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Abstract Background Renal cold ischemia-reperfusion injury (CIRI), a pathological process during kidney transplantation, may result in delayed graft function and negatively impact graft survival and function. There is a lack of an accurate and non-invasive tool for evaluating the degree of CIRI. Multi-parametric MRI has been widely used to detect and evaluate kidney injury. The machine learning algorithms introduced the opportunity to combine biomarkers from different MRI metrics into a single classifier. Objective To evaluate the performance of multi-parametric magnetic resonance imaging for grading renal injury in a rat model of renal cold ischemia-reperfusion injury using a machine learning approach. Methods Eighty male SD rats were selected to establish a renal cold ischemia -reperfusion model, and all performed multiparametric MRI scans (DWI, IVIM, DKI, BOLD, T1mapping and ASL), followed by pathological analysis. A total of 25 parameters of renal cortex and medulla were analyzed as features. The pathology scores were divided into 3 groups using K-means clustering method. Lasso regression was applied for the initial selecting of features. The optimal features and the best techniques for pathological grading were obtained. Multiple classifiers were used to construct models to evaluate the predictive value for pathology grading. Results All rats were categorized into mild, moderate, and severe injury group according the pathologic scores. The 8 features that correlated better with the pathologic classification were medullary and cortical Dp, cortical T2*, cortical Fp, medullary T2*, ∆T1, cortical RBF, medullary T1. The accuracy(0.83, 0.850, 0.81, respectively) and AUC (0.95, 0.93, 0.90, respectively) for pathologic classification of the logistic regression, SVM, and RF are significantly higher than other classifiers. For the logistic model and combining logistic, RF and SVM model of different techniques for pathology grading, the stable and perform are both well. Based on logistic regression, IVIM has the highest AUC (0.93) for pathological grading, followed by BOLD(0.90). Conclusion The multi-parametric MRI-based machine learning model could be valuable for noninvasive assessment of the degree of renal injury.

Abstract Background Preeclampsia, one of the most lethal pregnancy-related diseases, is associated with the disruption of uterine spiral artery remodeling during placentation. However, the early molecular events leading to preeclampsia remain unknown. Results By analyzing placentas from preeclampsia, non-preeclampsia, and twin pregnancies with selective intrauterine growth restriction, we show that the pathogenesis of preeclampsia is attributed to immature trophoblast and maldeveloped endothelial cells. Delayed epigenetic reprogramming during early extraembryonic tissue development leads to generation of excessive immature trophoblast cells. We find reduction of de novo DNA methylation in these trophoblast cells results in selective overexpression of maternally imprinted genes, including the endoretrovirus-derived gene PEG10 (paternally expressed gene 10). PEG10 forms virus-like particles, which are transferred from the trophoblast to the closely proximate endothelial cells. In normal pregnancy, only a low amount of PEG10 is transferred to maternal cells; however, in preeclampsia, excessive PEG10 disrupts maternal vascular development by inhibiting TGF-beta signaling. Conclusions Our study reveals the intricate epigenetic mechanisms that regulate trans-generational genetic conflict and ultimately ensure proper maternal–fetal interface formation.

Abstract Background Klippel–Feil syndrome (KFS) is a rare congenital disorder characterized by the fusion of two or more cervical vertebrae during early prenatal development. This fusion results from a failure of segmentation during the first trimester. Although six genes have previously been associated with KFS, they account for only a small proportion of cases. Among the distinct subtypes of KFS, “sandwich fusion” involving concurrent fusion of C0-1 and C2-3 vertebrae is particularly noteworthy due to its heightened risk for atlantoaxial dislocation. In this study, we aimed to investigate novel candidate mutations in patients with “sandwich fusion.” Methods We collected and analyzed clinical data from 21 patients diagnosed with “sandwich fusion.” Whole-exome sequencing (WES) was performed, followed by rigorous bioinformatics analyses. Our focus was on the six known KFS-related genes (GDF3, GDF6, MEOX1, PAX1, RIPPLY2, and MYO18). Suspicious mutations were subsequently validated through in vitro experiments. Results Our investigation revealed two novel exonic mutations in the FGFR2 gene, which had not previously been associated with KFS. Notably, the c.1750A > G variant in Exon 13 of FGFR2 was situated within the tyrosine kinase domain of the protein, in close proximity to several established post-translational modification sites. In vitro experiments demonstrated that this certain mutation significantly impacted the function of FGFR2. Furthermore, we identified four heterozygous candidate variants in two genes (PAX1 and MYO18B) in two patients, with three of these variants predicted to have potential clinical significance directly linked to KFS. Conclusions This study encompassed the largest cohort of patients with the unique “sandwich fusion” subtype of KFS and employed WES to explore candidate mutations associated with this condition. Our findings unveiled novel variants in PAX1, MYO18B, and FGFR2 as potential risk mutations specific to this subtype of KFS.

