A body map of somatic mutagenesis in morphologically normal human tissues.

Somatic mutations that accumulate in normal tissues are associated with ageing and disease1,2. Here we performed a comprehensive genomic analysis of 1,737 morphologically normal tissue biopsies of 9 organs from 5 donors. We found that somatic mutation accumulations and clonal expansions were widespread, although to variable extents, in morphologically normal human tissues. Somatic copy number alterations were rarely detected, except for in tissues from the oesophagus and cardia. Endogenous mutational processes with the SBS1 and SBS5 mutational signatures are ubiquitous among normal tissues, although they exhibit different relative activities. Exogenous mutational processes operate in multiple tissues from the same donor. We reconstructed the spatial somatic clonal architecture with sub-millimetre resolution. In the oesophagus and cardia, macroscopic somatic clones that expanded to hundreds of micrometres were frequently seen, whereas in tissues such as the colon, rectum and duodenum, somatic clones were microscopic in size and evolved independently, possibly restricted by local tissue microstructures. Our study depicts a body map of somatic mutations and clonal expansions from the same individual.

Single-cell transcriptome sequencing reveals aberrantly activated inter-tumor cell signaling pathways in the development of clear cell renal cell carcinoma.

BACKGROUND: Aberrant intracellular or intercellular signaling pathways are important mechanisms that contribute to the development and progression of cancer. However, the intercellular communication associated with the development of ccRCC is currently unknown. The purpose of this study was to examine the aberrant tumor cell-to-cell communication signals during the development of ccRCC. METHODS: We conducted an analysis on the scRNA-seq data of 6 ccRCC and 6 normal kidney tissues. This analysis included sub clustering, CNV analysis, single-cell trajectory analysis, cell-cell communication analysis, and transcription factor analysis. Moreover, we performed validation tests on clinical samples using multiplex immunofluorescence. RESULTS: This study identified eleven aberrantly activated intercellular signaling pathways in tumor clusters from ccRCC samples. Among these, two of the majors signaling molecules, MIF and SPP1, were mainly secreted by a subpopulation of cancer stem cells. This subpopulation demonstrated high expression levels of the cancer stem cell markers POU5F1 and CD44 (POU5F1hiCD44hiE.T), with the transcription factor POU5F1 regulating the expression of SPP1. Further research demonstrated that SPP1 binds to integrin receptors on the surface of target cells and promotes ccRCC development and progression by activating potential signaling mechanisms such as ILK and JAK/STAT. CONCLUSION: Aberrantly activated tumor intercellular signaling pathways promote the development and progression of ccRCC. The cancer stem cell subpopulation (POU5F1hiCD44hiE.T) promotes malignant transformation and the development of a malignant phenotype by releasing aberrant signaling molecules and interacting with other tumor cells.

Burden of schizophrenia among Japanese patients: a cross-sectional National Health and Wellness Survey.

BACKGROUND: Schizophrenia places a great humanistic and financial burden to patients, families, and societies, and the burden is substantially impacted by comorbid conditions. This study aimed to estimate the lifetime prevalence of schizophrenia and to assess the health-related quality of life (HRQoL), work productivity, and indirect cost among schizophrenia patients with and without comorbidities (depressive symptoms, sleep disturbances, and anxiety problems). METHODS: This is a secondary analysis of existing data collected in 2019 from the Japan National Health and Wellness Survey. The schizophrenia patients were categorized based on their Patient Health Questionnaire-9 score, self-reported experience of sleep disturbances, and anxiety problems. The lifetime prevalence was estimated using the total number of diagnosed schizophrenia patients as the numerator and the total number of respondents as the denominator. The HRQoL was evaluated through the Short Form 12-Item (version 2) Health Survey and EuroQoL 5-dimensions scale. Work productivity and annual indirect costs were evaluated through the Work Productivity and Activity Impairment instrument and monthly wage rates. Multivariate analyses included the comparison of outcomes using generalized linear models. RESULTS: The study was conducted with 178 schizophrenia patients with an average age of 42.7 years old and an estimated lifetime prevalence of 0.59% (95% CI: 0.51%, 0.68%). Patients who experienced sleep disturbances, more severe depressive symptoms, and anxiety problems had lower HRQoL, higher levels of absenteeism, presenteeism, total work productivity and activity impairment, and almost twice more indirect costs, compared to those without these conditions. CONCLUSION: Comorbid conditions among patients with schizophrenia impact significantly on their quality of life, work productivity as well as indirect costs.

