Search

Trimethylamine N-oxide (TMAO) and phenylacetylglutamine (PAGln) are associated with acute myocardial infarction (AMI) and type 2 diabetes mellitus (T2DM). This study developed and validated a simple method firstly for simultaneously quantifying serum TMAO and PAGln using liquid chromatography-tandem mass spectrometry (LC-MS/MS).Serum samples from patients with T2DM, AMI, and healthy subjects were analyzed using a new LC-MS/MS method to evaluate TMAO and PAGln levels. Statistical analyses were performed to evaluate TMAO and PAGln distributions among different groups.Retention and separation of the two metabolites were achieved within 5 min. For both analytes, the assay was linear in a 0.02-10 µg/mL range, with 0.99 average linear correlation coefficients, and quantification limit values of approximately 0.010 µg/mL. The average recoveries of TMAO and PAGln were 96.3 % and 96.4 %, respectively. The intra-run and total coefficient variations were 3.5-4.8 % and 3.9-5.7 % respectively for TMAO; and 4.0-5.1 % and 4.6-6.3 % respectively for PAGln. TMAO and PAGln showed a moderate correlation (P 0.001) and their levels in patients with T2DM were significantly higher than those in healthy individuals (P 0.001). TMAO levels were higher in patients with T2DM than in patients with AMI (P 0.01). Patients with AMI had higher PAGln levels than healthy individuals (P 0.05). After adjusting for sex and age, the top tertile of PAGln was positively correlated with T2DM and AMI while that of TMAO was positively correlated with T2DM.Overall, a robust isotope dilution LC-MS/MS method was established, which may be beneficial for assessing the association between two metabolites with AMI and T2DM.

Objectives Measurement of the serum levels of vitamin B12 (VB12) is key for evaluating VB12 deficiency-dependent anemia. Immunoassay, the major method for determining VB12, tends to give false-normal results because of the presence of anti-intrinsic factor (IF-Ab) or other factors such as heterophilic antibodies et al. This study aimed to develop a liquid chromatography tandem mass spectrometry (LC-MS/MS) method that is helpful for distinguish false normal VB12 results measured by the immunoassay. Methods Different forms of VB12 were derivatized into CN-B12, which was collected through solid-phase extraction and analyzed via LC-MS/MS. 236 serum samples were measured both by LC-MS/MS and immunoassay, results were compared, and the IF-Ab effect was evaluated. Results The LC-MS/MS assay afforded a linear slope from 20 to 4,000 pmol/L for CN-B12. OH-VB12, methyl-VB12, and CoA-VB12 showed recovery within 89.3–109.5%. The intra-assay CV of VB12 was 2.6–4.1%, whereas the total CV was 9.3–9.8%. Passing–Bablok regression between LC-MS/MS and immunoassay results showed that the slope was 1.085 and the intercept was −15.691. The Bland–Altman plot showed that the mean difference and difference% were −34.6 pmol/L and 0.3%, respectively. Inter-rater agreement analysis showed that the linear weighted kappa value was 0.885, implying good agreement between the two methods. However, two samples were falsely elevated and one sample was falsely normal in the immunoassay compared with LC-MS/MS. The LC-MS/MS method helped in the distinction of false-normal VB12 results shown by the immunoassay. Conclusions The VB12 LC-MS/MS method can be used as an arbiter of clinically discordant immunoassay results.

Gestational diabetes mellitus (GDM) is the most common metabolic disturbance during pregnancy, with adverse effects on both mother and fetus. The establishment of early diagnosis and risk assessment model is of great significance for preventing and reducing adverse outcomes of GDM. In this study, the broad-scale perturbations related to GDM were explored through the integration analysis of metabolic and clinical phenotypes. Maternal serum samples from the first trimester were collected for targeted metabolomics analysis by using ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Statistical analysis was conducted based on the levels of the 184 metabolites and 76 clinical indicators from GDM women ( n =60) and matched healthy controls ( n =90). Metabolomics analysis revealed the down-regulation of fatty acid oxidation in the first trimester of GDM women, which was supposed to be related to the low serum level of dehydroepiandrosterone.While the significantly altered clinical phenotypes were mainly related to the increased risk of cardiovascular disease, abnormal iron metabolism, and inflammation. A phenotype panel established from the significantly changed serum indicators can be used for the early prediction of GDM, with the area under the receiver-operating characteristic curve (ROC) 0.83. High serum uric acid and C-reaction protein levels were risk factors for GDM independent of body mass indexes, with ORs 4.76 (95% CI: 2.08-10.90) and 3.10 (95% CI: 1.38-6.96), respectively. Predictive phenotype panel of GDM, together with the risk factors of GDM, will provide novel perspectives for the early clinical warning and diagnosis of GDM.

The features of indeterminate results (ITRs) due to high interferon gamma (IFN-γ 8.0 IU/mL) concentrations in Nil tubes of QuantiFERON-TB Gold in-Tube (QFT-GIT) have not been well studied. Therefore, this study aimed at investigating the features of ITRs and optimization alternatives for this method.We used the plasma exchange method to reduce the ITR rate due to high Nil concentrations (Nil 8.0 IU/mL) between March 2020 and September 2021 at Xiangya Hospital of Central South University in China. One hundred and eleven out of 28,193 patient samples were considered ITRs due to Nil 8.0 IU/mL. Of these 111, blood was re-sampled from 82 patients (pretreated group) who received the plasma exchange. Moreover, 40 out of 82 (blood volume ≥ 5 mL) received pretreated QFT-GIT and standard QFT-GIT (untreated group) simultaneously, while the remaining 42 received pretreated QFT-GIT only. The statistical difference between groups was evaluated. Cohen's kappa coefficient was used to assess the level of agreement between the pretreated and untreated group.Of the 28,193 subjects, 1,083 (3.8%) had ITRs, and 111 (0.4%) had ITRs due to Nil 8.0 IU/mL. The population studied had a mean age of 52.9 years, and 70.3% were men, which is a larger proportion than that in patients with ITR and the overall population. Significantly decreased IFN-γ levels in Nil tubes were detected using the pretreated QFT-GIT compared with standard QFT-GIT (p 0.01). The determinate results rate in the pretreated group was significantly higher than that of the untreated group (80% (32/40) vs 57.5%, (23/40), p = 0.03). Further comparison revealed that the pretreated group was consistent with the untreated group in 17/20 (85%) positive tests, 3/3 (100%) negative tests, and 6/17 (35.3%) ITRs. The overall agreement rate was 26/40 (65%) among all 40 subjects, and the κ value was 0.39 (minimal agreement). The majority of results obtained after pretreatment were positive (71.2%, 59/82) and the agreement rate between clinical diagnosis and pretreated QFT-GIT was at least 61.0% (39/59).Plasma exchange pretreated QFT-GIT yields more reliable results than untreated QFT-GIT when processing high Nil concentrations.