Abstract Background The presence of lymph node (LN) metastasis directly affects the treatment strategy for lung adenocarcinoma (LUAD). Next‐generation sequencing (NGS) has been widely used in patients with advanced LUAD to identify targeted genes, while early detection of pathologic LN metastasis using NGS has not been assessed. Methods Clinicopathologic features and molecular characteristics of 224 patients from Ruijin Hospital were analyzed to detect factors associated with LN metastases. Another 140 patients from Huashan Hospital were set as a test cohort. Results Twenty‐four out of 224 patients were found to have lymph node metastases (10.7%). Pathologic LN‐positive tumors showed higher mutant allele tumor heterogeneity (p

Summary: Metabolic diseases such as obesity and diabetes induce lipotoxic cardiomyopathy, which is characterized by myocardial lipid accumulation, dysfunction, hypertrophy, fibrosis and mitochondrial dysfunction. Here, we identify that mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH) is a pivotal regulator of cardiac fatty acid metabolism and function in the setting of lipotoxic cardiomyopathy. Cardiomyocyte-specific deletion of mGPDH promotes high-fat diet induced cardiac dysfunction, pathological hypertrophy, myocardial fibrosis, and lipid accumulation. Mechanically, mGPDH deficiency inhibits the expression of desuccinylase SIRT5, and in turn, the hypersuccinylates majority of enzymes in the fatty acid oxidation (FAO) cycle and promotes the degradation of these enzymes. Moreover, manipulating SIRT5 abolishes the effects of mGPDH ablation or overexpression on cardiac function. Finally, restoration of mGPDH improves lipid accumulation and cardiomyopathy in both diet-induced and genetic obese mouse models. Thus, our study indicates that targeting mGPDH could be a promising strategy for lipotoxic cardiomyopathy in the context of obesity and diabetes.

Abstract Background Maternal lipid metabolism fluctuations have been shown to increase the risk of adverse pregnancy outcomes. However, there is no consensus over what constitutes normal maternal lipid values during twin pregnancy. Therefore, the aim of this study was to establish a serum lipid reference range for a twin pregnancy. Methods A retrospective survey was conducted, from 2011 to 2021, at the Peking University Third Hospital. A total of 881 twin pregnancies, with lipid data from early and middle pregnancies, were included. After excluding those with adverse pregnancy outcomes, we performed a descriptive analysis of total cholesterol (TC), triglycerides (TG), high-density lipid cholesterol (HDL-C), and low-density lipid cholesterol (LDL-C) levels, using the mean and standard deviation to determine appropriate percentiles. We later determined the lipid reference range in early and middle pregnancy based on the initial results. We evaluated Inappropriate lipid levels associations with pregnancy outcomes, including gestational diabetes, pregnancy-induced hypertension, small for gestational age. Results (1) Serum levels of TC, TG, LDL-C, and HDL-C increased significantly from early to late pregnancy, where the greatest increase was observed in TG. (2) Based on the results, we recommend that TC, TG, and LDL-C serum reference values during early and middle pregnancy should be less than the 95th percentile. On the other hand, HDL-C should be greater than the 5th percentile. During early pregnancy, the values recommended are TC 1.02 mmol/L and LDL 1.25 mmol/L and LDL 1.10 mmol/L and LDL

In this study, we propose a novel approach to achieve an ultra-narrow bandwidth and high transmittance filter in the visible range. By employing TiO2 as the waveguide layer material, the coupling energy in the waveguide layer is enhanced, leading to a reduction in the full width half maximum (FWHM). Additionally, a double-layer dielectric film structure composed of SiO2 and Al2O3 is employed on the Ag grating to suppress random scattering leakage in the short wavelength range, resulting in reduced sidebands and improved transmittance of the resonant peak. To minimize wave loss between the metal grating and the waveguide layer, a SiO2 dielectric layer is introduced. By adjusting the metal grating period, the resonance peak position can be shifted across the entire visible range. The proposed approach offers a metal grating-based guided-mode resonance (GMR) transmissive filter with low sidebands, high transmittance, ultra-narrow bandwidth, and tunability in the entire visible range. Experimental validation of the proposed design is conducted, and the results demonstrate the effectiveness of this approach in achieving superior filter performance in the visible spectral range.