Fusing pre-trained convolutional neural networks features for multi-differentiated subtypes of liver cancer on histopathological images.

Liver cancer is a malignant tumor with high morbidity and mortality, which has a tremendous negative impact on human survival. However, it is a challenging task to recognize tens of thousands of histopathological images of liver cancer by naked eye, which poses numerous challenges to inexperienced clinicians. In addition, factors such as long time-consuming, tedious work and huge number of images impose a great burden on clinical diagnosis. Therefore, our study combines convolutional neural networks with histopathology images and adopts a feature fusion approach to help clinicians efficiently discriminate the differentiation types of primary hepatocellular carcinoma histopathology images, thus improving their diagnostic efficiency and relieving their work pressure. In this study, for the first time, 73 patients with different differentiation types of primary liver cancer tumors were classified. We performed an adequate classification evaluation of liver cancer differentiation types using four pre-trained deep convolutional neural networks and nine different machine learning (ML) classifiers on a dataset of liver cancer histopathology images with multiple differentiation types. And the test set accuracy, validation set accuracy, running time with different strategies, precision, recall and F1 value were used for adequate comparative evaluation. Proved by experimental results, fusion networks (FuNet) structure is a good choice, which covers both channel attention and spatial attention, and suppresses channel interference with less information. Meanwhile, it can clarify the importance of each spatial location by learning the weights of different locations in space, then apply it to the study of classification of multi-differentiated types of liver cancer. In addition, in most cases, the Stacking-based integrated learning classifier outperforms other ML classifiers in the classification task of multi-differentiation types of liver cancer with the FuNet fusion strategy after dimensionality reduction of the fused features by principle component analysis (PCA) features, and a satisfactory result of 72.46% is achieved in the test set, which has certain practicality.

The application of feature engineering in establishing a rapid and robust model for identifying patients with glioma.

The aim of the study is to evaluate the efficacy of the combination of Raman spectroscopy with feature engineering and machine learning algorithms for detecting glioma patients. In this study, we used Raman spectroscopy technology to collect serum spectra of glioma patients and healthy people and used feature engineering-based classification models for prediction. First, to reduce the dimensionality of the data, we used two feature extraction algorithms which are partial least squares (PLS) and principal component analysis (PCA). Then, the principal components were selected using the feature selection methods of four correlation indexes, namely, Relief-F (RF), the Pearson correlation coefficient (PCC), the F-score (FS) and term variance (TV). Finally, back-propagation neural network (BP), linear discriminant analysis (LDA) and support vector machine (SVM) classification models were established. To improve the reliability of the model, we used a fivefold cross validation to measure the prediction performance between different models. In this experiment, 33 classification models were established. Integrating 4 classification criteria, PLS-Relief-F-BP, PLS-F-Score-BP, PLS-LDA and PLS-Relief-F-SVM had better effects, and their accuracy rates reached 97.58%, 96.33%, 97.87% and 96.19%, respectively. The experimental results show that feature engineering can select more representative features, reduce computational time complexity and simplify the model. The classification model established in this experiment can not only increase the robustness of the model and shorten the discrimination time but also realize the rapid, stable and accurate diagnosis of glioma patients, which has high clinical application value.

Routine first-trimester ultrasound screening using a standardized anatomical protocol.

BACKGROUND: First-trimester ultrasound scans were introduced to China for nearly 20 years. The ability of first-trimester ultrasound screening to detect different malformations was variable. A recent systematic review concluded that the use of a standardized anatomic protocol was the most crucial factor to improve the sensitivity of first-trimester ultrasound screening for anomalies. Standardized sectional scans have long been used for routine anatomy screening during the second trimester. However, during the first trimester, most of the previous studies have described the observation of anatomic structures but have not specified clearly the standard sectional views. OBJECTIVE: We aimed to determine the performance of routine first-trimester scans using a standardized anatomic protocol for detecting structural abnormalities in China. STUDY DESIGN: This was a large retrospective study involving 59,063 sequential unselected pregnancies. Scans at 11 to 13+6 weeks were performed in a single center during a 7-year span. All fetuses were examined following a predefined protocol for standardized views. RESULTS: From October 2008 to December 2015, first-trimester scans were performed in 53,349 pregnant women with available outcome. Of these, there were 1578 (3%) pregnancies that presented with at least 1 fetal structural abnormality. The detection rate for first-trimester screening was 43.1% (95% confidence interval, 40.6%-45.5%). Routine first-trimester scans detected 95.6% of abdominal wall defects, 66.3% of nervous system defects, 33.8% of limbs and skeleton malformations, 30.8% of facial abnormalities, 21.2% of urogenital abnormalities, 18.4% of thoracic and lung abnormalities, and 4.1% of gastrointestinal tract abnormalities. During the first trimester, 37.7% of cardiac defects were identified and included 57.9% of major cardiac defects and 2.6% of mild cardiac defects. A robust high detection rate for anencephaly, exencephaly, cephalocele, holoprosencephaly, exomphalos, gastroschisis, Pentalogy of Cantrell, sirenomelia, and body stalk anomaly was achieved during routine first-trimester scans. CONCLUSION: A standardized anatomic protocol is advised when performing routine first-trimester ultrasound screening. It is recommended that screening for severe structural abnormalities should be extended to the first trimester.