Pedicular screws (PS) often are used in lumbar fusion. Cortical bone trajectory (CBT) is a novel technology in lumbar fusion with less evidence of clinical outcomes. Therefore, we conducted a meta-analysis to compare the efficacy and safety between CBT screw fixation and traditional PS in lumbar fusion surgery.Multiple databases were searched for the articles that compared CBT and traditional PS in lumbar fusion surgeries. Meta-analysis was conducted by RevMan 5.3 software. The following indicators were abstracted: visual analog scale (VAS) scores for back and leg pain, Oswestry Disability Index (ODI), Japanese Orthopaedic Association (JOA) score, surgical duration, complications, and blood loss. The quality of the articles was assessed by the Newcastle-Ottawa Scale or Cochrane Handbook.In total, 25 studies were included, involving a total of 1735 patients. There was no difference in preoperative VAS scores, JOA, ODI, postoperative VAS scores, and fusion rates. In addition, postoperative JOA (mean difference [MD] = 0.78, P = 0.02), ODI (MD = -2.09, P = 0.03), surgical duration (MD = -26.90, P = 0.02), complications (MD = 0.70, P = 0.03), and blood loss (MD = -85.27, P = 0.0009) showed greater improvement trends in the CBT group than the PS group, with significant difference.CBT reduced the rate of complications, surgical duration, blood loss, postoperative ODI, and JOA scores. The CBT technique, with better postoperative outcomes, achieved similar fusion rates compared with the PS technique.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging hemorrhagic fever with high mortality. Severe cases progressed rapidly, with deaths occurring within 2 weeks. Therefore, constructing a model to predict disease progression among hospitalized patients plays an important role in clinical practice. The development cohort included 121 patients with SFTS, 25 with severe SFTS, and 96 with mild SFTS. Two of the 64 variables were independent risk factors, including neurological symptoms (odds ratio [OR], 12.915; 95% confidence interval [CI], 3.342-49.916; P0.001) and aspartate aminotransferase/alanine aminotransferase levels (OR, 1.891; 95% CI, 1.272-2.813; P = 0.002). The model's area under the curve (AUC) was 0.882 (95% CI: 0.808-0.956). The mean AUC value obtained from the internal validation was 0.883 (95% CI: 0.809-0.957). The AUC in the external validation cohort was 0.873 (95% CI: 0.775-0.972). This model can be used to identify severely ill patients as early as possible with high predictive value, stability, and repeatability. This model can help clinicians with their treatment plans.

Alagille syndrome (ALGS) type 2 caused by mutations in NOTCH2 has genotypic and phenotypic heterogeneity. Diagnosis in some atypical patients with isolated hepatic presentation could be missed.Using 2087 patients with paediatric liver manifestations, NOTCH2 allele frequencies, in-silico prediction, protein domains and clinical features were analysed to define the pathogenicity of NOTCH2 variants for diagnosis of ALGS type 2.Among 2087 patients with paediatric liver manifestations, significantly more NOTCH2 variants were absent in gnomAD in patients with elevated γ-glutamyltransferase (GGT) (p = .041). Significantly more NOTCH2 variants which were absent in gnomAD were located in protein functional domains (p = .038). When missense variants were absent in gnomAD and predicted to be pathogenic by at least three out of seven in-silico tools, they were found to be significantly associated with liver manifestations with elevated GGT (p = .003). Comparing this to patients with likely benign (LB) variants, the patients with likely-pathogenic (LP) variants have significantly more liver manifestations with elevated GGT (p = .0001). Significantly more patients with LP variants had extra-hepatic phenotypes of ALGS compared with those patients with LB variants (p = .0004).When NOTCH2 variants are absent in gnomAD, null variants and missense variants which were predicted to be pathogenic by at least three in-silico tools could be considered pathogenic in patients with high GGT chronic liver diseases.

Copeptin, a glycosylated peptide of 39 amino acids, is the C-terminal segment of arginine vasopressin (AVP) precursor peptide, which is consisted of two other fragments, vasopressin and neurophysin Ⅱ. The main physiological functions of AVP are fluid and osmotic balance, cardiovascular homeostasis and regulation of the endocrine stress response. Numerous studies have demonstrated that the endogenous AVP in plasma is a meaningful biomarker to guide diagnosis and therapy of diseases associated with fluids disorders and stress. However, due to its instability, short half-time life in circulation and lack of readily available AVP assays, clinical measurement of AVP is restricted. In contrast to AVP, copeptin which is released in an equimolar mode with AVP from the pituitary, has emerged as a stable and simple-to-measure surrogate marker of AVP and displays excellent potential in diagnosis, differentiation and prognosis of various diseases. This review will discuss the studies on the clinical value of copeptin in different diseases, especially in AVP-dependent fluids disorders, as well as issues and prospects of the application of this potential biomarker.

The objective of this study is to describe the typical and atypical clinical and neuroimaging features of ALD in Chinese patients, which will help early diagnosis and intervention to improve prognosis of ALD.Forty-one patients in the Leukoencephalopathy Clinic of Neurology Department, Peking Union Medical College Hospital were enrolled. Detailed clinical manifestations and MRI features were analyzed. The relationship between phenotype and genotype as well as biochemical analysis was observed.The patients were classified according to phenotype and onset age, including 14 childhood cerebral ALD (CCALD), 8 adolescent cerebral ALD (adoCALD), 3 adult cerebral ALD (ACALD), 14 adrenomyeloneuropathy (AMN), and 2 ALD in women. AMN was the main presentation in adults. Visual impairment was usual onset symptom in CCALD and cognitive decline and psychiatric symptoms were found in adoCALD and ACALD. Typical MRI feature of CALD was symmetrical peri-ventricular "butterfly wings" like lesions in frontal and/or occipital lobe with peripheral DWI hyperintensities and Gd enhancement. Corpus callosum and internal capsule were always involved. Unilateral lesions were also possible. Cerebral AMN presented with centrum semiovale diffuse involvement. Spinocerebellar variant was a special subtype of AMN with obvious cerebellar and brainstem lesions. No relationships between phenotype and genotype as well as biochemical VLCFAs analysis were found.We emphasize that corpus callosum and internal capsule are always involved in ALD. A unilateral lesion is also possible. Neuroimaging of cerebral AMN is different from typical CALD with more centrum semiovale involvement. We support spinocerebellar variant was a rare subtype of AMN.

Developing intelligent and morphology-transformable nanomaterials that can spatiotemporally undergo stimulus-responsive size transformation holds great promise for improving the tumor delivery efficiency of drugs

Background Management of inoperable chronic thromboembolic pulmonary hypertension (CTEPH) remains a clinical challenge. Currently, riociguat, a soluble guanylate-cyclase stimulator is recommended by international guidelines. More recently, balloon pulmonary angioplasty (BPA) develops as an alternative treatment for inoperable CTEPH. Method This study is a single-center randomized controlled trial. Subjects with inoperable CTEPH are randomized into either a BPA combined with riociguat or riociguat monotherapy group (2:1) and observed for 12 months after initiation of treatment. The primary endpoint is the change in pulmonary vascular resistance from baseline to 12 months after initiation of treatment. The secondary endpoints include 6-min walk distance (6MWD), WHO-FC, NT-proBNP, SF-36, and other hemodynamic parameters. Safety endpoints are analyzed too. Discussion This study aims to compare the efficacy and safety of BPA combined with riociguat and riociguat monotherapy for inoperable CTEPH. Trial registration Chinese Clinical Trial Registry ChiCTR2000032403. Registered on 27 April 2020.

Progressive familial intrahepatic cholestasis type 1 (PFIC1) results from biallelic pathogenic variants in ATP8B1. This study sought second pathogenic variants in ATP8B1 by whole-genome sequencing (WGS) in four unrelated low γ-glutamyl transpeptidase cholestasis patients in whom clinical suspicion of PFIC1 was high and gene-panel or Sanger sequencing had identified only one pathogenic variant in ATP8B1. Sanger sequencing confirmed WGS findings and determined the origin of each variant. Novel nonrecurrent structural variants in three patients (patient 1 to patient 3) were identified in trans: g.55396652_55403080del (6427-bp deletion), g.55335906_55346620dup (10,715-bp duplication), and g.55362063_55364293dup (2231-bp duplication). One synonymous variant in patient 4 was recognized in trans (c.1029GA, p. Thr343Thr) and demonstrated as deleterious. In conclusion, WGS improves genetic diagnostic yield in PFIC1. These findings expand the gene-variant spectrum associated with familiar intrahepatic cholestasis 1 (FIC1) disease and for the first time report tandem duplication in ATP8B1 associated with cholestasis.

