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Ischemic diseases including myocardial infarction (MI) and limb ischemia are some of the greatest causes of morbidity and mortality worldwide. Cell therapy is a potential treatment but is usually limited by poor survival and retention of donor cells injected at the target site. Since much of the therapeutic effects occur via cell-secreted paracrine factors, including extracellular vesicles (EVs), we developed a porous material for cell encapsulation which would improve donor cell retention and survival, while allowing EV secretion. Human donor cardiac mesenchymal cells were used as a model therapeutic cell and the encapsulation system could sustain three-dimensional cell growth and secretion of therapeutic factors. Secretion of EVs and protective growth factors were increased by encapsulation, and secreted EVs had hypoxia-protective, pro-angiogenic activities in in vitro assays. In a mouse model of limb ischemia the implant improved angiogenesis and blood flow, and in an MI model the system preserved ejection fraction %. In both instances, the encapsulation system greatly extended donor cell retention and survival compared to directly injected cells. This system represents a promising therapy for ischemic diseases and could be adapted for treatment of other diseases in the future.

An unprecedented surge of COVID-19 cases in Taiwan in May 2021 led the government to implement strict nationwide control measures beginning May 15. During the surge, the government was able to bring the epidemic under control without a complete lockdown despite the cumulative case count reaching14,400 and780 deaths. We investigated the effectiveness of the public health and social measures instituted by the Taiwan government by quantifying the change in the effective reproduction number, which is a summary measure of the ability of the pathogen to spread through the population. The control measures that were instituted reduced the effective reproduction number from 2.0-3.3 to 0.6-0.7. This decrease was correlated with changes in mobility patterns in Taiwan, demonstrating that public compliance, active case finding, and contact tracing were effective measures in preventing further spread of the disease.

Background: The dysregulation of lipid metabolism plays an important role in the pathogenesis of Alzheimer’s disease (AD). Liver-type fatty acid-binding protein (L-FABP, also known as FABP1) is critical for fatty acid transport and may be involved in AD. Objective: To investigate whether the FABP1 level is altered in patients with AD, and its associations with levels of amyloid-β (Aβ) and tau in the plasma and cerebrospinal fluid (CSF). Methods: A cross-sectional study was conducted in a Chinese cohort consisting of 39 cognitively normal controls and 47 patients with AD. The levels of FABP1 in plasma, and Aβ and tau in CSF, were measured by enzyme-linked immunosorbent assay (ELISA). A single-molecule array (SIMOA) was used to detect plasma Aβ levels. Results: The level of plasma FABP1 was significantly elevated in the AD group (p = 0.0109). Further analysis showed a positive correlation of FABP1 with CSF total tau (t-tau) and phosphorylated tau (p-tau) levels. Besides, plasma FABP1/Aβ42 (AUC = 0.6794, p = 0.0071) and FABP1/t-tau (AUC = 0.7168, p = 0.0011) showed fair diagnostic efficacy for AD. When combined with other common AD biomarkers including plasma Aβ42, Aβ40, and t-tau, both FABP1/Aβ42 and FABP1/t-tau showed better diagnostic efficacy than using these biomarkers alone. Among all AUC analyses, the combination of plasma FABP1/t-tau and Aβ42 had the highest diagnostic value (AUC = 0.8075, p

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma and is a potentially curable disease. However, it is heterogenous, and the prognosis is poor if the tumor cells harbor fusions involving MYC and BCL2 or MYC and BCL6 (double-hit [DH] lymphoma), or fusions involving all three genes (triple-hit [TH] lymphoma). Fluorescence in situ hybridization is currently the gold standard for confirming the presence of DH/TH genotypes. However, the test is laborious and not readily available in some laboratories. Germinal center B (GCB) signatures and dual expression of MYC and BCL2 are commonly used as initial screening markers (traditional model) in clinical practice. Our study proposes immunohistochemical markers for more conveniently and accessibly screening DH/TH genotypes in DLBCL. We retrospectively reviewed the clinical and pathological parameters of patients with DLBCL. We assessed the proliferative index, apoptotic index, and tumor microenvironment (TME), with regard to T cells and CD11c(+) dendritic cells, in formalin-fixed paraffin-embedded tissue. We then generated a decision tree as a screening algorithm to predict DH/TH genotypes and employed decision curve analysis to demonstrate the superiority of this new model in prediction. We also assessed the prognostic significance of related parameters. Our study revealed that GCB subtypes, a Ki67 proliferative index higher than 70%, and BCL2 expression were significantly associated with DH/TH genotypes. Decreased CD11c(+) dendritic cells in the TME indicated additional risk. Our proposed screening algorithm outperformed a traditional model in screening for the DH/TH genotypes. In addition, decreased CD11c(+) dendritic cells in the DLBCL TME were an independent unfavorable prognosticator. In conclusion, we provide a convenient, well-performing model that predicts DH/TH genotypes in DLBCL. The prognostic significance of CD11c(+) dendritic cells in the TME might influence the classification and development of immunotherapy for DLBCL in the future.

Identifying patients with stage I non-small cell lung cancer (NSCLC) at increased risk of tumor recurrence following surgery remains a major challenge. The current study aimed to compare disease-free survival (DFS) rates after surgery between patients with clinically node-positive (cN+) and -negative (cN0) stage I NSCLC.Patients with pathological stage I resected NSCLC were identified from the lung cancer database of Changhua Christian Hospital in Taiwan. Patients with clinical N status 1 or 2 and pathological N status 0 were identified as the cN+/pN0 cohort, whereas others were identified as the cN0/pN0 cohort. Propensity score matching (PSM) was used to balance the baseline characteristics between both cohorts. Kaplan-Meier method and Cox proportional hazards model were used to evaluate DFS.From January 2010 to July 2019, 754 eligible patients were enrolled into the study, among whom 41 (5.4%) were cN+/pN0. The median follow-up time was 43.4 months. Before PSM, the 5-year DFS rate was 79.0% and 90.3% in cN+/pN0 and cN0/pN0 cohorts (log-rank test, p = 0.009), respectively. After a 1:4 PSM, multivariate analysis showed that the cN+/pN0 cohort still had a poorer DFS compared to the cN0/pN0 cohort in (hazard ratio, 3.17; p = 0.040).Among patients with stage I resected NSCLC, cN+ patients had a worse DFS compared to cN0 patients. Surgeons should therefore consider more aggressive adjuvant therapy or frequent follow-up in patients with surgically resected stage I NSCLC with cN+ status.

Background: The G protein-coupled receptor P2RY2 protein of the purinergic receptor family is involved in the pathogenesis of Alzheimer’s disease (AD). Naturally occurring antibodies against P2RY2 (NAbs-P2RY2) are present in human plasma, with their clinical relevance in AD unknown. Objective: To explore the alteration of NAbs-P2RY2 in AD patients and its associations with biomarkers and cognition of AD patients. Methods: The levels of naturally occurring antibodies against the four extracellular domains of P2RY2 (NAbs-P2RY2-1, NAbs-P2RY2-2, NAbs-P2RY2-3, and NAbs-P2RY2-4) were measured in the plasma of 55 AD patients, 28 non-AD dementia patients, and 70 cognitively normal participants. The correlations of autoantibody levels with cognitive scale scores, AD plasma biomarkers, and brain amyloid burden were examined. Results: NAbs-P2RY2-1, NAbs-P2RY2-3, and NAbs-P2RY2-4 were reduced in AD patients. Plasma levels of NAbs-P2RY2-2 and NAbs-P2RY2-3 levels were positively associated with cognitive and functional performances. Among these antibodies, plasma NAbs-P2RY2-2 levels were positively associated with plasma amyloid-β 42 levels. While plasma NAbs-P2RY2-3 levels were negatively associated with brain amyloid burden in AD patients. Conclusion: These findings indicate an alteration of humoral immunity against P2RY2 in AD patients. Further mechanistical investigations are needed to reveal the role of NAbs-P2RY2 in the pathogenesis of AD.

