Search

We propose a nonparametric method of constructing confidence interval for a scalar parameter from stochastic approximation through the efficient Robbins–Monro procedure proposed by Joseph (2004). Unlike the bootstrap method where the number of resampling is fixed in advance, the proposed procedure iteratively searches the endpoints in an optimal way such that the convergence is fast and the coverage is obtained accurately. Simulation and real data application illustrate its superiority over the usual Robbins–Monro procedure and common bootstrap methods. [ABSTRACT FROM AUTHOR]

This study aims to establish and validate a nomogram as a predictive model in patients with new-onset atrial fibrillation (AF) after dual-chamber cardiac implantable electronic device (pacemaker) implantation. A total of 1120 Chinese patients with new-onset AF after pacemaker implantation were included in this retrospective study. Patients had AF of at least 180/minute lasting 5 minutes or longer, detected by atrial lead and recorded at least 3 months after implantation. Patients with previous atrial tachyarrhythmias before device implantation were excluded. A total of 276 patients were ultimately enrolled, with 51 patients in the AF group and 225 patients in the non-AF group. Least absolute shrinkage and selection operator (LASSO) method was used to determine the best predictors. Through multivariate logistic regression analysis, a nomogram was drawn as a predictive model. Concordance index, calibration plot, and decision curve analyses were applied to evaluate model discrimination, calibration, and clinical applicability. Internal verification was performed using a bootstrap method. The LASSO method regression analysis found that variables including peripheral arterial disease, atrial pacing-ventricular pacing of at least 50%, atrial sense–ventricular sense of at least 50%, increased left atrium diameter, and age were important predictors of developing AF. In multivariate logistic regression, peripheral arterial disease, atrial pacing-ventricular pacing of at least 50%, and age were found to be independent predictors of new-onset AF. This nomogram may help physicians identify patients at high risk of new-onset AF after pacemaker implantation at an early stage in a Chinese population. [ABSTRACT FROM AUTHOR]

Background: Circulating fibrinogen to pre-albumin ratio (FPR) and albumin to fibrinogen ratio (AFR) are effective factors for predicting the prognosis of colorectal cancer (CRC). However, the role of these two ratios in diagnosing early-stage CRC and identifying the stage II CRC subgroup with high relapse risk remains unknown. This study aimed to assess the potential of FPR and AFR in differential diagnosis and risk stratification of early-stage CRC. Methods: A discovery (694 and 512 patients with benign colorectal polyps and stage I–II CRC, respectively) and validation (201 benign colorectal polyps cases and 202 stage I–II CRC individuals) cohorts were enrolled in this study. Receiver operating characteristic curve (ROC), Kaplan–Meier curve, and time-dependent ROC were used to evaluate the diagnostic efficacy of AFR and FPR in the two cohorts and overall population, and the discriminating role of FPR in identifying clinical high-relapse risk patients in comparison with common clinical characteristics in stage II CRC patients. Results: The area under the curve (AUC) of the preoperative circulating FPR was higher than that of AFR in the diagnosis of stage I–II CRC from colorectal adenomas and benign colorectal polyps in the discovery and validation cohorts and overall population. Carcinoembryonic antigen (CEA) combined with FPR could effectively discriminate early-stage CRC from colorectal adenomas or benign polyps. Preoperative FPR could effectively distinguish stage II subgroups with high and low relapse risk. It was superior to common clinical characteristics in identifying high-risk surgical patients who could benefit from adjuvant chemotherapy (CT) [time-dependent AUC: 0.637 vs. 0.511, p < 0.001 for predicting recurrence-free survival (RFS); 0.719 vs. 0.501, p < 0.001 for predicting overall survival (OS)]. Furthermore, CT treated stage II patients with FPR > 20 had the highest recurrence (31.16%) and death rates (21.88%), with similar highest recurrence (30.70%) and death (26.82%) rates found in non-CT-treated patients with FPR > 20. Stage II CRC patients with 20 ≥ FPR > 15 could significantly benefit from postoperative CT, as the recurrence (33.30%) and death (35.71%) rates within non-CT treated patients were approximately five times higher than those of the CT-treated cases (6.77% and 7.41% for the recurrence and death rates, respectively). No significant difference in recurrence rate was observed between L-FPR (≤ 15) patients with (10.00%) or without CT (9.76%), indicating that these patients might not require to receive adjuvant CT after curative resection. Conclusions: Preoperative FPR combined with CEA is superior to common tumor biomarkers, FPR, or AFR in distinguishing early-stage CRC from benign colorectal polyps. Circulating FPR can be an effective biomarker for identifying high-risk patients and choosing suitable therapeutics for early-stage CRC. [ABSTRACT FROM AUTHOR]