Background Hemoglobin A1c(HbA1c) is widely used to measure glycemic status and control in diabetes testing and treatment and is an important risk factor forcomplications of diabetes. Hemoglobin variants can interfere with the HbA1c testing method by reducing the life span of erythrocytes or due to differences in glycation degrees. In this study, glycation levels of the HbA, HbG-Coushatta, and HbG-Taipei β-chains (βA, βG-Coushatta, and βG-Taipei, respectively) were examined. Methods Blood samples from heterozygotic patients (HbG-Coushatta/HbA, HbG-Taipei/HbA) were analyzed. Glycation rateswere determined using high-performance liquid chromatography with tandem mass spectrometry. Ratios of glycated βG-Coushatta to glycated βA and glycated βG-Taipei to glycated βA were calculated by comparingareas under the curves from extracted ion chromatograms. Results βG-Coushatta and βG-Taipei were 6.08 ± 1.38% and 5.95 ± 0.93% glycated (respectively), which were significantly higher than βA chains(4.55 ± 1.30% and 4.51 ± 0.91%, respectively; p = 0.000). The total glycation degree (α + β) in HbG-Coushatta and HbG-Taipei heterozygotes were estimated to be 9% and 8% higher than those of HbA homozygotes (P＜0.001), respectively. Conclusion βG-Coushatta and βG-Taipei glycation degrees were significantly higher than βA, while the differences in total hemoglobin (α + β) were small and unlikely to impact the clinical interpretation of HbA1c results.

Organic fertilizers can be crucial in promoting sustainable agricultural development, but they are not used in a wide-ranging way among smallholder farmers in many developing countries. In China, cooperatives are considered essential subjects of agricultural technical training, but it is more common to join cooperatives without participating in their technical training. Thus, joining cooperatives or not cannot simply be used to assess the role of cooperatives in influencing the farmers’ production behavior. Based on survey data of 1160 citrus farmers in Sichuan Province, China, this study estimated the effect of the technical training provided by agricultural cooperatives on farmers’ adoption of organic fertilizers, taking into account the farmers’ ability and perception as the mediation variables. The findings showed that participating in the technical training provided by agricultural cooperatives could significantly enhance the likelihood that farmers will adopt organic fertilizers. The impact was 81.6% in influencing the farmer’s abilities and 7.64% in their perceptions of organic fertilizers. Furthermore, other variables, such as farm sizes, land transfers, and education levels, also make a difference in the effectiveness of the agricultural cooperatives’ technical training. This study provides support for developing pertinent policies to promote the complete adoption of agricultural cooperatives’ technical training functions and the widespread use of organic fertilizers.

Background Currently, the direct method is the main approach for establishment of reference interval (RI). However, only a handful of studies have described the effects of sample size on establishment of RI and estimation of sample size. We describe a novel approach for estimation of the sample size when establishing RIs using the transformed parametric and non-parametric methods. Methods A total of 3,697 healthy participants were enrolled in this study. We adopted a two-layer nested loop sample size estimation method to determine the effects of sample size on RI, using thyroid-related hormone as an example. The sample size was selected as the calculation result when the width of the confidence interval (CI) of the upper and lower limit of the RI were both stably Results Sample sizes for thyroid stimulating hormone (TSH), as required by parametric and non-parametric methods to establish RIs were 239 and 850, respectively. Sample sizes required by the transformed parametric method for free triiodothyronine (FT3), free thyroxine (FT4), total triiodothyronine (TT3) and total thyroxine (TT4) were all less than 120, while those required by the non-parametric method were more than 120. Conclusion We describe a novel approach for estimating sample sizes for establishment of RI. A corresponding open-source code has been developed and is available for applications. The established method is suitable for most analytes, with evidence based on thyroid-related hormones indicating that different sample sizes are required to establish RIs using different methods for analytes with different variations.

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a complex disease with a strong genetic component. More than 40 loci have been identified to be associated with the risk of NSCL/P by genome-wide association studies (GWASs), but the majority of these variants are mapped to non-coding regions of the genome. Expression quantitative trait locus (eQTL) studies have increasingly been integrated with GWASs to identify target genes for these non-coding variants. In this study, we generated a unique, lip-specific eQTL dataset from 40 NSCL/P patients. A total of 5158 eQTL SNPs (eSNPs) -689 eQTL genes were identified after multiple corrections. Then, we integrated nominal eQTL SNPs with NSCL/P risk SNPs and identified 243 variants associated with the expression of 18 genes in lip tissues. Functional annotation analysis indicated that these risk eSNPs were significantly enriched in transcription regulation and chromatin open regions on the genome. These susceptible genes were enriched in cell fate determination, the pluripotency of stem cells, and Wnt signaling pathways. Finally, 8 of the 18 susceptible genes were differentially expressed in NSCL/P case-control studies. In summary, we have generated a unique lip-specific eQTL resource and identified multiple associations for NSCL/P risk loci, which should inform functional studies of NSCL/P biology.

Colorectal cancer (CRC) is a malignant tumor and morbidity rates are among the highest in the world. The variation in CRC patients' prognosis prompts an urgent need for new molecular biomarkers to improve the accuracy for predicting the CRC patients' prognosis or as a complement to the traditional TNM staging for clinical practice. CRC patients' gene expression data of HTSeq‐FPKM and matching clinical information were downloaded from The Cancer Genome Atlas (TCGA) datasets. Patients were randomly divided into a training dataset and a test dataset. By univariate and multivariate Cox regression survival analyses and Lasso regression analysis, a prediction model which divided each patient into high‐or low‐risk group was constructed. The differences in survival time between the two groups were compared by the Kaplan–Meier method and the log‐rank test. The weighted gene co‐expression network analysis (WGCNA) was used to explore the relationship between all the survival‐related genes. The survival outcomes of patients whose overall survival (OS) time were significantly lower in the high‐risk group than that in the low‐risk group both in the training and test datasets. Areas under the ROC curves which termed AUC values of our 9‐gene signature achieved 0.823 in the training dataset and 0.806 in the test dataset. A nomogram was constructed for clinical practice when we combined the 9‐gene signature with TNM stage and age to evaluate the survival time of patients with CRC, and the C‐index increased from 0.739 to 0.794. In conclusion, we identified nine novel biomarkers that not only are independent prognostic indexes for CRC patients but also can serve as a good supplement to traditional clinicopathological factors to more accurately evaluate the survival of CRC patients., We identified a 9‐gene signature screened out based on batch survival analysis that can be used not only as an independent prognostic index for CRC patients but also as a favorable supplement to traditional clinicopathological factors for clinicians to more accurately and effectively evaluate the survival of CRC patients.

Obesity induces skeletal muscle dysfunction. The pathogenesis of which appears to substantially involve mitochondrial dysfunction, arising from impaired quality control. Exercise is a major therapeutic strategy against muscle dysfunction. Trimetazidine, a partial inhibitor of lipid oxidation, has been proposed as a metabolic modulator for several cardiovascular pathologies. However, the effects of Trimetazidine on regulating skeletal muscle function are largely unknown. Our present study used cell culture and obese mice models to test a novel hypothesis that Trimetazidine could improve muscle atrophy with similar results to exercise. In C2C12 cells, high palmitic acid-induced atrophy and mitochondrial dysfunction, which could be reversed by the treatment of Trimetazidine. In our animal models, with high-fat diet-induced obesity associated with skeletal muscle atrophy, Trimetazidine prevented muscle dysfunction, corrected metabolic abnormalities, and improved mitochondrial quality control and mitochondrial functions similarly to exercise. Thus, our study suggests that Trimetazidine successfully mimics exercise to enhance mitochondrial quality control leading to improved high-fat diet-induced muscle dysfunction.