The amount of residual triazophos in green tea was determined by gas chromatography tandem mass spectrometry (GC-MS/MS) and then the uncertainty was evaluated. According to ISO/IEC Guide 98-3: 2008 (GUM method) and GB/T 27411-2012 "Common uncertainty assessment methods and representations in testing laboratories" (control chart method), the uncertainty of the measurement results was analyzed and quantified. Results showed that, the evaluation results of the GUM method and the control chart method were (0.112±0.012) mg/kg, k=2 and (0.108±0.018) mg/kg, k=2, respectively. The main sources of uncertainty of the GUM method were mass concentration and instrument stability, which accounted for 38.9% and 24.7% of the total uncertainty respectively. The control chart method only performed statistical analysis of the test results, which was simple and easy to operate. It inspected the long-term trend of the test results and could be implemented in the application of internal quality control in daily testing work. The GUM method was suitable for re-examination of samples or the evaluation of uncertainty requirements by customers. The calculation was complex, but the uncertainty evaluation results could be obtained in the short term.

Introduction Antenatal care (ANC) is a critical measure to reduce maternal and perinatal morbidity and mortality. However, there are issues of too many visits and cumbersome procedures of ANC in many maternity hospitals of China. In the past 2 years, reduced-visit ANC models combined with remote monitoring have been recommended and implemented at most hospitals in China during the COVID-19 pandemic. Nevertheless, due to limited evaluations of the cost-effectiveness, policy-makers remain confused on how to appropriately integrate online delivery strategies with routine models to improve ANC quality and efficiency sustainably at scale. This trial aims to evaluate the effectiveness, acceptability and cost of a reduced-visit ANC model combined with telemedicine.Methods and analysis A single-blind, randomised controlled trial will be conducted among low-risk pregnant women at Peking University Third Hospital in Beijing. 1476 patients (738 in each group) would be required, and they will be randomly assigned in a 1:1 ratio to receive the reduced-visit ANC combined with telemedicine services or the routine ANC. The primary outcome is the composite rate of adverse maternal and perinatal outcomes which will be extracted from the medical records. Secondary outcomes include acceptability of ANC models, which is assessed by satisfaction with ANC, pregnancy-related stress and ANC costs measured from the perspectives of both service providers and demanders. Both intention-to-treat and per-protocol analyses will be performed. Non-inferiority tests will be used to compare the two ANC models for the primary outcome. A cost-effectiveness analysis comparing the two ANC models will be conducted by estimating the incremental cost-effectiveness ratios.Ethics and dissemination This study was approved by the ethical review committee of the Peking University Third Hospital (Beijing, China). The results of this study will be published in peer-reviewed scientific journals and presented at relevant academic conferences.Trial registration number NCT05290467.

Abstract Background Immunotherapy is an important treatment in oncology, but only a fraction of patients with head and neck squamous cell carcinoma (HNSCC) benefit from it. Therefore, the aim of this study was to identify predictive biomarkers of immunotherapy response for HNSCC in order to improve treatment outcomes. Methods Survival analyses and comparative efficacy evaluation were performed to investigate prognostic and therapeutic impact factors in patients with advanced HNSCC following immunotherapy, and to examine the effects of factors including gene mutations, tumor mutational burden (TMB), mutant-allele tumor heterogeneity (MATH), and immune cell infiltration on the survival and efficacy. Results Anti-PD-1 treatment led to a prolonged overall survival (OS) in HNSCC patients with gene mutations compared with those without the mutations, while no significant difference in the OS was found between the two groups of patients. And no marked association between the MATH value and OS was detected in HNSCC patients, whereas patients with either high TMB scores in tissues and blood or high immune cell infiltration displayed a significantly longer OS. Further analysis with efficacy as the primary endpoint revealed no significant differences in the tissue TMB, blood TMB, and MATH value between the patients who responded to immunotherapy and those who did not. Moreover, no significant differences in the expression percentages of positive immune cells in tumor, stroma, and total regions were identified between the above two groups of patients. Conclusion HNSCC is characterized by high mutation rate, high mutation burden, and high level of immune cell infiltration, and a subset of HNSCC patients respond to immunotherapy. Here, we showed that high mutation burden and immune cell infiltration may improve the prognosis of HNSCC patients with immunotherapy, while there was no remarkable effect on the efficacy.