Motivated by the goal of improving the efficiency of a sequential design with small sample size, we propose a novel Bayesian stochastic approximation method to estimate the root of a regression function. The method features adaptive local modeling and nonrecursive iteration. Consistency of the Bayes estimator is established. Simulation studies show its superiority in small-sample performance to Robbins–Monro type procedures. Extension to a version of generalized multivariate quantile is presented. • A novel Bayesian stochastic approximation method to estimate the root of a regression function. • Adaptive local modeling and nonrecursive iteration. • Superiority in small-sample performance to Robbins–Monro type procedures. • Extension to a version of generalized multivariate quantile. [ABSTRACT FROM AUTHOR]

Surgical resection remains the preferred approach for some patients with glioblastoma (GBM), and eradication of the residual tumour niche after surgical resection is very helpful for prolonging patient survival. However, complete surgical resection of invasive GBM is difficult because of its ambiguous boundary. Herein, a novel targeting material, c(RGDyk)-poloxamer-188, was synthesized by modifying carboxyl-terminated poloxamer-188 with a glioma-targeting cyclopeptide, c(RGDyk). Quantum dots (QDs) as fluorescent probe were encapsulated into the self-assembled c(RGDyk)-poloxamer-188 polymer nanoparticles (NPs) to construct glioma-targeted QDs-c(RGDyk)NP for imaging-guided surgical resection of GBM. QDs-c(RGDyk)NP exhibited a moderate hydrodynamic diameter of 212.4 nm, a negative zeta potential of –10.1 mV and good stability. QDs-c(RGDyk)NP exhibited significantly lower toxicity against PC12 and C6 cells and HUVECs than free QDs. Moreover, in vitro cellular uptake experiments demonstrated that QDs-c(RGDyk)NP specifically targeted C6 cells, making them display strong fluorescence. Combined with ultrasound-targeted microbubble destruction (UTMD), QDs-c(RGDyk)NP specifically accumulated in glioma tissue in orthotropic tumour rats after intravenous administration, evidenced by ex vivo NIR fluorescence imaging of bulk brain and glioma tissue sections. Furthermore, fluorescence imaging with QDs-c(RGDyk)NP guided accurate surgical resection of glioma. Finally, the safety of QDs-c(RGDyk)NP was verified using pathological HE staining. In conclusion, QDs-c(RGDyk)NP may be a potential imaging probe for imaging-guided surgery. [ABSTRACT FROM AUTHOR]