Background Two major forms of gastrin, gastrin-17 (G17) and gastrin-34 (G34), exist in blood. However, conventional immunoassay methods can only quantify total gastrin or G17 alone. Here, we aimed to establish a liquid chromatography–tandem mass spectrometry (LC–MS/MS) method to quantify G17 and G34 simultaneously. Methods Serum samples were prepared by anion-exchange solid-phase extraction. The analytical performance of the LC–MS/MS method was validated and the method was compared to chemiluminescence immunoassay (CLIA) and radioimmunoassay (RIA). The G17 and G34 concentrations in 245 serum samples from healthy controls, individuals with gastrinoma, and individuals with other diseases were analyzed. Results The total runtime of the LC–MS/MS method was 6 min. No substantial matrix effect was observed with internal standard correction. The intraassay coefficients of variation (CVs) for G17 and G34 were 4.0%–14.2% and 4.4%–10.4%, respectively, and total CVs were 5.2%–14.1% and 4.6%–12.4%, respectively. The correlation coefficient between LC–MS/MS and CLIA was 0.87, and between LC–MS/MS and RIA was 0.84. The G17+G34 concentrations for 87.5% of individuals with gastrinoma were higher than the 95th percentile of healthy controls (18.1 pg/mL), whereas the concentrations for individuals with other diseases and gastrinoma overlapped. Based on the Youden indices calculated for G17+G34, G34, and G17, the most specific biomarker was G17 (96.9% clinical specificity at 209.8 pg/mL) for gastrinoma. Conclusions This method should aid in the diagnosis of diseases associated with increased gastrin concentrations.

Pretargeted imaging has emerged as a promising approach to advance nuclear imaging of malignant tumors, however, the application of pretargeted strategy for multimodality imaging of enzyme activity in vivo is challenging. Herein, we combine the enzyme-mediated fluorogenic reaction and in situ self-assembly with the inverse electron demand Diels-Alder (IEDDA) reaction to develop an activatable pretargeted strategy for multimodality imaging. The trans -cyclooctene (TCO) bearing small-molecule probe, P-FFGd-TCO , can be activated by alkaline phosphatase and in situ self-assembles into nanoaggregates ( FMNPs-TCO ) retained on the membranes, permitting to (1) amplify near-infrared (NIR) fluorescence (FL) and magnetic resonance imaging (MRI) signals, and (2) enrich TCOs to promote IEDDA ligation. The Gallium-68 ( 68 Ga) labeled tetrazine can readily conjugate the tumor-retained FMNPs-TCO to enhance radioactivity uptake in tumors. Hence, strong NIR FL, MRI and positron emission tomography (PET) signals are concomitantly achieved, allowing for pretargeted multimodality imaging of ALP activity in HeLa tumor-bearing mice.

The objective of this study is to investigate the impact of preconceptional exposure to oil-based iodinated contrast in the hysterosalpingography (HSG) on pregnant women and their offspring's iodine status, thyroid function, and the outcomes of pregnancy. A cross-sectional evaluation of iodine status was performed on pregnant women with the preconceptional experience of ethiodized-oil HSG. For those found to have iodine excess (with serum iodine concentration (SIC) > 92 μg/L), a prospective follow-up was conducted until termination of the pregnancy or 1 week postpartum. Among 70 of 425 pregnant women with preconceptional ethiodized-oil HSG, iodine excess was initially confirmed in 38 (54.3%), with an elevated SIC (294.00 μg/L [142.00, 123.20]) and urinary iodine-to-creatinine ratio (UI/Cr) (830.00 μg/g Cr [437.50, 255.30]), both higher than the normative data (P = 0.000, P = 0.000). Subsequent follow-up in pregnancy showed a downward trend in both SIC and UI/Cr. Thirty-four women delivered healthy neonates at full term, though the other 4 cases of premature birth, abnormal fetal karyotype, spontaneous abortion, and neonatal cardiac defect were reported. After delivery, the iodine concentration in maternal breast milk and neonatal urine was 584.50 μg/L [328.50, 1507.50] and 424.00 μg/L [277.00, 657.50], respectively, both higher than normative data (P = 0.001, P = 0.015). For thyroid evaluation, 25 cases (65.79%) of clinical or subclinical hypothyroidism and 2 cases (5.26%) of thyrotoxicosis were confirmed in women with iodine excess. Neither goiter nor thyroid dysfunction was detected in any offspring. Preconceptional exposure to oil-based contrast in HSG might exert a far-reaching impact on maternal and offspring iodine status, and tend to result in increased risk of maternal thyroid dysfunction.

Background Unprotected anal intercourse (UAI) within the context of concurrent sexual relationship are prevalent among men who have sex with men (MSM) who have regular male sex partners and it aggravates the risk of HIV infection among this community. The aim of this study was to assess the effect of intimate relationship characteristics on UAI among MSM couples at the dyadic level. Methods Two hundred four MSM couples were recruited from a HIV testing clinic from April 2017 to April 2018 in Guangzhou, China. The actor-partner interdependence model (APIM) was applied for dyadic analysis. Each MSM couple was divided into the insertive role and the receptive role according to their regular anal sex role. In this context, actor effect is the impact of an MSM’s intimate relationship characteristics on his own UAI, and partner effect is the impact of his partner’s intimate relationship characteristics on his UAI. Results Of the 408 participants, 58.82% had UAI with regular male sex partner (UAI-RP) and 8.09% had concurrent UAI. Intimate relationship characteristics were associated with concurrent UAI, but not associated with UAI-RP. For the receptive role, his relationship investment exerted significant actor and partner effects on concurrent UAI (AORactor = 1.31, P AORpartner = 1.17, P AORactor = 6.43, P = 0.044). Conclusions Relationship investment and violence experience influenced concurrent UAI among MSM couples and it varied in different sex roles. Additional assistance on empowerment, relationship therapy and sexual agreement is urgently needed to reduce their high possibility on engagement of HIV-related risk behaviors.

Background Reference values of cardiopulmonary exercise testing (CPX) vary with race/ethnicity. Chinese Americans are the fastest-growing racial/ethnic group in the United States. However, there is limited information about the reference values of cardiopulmonary exercise testing (CPX) variables in the Chinese population. Methods As part of the Xiangya Hospital Exercise Testing project (the X-ET project), this cross-sectional study screened 20,696 consecutive CPXs performed by 17,802 unique individuals at Xiangya Hospital of Central South University, China, from January 1, 2002, to December 31, 2019. A total of 964 unique healthy adults/tests (42% female) aged 49 ± 12 who completed a maximal ramp incremental CPX with cycle ergometry were included in this study. The reference values of primary CPX variables were expressed as the lower limit or upper limit of normal. Stepwise linear regression was used to fit the equations of key CPX variables. Predictive accuracy analysis for the equations with a comparison between present and previous studies were performed. Results Peak oxygen consumption ( V O2), carbon dioxide production, ventilation/min, work rate, and V O2 at the anaerobic threshold were regressed on age, height, weight, and sex. These predictive equations showed good in- and out-sample predictive accuracy. Comparison with prior research revealed that prediction equations of peak V O2 resultant from studies in which populations were entirely or primarily Caucasian had overestimated our subjects' actual values. Conclusion The reference values and predicted equations of CPX variables in this study may provide a more appropriate framework to interpret the response to maximal ramp incremental cycle ergometry in the Chinese adult population.

To establish and validate a robust LC-MS/MS method for simultaneously measuring 8-oxoGuo, 8-oxodG, and NMN in serum and urine to evaluate the oxidative stress status.A Waters TQ-XS triple quadrupole mass spectrometer system coupled with an Acquity UPLC Primer HSS T3 column was chosen. The clinical performance was verified according to the CLSI C62-A and EP-15 guidelines. Furthermore, matched serum and urine samples from 22 apparently healthy check-ups, 20 patients with atherosclerosis, and 18 individuals with dementia were evaluated.The recovery for serum 8-oxoGuo, urine 8-oxoGuo, serum 8-oxodG, urine 8-oxodG, serum NMN, and urine NMN was 88.8-112.4%, 102.4-114.1%, 88.5-107.7%, 94.9-102.6%, 98.4-108.9%, and 88.5-108.6%, respectively. Based on the inter-assay results, total coefficient of variation, matrix effect, and carryover, the LC-MS/MS method was deemed robust. The limit of quantification was 0.017, 0.018, and 0.150 nmol/L for 8-oxoGuo, 8-oxodG, and NMN, respectively, which are suitable for accurate measurements in human serum and urine samples. Higher 8-oxoGuo and 8-oxodG levels and lower NMN levels, indicative of significantly higher oxidative stress status, were found in patients with dementia compared to healthy subjects.We established and validated a robust LC-MS/MS method to simultaneously measure 8-oxoGuo, 8-oxodG, and NMN in serum and urine.