microRNA-802 inhibits cell proliferation and induces apoptosis in human cervical cancer by targeting serine/arginine-rich splicing factor 9.

microRNAs (miRNAs) play crucial roles in cancer development and progression by targeting mRNAs for degradation and/or translational repression. microRNA-802 (miR-802) has been reported as a tumor suppressor and its deregulation is observed in various human cancers. However, the prognostic value of miR-802 and its underlying mechanisms involved in human cervical cancer are poorly investigated. The purposes of this study were to explore the role of miR-802 in cervical cancer and to clarify the regulation of serine/arginine-rich splicing factor 9 (SRSF9) by miR-802. Here, we found that miR-802 was downregulated in both cervical cancer tissues and cell lines. Transfection of a miR-802 mimic into cervical cancer cells inhibited their proliferation and colony formation, and promoted cell cycle arrest at the G0/G1 phase and cell apoptosis. In addition, we found that miR-802 could directly target the 3'-untranslated region of SRSF9 and suppress SRSF9 expression. Rescue experiments revealed that overexpression of SRSF9 partially reversed the inhibition effect of miR-802 in cervical cancer cells. Overall, these findings demonstrate that miR-802 functions as a tumor suppressor in cervical cancer by targeting SRSF9, suggesting that miR-802 might serve as a potential therapeutic target in cervical cancer.

915-MHz microwave-assisted laparoscopic hepatectomy: a new technique for liver resection.

BACKGROUND: Hemorrhage during the liver transection is the major hazard for laparoscopic hepatectomy (LH). We aimed to evaluate the feasibility and safety of a 915-MHz microwave device used in LH. METHODS: Data were retrospectively analyzed regarding 60 patients who underwent LH with or without 915-MHz microwave coagulation at our center from January 2016 to June 2016. 30 patients underwent the 915-MHz microwave-assisted LH (MW group), and 30 patients otherwise were considered as control group. RESULTS: No perioperative mortality was observed. Intraoperative blood loss amounts in microwave group and control group were 26.83 ml and 186.33 ml, respectively (P < 0.001). The durations of parenchyma transaction (55.17 vs. 70.83 min, P < 0.001), blood occlusion (2.17 vs. 25.33 min, P < 0.001), and operation (120.67 vs. 148.00 min, P < 0.001) were much shorter in microwave group compared with control group. Lower incidence of postoperative complications (0.0 vs. 14.3%, P = 0.038) and shorter length of postoperative hospital stay (6.00 vs. 7.23 days, P = 0.027) were also noted in the microwave group, compared with the control group. CONCLUSION: 915-MHz microwave-assisted LH was found to be safe and efficient.

Increased Levels of Glycated Hemoglobin A1c and Iron Deficiency Anemia: A Review.

Worldwide, the prevalence of diabetes remains high. Studies have shown that iron deficiency anemia (IDA) is associated with increased levels of glycated hemoglobin A1c (HbA1c), but the mechanism remains unclear. Hematological changes, iron metabolism, study methodology, and other factors could affect the results of diagnostic investigations, leading to false results. Red blood cell turnover in the bone marrow and the quality and heterogeneity of erythrocytes may influence the rate of hemoglobin glycation. By changing the structure of hemoglobin and inducing peroxidation, iron deficiency accelerates glycation. This review aims to discuss the possible causes of the association between increased levels of HbA1c and IDA.

Video-Assisted Thoracoscopic Left Cardiac Sympathetic Denervation in Chinese Patients with Long QT Syndrome.