Abstract Background Fetal growth velocity standards have yet to be established for the Chinese population. This study aimed to establish such standards suitable for the Chinese population. Methods We performed a multicenter, population–based longitudinal cohort study including 9075 low–risk singleton pregnant women. Data were collected from the clinical records of 24 hospitals in 18 provinces of China. Demographic characteristics, reproductive history, fetal ultrasound measurements, and perinatal outcome data were collected. The fetal ultrasound measurements included biparietal diameter (BPD), abdominal circumference (AC), head circumference (HC), and femur diaphysis length (FDL). We used linear mixed models with cubic splines to model the trajectory of four ultrasound parameters and estimate fetal weight. Fetal growth velocity was determined by calculating the first derivative of fetal size curves. We also used logistic regression to estimate the association between fetal growth velocities in the bottom 10th percentile and adverse perinatal outcomes. Results Fetal growth velocity was not consistent over time or among individuals. The estimated fetal weight (EFW) steadily increased beginning at 12 gestational weeks and peaked at 35 gestational weeks. The maximum velocity was 211.71 g/week, and there was a steady decrease in velocity from 35 to 40 gestational weeks. The four ultrasound measurements increased in the early second trimester; BPD and HC peaked at 13 gestational weeks, AC at 14 gestational weeks, and FDL at 15 gestational weeks. BPD and HC also increased from 19 to 24 and 19 to 21 gestational weeks, respectively. EFW velocity in the bottom 10th percentile indicated higher risks of neonatal complications (odds ratio [OR] = 2.23, 95% confidence interval [CI]: 1.79–2.78) and preterm birth

IntroductionDespite the important clinical significance, limited data on the joint contribution of prepregnancy body mass index (BMI) and gestational weight gain (GWG) to preeclampsia, the second leading cause of maternal mortality worldwide. This study aimed to estimate the risk of preeclampsia by GWG among women with varied prepregnancy BMI.MethodsWe conducted a retrospective cohort study using data of 117 738 singleton pregnant women aged 18–49 years from 150 maternity hospitals in China between 2015 and 2018. GWG was calculated as the measured weight at the time of preeclampsia assessment minus prepregnancy weight; GWG velocity was calculated as the GWG divided by the gestational age at weighing. The non-linear associations of GWG with preeclampsia were examined by restricted cubic spline regression analysis according to prepregnancy BMI. The association of the GWG categories with preeclampsia was further examined by performing robust Poisson regression stratified by the prepregnancy BMI categories.ResultsAmong participants, 2426 (2.06%) were diagnosed with preeclampsia. Compared to women with normal BMI, those who were overweight and obese had 1.92- fold (95%CI, 1.73–2.14) and 5.06- fold (95%CI, 4.43–5.78) increased risks for preeclampsia, respectively. The association of GWG velocity with preeclampsia was presented as a J-shaped curve with the varied inflexion point (where the rate of preeclampsia was 2%), which was 0.54, 0.38, and 0.25 kg/week in women with normal BMI, overweight, and obesity, respectively; a steep risk rise was observed along with GWG velocity beyond the inflexion points. The overall adjusted relative risk for preeclampsia was calculated among women with the different GWG categories of GWG.ConclusionsThe findings highlight that high prepregnancy BMI and exceed GWG contributed to increased risk of preeclampsia with a superimposed effect and underscore the need to optimize the recommendations for GWG for women with different prepregnancy BMI.

IntroductionPre-eclampsia is the second leading cause of maternal mortality worldwide. The controversy for the association of vitamin E with pre-eclampsia has raged unabated for two decades. We aimed to determine the association of vitamin E level in the first trimester and the gestational change with pre-eclampsia.Materials and MethodsA retrospective cohort study was conducted among singleton pregnant women aged 15–49 years at 137 hospitals in China. Serum vitamin E concentrations in the first trimester and at pre-eclampsia assessment time were uniformly quantified in a laboratory by high performance liquid chromatography. Logistic regression models with restricted cubic splines were performed to reveal a non-linear association of vitamin E concentrations in the first trimester and the gestational change with pre-eclampsia.ResultsWe included 73 317 participants (47.8% aged 25–29 years) and 2.28% were diagnosed with pre-eclampsia. Higher risk was observed in those with lower concentration in the first trimester and greater gestational decrease, with a range from 0.81 to 80.60%. A non-linear L-shaped association was observed between vitamin E concentrations in the first trimester and pre-eclampsia, suggesting a threshold at 7.3 mg/L and a ceiling effect: the risk saw a steep rise when the concentrations in the first trimester were < 7.3 mg/L but was relatively flat beyond the inflection point. Sharply increased pre-eclampsia risk was also found in those with gestational vitamin E decrease after accounting for the baseline status in the first trimester. However, gestational vitamin E increase was associated with decreased pre-eclampsia risk when the baseline concentrations were < 7.3 mg/L but did not confer additional benefits when it was above the threshold.ConclusionWe demonstrated alarmingly high pre-eclampsia risk in women with vitamin E concentrations of < 7.3 mg/L in the first trimester and gestational vitamin E decrease. These findings underscore the need to supplement vitamin E among pregnant women with low baseline status.