It is currently unclear for the necessary of pre-heating urine samples for the accurate determination of 8-oxo-7,8-dihydroguanosine (8-oxoG) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG). Thus, we conducted this study to evaluate the effect of pre-heat (i.e., to 37°C) on the accurate measurement of 8-oxoG and 8-oxodG in frozen urine samples.Random urine samples from six healthy volunteers, six patients with renal dysfunction, and six patients with systematic diseases such as diabetes were collected, split, and stored at -80°C for up to 1 month. The frozen samples were thawed at room temperature (RT) or 37°C for different time, 10-fold diluted with ddH2O containing 1% formic acid, and determined by self-established LC-MS/MS method coupled with an ACQUITY™ Primer HSS T3 column.Thawing the samples at RT for 30 or 120 min, or at 37°C for 15 or 90 min did not affect the determination of 8-oxoG and 8-oxodG in urine samples. Moreover, no significant difference between thawing the urine samples at RT and 37°C was found after storing at -80°C for 1-3 months.It is not always necessary to pre-heat the frozen urine samples to release 8-oxoG and 8-oxodG from precipitates, which is associated with different pre-treatment and determination methods.

To observe the clinical effect of moxibustion combined with plucking technique at Jiquan (HT 1) for preventing peripherally inserted central catheter (PICC)-related venous thrombosis in the upper limbs of malignant tumor patients.A total of 80 malignant tumor patients undergoing PICC were randomized into an observation group and a control group, 40 cases in each one. In the control group, the routine care for PICC was exerted. In the observation group, besides the routine care, moxibustion combined with plucking technique at Jiquan (HT 1) was added. Mild moxibustion was exerted along the venous distribution of PICC (avoiding the entry site) for 10 to 15 min, and then, the circling moxibustion was applied to Quchi (LI 11), Xuehai (SP 10) and Tianfu (LU 3), 3 to 5 min at each acupoint. Finally, plucking technique was given at Jiquan (HT 1) for 5 to 10 min. This combined therapy was intervened since the 2nd day of PICC placement, once daily, 5 times a week, for 3 weeks totally. The incidence of the PICC-related venous thrombosis in the upper limbs was compared between the two groups on day 42 of placement. On day 2, 7, 14, 21, 28, 35 and 42 of PICC placement, the peak systolic velocity (PSV) and the end-diastolic velocity (EDV) of the subclavicular vein on the placement side were observed separately in the two groups.The incidence of the PICC-related venous thrombosis in the upper limbs in the observation group was lower than that in the control group (2.5% [1/40]The combined treatment of moxibustion with plucking technique at Jiquan (HT 1) can effectively prevent PICC-related venous thrombosis in the upper limbs and improve venous blood flow velocity in malignant tumor patients.

Background:Lung cancer is the leading cause of cancer-associated mortality in the world. Traditional cancer therapies prolong the life expectancy of patients but often suffer from adverse reactions. Photodynamic Therapy (PDT) has been recommended as a treatment option for lung cancer in several countries, due to its non-invasive procedures, high selectivity and weak side effects.Objective:We have designed and synthesized a biotin receptor-targeted silicon phthalocyanine (IV) (compound 1) which showed a good therapeutic effect on biotin receptor-positive tumors. Since the overexpression of Biotin Receptor (BR) is also present in human lung cancer cells (A549), we explored the therapeutic properties of compound 1 on A549 xenograft tumor models.Methods:The selectivity of compound 1 toward A549 cells was studied with a fluorescence microscope and IVIS Spectrum Imaging System. The cytotoxicity was measured using the MTT assay. In vivo anti-tumor activity was investigated on the nude mice bearing A549 xenografts.Results:In vitro assays proved that compound 1 could selectively accumulate in A549 cells via the BR-mediated internalization. In vivo imaging and distribution experiments showed that compound 1 could selectively accumulate in tumor tissues of tumor-bearing mice. After 16 days of the treatment, the volumes of tumor in the PDT group were obviously smaller than that in other groups.Conclusion:This study demonstrates that compound 1 is a promising photosensitizer and has broad application prospects in clinical PDT of lung cancers.

Programmed cell death ligand 1 (PD‐L1), inducing T cell exhaustion to facilitate immune escape of tumor cells, is upregulated by interleukin 6 (IL‐6) in T cell lymphoma and ovarian cancer. The purpose of this study is to investigate the expression of IL‐6 and PD‐L1 in thyroid cancer, and whether IL‐6 regulates PD‐L1 expression. As a result, IL‐6 and PD‐L1 were highly expressed in thyroid cancer tissues. Multivariate logistic analysis showed that tumor size, distant metastasis, and risk stratification were significantly associated with IL‐6 expression (P, IL‐6 and PD‐L1 are highly expressed in thyroid cancer and correlate with disease aggressiveness. IL‐6 activates the MAPK and JAK‐STAT3 signaling pathways in thyroid cancer. In addition, IL‐6 promotes PD‐L1 transcription through the MAPK and JAK‐STAT3 signaling pathways, which function via transcription factors c‐Jun and stat3.

Background: It is important to properly understand the molecular mechanisms of aggressive tumors among papillary thyroid carcinomas (PTCs) that are often the most indolent. Hypoxia inducible factor-1α (HIF-1α), induced by hypoxia, plays pivotal roles in the development and metastasis of the many tumors, including PTCs. Upregulation of telomerase reverse transcriptase (TERT) activity is found in highly invasive PTCs. Further, previous studies have reported that autophagy serves as a protective mechanism to facilitate PTC cell survival. We, therefore, hypothesized that there was a link between HIF-1α, TERT, and autophagy in promoting PTC progression. Methods: Immunohistochemistry staining was conducted to evaluate the expressions of HIF-1α, TERT, and autophagy marker, LC3-II, in matched PTC tumors and corresponding nontumor tissues. Two PTC cell lines (TPC-1 and BCPAP) were used in subsequent cytological function studies. Cell viability, proliferation, apoptosis, migration, and invasion were assessed during hypoxia, genetic enhancement and inhibition of TERT, and chemical and genetic inhibition of autophagy. The protein expression levels of the corresponding biomarkers were determined by Western blotting, and autophagy flow was detected. We characterized the molecular mechanism of PTC cell progression. Results: The protein expression levels of HIF-1α, TERT, and LC3-II were upregulated in PTCs and were significantly correlated with high tumor-node-metastasis stage. Further, an in vitro study indicated that HIF-1α induced by hypoxia functioned as a transcriptional activator by binding with sequences potentially located in the TERT promoter and was positively correlated with the malignant behavior of PTC cell lines. Overexpression of TERT inhibited the kinase activity of mammalian target of rapamycin (mTOR), resulting in the activation of autophagy. Functionally, TERT-induced autophagy provided a survival advantage to PTC cells during hypoxia stress. Conclusions: We identified a novel molecular mechanism involving the HIF-1α/TERT axis, which promoted PTC progression by inducing autophagy through mTOR during hypoxia stress. These findings may provide a basis for the new treatment of aggressive PTCs.