Fragment crystallizable (Fc) fusion is commonly used for extending the half-life of biotherapeutics such as cytokines. In this work, we studied the pharmacokinetics of Fc-fused interleukin-10 (IL-10) proteins that exhibited potent antitumor activity in mouse syngeneic tumor models. At pharmacologically active doses of ≥0.1 mg/kg, both mouse Fc-mouse IL-10 and human Fc-human IL-10, constructed as the C terminus of the Fc domain fused with IL-10 via a glycine-serine polypeptide linker, exhibited nonlinear pharmacokinetics after intravenous administration to mice at the doses of 0.05, 0.5, and 5 mg/kg. With a nominal dose ratio of 1:10:100; the ratio of the area under the curve for mouse Fc-mouse IL-10 and human Fc-human IL-10 was 1:181:1830 and 1:75:633, respectively. In contrast, recombinant mouse or human IL-10 proteins exhibited linear pharmacokinetics in mice. Compartmental analysis, using the Michaelis-Menten equation with the in vitro IL-10 receptor alpha binding affinity inputted as the K

Yuan Cheng,1,2,* Fushun Kou,1,2,* Xiaosi Zhang,1,2 Yi Dai,3 Lei Shi,2 Chune Xie,2 Xiaohong Li,2 Junxiang Li2 1Second Clinical Medical College, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2Department of Gastroenterology, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 3Department of Pharmacotherapy and Oriental Medicine, School of Pharmacy, Hyogo University of Health Sciences, Hyogo, Japan*These authors contributed equally to this workCorrespondence: Junxiang Li; Xiaohong Li, Department of Gastroenterology, Dongfang Hospital, Beijing University of Chinese Medicine, No. 6, 1st Section Fangxingyuan, Fangzhuang, Fengtai District, Beijing, 100078, People’s Republic of China, Email junxiangli1226@126.com; lxhktxz@163.comPurpose: Proton pump inhibitors, as the first-line drugs for treating gastroesophageal reflux disease (GERD), are unable to completely relieve patients’ symptoms and patients are prone to recurrence after prolonged drug withdrawal. Thus, it is crucial to find herbal medicines as a complementary and alternative treatment. Hewei Jiangni granule (HWJNG) is a classical Chinese medicinal formula with clinical therapeutic effects on GERD, but its pharmacological mechanism of action remains unclear. This study aimed to explore and then verify the pharmacological mechanisms of HWJNG in GERD therapy.Methods: A network pharmacology approach was applied to explore and then verify the pharmacological mechanisms of HWJNG in GERD therapy. The active ingredients of HWJNG, as well as therapeutic targets of GERD were acquired from specialized databases. The “herb-ingredient-gene-target” network for HWJNG in GERD treatment was built. The protein–protein interaction (PPI) network was constructed to screen the core coincident targets. Then, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. The core targets and signaling pathways associated with the anti-neurogenic inflammatory effect were partially verified via experiments in vivo at molecular level.Results: In total, 179 chemical ingredients in HWJNG and 298 intersection targets between GERD and HWJNG were selected from databases. A large proportion of core targets and top signaling pathways were involved in neurogenic inflammation. HWJNG significantly alleviated pathological injuries of esophagus and reversed dilated intracellular spaces. Additionally, HWJNG markedly inhibited the excessive release of inflammatory cytokines such as interleukin (IL)-1β, IL-6, tumor necrosis factor receptor (TNF-a), as well as regulated stimulation sensors including transient receptor potential vanilloid type 1 (TRPV1) and its related neuroinflammatory mediators in GERD mice.Conclusion: HWJNG is a promising therapeutic strategy for GERD treatment via regulation of multiple targets and pathways, its effects in alleviating neurogenic inflammation are especially acknowledged.Keywords: Hewei Jiangni granule, gastroesophageal reflux disease, network pharmacology, neurogenic inflammation

This network meta-analysis aimed to compare the efficacy and safety of intravenous (IV) hydralazine, oral nifedipine, and IV labetalol with different dosage regimens in the treatment of severe hypertension during pregnancy. A comprehensive literature search was performed on PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov for randomized controlled trials (RCTs) exploring the effects of hydralazine, nifedipine, and labetalol in the treatment of severe hypertension during pregnancy. A total of 21 RCTs with 2183 patients comparing 7 regimens (oral nifedipine 50,60,90 mg; hydralazine 15,25 mg; and labetalol 220,300 mg) were identified. Compared with IV labetalol 300 mg, nifedipine 50,60, and 90 mg significantly improved the successful treatment rate of severe hypertension during pregnancy, nifedipine 50 and 90 mg and IV hydralazine 25 mg required significantly fewer doses to achieve target blood pressure (BP), and nifedipine 50 mg took significantly shorter time to achieve target BP. Subgroup analysis showed that only nifedipine 50 mg tablets, not capsules, required a significantly shorter time and fewer doses to achieve target BP than IV labetalol 300 mg. Moreover, nifedipine 60,90 mg showed superior effectiveness than IV hydralazine 15,25 mg in the successful treatment rate of severe hypertension during pregnancy. SUCRA analysis suggested that nifedipine 50,60,90 mg as the better regimens with the lower rates of overall ADR and neonatal complications. These findings demonstrated the superiority of oral nifedipine 50,60,90 mg, especially oral nifedipine 50 mg tablets, in the treatment of severe hypertension during pregnancy than IV labetalol 300 mg, while oral nifedipine 60,90 mg also showed superiority in the successful treatment rate of severe hypertension during pregnancy than IV hydralazine 15,25 mg. However, the limitations of the underlying data indicate that future large-scale and rigorous RCTs are needed to confirm such findings.

KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) is highly immunosuppressive and resistant to targeted and immunotherapies. Among the different PDAC subtypes, basal-like mesenchymal PDAC, which is driven by allelic imbalance, increased gene dosage and subsequent high expression levels of oncogenic KRAS, shows the most aggressive phenotype and strongest therapy resistance. In the present study, we performed a systematic high-throughput combination drug screen and identified a synergistic interaction between the MEK inhibitor trametinib and the multi-kinase inhibitor nintedanib, which targets KRAS-directed oncogenic signaling in mesenchymal PDAC. This combination treatment induces cell-cycle arrest and cell death, and initiates a context-dependent remodeling of the immunosuppressive cancer cell secretome. Using a combination of single-cell RNA-sequencing, CRISPR screens and immunophenotyping, we show that this combination therapy promotes intratumor infiltration of cytotoxic and effector T cells, which sensitizes mesenchymal PDAC to PD-L1 immune checkpoint inhibition. Overall, our results open new avenues to target this aggressive and therapy-refractory mesenchymal PDAC subtype.

Prediction models with or without radiomic analysis for microvascular invasion (MVI) in hepatocellular carcinoma (HCC) have been reported, but the potential for model-predicted MVI in surgical planning is unclear. Therefore, we aimed to explore the effect of predicted MVI on early recurrence after anatomic resection (AR) and non-anatomic resection (NAR) to assist surgical strategies.Patients with a single HCC of 2-5 cm receiving curative resection were enrolled from 2 centers. Their data were used to develop (n = 230) and test (n = 219) two prediction models for MVI using clinical factors and preoperative computed tomography images. The two prediction models, clinico-radiologic model and clinico-radiologic-radiomic (CRR) model (clinico-radiologic variables + radiomic signature), were compared using the Delong test. Early recurrence based on model-predicted high-risk MVI was evaluated between AR (n = 118) and NAR (n = 85) via propensity score matching using patient data from another 2 centers for external validation.The CRR model showed higher area under the curve values (0.835-0.864 across development, test, and external validation) but no statistically significant improvement over the clinico-radiologic model (0.796-0.828). After propensity score matching, difference in 2-year recurrence between AR and NAR was found in the CRR model predicted high-risk MVI group (P = 0.005) but not in the clinico-radiologic model predicted high-risk MVI group (P = 0.31).The prediction model incorporating radiomics provided an accurate preoperative estimation of MVI, showing the potential for choosing the more appropriate surgical procedure between AR and NAR.