Objectives: To examine the association between vitamin E (VE) status and gestational diabetes mellitus (GDM). Methods: A retrospective cohort study was conducted by using data of 52,791 women at 137 hospitals across 22 provinces of China. A fasting plasma glucose (FPG) level of ≥5.1 mmol/L between the 24th and 40th weeks of gestation was used as the criteria for the diagnosis of GDM. Mean FPG level and GDM rate were calculated within each combination of the first-trimester VE concentration categories and gestational change categories. The associations of the first-trimester VE concentrations and gestational VE change with FPG and GDM were examined by employing generalized additive models (GAMs). Results: 7162 (13.57%) cases were diagnosed with GDM. The GDM rate was 22.44%, 11.50%, 13.41%, 12.87%, 13.17%, 13.44%, 12.64%, and 14.24% among women with the first-trimester VE concentrations of

Background: Pregnancy anemia is a global health concern. However, to our knowledge, there still has little consensus on the reference value of hemoglobin levels. Particularly, little evidence from China was accessible in most existing guidelines. Objective: To evaluate hemoglobin levels and anemia prevalence of pregnant women in China and offer evidence for anemia and its reference values in China. Methods: A multi-center retrospective cohort study was conducted among 143,307 singleton pregnant women aged 15–49 at 139 hospitals in China, with hemoglobin concentrations routinely tested at each prenatal visit. Subsequently, a restricted cubic spline was performed to reveal a non-linear variation of hemoglobin concentrations during the gestational week. The Loess model was used to describe the changes in the prevalence of different degrees of anemia with gestational age. Multivariate linear regression model and Logistic regression model were applied to explore influencing factors of gestational changes in hemoglobin level and anemia prevalence, respectively. Results: Hemoglobin varied nonlinearly with gestational age, and the mean hemoglobin levels decreased from 125.75 g/L in the first trimester to 118.71 g/L in the third trimester. By analyzing hemoglobin levels with gestational age and pregnancy period, we proposed new criteria according to 5th percentile hemoglobin concentration in each trimester as a reference for anemia, with 108 g/L, 103 g/L, and 99 g/L, respectively. According to WHO’s criteria, the prevalence of anemia sustainably increased with gestational age, with 6.2% (4083/65,691) in the first trimester, 11.5% (7974/69,184) in the second trimester and 21.9% (12,295/56,042) in the third trimester, respectively. In subsequent analysis, pregnant women in non-urban residents, multiparity, and pre-pregnancy underweight tended to have lower hemoglobin levels. Conclusions: This research, the first large-sample study to present a set of gestational age-specific reference centiles for hemoglobin levels in China, could be used to obtain a better understanding of the overall levels of hemoglobin in Chinese healthy pregnant women and ultimately offer clues for a more precise hemoglobin reference value of anemia in China.

BackgroundHead and neck squamous cell carcinoma (HNSCC) is one of the most common malignant cancers. The treatment of HNSCC remains challenging despite recent progress in targeted therapies and immunotherapy. Research on predictive biomarkers in clinical settings is urgently needed.MethodsNext-generation sequencing analysis was performed on tumor samples from 121 patients with recurrent or metastatic HNSCC underwent sequencing analysis. Clinicopathological information was collected, and the clinical outcomes were assessed. Progression-free survival (PFS) was estimated using the Kaplan-Meier method and cox regression model was used to conduct multivariate analysis. Fisher’s exact tests were used to calculate clinical benefit. A p value of less than 0.05 was designated as significant (p < 0.05).ResultsChromosome 11q13 amplification (CCND1, FGF3, FGF4, and FGF19) and EGFR mutations were significantly associated with decreased PFS and no clinical benefits after treatment with a programmed death 1 (PD-1) inhibitor. The same results were found in the combined positive score (CPS) ≥ 1 subgroup. In patients who were treated with an EGFR antibody instead of a PD-1 inhibitor, a significant difference in PFS and clinical benefits was only observed between patients with CPS ≥ 1 and CPS < 1.ConclusionChromosome 11q13 amplification and EGFR mutations were negatively correlated with anti-PD-1 therapy. These markers may serve as potential predictive biomarkers to identify patients for whom immunotherapy may be unsuitable.