Long QT syndrome is a rare but potentially lethal cardiac channelopathy. The primary aim of the study was to investigate the long-term effects of video-assisted thoracoscopic (VATS) left cardiac sympathetic denervation (LCSD) in Chinese patients with long QT syndrome.VATS-LCSD was performed in eight Chinese patients with LQTS. Twelve-lead ECGs and 24-hour Holter monitoring ECGs were recorded before and after surgery. The medical charts were reviewed to obtain patient data, and the patients who had been lost to follow-up were contacted through telephone.The average QTc was shortened from 534 ± 52.7 to 503 ± 43.7 ms (P = 0.030) 24 hours post-surgery and down to 486 ± 34.8 ms (P = 0.021) 1 week post-surgery, with the heart rate unchanged. The average QT dispersion was reduced from 67 ± 17.5 to 21 ± 3.9 ms (P < 0.001) 24 hours post-surgery and remained shortened 1 week later (30 ± 8.1 ms, P < 0.001). Moreover, the 24-hour ECG showed that the QTc was shortened from 552 ± 95.9 to 497 ± 19.7 ms at the minimum heart rate (P = 0.008), and was decreased from 594 ± 144 to 495 ± 74.1 ms at the maximum heart rate (P= 0.04), while the minimum and maximum heart rates were comparable before and after surgery. No death was observed during the follow-up period and the clinical symptoms improved in all patients. The annual event rate decreased from 4 ± 3.50 to 0.63 ± 1.37 events/year (P = 0.034) after surgery.These findings indicate that LCSD shortens the QTc, with the heart rate remaining unchanged. QTd might be a useful parameter for evaluating the efficacy of VATS-LCSD. LCSD could improve patients' life quality by reducing cardiac events.

C6 ceramide sensitizes the anti-hepatocellular carcinoma (HCC) activity by AZD-8055, a novel mTORC1/2 dual inhibitor.

Aberrant activation of mammalian target of rapamycin (mTOR) plays pivotal roles in promoting hepatocellular carcinoma (HCC) tumorigenesis and chemoresistance. Here, we tested the potential anti-HCC activity by a novel mTOR complex 1/2 (mTORC1/2) dual inhibitor AZD-8055 and, more importantly, the potential AZD-8055 sensitization effect by a cell-permeable short-chain ceramide (C6). We showed that AZD-8055 mainly exerted moderate cytotoxic effect against a panel of HCC cell lines (HepG2, Hep3B, and SMMC-7721). Co-treatment of C6 ceramide remarkably augmented AZD-8055-induced HCC cytotoxicity. Meanwhile, C6 ceramide dramatically potentiated AZD-8055-induced HCC cell apoptotic death. Further studies demonstrated that AZD-8055 and C6 ceramide synergistically induced anti-survival and pro-apoptotic activity in primary cultured human HCC cells, but not in the non-cancerous human hepatocytes. Signaling studies showed that AZD-8055 and C6 ceramide synergistically suppressed Akt-mTOR complex 1/2 cascade activation. In vivo, AZD-8055 oral administration suppressed HepG2 hepatoma xenograft growth in nude mice, while moderately improving mice survival. Its anti-tumor activity was dramatically potentiated with co-administration of a liposome-packed C6 ceramide. Together, these results demonstrate that concurrent targeting mTORC1/2 by AZD-8055 exerts anti-tumor ability in preclinical HCC models, and its activity is further sensitized with co-administration of C6 ceramide.

MiR-24-3p enhances cell growth in hepatocellular carcinoma by targeting metallothionein 1M.

Dysregulation of microRNAs has been demonstrated to contribute to malignant progression of cancers, including hepatocellular carcinoma (HCC). MiR-24-3p was previously reported to be significantly upregulated in HCC. However, the potential role and mechanism of action of miR-24-3p in the initiation and progression of HCC remain largely unknown. Quantitative reverse transcription polymerase chain reaction demonstrated that miR-24-3p was significantly upregulated in HCC tumor tissues compared with nontumor tissues. The cell viability, colony formation assay, and tumorigenicity assays in nude mice showed that miR-24-3p could enhance HCC cell growth in vitro and in vivo. Metallothionein 1M was verified as an miR-24-3p target gene by using dual-luciferase reporter assays, quantitative reverse transcription polymerase chain reaction, and Western blotting, which was involved in miR-24-3p regulated HCC cell growth. These results indicated that miR-24-3p plays an important role in the initiation and progression of HCC by targeting metallothionein 1M, and the miR-24-3p/metallothionein 1M pathway may contribute to the development of novel therapeutic strategies for HCC in the future.