The global "myopia boom" has raised significant international concerns. Despite a higher myopia prevalence in Asia, previous large-scale genome-wide association studies (GWASs) were mostly based on European descendants. Here, we report a GWAS of spherical equivalent (SE) in 1852 Chinese Han individuals with extreme SE from Guangzhou (631 -6.00D and 574 0.00D) and Wenzhou (593 -6.00D and 54 -1.75D), followed by a replication study in two independent cohorts with totaling 3538 East Asian individuals. The discovery GWAS and meta-analysis identify three novel loci, which show genome-wide significant associations with SE, including 1q25.2 FAM163A, 10p11.22 NRP1/PRAD3, and 10p11.21 ANKRD30A/MTRNR2L7, together explaining 3.34% of SE variance. 10p11.21 is successfully replicated. The allele frequencies of all three loci show significant differences between major continental groups (P 0.001). The SE reducing (more myopic) allele of rs10913877 (1q25.2 FAM163A) demonstrates the highest frequency in East Asians and much lower frequencies in Europeans and Africans (EAS = 0.60, EUR = 0.20, and AFR = 0.18). The gene-based analysis additionally identifies three novel genes associated with SE, including EI24, LHX5, and ARPP19. These results provide new insights into myopia pathogenesis and indicate the role of genetic heterogeneity in myopia epidemiology among different ethnicities.

Introduction: Renal interstitial inflammation often presents in immunoglobulin A nephropathy (IgAN), but its predictive role in kidney disease progression remains controversial. Methods: This retrospective two-center cohort study included 1,420 adult IgAN patients between January 2003 and May 2018 followed for a median of approximately 7 years at two Chinese hospitals. The predictor was renal interstitial inflammation within the total cortical interstitium (none/mild [0–25%], moderate [26–50%], or severe [>50%]). For the further propensity score matching analyses, the participants with moderate and severe level of interstitial inflammation were pooled to match those with none/mild level of interstitial inflammation. The outcomes included the rate of kidney function decline, and the composite kidney endpoint event defined as a >40% reduction in the estimated glomerular filtration rate, end-stage kidney disease. Linear regression and Cox proportional hazards regression analyses were used to examine the association between interstitial inflammation and the outcomes. The predictive performance of the model also assessed using multivariate logistic regression analyses with the receiver operating characteristic curve analysis. Reclassification was assessed using the continuous net reclassification improvement and integrated discrimination improvement adapted for censoring for the assessment of the model with or without interstitial inflammation. Results: For the check of reproducibility, the kappa statistic was 0.71, and intraclass correlation coefficient was 0.77. After adjustment for relating covariates, a higher level of interstitial inflammation was associated with a faster rate of kidney function decline (eGFR slope [mL/min/1.73 m2] of 1.34 [95% CI: −2.56 to 5.23], 3.50 [95% CI: −0.40 to 7.40], and 7.52 [95% CI: 3.02 to 12.01]) in the patients with none/mild, moderate, and severe interstitial inflammation, respectively, in the multivariable linear regression models and with an increased risk of kidney disease progression (HR for moderate vs. none/mild, 1.85; 95% CI: 1.10–3.13; HR for severe vs. none/mild, 2.95; 95% CI: 1.52–5.73) in the multivariable Cox proportional hazards models. Analyses in the propensity score-matched cohort, subgroups, and the sensitive analyses yielded consistent results. The receiver operating curves indicated a higher area under the curve of 0.83 in the model with interstitial inflammation compared with 0.81 in that without interstitial inflammation. In addition, incorporating interstitial inflammation into the International IgAN Risk Prediction Tool improved the diagnostic power of the algorithm to predict risk of progression. Conclusion: Interstitial inflammation is a reproducible pathologic parameter that may be adopted as a predictor for kidney disease progression in patients with IgAN.

Sorafenib is a first-line molecular-target drug for advanced hepatocellular carcinoma (HCC), and reducing sorafenib resistance is an important issue to be resolved for the clinical treatment of HCC. In the current study, we identified that ABCC5 is a critical regulator and a promising therapeutic target of acquired sorafenib resistance in human hepatocellular carcinoma cells. The expression of ABCC5 was dramatically induced in sorafenib-resistant HCC cells and was remarkably associated with poor clinical prognoses. The down-regulation of ABCC5 expression could significantly reduce the resistance of sorafenib to HCC cells. Importantly, activation of PI3K/AKT/NRF2 axis was essential for sorafenib to induce ABCC5 expression. ABCC5 increased intracellular glutathione (GSH) and attenuated lipid peroxidation accumulation by stabilizing SLC7A11 protein, which inhibited ferroptosis. Additionally, the inhibition of ABCC5 enhanced the anti-cancer activity of sorafenib in vitro and in vivo. These findings demonstrate a novel molecular mechanism of acquired sorafenib resistance and also suggest that ABCC5 is a new regulator of ferroptosis in HCC cells.

Background\ud The use of accurate prediction tools and early intervention are important for addressing severe coronavirus disease 2019 (COVID-19). However, the prediction models for severe COVID-19 available to date are subject to various biases. This study aimed to construct a nomogram to provide accurate, personalized predictions of the risk of severe COVID-19.\ud \ud Methods\ud This study was based on a large, multicenter retrospective derivation cohort and a validation cohort. The derivation cohort consisted of 496 patients from Jiangsu Province, China, between January 10, 2020, and March 15, 2020, and the validation cohort contained 105 patients from Huangshi, Hunan Province, China, between January 21, 2020, and February 29, 2020. A nomogram was developed with the selected predictors of severe COVID-19, which were identified by univariate and multivariate logistic regression analyses. We evaluated the discrimination of the nomogram with the area under the receiver operating characteristic curve (AUC) and the calibration of the nomogram with calibration plots and Hosmer-Lemeshow tests.\ud \ud Results\ud Three predictors, namely, age, lymphocyte count, and pulmonary opacity score, were selected to develop the nomogram. The nomogram exhibited good discrimination (AUC 0.93, 95% confidence interval [CI] 0.90–0.96 in the derivation cohort; AUC 0.85, 95% CI 0.76–0.93 in the validation cohort) and satisfactory agreement.\ud \ud Conclusions\ud The nomogram was a reliable tool for assessing the probability of severe COVID-19 and may facilitate clinicians stratifying patients and providing early and optimal therapies.

Background For lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) sensitive mutation and synchronous brain metastasis (syn‐BM), when and how to apply radiotherapy (RT) during first‐line tyrosine kinase inhibitor (TKI) treatment remains debatable. Methods From a real‐world multicenter database, EGFR‐mutant patients with syn‐BM diagnosed between 2010–2020 and treated with first‐line TKIs were enrolled and divided into upfront TKI + RT and upfront TKI groups. Median intracranial progression‐free survival (mIC‐PFS), median overall survival (mOS), and their risk factors were estimated. Results There were 60 and 186 patients in the upfront TKI + RT group and upfront TKI group, respectively. Their mIC‐PFS were 28.9 months (m) and 17.5 m (p = 0.023), and mOS were 42.7 m and 40.1 m (p = 0.51). Upfront brain RT improved mIC‐PFS in patients ≤60‐year‐old (p = 0.035), with symptomatic BM (p = 0.002), and treated with first‐generation TKIs (p = 0.012). There was no significant difference in mOS in any subgroup. Upfront brain stereotactic radiosurgery (SRS) showed a trend of better mIC‐PFS and mOS. mIC‐PFS was independently correlated with symptomatic BM (HR = 1.54, p = 0.030), EGFR L858R mutation (HR = 1.57, p = 0.019), and upfront brain RT (HR = 0.47, p = 0.001). mOS was independently correlated with being female (HR = 0.54, p = 0.007), ECOG 3–4 (HR = 10.47, p 3 (HR = 2.19, p = 0.002), and third‐generation TKI (HR = 0.54, p = 0.044) or antiangiogenic drugs (HR = 0.11, p = 0.005) as first/second‐line therapy. Conclusions Upfront brain RT based on first‐line EGFR‐TKI might improve IC‐PFS but not OS in EGFR‐mutant lung adenocarcinoma patients, indicating potential survival benefit from brain SRS and early application of drugs with higher intracranial activity., To our best knowledge, this is the most extensive multicenter real‐world study (Fig.1) on epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma with synchronous brain metastasis (BM) and treated with first‐line EGFR targeting tyrosine kinase inhibitor (TKI). On the basis of first‐line EGFR‐TKI therapy, additional upfront brain radiation therapy (RT) could improve intracranial progression free survival (PFS) (Fig.2a), particularly for patients with BM symptom and 1st‐generation EGFR‐TKI (Fig.4a). With no OS improvement (Fig.2d, Fig.3b, Fig.4b), upfront whole‐brain irradiation could be deferred during the first‐line EGFR‐TKI treatment; however, upfront brain stereotactic radio‐surgery (SRS) might have potential OS benefit (Fig.3d).