Pulmonary fibrosis has been characterized by abnormal proliferation of fibroblasts and massive deposition of the extracellular matrix, which results from a complex interplay of chronic injury and inflammatory responses. MicroRNA-301a (miR-301a) is activated by multiple inflammatory stimulators, contributing to multiple tumorigenesis and autoimmune diseases. This study showed that miR-301a was overexpressed in a bleomycin-induced murine model of pulmonary fibrosis and patients with idiopathic pulmonary fibrosis (IPF). In addition, miR-301a was activated by transforming growth factor β (TGF-β) and interleukin 6 (IL-6) in normal and IPF fibroblasts, which was markedly reversed by the signal transducer and activator of transcription 3 (STAT3) inhibitor. The genetic ablation of miR-301a in mice reduced bleomycin-induced lung fibrosis, and the downregulation of miR-301a restrained proliferation and activation of fibroblasts. Furthermore, this study demonstrated that TSC1 was a functional target of miR-301a in fibroblasts, and the negative regulation of TSC1 by miR-301a promoted the severity of pulmonary fibrosis through the mammalian target of rapamycin (mTOR) signaling pathway. The blocking of miR-301a by the intravenous injection of antagomiR-301a inhibited the proliferation of fibroblasts and the structural destruction of lung tissues in the bleomycin-induced lung fibrosis mouse model. The findings revealed the crucial role of the miR-301a/TSC1/mTOR axis in the pathogenesis of pulmonary fibrosis, suggesting that miR-301a might serve as a potential therapeutic target.

Gramicidin is a well-known antibiotic and recently was reported to induced tumour cell death, however, little is understood about the molecular mechanism of gramicidin as a therapeutic agent for solid tumours. Here, we investigated the role of gramicidin in cholangiocarcinoma cells. We found that gramicidin A inhibits cholangiocarcinoma cell growth and induced the necrotic cell death. We used next generation sequencing to analyse gene expression profiles of cholangiocarcinoma cells treated with gramicidin. We identified 265 differentially expressed genes in cholangiocarcinoma cells between PBS treatment and gramicidin treatment. EGR4 was confirmed to be a target of gramicidin-induced cell growth inhibition. Furthermore, we demonstrated that downregulation of EGR4 in cholangiocarcinoma cells leads to restraining tumour cell growth. Of note, EGR4 was expressed at highest levels in cholangiocarcinoma tissues among 17 types of human cancers, and EGR4 expression positively correlated with several growth factors associated with cholangiocarcinoma. Our findings ascertain that EGR4 is a potential target in cholangiocarcinoma and suppressing EGR4 by gramicidin establish an essential mechanism for bile duct carcinoma progression.

Background: We investigated the mutational landscape of circulating tumor DNA (ctDNA) in predicting tumor response to first-line treatment in patients with metastatic colorectal cancer (mCRC). Methods: We included 41 patients with initially unresectable mCRC, treated with 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX)/5-fluorouracil/leucovorin/irinotecan (FOLFIRI) with/without bevacizumab (Bev)/cetuximab (Cet). Blood samples were prospectively collected at two timepoints: at baseline and after four cycles of first-line treatment. Mutational status of 1086 genes were studied in ctDNA by targeted next-generation sequencing (NGS). Molecular mutational burden (MMB) was defined as mean mutation frequency among obtained mutations for each gene. To evaluate the association between molecular characteristics of cfDNA and therapeutic response better, we divided these patients into MMB-high and MMB-low group according to the median value of MMB (0.3). Results: Among the 41 enrolled patients, alterations of six genes ( TRIM24 , SPEN , RNF43 , PRKAR1A , KRAS , and KDM5 C ) were found at baseline. Baseline MMB of six genes was significantly lower in partial response (PR)/stable disease (SD) patients than progression disease (PD) patients ( p = 0.0012). Further analysis demonstrated that genomic profiling of ctDNA from pretreatment blood samples was significantly different between PR/SD (non-PD) group and PD group. By comparing the baseline levels of KRAS MMB in the two subgroups, we found that PD cases were all MMB-high, whereas non-PD cases were mainly in MMB-low subgroup. Furthermore, patients with low-KRAS MMB had superior response rate, significantly longer progression-free survival (PFS) and longer overall survival (OS) than high-KRAS MMB group. Conclusions: This prospective and serial genomic profiling study revealed the utility of ctDNA in predicting clinical outcomes in mCRC patients under first-line treatment. Levels of KRAS MMB might aid in monitoring therapeutic efficacy in mCRC patients at pretreatment/after four cycles of first-line treatment.