Saturated long-chain esters of isopulegol as novel permeation enhancers for transdermal drug delivery.

PURPOSE: Saturated long-chain esters of isopulegol were synthesized and their activities as permeation enhancers for transdermal delivery of amlodipine and flurbiprofen were investigated, in contrast to the saturated fatty acids and isopulegol, as well as their physical mixtures. METHODS: In vitro permeation experiments, confocal laser scanning microscopy (CLSM) and attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy were introduced to investigate the regulation of enhancers in the skin permeability and biophysical properties. With in vitro cytotoxicity test and in vivo erythema model, the skin irritation of enhancers was evaluated. RESULTS: The esters significantly increased the permeation of amlodipine and flurbiprofen, whereas saturated fatty acids and isopulegol had no such effect and even decreased the drug permeation when they were used alone or in combination. These results were supported by CLSM and ATR-FTIR studies, which revealed that only the esters could decrease the order of the alkyl chains in the skin lipids. Additionally, almost no skin irritation and cytotoxicity were observed for these esters. CONCLUSIONS: Saturated long-chain esters of isopulegol are shown to be suitable permeation enhancers for transdermal drug delivery. Covalent attachment of isopulegol and saturated fatty acids might represent a promising strategy to design novel and potent permeation enhancers.

Target prediction and potential application of dihydroartemisinin on hepatocarcinoma treatment.

With high incidence of hepatocarcinoma and limited effective treatments, most patients suffer in pain. Antitumor drugs are single-targeted, toxicity, causing adverse side effects and resistance. Dihydroartemisinin (DHA) inhibits tumor through multiple mechanisms effectively. This study explores and evaluates safety and potential mechanism of DHA towards human hepatocarcinoma based on network pharmacology in a comprehensive way. Adsorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of DHA were evaluated with pkCSM, SwissADME, and ADMETlab. Potential targets of DHA were obtained from SwissTargetPrediction, Drugbank, TargetNET, and PharmMapper. Target gene of hepatocarcinoma was obtained from OMIM, GeneCards, and DisGeNET. Overlapping targets and hub genes were identified and analyzed for Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome pathway. Molecular docking was utilized to investigate the interactions sites and hydrogen bonds. Cell counting kit-8 (CCK8), wound healing, invasion, and migration assays on HepG2 and SNU387 cell proved DHA inhibits malignant biological features of hepatocarcinoma cell. DHA is safe and desirable for clinical application. A total of 131 overlapping targets were identified. Biofunction analysis showed targets were involved in kinase activity, protein phosphorylation, intracellular reception, signal transduction, transcriptome dysregulation, PPAR pathway, and JAK-STAT signaling axis. Top 9 hub genes were obtained using MCC (Maximal Clique Centrality) algorithm, namely CDK1, CCNA2, CCNB1, CCNB2, KIF11, CHEK1, TYMS, AURKA, and TOP2A. Molecular docking suggests that all hub genes form a stable interaction with DHA for optimal binding energy were all less than - 5 kcal/mol. Dihydroartemisinin might be a potent and safe anticarcinogen based on its biological safety and effective therapeutic effect.

PMFFNet: A hybrid network based on feature pyramid for ovarian tumor segmentation.

Ovarian cancer is a highly lethal malignancy in the field of oncology. Generally speaking, the segmentation of ovarian medical images is a necessary prerequisite for the diagnosis and treatment planning. Therefore, accurately segmenting ovarian tumors is of utmost importance. In this work, we propose a hybrid network called PMFFNet to improve the segmentation accuracy of ovarian tumors. The PMFFNet utilizes an encoder-decoder architecture. Specifically, the encoder incorporates the ViTAEv2 model to extract inter-layer multi-scale features from the feature pyramid. To address the limitation of fixed window size that hinders sufficient interaction of information, we introduce Varied-Size Window Attention (VSA) to the ViTAEv2 model to capture rich contextual information. Additionally, recognizing the significance of multi-scale features, we introduce the Multi-scale Feature Fusion Block (MFB) module. The MFB module enhances the network's capacity to learn intricate features by capturing both local and multi-scale information, thereby enabling more precise segmentation of ovarian tumors. Finally, in conjunction with our designed decoder, our model achieves outstanding performance on the MMOTU dataset. The results are highly promising, with the model achieving scores of 97.24%, 91.15%, and 87.25% in mACC, mIoU, and mDice metrics, respectively. When compared to several Unet-based and advanced models, our approach demonstrates the best segmentation performance.