Recombinant tissue-type plasminogen activator (rtPA) is the clot lysis drug approved for clinical use, and is characterised by a short half-life and substantial inactivation by plasminogen activator inhibitor-1 (PAI-1). We previously discovered that a tPA mutation (A419Y) at the protease domain led to enhanced fibrinolysis activity. In the present study, we studied the mechanism of such mutation in enhancing the proteolytic activity, and whether such enhancement persists in reteplase, an United States Food and Drug Administration-approved tPA truncated variant. We constructed and expressed a series of reteplase-based mutants, including rPAG (glycosylated rPA), rPAG -Y (with A419Y mutant at rPAG ), rPAG -A4 (tetra-alanine mutation at 37-loop of rPAG ), and rPAG -A4/Y (with both) and evaluated their plasminogen activation and PAI-1 resistance. Surface plasmon resonance analysis showed that the rPAG had fibrin affinity comparable to full-length tPA. Moreover, rPAG -Y had 8·5-fold higher plasminogen activation and stronger tolerance to PAI-1 compared to rPAG . We also found that the mutations containing tetra-alanine (rPAG -A4 and rPAG -A4/Y) had dramatically reduced plasminogen activation and impaired clot lysis. In a pulmonary embolism murine model, rPAG -Y displayed a more efficient thrombolytic effect than rPAG . These results identified a novel mutant reteplase variant of tPA with increased fibrinolytic activity, laying the foundation for the development of a new potent fibrinolytic agent.

Nicotinamide mononucleotide (NMN) or Nicotinamide-1-ium-1-β-D-ribofuranoside 5'-phosphate is a nucleotide that can be converted into nicotinamide adenine dinucleotide (NAD) in human cells. NMN has recently attracted great attention because of its potential as an anti-aging drug, leading to great efforts for its effective manufacture. The chemical synthesis of NMN is a challenging task since it is an isomeric compound with a complicated structure. The majority of biological synthetic routes for NMN is through the intermediate phosphoribosyl diphosphate (PRPP), which is further converted to NMN by nicotinamide phosphoribosyltransferase (Nampt). There are various routes for the synthesis of PRPP from simple starting materials such as ribose, adenosine, and xylose, but all of these require the expensive phosphate donor adenosine triphosphate (ATP). Thus, an ATP regeneration system can be included, leading to diminished ATP consumption during the catalytic process. The regulations of enzymes that are not directly involved in the synthesis of NMN are also critical for the production of NMN. The aim of this review is to present an overview of the biological production of NMN with respect to the critical enzymes, reaction conditions, and productivity.

BackgroundTo investigate the renal dysfunction in patients with hyperuricemia by employing a multiparametric MRI protocol, consisting of quantitative water molecule diffusion, microstructure, microscopic perfusion, and oxygenation measurements in kidneys.Materials and methodsA total of 48 patients with hyperuricemia (HU) and 22 age-matched healthy control subjects (HC) were enrolled in the study. For each participant, three different functional magnetic resonance imaging (fMRI) sequences were acquired and analyzed, including intravoxel incoherent motion imaging (IVIM), diffusion tensor imaging (DTI), and blood-oxygen-level-dependent MRI (BOLD). Thereafter, an independent two-samplet-test was applied to discover the significant differences of MRI indices between the hyperuricemia (HU) and HC groups, and the specific potential biomarkers between two subgroups of HU group (asymptomatic hyperuricemia group (AH) and gouty arthritis group (GA)). Further, multivariate logistic regression analyses were performed to classify the AH from the GA group using the MRI indices with significant between-group differences. The receiver operating characteristic (ROC) curve was plotted, and the area under the ROC curve (AUC) was calculated to assess the performance of each MR index for differentiation between the AH and GA groups.ResultsTen parametric values of the HU group were significantly lower than those of the HC group among the 14 fMRI parameters (P *, andfvalues and medullary D and R2*values had significant differences between the AH and GA groups (P fvalues and medullary R2* value gave the best diagnostic efficacy, yielding an AUC, sensitivity, and specificity of 0.967 ± 0.022, 91.67%, and 95.83%, respectively.ConclusionsA multiparametric MR analysis plays an important role in the evaluation of renal dysfunction in hyperuricemia from multiple perspectives. It could be a promising method for noninvasive detection and identification of the early-stage renal damage induced by hyperuricemia.

Among the lymphatic system in the human body, the spleen is the most extensive one and has hematopoietic, hemofiltration, blood storage, and immune functions. As a new method of preserving the spleen, laparoscopic partial splenectomy (LPS) has been increasingly applied in clinical practice with people's deeper insights into minimally invasive treatment and the development of technical equipment. Compared with conventional open splenectomy, LPS can preserve normal spleen tissue as much as possible, decrease the occurrence of complications after total splenectomy, and reduce postoperative hospital stay. The bipolar radiofrequency excision hemostatic device used for LPS can solidify the splenic tissue and close the small blood vessels, which reduces the hemorrhage of the spleen cross-section and clears the operative field, thus achieving the ideal effect of "bloodless partial splenectomy". Therefore, under the premise of strictly mastering the indications and fully understanding the vascular anatomy of the spleen, the application of the bipolar radiofrequency excision hemostatic device in LPS is worthy of clinical promotion.

BACKGROUND Encrustation of the ureteral stent is a common complication that occurs after a prolonged indwelling duration. Other identified risk factors in the literature include urinary sepsis, chemotherapy, chronic renal failure, metabolic or congenital abnormalities, and nephrolithiasis. This report presents the case of a 39-year-old man with nephrolithiasis and fragmentation of a calcified right ureteric stent that required ureteroscopy and laser lithotripsy. CASE REPORT A 39-year-old man was initially admitted for ureteroscopy and laser lithotripsy after the diagnosis of bilateral urolithiasis. Ureteral stents were placed. One postoperative month later, the patient returned for follow-up and stent withdrawal. Follow-up computed tomography revealed a normal left kidney, intact bilateral ureteral stents, and residual right renal stones. However, an attempt to completely withdraw the stent failed and the patient had to undergo a secondary right ureteroscopy with laser lithotripsy. The fragmented proximal section of a calcified right ureteral stent with occluded lumen was found intraoperatively and sent for product analyses. After successful reintervention, the patient had a new right ureteral stent placed, which was successfully withdrawn during his next follow-up. CONCLUSIONS Ureteral stent encrustation may occur earlier than anticipated, possibly due to underlying patient risk factors. Complications, such as fragmentation of the ureteral stent, may occur during withdrawal. Physicians should be aware of any predictors for early ureteral stent encrustation to prevent unnecessary reintervention.

Few studies have simultaneously examined the influence of clinical characteristics of patients with pneumonia, the vancomycin pharmacokinetic/pharmacodynamic (PK/PD) index, and the phenotypic and genetic characteristics of methicillin-resistant Staphylococcus aureus (MRSA) strains. We assessed risk factors for vancomycin failure in patients with MRSA pneumonia by analyzing these influences in a prospective multicenter study.