Clinical trials indicated that PD-1/PD-L1 inhibitors significantly improve the survival rate of patients with advanced non-small cell lung cancer (NSCLC) and induce immune-related adverse events (irAEs). Thus, the molecular and immune characteristics during PD-1/PD-L1 inhibitor therapy are worth investigating further. We report the case of a 62-year-old male patient diagnosed with stage IIIA squamous cell lung carcinoma (SQCC) who responded to neoadjuvant and adjuvant nivolumab combined chemotherapy but died from anastomosis leakage or/and irAEs. In the pretreatment tumor biopsy, PD-L1 expression was negative and a few T cells, NK cells, and macrophages had infiltrated the tumor. Wild-type EGFR/STK11, mutant TP53, microsatellite stability, and low tumor mutational burden were also found at baseline. After neoadjuvant immunochemotherapy, the tumor was significantly reduced, PD-L1 expression levels were increased by 50%, and more CD8+ and CD8+ PD-1+ T cells had infiltrated the resected tumor tissue. Immune-related lung injury occurred during adjuvant immunochemotherapy, and serum levels of C-reactive protein, IL-13, IL-4, eotaxin, VEGF-A, IL-8, and IFN-gamma were increased. This case demonstrates a squamous cell lung carcinoma patient who responded to neoadjuvant immunochemotherapy that reshaped the tumor immune environment from “cold” to “hot.” Unfortunately, the patient eventually died from anastomosis leakage or/and irAEs during adjuvant immunochemotherapy.

Performance effective task scheduling algorithms are essential for taking advantage of the heterogeneous multi-processor in heterogeneous computing environments. In this paper, we present a task scheduling algorithm named as Dependency-ratio Bundling Earliest Finish Time (DBEFT). DBEFT is a list based scheduling algorithm combined with task duplication, which can achieve high performance and low time complexity simultaneously. DBEFT selects the task from the perspective of extending parallelism between tasks instead of giving priorities to tasks on the critical path. Also, DBEFT reduces communication cost by adopting a bundling scheduling strategy. The experiments were conducted on both random graph set and real-world applications, and the results show that DBEFT obtained significant performance improvement, outperforming CEFT by 15%, PEFT by 30% and HEFT 33% in terms of SLR respectively.

BackgroundTumor mutation burden has been proven to be a good predictor for the efficacy of immunotherapy, especially in patients with hypermutation. However, most research focused on the analysis of hypermutation in individual tumors, and there is a lack of integrated research on the hypermutation across different cancers. This study aimed to characterize hypermutated patients to distinguish between these patients and non-hypermutated patients.MethodsA total of 5,980 tumor samples involving 23 types of solid tumors from the in-house database were included in the study. Based on the cutoff value of tumor mutation burden (TMB), all samples were divided into hypermutated or non-hypermutated groups. Microsatellite instability status, PD-L1 expression and other mutation-related indicators were analyzed.ResultsAmong the 5,980 tumor samples, 1,164 were selected as samples with hypermutation. Compared with the non-hypermutated group, a significant increase in the mutation rates of DNA mismatch repair genes and polymerase genes was detected in the hypermutated group, and there was an overlap between high TMB and high microsatellite instability or high PD-L1. In addition, we found that EGFR, KRAS and PIK3CA had a high frequency of both single nucleotide variation and copy number variation mutations. These identified mutant genes were enriched in the oncogenic signaling pathway and the DNA damage repair pathway. At the same time, the somatic cell characteristics and distribution of the two groups were significantly different.ConclusionsThis study identified genetic and phenotypic characteristics of hypermutated tumors and demonstrated that DNA damage repair is critically involved in hypermutation.

To investigate changes in coagulation during twin pregnancies. Methods: A total of 108 women with twin pregnancies and 442 women with singleton pregnancies were recruited. Coagulation tests, including fibrinogen (Fib), activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT), were performed during the course of the pregnancy. The level of fibrinogen gradually increased during singleton pregnancies, while the APTT and PT levels showed a decreasing trend with increasing gestational weeks. In twin pregnancies, the changes in PT and TT were similar, but other parameters displayed a different trend. Fibrinogen showed no significant difference between the second and third trimesters, while APTT showed an increasing trend from the second trimester to the third trimester. Compared with singleton pregnancies, the level of fibrinogen was higher in women pregnant with twins. APTT was longer in women pregnant with twins than in women with singleton pregnancies in the third trimester. PT was shorter in women pregnant with twins than in women with singleton pregnancies in the first and third trimesters. TT was shorter in women pregnant with twins than in women with singleton pregnancies in the first and second trimesters. Through this retrospective longitudinal analysis, this study presents the main coagulation parameter changes in singleton and twin pregnancies and confirms that coagulation is more enhanced in twin pregnancies than in singleton pregnancies.