Background: TAMs (tumor-associated macrophages) infiltration promotes the progression of esophageal cancer (EC). However, the underlying mechanisms remain unclear. Methods: Abnormal expression of LINC01592 from EC microarrays of the TCGA database was analyzed. LINC01592 expression level was validated in both EC cell lines and tissues. Stable LINC01592 knockdown and overexpression of EC cell lines were established. In vitro and in vivo trials were conducted to test the impact of LINC01592 knockdown and overexpression on EC cells. RNA binding protein immunoprecipitation (RIP), RNA pulldown assays, and Immunofluorescence (IF) were used to verify the combination of E2F6 and LINC01592. The combination of E2F6 and NBR1 was verified through the utilization of ChIP and dual luciferase reporter assays. Results: LINC01592 is carried and transferred by exosomes secreted by M2-TAMs to tumor cells. The molecular mechanism underlying the promotion of NBR1 transcription involves the direct binding of LINC01592 to E2F6, which facilitates the nuclear entry of E2F6. The collaborative action of LINC01592 and E2F6 results in improved NBR1 transcription. The elevation of NBR1 binding to the ubiquitinated protein MHC-I via the ubiquitin domain caused a higher degradation of MHC-I in autophagolysosomes and a reduction in MHC-I expression on the exterior of cancerous cell. Consequently, this caused cancerous cells to escape from CD8+ CTL immune attack. The tumor-promoting impacts of LINC01592, as well as the growth of M2-type macrophage-driven tumors, were significantly suppressed by the interruption of E2F6/NBR1/MHC-I signaling through the effect of siRNA or the corresponding antibody blockade. Significantly, the suppression of LINC01592 resulted in an upregulation of MHC-I expression on the tumor cell membrane, thereby enhancing the efficacy of CD8+ T cell reinfusion therapy. Conclusions: The investigation conducted has revealed a significant molecular interaction between TAMs and EC via the LINC01592/E2F6/NBR1/MHC-I axis, which facilitates the progression of malignant tumors. This suggests that a therapeutic intervention targeting this axis may hold promise for the treatment of the disease. [ABSTRACT FROM AUTHOR]

Introduction: The B cell survival factor B lymphocyte stimulator (BLyS) is elevated in patients with systemic lupus erythematosus (SLE) and associated with disease activity. Belimumab, a monoclonal antibody specific for soluble BLyS, is approved for the treatment of adults with active, autoantibody-positive SLE receiving standard therapy. Ethnicity is one of the factors that can potentially affect the pharmacokinetics (PK) of therapeutic monoclonal antibodies, and therefore their efficacy and safety. Methods: This phase 1, open-label study (200909) evaluated the pharmacokinetics (PK, primary objective), pharmacodynamics (PD), and safety (secondary objectives) of belimumab in Chinese patients with SLE (N = 20). Blood samples were taken up to 84 days after a single intravenous (IV) dose of belimumab 10 mg/kg. Results: Peak serum concentrations of belimumab (Cmax) were obtained within the 1-h infusion. Geometric mean Cmax, area under the concentration–time curve (time 0 to last quantifiable concentration), terminal half-life, systemic clearance, and volume of distribution were 221 μg/mL, 2395 day·μg/mL, 14.6 days, 4.06 mL/day/kg, and 85.7 mL/kg, respectively. Decreases in CD20+, CD20+/CD27− naïve, CD20+/CD69+ active, CD20+/CD138+ plasmacytoid, CD19+/CD27BRIGHT/CD38BRIGHT SLE subset, and CD20−/CD138+ plasma B Cells post-dose were accompanied by an increase in CD20+/CD27+ memory B cells. Four cases of upper respiratory tract infection (three mild, one moderate) and one case of mild pharyngitis were possibly drug-related; all resolved during the study. Conclusion: PK of a single belimumab 10 mg/kg IV dose in Chinese patients with SLE were similar to those observed previously in Japanese and American (white and African-American) patients with SLE. PD results were consistent with belimumab inhibiting BLyS, and belimumab was well tolerated. These data support the use of belimumab in Chinese patients with SLE. Trial Registration: ClinicalTrials.gov identifier, NCT02880852. [ABSTRACT FROM AUTHOR]

Density functional theory (DFT) calculations were applied to analyze the effect of various solvents (water, dimethyl sulfoxide (DMSO), acetonitrile, ethanol, pyridine, chloroform and carbon tetrachloride (CCl 4 )) on the intramolecular hydrogen-bond and anti-oxidative properties and of apigenin molecule. The different polarities of the seven solvents adequately cover the range of possible environments and enable informative comparisons from the results of DFT calculations. The solvent effects were introduced by using Tomasi's polarized continuum model (PCM). With the increasing dielectric constant of the environment, the geometry of apigenin monomer is more planar and apigenin molecule is more stable. Medium strength intramolecular hydrogen-bond was found between H5 and O4 in the apigenin molecule. With the increasing dielectric constant of the environment, the strength of the intramolecular hydrogen-bond was enhanced. Besides, the O5–H5⋯O4 intramolecular hydrogen-bond in apigenin molecule is the closed-shell interaction and considered to possess a dominant character of the covalent interactions in different environments. Solvents induce significant changes in enthalpies of charged species of apigenin. Thus, the preferred thermodynamically mechanism of the anti-oxidative progress for apigenin can be altered by the solvents. For the anti-oxidative progress, hydrogen atom transfer (HAT) is the thermodynamically dominant mechanism in vacuum, CCl 4 and chloroform phases, while sequential proton loss electron transfer (SPLET) is more favored in pyridine, ethanol, acetonitrile, DMSO and water phases. [ABSTRACT FROM AUTHOR]