Endometrial cancer (EC) is a common female reproductive tumor worldwide. Nonetheless, the pathogenesis of EC still remains ambiguous and associated epigenetic mechanism still to be explored. The goal of this study is to investigate whether gene methylation signature is associated with overall survival (OS) for EC patients. In this study, a 10-gene methylation risk model was built and the OS in high- and low-risk groups was significant different. The area under the ROC curve (AUC) of this model was 0.856 at 5 years survival. The nomogram could accurately predict the OS in EC patients, with concordance index and AUC at 5 year survival reached 0.796 and 0.792, respectively. Furthermore, we verified the nomogram with 24 patients in our center and the Kaplan-Meier survival curve also proved to be significantly different (p 0.01). WGCNA revealed a key gene group for the model and further bioinformatics analysis indicated 6 genes as the hub genes in the module. Knockdown of MMP12 inhibited the proliferation, invasion and metastasis of EC cells. After all, a methylation signature and a nomogram based on this signature were constructed, and they could both predict survival in patients with EC. Moreover, WGCNA model identified MMP12 as a potential target for the treatment of EC.

This study investigated associations between chest computed tomography (CT) pulmonary opacity score on admission and clinical features and outcomes in COVID-19 patients. The retrospective multi-center cohort study included 496 COVID-19 patients in Jiangsu province, China diagnosed as of March 15, 2020. Patients were divided into four groups based on the quartile of pulmonary opacity score: ≤ 5%, 6-20%, 21-40% and 41% +. CT pulmonary opacity score was independently associated with age, single onset, fever, cough, peripheral capillary oxygen saturation, lymphocyte count, platelet count, albumin level, C-reactive protein (CRP) level and fibrinogen level on admission. Patients with score ≥ 41% had a dramatic increased risk of severe or critical illness [odds ratio (OR), 15.58, 95% confidence interval (CI) 3.82-63.53), intensive care unit (ICU)] admission (OR, 6.26, 95% CI 2.15-18.23), respiratory failure (OR, 19.49, 95% CI 4.55-83.40), and a prolonged hospital stay (coefficient, 2.59, 95% CI 0.46-4.72) compared to those with score ≤ 5%. CT pulmonary opacity score on admission, especially when ≥ 41%, was closely related to some clinical characteristics and was an independent predictor of disease severity, ICU admission, respiratory failure and long hospital stay in patients with COVID-19.

Towards repairing bone defects, calcium sulfate and calcium phosphate cement have been recognized as promising bone grafts. However, the current bone cements are generally lack of proper porosity for cell migration and new tissue formation. On the other hand, porous scaffold cannot be delivered by injection, which limits its use its clinical use. Herein, we develop a novel tricalcium phosphate/calcium sulfate granule to overcome the limitations of injectable cements and traditional scaffolds. The biocompatible granule underwent in situ self-setting to form scaffold with porous structure after injection. It contributes to calcium deposition and upregulation of osteogenic genes of mesenchymal stem cells in a time-dependent manner. Within three months, cavitary bone defects of distal rabbit femurs implanted the granules exhibited better bone formation than those with those implanted with autologous bone.

To explore the therapeutic effects of biofeedback in the treatment of faecal incontinence (FI) after surgery for anorectal malformation (ARM).Clinical data were collected from paediatric patients for postoperative biofeedback due to FI caused by ARM between May 2017 and November 2021. The data included the duration of symptoms, the integrity of the anal sphincter, anorectal manometry parameters, and FI scores. These patients were divided into the low ARM group (group A) and the high ARM group (group B).A total of 45 paediatric patients were enrolled in the study. There were 28 cases in group A and 17 cases in group B. The differences in age, gender, and body weight were not statistically significant between the two groups (Biofeedback plays a positive role in the treatment of FI in paediatric patients following surgery for ARM. Symptom duration and anal sphincter integrity were found to be the main factors influencing the therapeutic effect of biofeedback.

ObjectiveIn an era of increasingly expensive intensive care costs, it is essential to evaluate early whether the length of stay (LOS) in the intensive care unit (ICU) of obesity patients with sepsis will be prolonged. On the one hand, it can reduce costs; on the other hand, it can reduce nosocomial infection. Therefore, this study aimed to verify whether ICU prolonged LOS was significantly associated with poor prognosis poor in obesity patients with sepsis and develop a simple prediction model to personalize the risk of ICU prolonged LOS for obesity patients with sepsis.MethodIn total, 14,483 patients from the eICU Collaborative Research Database were randomized to the training set (3,606 patients) and validation set (1,600 patients). The potential predictors of ICU prolonged LOS among various factors were identified using logistic regression analysis. For internal and external validation, a nomogram was developed and performed.ResultsICU prolonged LOS was defined as the third quartile of ICU LOS or more for all sepsis patients and demonstrated to be significantly associated with the mortality in ICU by logistic regression analysis. When entering the ICU, seven independent risk factors were identified: maximum white blood cell, minimum white blood cell, use of ventilation, Glasgow Coma Scale, minimum albumin, maximum respiratory rate, and minimum red blood cell distribution width. In the internal validation set, the area under the curve was 0.73, while in the external validation set, it was 0.78. The calibration curves showed that this model predicted probability due to actually observed probability. Furthermore, the decision curve analysis and clinical impact curve showed that the nomogram had a high clinical net benefit.ConclusionIn obesity patients with sepsis, we created a novel nomogram to predict the risk of ICU prolonged LOS. This prediction model is accurate and reliable, and it can assist patients and clinicians in determining prognosis and making clinical decisions.

Background: In Taiwan, services provided by patients’ peers in the mental health care system are still lacking. Therefore, this study aimed to develop a community setting model by a training program for severe mental illness (SMI) patients’ peers that also have SMI in Taiwan. Method: This training program comprised of 13-h lectures, 15-h practice classes, and an eight-week internship. In 2018 and 2019, the trainees provided one-to-one services to service users with SMI during the internship at a halfway house. The satisfaction and outcomes among all participants were measured in this training course. Results: The total mean satisfaction score in the training course for trainees (10 items, n = 13) and internship services for service users (12 items, n = 29) were 4.7 ± 0.4 and 4.6 ± 0.5, respectively. Among the trainees, 11 demonstrated improved Brief Psychiatric Rating Scale-18 (BPRS-18), Chinese Health Questionnaire-12 (CHQ-12), and Global Assessment of Functioning (GAF) scores after the whole training course. Among the 29 service users, their scores in the BPRS-18 and CHQ-12 decreased, whereas their scores in the GAF increased significantly under the internship service. Conclusion: In this pilot study, the trainees and service users who received internship services felt satisfied. The service providers and users with SMI both showed better clinical outcomes.

Data from previous studies of the MVC-COV1901 vaccine, a subunit vaccine against SARS-CoV-2 based on the stable prefusion spike protein (S-2P) adjuvanted with CpG 1018 adjuvant and aluminum hydroxide, suggest that the vaccine is generally safe and elicits a good immune response in healthy adults and adolescents. By comparing with AZD1222, this study adds to the findings from previous trials and further evaluates the breadth of protection offered by MVC-COV1901.In this phase 3, parallel group, randomized, double-blind, active-controlled trial conducted in 2 sites in Paraguay, we assigned adults aged 18-91 years in a 1:1 ratio to receive intramuscular doses of MVC-COV1901 or AZD1222 administered as scheduled in the clinical trial. Serum samples were collected on the day of vaccination and 14 days after the second dose. Primary and secondary safety and immunogenicity endpoints were assessed. In addition, other outcomes investigated were cross-reactive immunity against the Omicron strain and the induction of IgG subclasses.A total of 1,030 participants underwent randomization. Safety data was derived from this set while primary immunogenicity data involved a per-protocol immunogenicity (PPI) subset including 225 participants. Among the participants, 58% are seropositive at baseline. When compared against AZD1222, MVC-COV1901 exhibited superiority in terms of neutralizing antibody titers and non-inferiority in terms of seroconversion rates. Reactogenicity was generally mild and no serious adverse event was attributable to MVC-COV1901. Both vaccines have a Th1-biased response predominated by the production of IgG1 and IgG3 subclasses. Omicron-neutralizing titers were 44.5 times lower compared to wildtype-neutralizing titers among seronegative individuals at baseline. This fold-reduction was 3.0 times among the seropositive.Safety and immunogenicity data of MVC-COV1901 from the study in Paraguay confirm previous results. The previous infection coupled with vaccination of this vaccine may offer protection against the Omicron strain though its durability is still unknown.

