKI-73, a novel cyclin-dependent kinases (CDK) inhibitor, potently blocks CDK9, triggered apoptosis and dramatically repressed DLBCL cell growth owing to CDK9 inhibition. CDK9 inhibitors specifically elevated the trimethylation of H3K27, which we speculate was due to reduced expression of JMJD3/UTX. Considering the important role of the trimethylation of H3K27 in tumor progression, the synergistic effect of the combination therapy of CDK9 inhibitors with EZH2 inhibitors was investigated. EZH2 inhibitors reversed the upregulation of trimethylation of H3K27, and synergistically inhibited DLBCL and other solid tumors growth in vitro and in vivo These findings provide a rational basis for the application of CDK9 inhibitors in combination with EZH2 inhibitors in clinical trials.

Antioxidant protein peroxiredoxin 6 suppresses the vascular inflammation, oxidative stress and endothelial dysfunction in angiotensin II-induced endotheliocyte.

Cardiovascular disease (CVD) states are associated with endothelial dysfunction (ED) and increased production of ROS in endothelial cells. The present study aimed to explore the protective effects of antioxidant protein peroxiredoxin 6 (PRDX6) on angiotensin II (AngII)­induced human umbilical vein endothelial cell (HUVEC) dysfunction. To investigate cell viability, levels of inflammatory molecules and proteins were assayed using the CCK-8 assay and evaluated by ELISA and Western blot. NO and ROS levels were determined by Griess assay and the fluorescent probe DCFH-DA. Cell migration capacity was assessed by Transwell assay. AngII decreased cell viability and PRDX6, upregulated the expression levels of TNF-α, IL-6, IL-1ß, LDH and MDA, stimulated ROS production, and reduced NO synthase, the expressions of eNOS, MnSOD, ICAM-1, VCAM-1, and activated the MAPK family of signaling proteins. However, the stimulatory effects of AngII on HUVECs were remarkably suppressed by PRDX6. Furthermore, mercaptosuccinate (MS; PRDX6 inhibitor) had similar effects as AngII in aggravating HUVECs damage. Conversely, these adverse events caused by AngII and MS were obviously reversed by ML3404 and SP600125. The present study indicated that PRDX6 overexpression inactivated p38 MAPK and JNK pathway through decrease AngII-induced inflammation, oxidative stress and endothelial dysfunction leading to attenuation of endothelial cell damage.

Extended Range of Dipole-Dipole Interactions in Periodically Structured Photonic Media.

The interaction between quantum two-level systems is typically short range in free space and in most photonic environments. We show that diminishing momentum isosurfaces with equal frequencies can create a significantly extended range of interaction between distant quantum systems. The extended range is robust and does not rely on a specific location or orientation of the transition dipoles. A general relation between the interaction range and properties of the isosurface is described for structured photonic media. It provides a new way to mediate long-range quantum behavior.