Aims. To assess the maresin 1 (MaR1) contents in type 2 diabetic patients with or without diabetic foot ulcer and to analyze the association of MaR1 concentrations with several metabolism-related parameters. Methods. Plasma MaR1 concentrations were analyzed in 96 subjects with normal glucose tolerant (NC, n=43), type 2 diabetes (T2DM, n=40), or diabetic foot ulcer (DFU, n=13). The intravenous glucose tolerance test (IVGTT) and biochemical parameters were measured in all participants. Results. Plasma MaR1 concentrations were significant decreased in type 2 diabetes patient with or without DFU compared with NC (both P

Abstract Conventional luminescent information is usually visible under either ambient or UV light, hampering their potential application in smart confidential information protection. In order to address this challenge, herein, light‐triggered luminescence ON‐OFF switchable hybrid hydrogels are successfully constructed through in situ copolymerization of acrylamide, lanthanide complex, and diarylethene photochromic unit. The open‐close behavior of the diarylethene ring in the polymer could be controlled by UV and visible light irradiation, where the close form of the ring features fluorescence resonance energy transfer with the lanthanide complex. The hydrogel‐based blocks with tunable emission colors are then employed to construct 3D information codes, which can be read out under a 254 nm UV lamp. The exposure to 300 nm UV light leads to the luminescence quenching of the hydrogels, thus erasing the encoded information. Under visible light (>450 nm) irradiation, the luminescence is recovered to make the confidential information readable again. Thus, by simply alternating the exposure to UV and visible lights, the luminescence signals could become invisible and visible reversibly, allowing for reversible multiple information encryption and decryption.

Human errors are one of the major contributors of accidents. In order to improve the safety performance, human errors have to be addressed. Human Factors Analysis and Classification System (HFACS) has been developed as an analytical framework for the investigation of the role of human errors in aviation accidents. However, the HFACS framework did not reveal the relationships describing the effect among diverse factors at different levels. Similarly, its interior structure was not exposed. As a result, it is difficult to identify critical paths and key factors. Therefore, an improved Human Factors Analysis and Classification System in the construction industry (I-HFACS) was developed in this study. An analytical I-HFACS mechanism was designed to interpret how activities and decisions made by upper management lead to operator errors and subsequent accidents. Critical paths were highlighted. Similarly, key human factors were identified, that is, “regulatory factors,” “organizational process,” “supervisory violations,” “adverse spiritual state,” “skill underutilization,” “skill-based errors,” and “violations.” Findings provided useful references for the construction industry to improve the safety performance.

The complex pathogenesis of Alzheimer’s disease (AD) involves multiple contributing factors, including amyloid β (Aβ) peptide accumulation, inflammation and oxidative stress. Effective therapeutic strategies for AD are still urgently needed. Triptolide is the major active compound extracted from Tripterygium wilfordii Hook.f., a traditional Chinese medicinal herb that is commonly used to treat inflammatory diseases. The 5-month-old 5XFAD mice, which carry five familial AD mutations in the β-amyloid precursor protein (APP) and presenilin-1 (PS1) genes, were treated with triptolide for 8 weeks. We observed enhanced spatial learning performances, and attenuated Aβ production and deposition in the brain. Triptolide also inhibited the processing of amyloidogenic APP, as well as the expression of βAPP-cleaving enzyme-1 (BACE1) both in vivo and in vitro. In addition, triptolide exerted anti-inflammatory and anti-oxidative effects on the transgenic mouse brain. Triptolide therefore confers protection against the effects of AD in our mouse model and is emerging as a promising therapeutic candidate drug for AD.

Internet of Things (IoT) technology allows us to measure, compute, and decide about the physical world around us in a quantitative and intelligent way. It makes all kinds of intelligent IoT devices popular. We are continually perceived and recorded by intelligent IoT devices, especially vision devices such as cameras and mobile phones. However, a series of security issues have arisen in recent years. Sensitive data leakage is the most typical and harmful one. Whether we are just browsing files unintentionally in sight of high-definition (HD) security cameras, or internal ghosts are using mobile phones to photograph secret files, it causes sensitive data to be captured by intelligent IoT vision devices, resulting in irreparable damage. Although the risk of sensitive data diffusion can be reduced by optical character recognition (OCR)-based packet filtering, it is difficult to use it with sensitive data presented in table form. This is because table images captured by the intelligent IoT vision device face issues of perspective transformation, and interferences of circular stamps and irregular handwritten signatures. Therefore, a table-recognition algorithm based on a directional connected chain is proposed in this paper to solve the problem of identifying sensitive table data captured by intelligent IoT vision devices. First, a Directional Connected Chain (DCC) search algorithm is proposed for line detection. Then, valid line mergence and invalid line removal is performed for the searched DCCs to detect the table frame, to filter the irregular interferences. Finally, an inverse perspective transformation algorithm is used to restore the table after perspective transformation. Experiments show that our proposed algorithm can achieve accuracy of at least 92%, and filter stamp interference completely.