Temozolomide (TMZ) is a chemotherapeutic agent that has been the first-line standard of care for the aggressive brain cancer glioblastoma (GBM) since 2005. Although initially beneficial, TMZ resistance is universal and second-line interventions are an unmet clinical need. Here, we took advantage of the known mechanism of action of TMZ to target guanines (G) and investigated G-rich G-quadruplex (G4) and splice site changes that occur upon TMZ resistance. We report that TMZ-resistant GBM has guanine mutations that disrupt the G-rich DNA G4s and splice sites that lead to deregulated alternative splicing. These alterations create vulnerabilities, which are selectively targeted by either the G4-stabilizing drug TMPyP4 or a novel splicing kinase inhibitor of cdc2-like kinase. Last, we show that the G4 and RNA binding protein EWSR1 aggregates in the cytoplasm in TMZ-resistant GBM cells and patient samples. Together, our findings provide insight into targetable vulnerabilities of TMZ-resistant GBM and present cytoplasmic EWSR1 as a putative biomarker.

Early recognition of adult-onset immunodeficiency associated with neutralizing anti-interferon gamma autoantibodies (anti-IFNγ Abs) remains difficult, and misdiagnoses have been reported. Although febrile lymphadenopathy is among the most common initial manifestations of this disorder, no comprehensive clinicopathologic analysis of lymphadenopathy in patients with anti-IFNγ Abs has been reported. Here, we describe 26 lymph node biopsy specimens from 16 patients. All patients exhibited concurrent disseminated nontuberculous mycobacterial infections, and 31% received a tentative diagnosis of lymphoma at initial presentation. We found 3 distinct histomorphologic patterns: well-formed granuloma (46%), suppurative inflammation or loose histiocytic aggregates (31%), and lymphoproliferative disorder (LPD, 23%). The latter shared some of the features of malignant T-cell lymphoma, IgG4-related disease, and multicentric Castleman disease. Half of the specimens with LPD had monoclonal T cells, and 33.3% were indistinguishable from angioimmunoblastic T-cell lymphoma as per current diagnostic criteria. All lymphadenopathy with LPD features regressed with antibiotics without administration of cytotoxic chemotherapy or immunotherapy. The median follow-up time was 4.3 years. Our study highlights the substantial challenge of distinguishing between lymphoma and other benign lymphadenopathy in the setting of neutralizing anti-IFNγ Abs. Increased vigilance and multidisciplinary discussion among clinicians and pathologists are required to achieve the most appropriate diagnosis and management.

Increasing proofs have declared that liver cancer stem cells (CSCs) are the main contributors to tumor initiation, metastasis, therapy resistance, and recurrence of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying CSCs regulation remain largely unclear. Recently, PCNA-associated factor (PAF) was identified to play a key role in maintaining breast cancer cell stemness, but its role in liver cancer stem cells has not been declared yet. Herein, we found that both mRNA and protein expression levels of PAF were significantly higher in HCC tissues and cell lines than normal controls. CSC-enriched hepatoma spheres displayed an increase in PAF expression compared to monolayer-cultured cells. Both loss-of-function and gain-of-function experiments revealed that PAF enhanced sphere formation and the percentage of CD133(+) or EpCAM(+) cells in HCCLM3 and Huh7 cells. In the xenograft HCC tumor model, tumor initiation rates and tumor growth were suppressed by knockdown of PAF. Mechanistically, PAF can amplify the self-renewal of liver CSCs by activating β-catenin signaling. Taken together, our results demonstrate that PAF plays a crucial role in maintaining the hepatoma cell stemness by β-catenin signaling. Abbreviations: CSCs: cancer stem cells; HCC: hepatocellular carcinoma; PAF: pCNA-associated factor.

Background Side effects of long-term acid suppression have increased the scholars’ interest in nonpharmacologic intervention. Aims We summarized an umbrella review of the association between environmental factors and gastroesophageal reflux disease (GERD) and assessed their credibility. Methods We appraised systematic reviews and meta-analyses. For each meta-analysis, we considered the effect size, 95% confidence interval, the heterogeneity, small-study effects, P-value for excess significance and largest study significant, then we graded the evidence according to Assessment of Multiple Systematic Reviews and the GRADE assessment. Results 23 publications met the inclusion criteria (13 meta-analyses and 10 systematic reviews), which evaluated 24 environmental factors. Among observational studies, we identified 7 risk factors: overweight/obesity [GERD/erosive esophagitis (EE)/GERD symptom], central adiposity [EE], smoking [GERD], alcohol [GERD/EE/non-erosive reflux disease (NERD)], NSAID [GERD], coffee [EE], Helicobacter pylori eradication [EE], and 1 protective factor: physical activity [GERD], this was based on a suggestive evidence of credibility. Across intervention studies, we identified 1 risk factor-Helicobacter pylori eradication [GERD] and 1 protective factor-breathing exercises [GERD], evidence for both was low grade. Conclusions We found varying levels of evidence for different environmental factors of GERD. None of them was proven to be convincing or highly recommended.

Objective Through this study, we aimed to evaluate the efficacy and safety of the intraoral negative air pressure device (iNAP) in patients with moderate to severe obstructive sleep apnea (OSA) in Taiwan. Design Crossover and evaluator-blind, self-control design. Setting Academic medical center. Patients A total of 35 patients provided their consent to participate in this study; however, only 34 patients (30 men [87.5%] and four women [12.50%]) were eligible and randomized to the Clinical Cohort and Safety Cohort. The mean age of the 32 evaluable patients (PE cohort) was 47.4 ± 11.2 years, and their mean BMI was 26.5 ± 3.2 kg/m2. Measurements and results The clinical response rate was 75% (24/32 patients) comparing the treatment polysomnography values to the baseline values. The mean (±standard deviation) baseline apnea-hypopnea index was 32.0 ± 11.3 events/h, which decreased significantly to 8.7 ± 9.4 events/h. Mo medical device-related adverse event or serious adverse event occurred during the study period. Conclusions Compared with the previous oral pressure therapy device, the iNAP treated approximately three-fourths of the patients with OSA and had a superior comfort and safety profile. Thus, the iNAP device could be an alternative treatment solution for patients with moderate to severe OSA.

Immune checkpoint inhibitors (ICIs) have emerged as promising therapies for the treatment of cancer. However, existing ICIs, namely PD-(L)1 and CTLA-4 inhibitors, generate durable responses only in a subset of patients. TIGIT is a co-inhibitory receptor and member of the DNAM-1 family of immune modulating proteins. We evaluated the prevalence of TIGIT and its cognate ligand, PVR (CD155), in human cancers by assessing their expression in a large set of solid tumors. TIGIT is expressed on CD4+ and CD8+ TILs and is upregulated in tumors compared to normal tissues. PVR is expressed on tumor cells and tumor-associated macrophages from multiple solid tumors. We explored the therapeutic potential of targeting TIGIT by generating COM902, a fully human anti-TIGIT hinge-stabilized IgG4 monoclonal antibody that binds specifically to human, cynomolgus monkey, and mouse TIGIT, and disrupts the binding of TIGIT with PVR. COM902, either alone or in combination with a PVRIG (COM701) or PD-1 inhibitor, enhances antigen-specific human T cell responses in-vitro. In-vivo, a mouse chimeric version of COM902 in combination with an anti-PVRIG or anti-PD-L1 antibody inhibited tumor growth and increased survival in two syngeneic mouse tumor models. In summary, COM902 enhances anti-tumor immune responses and is a promising candidate for the treatment of advanced malignancies.