Background Thyroid diseases are highly prevalent worldwide, but their diagnosis remains a challenge. We established reference intervals (RIs) for thyroid-associated hormones and evaluated the prevalence of thyroid diseases in China. Methods After excluding outliers based on the results of ultrasound screening, thyroid antibody tests, and the Tukey method, the medical records of 20,303 euthyroid adults, who visited the Department of Health Care at Peking Union Medical College Hospital from January 2014 to December 2018, were analyzed. Thyroid-associated hormones were measured by the Siemens Advia Centaur XP analyzer. The RIs for thyroid-associated hormones were calculated according to the CLSI C28-A3 guidelines, and were compared with the RIs provided by Siemens. The prevalence of thyroid diseases over the five years was evaluated and compared using the chi-square test. Results The RIs for thyroid stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), total thyroxine (TT4), and total triiodothyronine (TT3) were 0.71-4.92 mIU/L, 12.2-20.1 pmol/L, 3.9-6.0 pmol/L, 65.6-135.1 nmol/L, and 1.2-2.2 nmol/L, respectively. The RIs of all hormones except TT4 differed significantly between males and females. The RIs of TSH increased with increasing age. The prevalence of overt hypothyroidism, overt hyperthyroidism, subclinical hypothyroidism, and subclinical hyperthyroidism was 0.5% and 0.8%, 0.2% and 0.6%, 3.8% and 6.1%, and 3.3% and 4.7% in males and females, respectively, which differed from those provided by Siemens. Conclusions Sex-specific RIs were established for thyroid-associated hormones, and the prevalence of thyroid diseases was determined in the Chinese population.

Mutations in the MYO5B gene cause in some patients low gamma-glutamyltransferase (low-GGT) cholestatic liver disease (CLD) and in other patients microvillus inclusion disease (MVID, a congenital diarrheal and malabsorption disorder). Overlap of symptoms occurs but more MVID patients present cholestasis than CLD patients present diarrhea. Clinical observations indicate that MYO5B mutations can cause but also protect against CLD. This complicates family counseling and therapeutic decisions. Here we have reviewed the literature on MYO5B mutations in relation to CLD. It appears that variations in the clinical presentation of low-GGT CLD can be attributed to the coincident expression but unequal effects of MYO5B mutations in hepatocytes versus enterocytes, two cell types that jointly constitute the core of the enterohepatic circulation. Therefore, contrasting other low-GGT CLDs, those associated with MYO5B mutations should be viewed as a disease of the enterohepatic circulation rather than solely of the liver.

With the recent developments in information technology, real world big data studies (RWBDSs) have attracted increasing attention in the field of medicine. In RWBDSs, clinical laboratory data is an important part of the wider scope of real-world medical data, and its standardized use is critical for the generation of high-quality real-world evidence. To improve the core functioning and competitiveness of clinical laboratories as well as provide high-quality medical services for patients, it is important to construct an information analysis model and perform RWBDSs. However, among the majority of developing countries, as well as in some developed countries, due to the poorly developed neglect of data formatting standards information construction and the lack of consideration for, and experience with, the ideas and methods of RWBDSs, many clinical laboratories are unable to make use of the vast amount of data stored in their systems. Additionally, in the literature, there remain many areas that require improvements, such as the correct misuse of research methods, appropriate unreasonable data presentation methods, and optimal opaque methods for data cleaning, storage, and mining. In this review, we describe both the advantages and disadvantages of RWBDSs in laboratory medicine. In addition, we summarize the current application and methods of RWBDS in laboratory medicine from seven different perspectives: the establishment of a reference interval, patient data-based real time quality control, diagnostic or prognostic modeling, epidemiological investigation, laboratory management, analysis of sources of variations for analytes, and external quality assessment. Finally, we discuss the future prospects of this research. This review can provide the basis for clinical laboratories to carry out real world research; additionally, it promotes and standardizes RWBDS in laboratory medicine.

Background Given that both insufficient and excess maternal iodine have adverse consequences such as poor cognitive performance, delayed physical development and increased fetal and infant mortality, the determination of maternal iodine status is very important. In this study, we established and verified a method involving inductively coupled plasma-mass spectrometry (ICP-MS) technology for the rapid determination of the amniotic fluid iodine concentration (AFIC), breast milk iodine concentration (BMIC) and cerebrospinal fluid (CSF) iodine concentration (CSFIC). Method Amniotic fluid, breast milk and CSF were collected from residual samples at Peking Union Medical College Hospital (PUMCH). The linearity, detection limit, precision, recovery, carryover and matrix effect of the testing method using ICP-MS technology were thoroughly evaluated according to the EP-10-A2 evaluation protocol approved by the Clinical and Laboratory Standards Institute (CLSI) guidelines. Furthermore, we evaluated the AFIC, BMIC and CSFIC distributions among clinical patients from PUMCH. Results The correlation coefficient (r) was higher than 0.99 (0.995–1.000). The limit of detection (LOD) was 0.233 µg/L, and the limit of quantification (LOQ) was 0.778 µg/L. For amniotic fluid, breast milk and CSF, the assay repeatabilities were 1.5%–1.8%, 1.9%–4.0% and 1.8%–4.0%, respectively, and the within-laboratory coefficient of variations (CV%) over five days were 3.3%–9.2%, 7.2%–8.0% and 3.2%–7.8%, respectively. The recovery rates ranged from 97.7% to 109.8%. Moreover, the median concentrations of iodine in the amniotic fluid, breast milk and CSF of the patients from PUMCH were 176.3 µg/L, 136.0 µg/L, and 81.8 µg/L, respectively. Conclusion A rapid, stable and accurate method that incorporates ICP-MS technology for the determination of iodine concentration was established for amniotic fluid, breast milk and CSF in this study.

Both thyroid-stimulating immunoglobulins immunoassay (TSI IA) and thyrotrophin receptor antibody immunoassay (TRAb IA) are commonly used for the diagnosis of Graves’ disease (GD). The aim of the present study was to compare the clinical diagnostic performance of these two methods. Sera were obtained from 1103 subjects presenting a variety of clinical conditions from three centers: 100 subjects with untreated GD, 200 with treated GD, 62 with autoimmune thyroid disease(AIT), 216 with other thyroid diseases (OTHER-T), 214 with non-thyroid autoimmune diseases (NTAD), 191 with other diseases (OD), and 120 healthy subjects (HS). Both TSI and TRAb IAs were performed for all 1013 serum samples. Bioassay was performed for 86 samples whose TSI results were inconsistent the TRAb assay results. Comparing untreated GD patients with the control groups (AIT, NTAD, OTHER-T, OD, and HS) resulted in an area under the curve (AUC) of 0.992 for the TSI IA and 0.989 for the TRAb IA with no statistically significant difference observed between these AUC values (P = 0.2733). The best TSI CDP (clinical decision point) value was 0.42 IU/L. The differences in sensitivity (100% vs. 95%, P = 0.7991) and specificity (97.1% vs. 97.6%, P = 0.9426) between the TSI and TRAb IA were not statistically significant. TSI IA had a higher agreement with the TSI bioassay than TRAb IA. The clinical diagnostic performance of the TSI IA for diagnosing Graves’ disease was very similar to that of the TRAb IA. TSI IA can be used to diagnose GD in the Chinese.

Background Despite recent progress in screening survival-related genes, there have been few attempts to apply methods based on cancer stem cells (CSCs) for prognosis. We aimed to identify a CSC-based model to predict survival in colorectal cancer (CRC) patients. Material/Methods Differentially expressed genes between CRC and normal tissues and between CD133- and CD133+ cells were obtained from The Cancer Genome Atlas and Gene Expression Omnibus, and intersections were evaluated. Gene Ontology functional and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyzes were performed. STRING was used to investigate interactions between the encoded proteins and the Kaplan-Meier method to verify mRNAs associated with survival. A prognostic model based on CSCs was established via univariate and multivariate Cox regression. Receiver operating characteristic curve analysis was conducted to test the model’s sensitivity and specificity. The KS test was applied to provide evidence for relationships between expression levels of nine mRNAs in our model and pathological stage. Results In total, 155 common differentially expressed mRNAs were identified, and nine (AOC1, UCN, MTUS1, CDC20, SNCB, MAT1A, TUBB2B, GABRA4 and ALPP) were screened after regression analyses to establish a predictive model for classifying patients into high- and low-risk groups with significantly different overall survival times, especially for stage II and IV patients. Conclusions We developed a novel model that provides additional and powerful prognostic information beyond conventional clinicopathological factors for CRC survival prediction. It also provides new insight into the molecular mechanisms underlying the transition from normal tissues to CSCs and formation of tumor tissues.