Cancer elicited inflammation is the main environmental cause leading to carcinogenesis and metastasis of non-small cell lung cancer (NSCLC). Roles of the inflammatory biomarker in predicting the clinical efficacy of tyrosine kinase inhibitor (TKI) and prognosis of naive patients with advanced NSCLC need to be determined, and the best inflammatory predicted biomarker remains unknown. A total of 178 eligible advanced NSCLC patients (124 and 54 cases within discovery and validation cohorts, respectively) who received first-line EGFR-TKI between July of 2014 and October of 2020 were enrolled in the present study. We detected circulating immune cell counting, albumin (Alb), pre-albumin (pAlb), ALP, AST, LDH, GGT, HDL-c, and fibrinogen (Fib) concentrations, and calculated 22 inflammatory ratios and scores. Logistic regression and Cox proportional hazards models were used to assess the impact of these ratios and scores on objective response and disease control rate (ORR and DCR) as well as progression-free survival (PFS) in these patients. Twenty-five percentage and 24.07% of NSCLC patients were observed objective response to the treatment of first-line EGFR-TKI in discovery and validation cohort, respectively. Univariate and multivariate Cox regression showed that high PLR, NPS, SII, SIS, mSIS, GLR and FPR as well as low PNI were significantly associated with poor PFS in discovery cohort. However, only high SII and FPR were found to be associated with unsatisfactory outcome in validation cohort. Time-dependent areas under ROC of FPR were 0.702 (0.517–0.888) in discovery cohort, and 0.767 (0.613–0.921) in validation cohort, which were extremely higher than the other biomarkers. The patients with FPR-SII combined score 2 harbored worse prognosis compared to the combined score 0 in discovery (p log-rank = 0.003, adjusted HR = 2.888, 95%CI = 1.500–5.560) and validation cohort (p log-rank = 0.001, adjusted HR = 3.769, 95%CI = 1.676–8.478) as well as overall population (p log-rank < 0.001, adjusted HR = 3.109, 95%CI = 1.878–5.147), and its time-dependent AUCs were 0.747 (0.594–0.900) and 0.815 (0.688–0.942) in the two cohorts, respectively, which were significantly higher than the single biomarker in the two cohorts. The patients with high FPR and FPR-SII score harbored worse DCR than the low patients in the two cohorts and overall population, respectively. Moreover, the similar poor survival was observed in advanced high-FPR NSCLC patients with different treatment options, however, the survival of low-FPR patients with treatment of single TKI, radiotherapy or chemotherapy or radio-chemotherapy combined TKI was good compared to the high-FPR patients with radio-chemotherapy combined TKI, and the survival differences were observed between TKI (p log-rank < 0.001) or radiotherapy combined TKI (p log-rank = 0.014) treated low-FPR patients and the high FPR patients. Additionally, FPR-SII combined score could monitor the progression of the disease in real-time, and the median month of the positive score appearance was significantly earlier than CT/MRI detection (p < 0.001 for 3 months vs. 13 months). High-grade cancer elicited inflammation could attenuates response and outcome in tyrosine kinase inhibitor naive patients with advanced NSCLC. FPR-SII combined score was the best inflammatory biomarker to monitor and predict the progression of advanced NSCLC patients with treatment of TKI. [Display omitted] [ABSTRACT FROM AUTHOR]