Establish patient-derived tumor xenograft (PDTX) from advanced GICs and assess the clinical value and applicability of PDTX for the treatment of advanced gastrointestinal cancers. Patients with advanced GICs were enrolled in a registered multi-center clinical study (ChiCTR-OOC-17012731). The performance of PDTX was evaluated by analyzing factors that affect the engraftment rate, comparing the histological consistency between primary tumors and tumorgrafts, examining the concordance between the drug effectiveness in PDTXs and clinical responses, and identifying genetic variants and other factors associated with prognosis. Thirty-three patients were enrolled in the study with the engraftment rate of 75.8% (25/33). The success of engraftment was independent of age, cancer types, pathological stages of tumors, and particularly sampling methods. Tumorgrafts retained the same histopathological characteristics as primary tumors. Forty-nine regimens involving 28 drugs were tested in seventeen tumorgrafts. The median time for drug testing was 134.5 days. Follow-up information was obtained about 10 regimens from 9 patients. The concordance of drug effectiveness between PDTXs and clinical responses was 100%. The tumor mutation burden (TMB) was correlated with the effectiveness of single drug regimens, while the outgrowth time of tumorgrafts was associated with the effectiveness of combined regimens. The engraftment rate in advanced GICs was higher than that of other cancers and meets the acceptable standard for applying personalized therapeutic strategies. Tumorgrafts from PDTX kept attributes of the primary tumor. Predictions from PDTX modeling closely agreed with clinical drug responses. PDTX may already be clinically applicable for personalized medication in advanced GICs.

Objectives: We aimed to investigate the relationship between obstructive sleep apnea (OSA) risk and respiratory inflammation evaluated by the exhaled breath condensate (EBC) interleukin-6 (IL-6) an...

Background Drug-resistance and severe side effects of chemotherapeutic agents result in unsatisfied survival of patients with lung cancer. CXCLs/CXCR2 axis plays an important role in progression of cancer including lung cancer. However, the specific anti-cancer mechanism of targeting CXCR2 remains unclear. Methods Immunohistochemical analysis of CXCR2 was performed on the microarray of tumor tissues of clinical lung adenocarcinoma and lung squamous cell carcinoma patients. CCK8 test, TUNEL immunofluorescence staining, PI-Annexin V staining, β-galactosidase staining, and Western blot were used to verify the role of CXCR2 in vitro. Animal models of tail vein and subcutaneous injection were applied to investigate the therapeutic role of targeting CXCR2. Flow cytometry, qRT-PCR, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry analysis were performed for further mechanistic investigation. Results The expression of CXCR2 was elevated in both human lung cancer stroma and tumor cells, which was associated with patients’ prognosis. Inhibition of CXCR2 promoted apoptosis, senescence, epithelial-to-mesenchymal transition (EMT), and anti-proliferation of lung cancer cells. In vivo study showed that tumor-associated neutrophils (TANs) were significantly infiltrate into tumor tissues of mouse model, with up-regulated CXCLs/CXCR2 signaling and suppressive molecules, including Arg-1 and TGF-β. SB225002, a selective inhibitor of CXCR2 showed promising therapeutic effect, and significantly reduced infiltration of neutrophils and enhanced anti-tumor T cell activity via promoting CD8+ T cell activation. Meanwhile, blockade of CXCR2 could enhance therapeutic effect of cisplatin via regulation of neutrophils infiltration. Conclusions Our finds verify the therapeutic effects of targeting CXCR2 in lung cancer and uncover the potential mechanism for the increased sensitivity to chemotherapeutic agents by antagonists of CXCR2.

Activated EGFR signalling drives tumorigenicity in 50% of glioblastoma (GBM). However, EGFR-targeting therapy has proven ineffective in treating patients with GBM, indicating that there is redundant EGFR activation. Circular RNAs are covalently closed RNA transcripts that are involved in various physiological and pathological processes. Herein, we report an additional activation mechanism of EGFR signalling in GBM by an undescribed secretory E-cadherin protein variant (C-E-Cad) encoded by a circular E-cadherin (circ-E-Cad) RNA through multiple-round open reading frame translation. C-E-Cad is overexpressed in GBM and promotes glioma stem cell tumorigenicity. C-E-Cad activates EGFR independent of EGF through association with the EGFR CR2 domain using a unique 14-amino-acid carboxy terminus, thereby maintaining glioma stem cell tumorigenicity. Notably, inhibition of C-E-Cad markedly enhances the antitumour activity of therapeutic anti-EGFR strategies in GBM. Our results uncover a critical role of C-E-Cad in stimulating EGFR signalling and provide a promising approach for treating EGFR-driven GBM.

Hounsfield unit (HU) of perihematomal edema (PHE) may be a predictor of prognosis of intracerebral hemorrhage (ICH). Our study evaluated whether PHE mean HU at the 72 hours after ICH predicts outcome, and how it compares against other PHE measures.Patients with ICH from a tertiary medical institution were included. PHE was segmented by the semiautomatic plane method to measure volume and mean HU. Outcomes of interest was poor 90-day prognosis (modified Rankin Scale score ≥3). Logistic regression was used to assess relationships with outcome.Data from a total of 159 patients with ICH were collected. The median mean HU of PHE at 72 hours was 22.1 (IQR: 19.2-25.0). Binary logistic regression showed that the 72-hour PHE mean HU was negatively correlated with the poor prognosis of patients with ICH (OR 0.59, 95% CI 0.47-0.75, P0.05). The receiver operator curves of meaningful indicators revealed that the area under the curve (AUC) of PHE mean HU at 72 hours was larger and the difference of AUC between PHE mean HU with PHE absolute volume or extension distance were statistically significant (P0.05). The 72-hour PHE mean HU has a higher value in predicting adverse prognosis of patients with ICH.The PHE mean HU at 72 hours was negatively correlated with the poor prognosis of patients with ICH. The prediction ability of PHE mean HU at 72 hours was better than PHE absolute volume and extension distance, contributing to a rather good index for predicting outcome of ICH.

The coronavirus 2019 (COVID‐19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has spread across the world and is responsible for over 1,686,267 deaths worldwide. Co‐infection with influenza A virus (IFV‐A) during the upcoming flu season may complicate diagnosis and treatment of COVID‐19. Little is known about epidemiology and outcomes of co‐infection. Data for 213 COVID‐19 patients treated at Tongji Hospital in Wuhan from January 28, 2020 to March 24, 2020 were retrospectively analyzed. Ninety‐seven of the patients (45.5%) tested positive for anti‐ IFV‐A immunoglobulin M antibodies. The clinical characteristics were described and analyzed for patients with SARS‐CoV‐2 infection only and patients with SARS‐CoV‐2/IFV‐A co‐infection. Patients with co‐infection showed similar patterns of symptoms and clinical outcomes to patients with SARS‐CoV‐2 infection only. However, an increased expression of serum cytokines (interleukin‐2R [IL‐2R], IL‐6, IL‐8, and tumor necrosis factor‐α) and cardiac troponin I, and higher incidence of lymphadenopathy were observed in patients with SARS‐CoV‐2 infection only. Male patients and patients aged less than 60 years in the SARS‐CoV‐2 infection group also had significantly higher computed tomography scores than patients in co‐infection group, indicating that co‐infection with IFV‐A had no effect on the disease outcome but alleviated inflammation in certain populations of COVID‐19 patients. The study will provide a reference for diagnosing and treating IFV‐A and SARS‐CoV‐2 co‐infection cases in the upcoming flu season.

Coronavirus disease 2019 (COVID-19) has become the greatest threat to human society in a century. To better devise control strategies, policymakers should adjust policies based on scientific evidence in hand. Several countries have limited the epidemics of COVID-19 by prioritizing containment strategies to mitigate the impacts on public health and healthcare systems. However, asymptomatic/pre-symptomatic transmission of COVID-19 complicated traditional symptom-based approaches for disease control. In addition, drastic population-based interventions usually have significant societal and economic impacts. Therefore, in Taiwan, the containment strategies consisted of the more extended case-based interventions (e.g., case detection with enhanced surveillance and contact tracing with active monitoring and quarantine of close contacts) and more targeted population-based interventions (e.g., face mask use in recommended settings and risk-oriented border control with corresponding quarantine requirement). The success of the blended approach emphasizes not only the importance of evidence-supported policymaking but also the coordinated efforts between the government and the people., Highlights • Understanding the transmission dynamics better informs the policy calibration and resource allocation. • Prioritizing containment strategies for mitigation helps preserve public health capacity. • Pre-symptomatic transmission plays a key role in devising COVID-19 control strategies. • The blended approach combining case- and population-based interventions was critical.