Pulmonary histoplasmosis on the Chinese mainland: two case reports and literature review.

INTRODUCTION: Pulmonary histoplasmosis is a fungal disease that is endemic in North and Central America. It is relatively rare in China and commonly misdiagnosed as tuberculosis or cancer due to nonspecific clinical and radiographic manifestations. Rapid and accurate pathogen tests are critical for the diagnosis of pulmonary histoplasmosis. METHODOLOGY: We report two cases of pulmonary histoplasmosis. We collected all the relevant case reports on the Chinese mainland (from 1990 to 2022) to analyze features of this disease among Chinese patients. RESULTS: A total of 42 articles reporting 101 cases were identified, and the two cases reported in this article were also included for analysis. Sixty-three (61.2%) patients had respiratory symptoms and 35 (34.0%) patients were asymptomatic. The most common radiographic findings were pulmonary nodules or masses (81.6%). Twenty-two (21.4%) patients were misdiagnosed as tuberculosis, and 37 (35.9%) were misdiagnosed as lung tumors before pathological findings. Metagenomic next­generation sequencing (mNGS) testing provided a rapid diagnostic and therapeutic basis for three patients. CONCLUSIONS: Clinical features and imaging findings of pulmonary histoplasmosis are not specific. Relevant epidemiological history and timely pathogen detection are important for diagnosis. mNGS can shorten the time required for diagnosis and allow earlier initiation of targeted antibiotic therapy.

Expression of circular RNA has-circ-0009158 and identification of associated miRNA-mRNA network in hepatocellular carcinoma.

Primary hepatocellular carcinoma (HCC) affects people all over the world. Circular RNAs are involved in the growth and development of several malignancies and regulate a number of biological processes. However, the roles of has-circ-0009158 in HCC remain unknown. This study explored the expression and associated miRNA-mRNA network of has-circ-0009158 in HCC. Quantitative real-time polymerase chain reaction was used to measure the expression of hsa-circ-0009158 in the HCC tissues of 143 patients and four human HCC cell lines. Then, the potential relationship of hsa-circ-0009158 expression with clinical characteristics and prognosis of patients was analyzed using the GO and KEGG databases. Correlated miRNA-mRNA networks were forecasted using the TCGA database and Cytoscape software. The hsa-circ-0009158 expression was significantly upregulated in HCC tissues and cell lines (P<0.001). The multivariate Cox analysis revealed that HCC patients were associated with high hsa-circ-0009158 expression. The bioinformatics analysis screened 1 miRNA, and 248 mRNAs associated with the circRNA in HCC. A pathway analysis suggested that the differentially expressed genes (DEGs) may be linked to the development and growth of HCC tumors. Ten hub genes (MELK, NCAPG, BUB1B, BIRC5, CDCA8, CENPF, BUB1, CDK1, TTK, TPX2) were identified from the PPI network based on the 248 genes. Additionally, the 10 hub genes that were verified had an association between high expression levels and low overall survival rates. As a result, the high expression of hsa-circ-0009158 was found to be a separate risk factor for recurrence and a poor prognosis in HCC patients.

External Validation of the Risk Assessment Model of Venous Thromboembolism in Multicenter Internal Medicine Inpatients.