C6-ceramide is an exogenous short-chain ceramide which can induce apoptosis of multiple cancer cells. Salivary adenoid cystic carcinoma (SACC) is a common salivary gland cancer, which possesses of high rate of local recurrence and distant metastasis. The mechanism of ceramide-induced SACC-83 and SACC-LM cell apoptosis has not been revealed. In our study, gene expression microarray was used to discover that the unfolded protein response (UPR) pathway, especially PRKR-like endoplasmic reticulum kinase (PERK) pathway, was the major activated pathway after treatment of c6-ceramide. D1ER, an endoplasmic-reticulum-targeted Ca2+ indicator, was used to measure Ca2+ release from endoplasmic reticulum (ER) dynamically. We found that inositol 1,4,5-trisphosphate receptor 3 (IP3R3) was activated, leading to Ca2+ release from ER, soon after c6-ceramide treatment. IP3R3 silencing could block UPR, although it could not prevent SACC-83 and SACC-LM cells from apoptosis. Moreover, we found that C/EBP-homologous protein could upregulate in a UPR-independent way. Mitochondria outer membrane permeabilization might play an important role in inducing SACC cell apoptosis.

Neuroblastoma breakpoint family, member 1 (

TMEM67 (mecklin or MKS3) locates in the transition zone of cilia. Dysfunction of TMEM67 disrupts cilia-related signaling and leads to developmental defects of multiple organs in humans. Typical autosomal recessive TMEM67 defects cause partial overlapping phenotypes, including abnormalities in the brain, eyes, liver, kidneys, bones, and so forth. However, emerging reports of isolated nephronophthisis suggest the possibility of a broader phenotype spectrum. In this study, we analyzed the genetic data of cholestasis patients with no obvious extrahepatic involvement but with an unexplained high level of gamma-glutamyl transpeptidase (GGT). We identified five Han Chinese patients from three unrelated families with biallelic nonnull low-frequency TMEM67 variants. All variants were predicted pathogenic in silico, of which p. Arg820Ile and p. Leu144del were previously unreported. In vitro studies revealed that the protein levels of the TMEM67 variants were significantly decreased; however, their interaction with MKS1 remained unaffected. All the patients, aged 7-39 years old, had silently progressive cholestasis with elevated GGT but had normal bilirubin levels. Histological studies of liver biopsy of patients 1, 3, and 5 showed the presence of congenital hepatic fibrosis. We conclude that variants in TMEM67 are associated with a mild phenotype of unexplained, persistent, anicteric, and high GGT cholestasis without typical symptoms of TMEM67 defects; this possibility should be considered by physicians in gastroenterology and hepatology.

Background A retrospective study and a randomized controlled trial published in a high quality journal in late 2018 have shown that laparoscopic radical hysterectomy (RH) was associated with worse survival than abdominal RH among patients with early stage cervical cancer. Radical hysterectomy in cervical cancer has been a classic landmark surgery in gynecology, therefore this conclusion is pivotal. The current trial is designed to reconfirm whether there is a difference between laparoscopic RH and abdominal RH in cervical cancer (stage IA1 with LVSI, IA2) patient survival under stringent operation standards and consistent tumor-free technique. This paper reports the rationale, design, and implementation of the trial. Methods This is an investigator-initiated, prospective, randomized, open, blinded endpoint (PROBE) controlled trial. A total of 690 patients with stage IA1 (with intravascular), and IA2 cervical cancer will be enrolled over a period of three years. Patients are randomized (1:1) to either the laparoscopic RH or the abdominal RH group. Patients will then be followed-up for at least five years. The primary endpoint will be 5-year progression-free survival. Secondary endpoints will include 5-year overall survival rates, recurrence rates, operation time, intraoperative blood loss, surgery-related complications, and quality of life. Discussion The results of the trial will provide valuable evidence for guiding clinical decision of choosing appropriate treatment strategies for stage IA1 (LVSI) and stage IA2 cervical cancer patients. Trial registration ClinicalTrials.gov (NCT04934982, Registered on 22 June 2021).

Background A retrospective study and a randomized controlled trial published in late 2018 have shown that laparoscopic radical hysterectomy (RH) was associated with worse survival than abdominal RH among patients with early-stage cervical cancer. Radical hysterectomy in cervical cancer has been a classic landmark surgery in gynecology; therefore, this conclusion is pivotal. The current trial is designed to reconfirm whether there is a difference between laparoscopic RH and abdominal RH in cervical cancer (stages IB1, IB2, and IIA1) patient survival under stringent operation standards and consistent surgical oncologic principles. Methods/design This is an investigator-initiated, Prospective, Randomized, Open, Blinded End-point (PROBE)-controlled non-inferiority trial. A total of 780 patients with stage IB1, IB2, and IIA1 cervical cancer will be enrolled over a period of 3 years. Patients are randomized (1:1) to either the laparoscopic RH or the abdominal RH group. Patients will then be followed up for at least 5 years. The primary endpoint will be 5-year progression-free survival, and secondary endpoints include 5-year overall survival, recurrence, and quality of life measurements. Discussion The debate on laparoscopic versus abdominal RH is still ongoing, and high-quality evidences are needed to guide clinical practice. The study results will provide more convincing evidence-based information for early-stage cervical cancer patients and their gynecologic cancer surgeons in their choice of surgical method. Trial registration ClinicalTrials.govNCT04929769. Registered on 18 June 2021

The chronic kidney disease-mineral and bone disorder（CKD-MBD) is known to be associated with increased mortality in dialysis patients, but whether current global guidelines for CKD-MBD, which were primarily developed from hemodialysis, are suitable for peritoneal dialysis (PD) patients practice require further investigation.This is a single-center retrospective cohort study. In total 491 prevalent PD patients (median follow-ups: 34 months) from Peking Union Medical College Hospital (PUMCH) from January 2004 to December 2017 were included and followed until 30 June 2018. In the first dialysis year, the average levels of serum calcium, albumin-corrected calcium (CorCa), phosphorus, and parathyroid hormone (PTH) levels were the interested predictors in Cox proportional regression model.Of these PD patients (age 58 ± 17 years), 52% were male and 36% had diabetic nephropathy. In Cox regression over first-year mean parameters, PTH100 pg/mL (HR = 1.97, 95% CI 1.32 to 2.94,As one of the largest PD cohort study focusing on CKD-MBD, we demonstrated that the level of CKD-MBD markers in the first PD year are independent predictors of all-cause mortality. PTH 100-300 pg/mL might be the best target for Chinese PD patients.

International audience; Processed foods often include food additives such as xanthan gum, a complex polysaccharide with unique rheological properties, that has established widespread use as a stabilizer and thickening agent. Xanthan gum's chemical structure is distinct from those of host and dietary polysaccharides that are more commonly expected to transit the gastrointestinal tract, and little is known about its direct interaction with the gut microbiota, which plays a central role in digestion of other dietary fibre polysaccharides. Here we show that the ability to digest xanthan gum is common in human gut microbiomes from industrialized countries and appears contingent on a single uncultured bacterium in the family Ruminococcaceae. Our data reveal that this primary degrader cleaves the xanthan gum backbone before processing the released oligosaccharides using additional enzymes. Some individuals harbour Bacteroides intestinalis that is incapable of consuming polymeric xanthan gum but grows on oligosaccharide products generated by the Ruminococcaceae. Feeding xanthan gum to germfree mice colonized with a human microbiota containing the uncultured Ruminococcaceae supports the idea that the additive xanthan gum can drive expansion of the primary degrader Ruminococcaceae, along with exogenously introduced B. intestinalis. Our work demonstrates the existence of a potential xanthan gum food chain involving at least two members of different phyla of gut bacteria and provides an initial framework for understanding how widespread consumption of a recently introduced food additive influences human microbiomes.