This study is aimed at identifying the roles of AGE/RAGE and ET-1 in deep vein thrombosis (DVT). Advanced glycation end products (AGEs) in glycated human serum albumin (M-HSA) were detected by ELISA. The viability of HUVECs was examined by CCK-8 assay. Flow cytometry was performed to detect cell apoptosis, followed by ELISA for the detection of inflammatory cytokine level and oxidative stress level in HUVECs. Immunofluorescence was performed to detect ET-1 and eNOS expression. The expression of specific proteins was assayed by western blot. As a result, decreased HUVEC viability was observed after stimulation with M-HSA, whereas RAGE inhibitor improved it. Cell apoptosis showed the opposite trend. Additionally, M-HSA-induced inflammatory cytokine release and oxidative stress of HUVECs were both alleviated by RAGE inhibitor. RAGE inhibitor also increased the levels of NO and eNOS while decreasing the level of ET-1 in M-HSA-stimulated HUVECs. Furthermore, decreased protein expression of Bax, cleaved-caspase3, RAGE, p65, ET-1 and iNOS was observed after treatment with RAGE inhibitor, in addition to increased protein expression of Bcl-2 and eNOS. In conclusion, blocking AGE/RAGE pathway downregulates ET-1, thereby mitigating HUVEC damage in DVT., GRAPIC ABSTRACT

What is known and objective Gut microbiota plays an important role in shaping immune responses. Several studies have reported that antibiotics may alter gut microbiota diversity and compromise the therapeutic response to immune checkpoint inhibitors (ICIs). Nevertheless, the impact of a specific class of antibiotics on ICIs therapy is still not known. The aim of this study was to analyse the influence of antibiotics on the clinical outcomes of non-small cell lung cancer (NSCLC) patients treated with ICIs and to compare the effects of fluoroquinolones vs. other broad-spectrum antibiotics. Methods This retrospective cohort study (n = 340) analysed data from Chang Gung Research Database, which comprises work from seven medical institutions in Taiwan. Patients with NSCLC who received ICIs between January 2016 and March 2019 were evaluated. The data of patients who received antibiotics (ie fluoroquinolone) within 30 days prior to ICIs therapy were analysed. Overall survival (OS) was the goal of our study and was calculated from the time the ICIs therapy start. Survival analysis was estimated using the Kaplan-Meier and Cox statistics. Results A total of 340 patients were identified for analysis. Of the 340 patients, only over one third (38%) of patients received antibiotics 30 days prior to ICI therapy. These patients exhibited a shorter OS compared with those not receiving antibiotics (median OS, 266 days vs. 455 days; hazard ratio (HR), 2.9; 95% confidence interval (CI), 1.1-8.1, p = 0.003). In this study, 127 out of 128 patients who were exposed to antibiotics had received at least one broad-spectrum antibiotic. We observed patients who had received fluoroquinolone had a shorter OS compared with those receiving other broad-spectrum antibiotics (median OS, 121 days vs. 370 days; HR, 1.582; 95% CI 1.007-2.841; p = 0.047). What is new and conclusion Antibiotic treatment, especially fluoroquinolone, prior to ICIs therapy was associated with poorer clinical efficacy in NSCLC patients. Antibiotics should not be withheld when there is a clear need for them despite the possibility of interfering with the microbiome, which may, in turn, adversely affect the ICI's effectiveness. However, one should consider avoiding the use of fluoroquinolones antibiotics.

Inactivation of Pten gene through deletions and mutations leading to excessive pro-growth signaling pathway activations frequently occurs in cancers. Here, we report a Pten derived pro-cancer growth gene fusion Pten-NOLC1 originated from a chr10 genome rearrangement and identified through a transcriptome sequencing analysis of human cancers. Pten-NOLC1 fusion is present in primary human cancer samples and cancer cell lines from different organs. The product of Pten-NOLC1 is a nuclear protein that interacts and activates promoters of EGFR, c-MET, and their signaling molecules. Pten-NOLC1 promotes cancer proliferation, growth, invasion, and metastasis, and reduces the survival of animals xenografted with Pten-NOLC1-expressing cancer cells. Genomic disruption of Pten-NOLC1 induces cancer cell death, while genomic integration of this fusion gene into the liver coupled with somatic Pten deletion produces spontaneous liver cancers in mice. Our studies indicate that Pten-NOLC1 gene fusion is a driver for human cancers.

Deficits in the clearance of amyloid β-protein (Aβ) play a pivotal role in the pathogenesis of sporadic Alzheimer’s disease (AD). The roles of blood monocytes in the development of AD remain unclear. In this study, we sought to investigate the alterations in the Aβ phagocytosis function of peripheral monocytes during ageing and in AD patients. A total of 104 cognitively normal participants aged 22–89 years, 24 AD patients, 25 age- and sex-matched cognitively normal (CN) subjects, 15 Parkinson’s disease patients (PD), and 15 age- and sex-matched CN subjects were recruited. The Aβ uptake by blood monocytes was measured and its alteration during ageing and in AD patients were investigated. Aβ1-42 uptake by monocytes decreased during ageing and further decreased in AD but not in PD patients. Aβ1-42 uptake by monocytes was associated with Aβ1-42 levels in the blood. Among the Aβ uptake-related receptors and enzymes, the expression of Toll-like receptor 2 (TLR2) was reduced in monocytes from AD patients. Our findings suggest that monocytes regulate the blood levels of Aβ and might be involved in the development of AD. The recovery of the Aβ uptake function by blood monocytes represents a potential therapeutic strategy for AD.

Background This study aimed to explore the prognostic role of DNA methylation pattern in endometrial cancer (EC) patients. Methods Differentially methylated genes (DMGs) of EC patients with distinct survival from The Cancer Genome Atlas (TCGA) database were analyzed to identify methylated genes as biomarkers for EC prognosis. The Least Absolute Shrinkage and Selection Operator (LASSO) analysis was used to construct a risk score model. A nomogram was built based on analysis combining the risk score model with clinicopathological signatures together, and then verified in the validation cohort and patients in our own center. Results In total, 157 DMGs were identified between different prognostic groups. Based on the LASSO analysis, five genes (GBP4, OR8K3, GABRA2, RIPPLY2, and TRBV5‐7) were screened for the establishment of risk score model. The model outperformed in prognostic accuracy at varying follow‐up times (AUC for 3 years: 0.824, 5 years: 0.926, and 7 years: 0.853). Multivariate analysis identified four independent risk factors including menopausal status (HR = 3.006, 95%CI: 1.062–8.511, p = 0.038), recurrence (HR = 2.116, 95%CI: 1.061–4.379, p = 0.046), lymph node metastasis (LNM, HR = 3.465, 95%CI: 1.225–9.807, p = 0.019), and five‐DNA methylation risk model (HR = 3.654, 95%CI: 1.458–9.161, p = 0.006) in training cohort. The performance of the nomogram was good in the training (AUC = 0.828), validation (AUC = 0.866) and the whole cohorts (AUC = 0.843). Furthermore, we verified the nomogram with 24 patients in our center and the Kaplan–Meier survival curve also proved to be significantly different (p, In this study, we revealed a five‐DNA risk model based on methylation profiling based on TCGA database. The prognostic accuracy for 5‐year survival reached to 0.926 by AUC. Furthermore, we established and validated an EC prognostic nomogram consisting of five‐DNA methylation risk model and clinicopathological characteristics, and the nomogram outperformed in training (AUC = 0.828) and validation (AUC = 0.866) cohorts. This nomogram could also be expected to serve as a predictive tool for patients in different subgroups.