To external validate the risk assessment model (RAM) of venous thromboembolism (VTE) in multicenter internal medicine inpatients. We prospectively collected 595 internal medical patients (310 with VTE patients, 285 non-VTE patients) were from Beijing Shijitan Hospital, Beijing Chaoyang Hospital, and the respiratory department of Beijing Tsinghua Changgeng Hospital from January 2022 to December 2022 for multicenter external validation. The prediction ability of Caprini RAM, Padua RAM, The International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) RAM, and Shijitan (SJT) RAM were compared. This study included a total of 595 internal medicine inpatients, including 242 (40.67%) in the respiratory department, 17 (2.86%) in the respiratory intensive care unit, 49 (8.24%) in the neurology department, 34 (5.71%) in the intensive care unit, 26 (4.37%) in the geriatric department, 22 (3.70%) in the emergency department, 71 (11.93%) in the nephrology department, 63 (10.59%) in the cardiology department, 24 (4.03%) in the hematology department, 6 (1.01%) in the traditional Chinese medicine department, 9 (1.51%) cases in the rheumatology department, 7 (1.18%) in the endocrinology department, 14 (2.35%) in the oncology department, and 11 (1.85%) in the gastroenterology department. Multivariate logistic regression analysis showed that among internal medicine inpatients, age > 60 years old, heart failure, nephrotic syndrome, tumors, history of VTE, and elevated D-dimer were significantly correlated with the occurrence of VTE (P < .05). The incidence of VTE increases with the increase of D-dimer. It was found that the effectiveness of SJT RAM (AUC = 0.80 ± 0.03) was better than Caprini RAM (AUC = 0.74 ± 0.03), Padua RAM (AUC = 0.72 ± 0.03) and IMPROVE RAM (AUC = 0.52 ± 0.03) (P < .05). The sensitivity and Yoden index of SJT RAM were higher than those of Caprini RAM, Pauda RAM, and IMPROVE RAM (P < .05), but specificity was not significantly different between the 4 models (P > .05). The SJT RAM derived from general hospitalized Chinese patients has effective and better predictive ability for internal medicine inpatients at risk of VTE.

The TOPLESS interactome: a framework for gene repression in Arabidopsis.

Transcription factors activate or repress target gene expression or switch between activation and repression. In animals and yeast, Groucho/Tup1 corepressor proteins are recruited by diverse transcription factors to induce context-specific transcriptional repression. Two groups of Groucho/Tup1-like corepressors have been described in plants. LEUNIG and LEUNIG_HOMOLOG constitute one group and TOPLESS (TPL) and the four TPL-related (TPR) corepressors form the other. To discover the processes in which TPL and the TPR corepressors operate, high-throughput yeast two-hybrid approaches were used to identify interacting proteins. We found that TPL/TPR corepressors predominantly interact directly with specific transcription factors, many of which were previously implicated in transcriptional repression. The interacting transcription factors reveal that the TPL/TPR family has been coopted multiple times to modulate gene expression in diverse processes, including hormone signaling, stress responses, and the control of flowering time, for which we also show biological validation. The interaction data suggest novel mechanisms for the involvement of TPL/TPR corepressors in auxin and jasmonic acid signaling. A number of short repression domain (RD) sequences have previously been identified in Arabidopsis (Arabidopsis thaliana) transcription factors. All known RD sequences were enriched among the TPL/TPR interactors, and novel TPL-RD interactions were identified. We show that the presence of RD sequences is essential for TPL/TPR recruitment. These data provide a framework for TPL/TPR-dependent transcriptional repression. They allow for predictions about new repressive transcription factors, corepressor interactions, and repression mechanisms and identify a wide range of plant processes that utilize TPL/TPR-mediated gene repression.

Donepezil accelerates the release of PLGA microparticles via catalyzing the polymer degradation regardless of the end groups and molecular weights.

Poly (lactic-co-glycolic acid) (PLGA) is one of the most successful polymers for sustained parenteral drug products in the market. However, rational selection of PLGA in the formulations is still challenging due to the lack of fundamental studies. The present study aimed to investigate the influence of donepezil (DP) on the in-vitro and in-vivo performance of PLGA sustained microspheres. Three kinds of PLGAs with different end groups and molecular weights were selected. Then DP-loaded PLGA microspheres (DP-MSs) with similar particle size, drug loading, and encapsulation efficiency were prepared using an o/w emulsion-solvent evaporation method. Laser diffraction and scanning electron microscopy showed that the prepared DP-MSs were about 35 µm and spherical in shape. Differential scanning calorimetry and X-ray diffraction indicated that DP was in an amorphous state inside the microspheres. Unexpectedly, the molecular weight and end group of PLGAs did not significantly influence the in-vitro and in-vivo performance of the DP-MSs. The gel permeation chromatography indicated that the degradation rates of PLGAs were accelerated with the incorporation of DP into the microspheres, and the molecular weight of all three kinds of PLGAs sharply dropped to about 11,000 Da within the initial three days. The basic catalysis effect induced by DP might be responsible for the accelerated degradation of PLGAs, which led to similar in-vitro release profiles of DP from different PLGA matrices. A point-to-point level A correlation between the in-vitro release and the in-vivo absorption was observed, which confirmed the accelerated release of DP from the DP-MSs in-vivo. The results indicated that the influence of DP on the degradation of PLGA should be considered when developing DP-sustained microspheres.