BackgroundChimeric antigen receptor (CAR)-based immunotherapy has shown great potential for the treatment of both hematopoietic malignancies and solid tumors. Nevertheless, multiple obstacles still block the development of CAR-based immunotherapy in the clinical setting. In this study, we aimed to summarize the research landscape and highlight the front lines and trends of this field.MethodsLiterature published from 2001 to 2021 was searched in the Web of Science Core Collection database. Full records and cited references of all the documents were extracted and screened. Bibliometric analysis and visualization were conducted using CiteSpace, Microsoft Excel 2019, VOSviewer and R software.ResultsA total of 5981 articles and reviews were included. The publication and citation results exhibited increasing trends in the last 20 years. Frontiers in Immunology and Blood were the most productive and most co-cited journals, respectively. The United States was the country with the most productive organizations and publications in the comprehensive worldwide cooperation network, followed by China and Germany. June, C.H. published the most papers with the most citations, while Maude, S.L. ranked first among the co-cited authors. The hotspots in CAR-based therapy research were multiple myeloma, safety and toxicity, solid tumors, CAR-engineered immune cells beyond T cells, and gene editing.ConclusionCAR-based immunotherapy is a promising treatment for cancer patients, and there is an emerging movement toward using advanced gene modification technologies to overcome therapeutic challenges, especially in solid tumors, and to generate safer and more effective universal CAR-engineered cell products.

Targeted radionuclide therapy (TRT) has been a promising strategy for cancer therapy, which can inhibit or kill cancer cells by selectively delivering radionuclide to target tissues. Herein, a legumain-targeted therapeutic agent [

ObjectivesDiagnosis of thyroid disease among individuals dwelling at high altitude remains a challenge. Reference intervals (RIs) for thyroid-associated hormones among Tibetans living at various high altitudes were established to improve diagnosis.MethodsOne thousand two hundred eighty-one subjects were randomly recruited from Nyingchi, Shigatse/Lhasa, and Ali of Tibet. Thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) were measured by the Cobas e601 electrochemiluminescence analyzer. We used multiple linear regression and variance component analysis to assess the effect of sex, age, and altitude on hormones. RIs were established by refineR algorithm and compared with those provided by the manufacturer.ResultsSerum TSH was significantly lower in males than in females, while FT3 and FT4 were higher in males. Both FT3 and FT4 decreased with increasing age. FT3 increased with altitude, while TSH and FT4 were less influenced by altitude. The RI for TSH was 0.764–5.784 μIU/ml, while for FT4, the RIs were 12.36–19.38 pmol/L in females and 14.84–20.18 pmol/L in males. The RIs for FT3 at Nyingchi, Shigatse/Lhasa, and Ali in females were 4.09–4.98, 4.31–5.45, and 4.82–5.58 pmol/L, while in males, the values were 4.82–5.41, 4.88–5.95, and 5.26–6.06 pmol/L, respectively. The obtained RIs for TSH and FT4 were generally higher, while that for FT3 was narrower than the RIs provided by Cobas.ConclusionsSpecific RIs were established for thyroid-associated hormones among Tibetans, which were significantly different from those provided by the manufacturer.

Cervical cancer is the fourth leading cause of cancer-related deaths in women worldwide. Although many sequencing studies have been carried out, the genetic characteristics of cervical cancer remain to be fully elucidated, especially in the Asian population. Herein, we investigated the genetic landscape of Chinese cervical cancer patients using a validated multigene next generation sequencing (NGS) panel. We analyzed 64 samples, consisting of 32 tumors and 32 blood samples from 32 Chinese cervical cancer patients by performing multigene NGS with a panel targeting 571 cancer-related genes. A total of 810 somatic variants, 2730 germline mutations and 701 copy number variations (CNVs) were identified. FAT1, HLA-B, PIK3CA, MTOR, KMT2D and ZFHX3 were the most mutated genes. Further, PIK3CA, BRCA1, BRCA2, ATM and TP53 gene loci had a higher frequency of CNVs. Moreover, the role of PIK3CA in cervical cancer was further highlighted by comparing with the ONCOKB database, especially for E545K and E542K, which were reported to confer radioresistance to cervical cancer. Notably, analysis of potential therapeutic targets suggested that cervical cancer patients could benefit from PARP inhibitors. This multigene NGS analysis revealed several novel genetic alterations in Chinese patients with cervical cancer and highlighted the role of PIK3CA in cervical cancer. Overall, this study showed that genetic variations not only affect the genetic susceptibility of cervical cancer, but also influence the resistance of cervical cancer to radiotherapy, but further studies involving a larger patient population should be undertaken to validate these findings.

Radioresistance of breast cancer is a major reason for therapeutic failure and limits further increases in the dose of radiation due to severe adverse effects. Recently, long noncoding RNAs (lncRNAs) have been shown to regulate cancer proliferation, chemoresistance, and radioresistance. Among these lncRNAs, lncRNA GAS5 expression was shown to be downregulated in breast cancer and related to trastuzumab resistance. However, its role in the radiation response is unclear. In this study, we demonstrated that lncRNA GAS5 expression was reduced in irradiated cells and that overexpression of GAS5 reduced cell viability and promoted cell apoptosis after irradiation. Moreover, overexpression of GAS5 resulted in increased G2/M arrest and unrepaired DNA damage, indicating a radiosensitizing role of GAS5 in breast cancer cells. Finally, we found that a GAS5-interacting miRNA, miR-21, reversed the radiosensitizing effects of GAS5 by inhibiting the apoptotic pathway. In conclusion, we found that lncRNA GAS5 sensitized breast cancer cells to ionizing radiation by inhibiting DNA repair and suppressing miR-21, identifying novel targets for breast cancer radiosensitization.

Twelve new diterpenoids, isoresbins A-L (1-12), together with twenty-eight known ones, were isolated from the aerial parts of Isodon oresbius. Their diverse structures included 6,7-seco-ent-kaurane, 7,20-epoxy-ent-kaurane, 6,7:8,15-diseco-ent-kaurane, and abietanes skeletons, which were elucidated by spectroscopic data interpretation, single-crystal X-ray diffraction, and quantum chemical calculation. Isoresbins A (1) and B (2) possessed a new rearranged 15(8 → 11)-abeo-6,7-seco-ent-kaurane skeleton. 1 and 5 promoted lysosomal function, which was evaluated by LysoTracker Red staining and DQ-ovalbumin dequenching assay. 1 showed cytotoxicity against six human tumor cell lines with IC

ObjectiveThe purpose of this study was to predict elevated TSH levels by developing an effective machine learning model based on large-scale physical examination results.MethodsSubjects who underwent general physical examinations from January 2015 to December 2019 were enrolled in this study. A total of 21 clinical parameters were analyzed, including six demographic parameters (sex, age, etc.) and 15 laboratory parameters (thyroid peroxidase antibody (TPO-Ab), thyroglobulin antibody (TG-Ab), etc.). The risk factors for elevated TSH levels in the univariate and multivariate Logistic analyses were used to construct machine learning models. Four machine learning models were trained to predict the outcome of elevated TSH levels one year/two years after patient enrollment, including decision tree (DT), linear regression (LR), eXtreme Gradient boosting (XGBoost), and support vector machine (SVM). Feature importance was calculated in the machine learning models to show which parameter plays a vital role in predicting elevated TSH levels.ResultsA total of 12,735 individuals were enrolled in this study. Univariate and multivariate Logistic regression analyses showed that elevated TSH levels were significantly correlated with gender, FT3/FT4, total cholesterol (TC), TPO-Ab, Tg-Ab, creatinine (Cr), and triglycerides (TG). Among the four machine learning models, XGBoost performed best in the one-year task of predicting elevated TSH levels (AUC (0.87(+/- 0.03))). The most critical feature in this model was FT3/FT4, followed by TPO-Ab and other clinical parameters. In the two-year task of predicting TSH levels, none of the four models performed well.ConclusionsIn this study, we trained an effective XGBoost model for predicting elevated TSH levels one year after patient enrollment. The measurement of FT3 and FT4 could provide an early warning of elevated TSH levels to prevent relative thyroid diseases.