bluuebunny/crossref_metadata_2025_split huggingface dataset:
CMTM6-Deficient Monocytes in ANCA-Associated Vasculitis Fail to Present the Immune Checkpoint PD-L1
Authors: Zeisbrich Markus , Chevalier Nina , Sehnert Bettina , Rizzi Marta , Venhoff Nils , Thiel Jens , Voll Reinhard E. 
Published: May 2021

ObjectivesANCA-associated vasculitides (AAV) affect small- and medium-sized blood vessels. In active disease, vessel wall infiltrates are mainly composed of monocytes and macrophages. Immune checkpoint molecules are crucial for the maintenance of self-tolerance and the prevention of autoimmune diseases. After checkpoint inhibitor therapy, the development of autoimmune vasculitis has been observed. However, defects of immune checkpoint molecules in AAV patients have not been identified yet.MethodsMonocytes and monocyte-derived macrophages from AAV patients and healthy age-matched controls were tested for surface expression of immunoinhibitory checkpoint programmed cell death ligand-1 (PD-L1). Using in vitro co-culture approaches, the effect of monocyte PD-L1 expression on CD4+ T cell activation and proliferation was tested.ResultsMonocytes from AAV patients displayed lower PD-L1 expression and a defective PD-L1 presentation upon activation, an effect that was correlated with disease activity. Lower PD-L1 expression was due to increased lysosomal degradation of PD-L1 in AAV monocytes. We identified a reduced expression of CMTM6, a protein protecting PD-L1 from lysosomal breakdown, as the underlying molecular defect. PD-L1low AAV monocytes showed increased stimulatory capacity and induced T cell activation and proliferation. Inhibiting lysosomal function corrected this phenotype by increasing PD-L1, thus normalizing the pro-stimulatory behavior of AAV monocytes.ConclusionsThis study identifies a defect of the immunoinhibitory checkpoint PD-L1 in monocytes from patients with AAV. Low expression of CMTM6 results in enhanced lysosomal degradation of PD-L1, thus providing insufficient negative signaling to T cells. Correcting this defect by targeting lysosomal function may represent a novel strategy to treat AAV.
Separate and Combined Effects of Geometrical and Mechanical Properties Changes Due to Aging on the Femoral Strength in Men and Women
Authors: Sahandifar Pooya , Kleiven Svein 
Published: May 2021

Aging, from 40 to +80 years old, causes geometrical and mechanical properties changes in the proximal femur. The subperiosteal width expands faster in men compared to women during aging, while the cortical thickness varies unequally in each sector and differently between men and women. Another change which occurs during aging is bone mechanical properties such as stiffness and ultimate strains. Numerical analysis allows us to study the potential effects of each of the age-dependent changes on the fracture forces separately and combined. We investigated the effects of the geometrical and bone mechanical properties changes due to aging on the femoral strength during a common falling scenario using a transverse isotropic continuum damage model. First, the femur model was adapted from a previously developed human body model named THUMS v4.02. Then, three sets of models were developed to address each of the changes separately and combined for both sexes. We found that the fracture forces in women are on average 1500 N less than in men of the same age. The age-dependent geometrical changes increased the fracture forces in men (25 N/decade), whereas it reduced the fracture forces by 116 N/decade in women. The mechanical properties changes reduced the fracture forces in men more than in women (354.5 N/ decade vs. 225.4 N/decade). When accounting for both geometrical and mechanical properties changes due to aging, the fracture forces decreased by 10.7% of the baseline in women per decade compared to 7.2% per decade in men.
Pre-operative/Neoadjuvant Therapy and Vascular Debranching Followed by Resection for Locally Advanced Pancreatic Cancer (PREVADER): Clinical Feasibility Trial
Authors: Ronellenfitsch Ulrich , Michalski Christoph W. , Michl Patrick , Krug Sebastian , Ukkat Joerg , Kleeff Joerg 
Published: May 2021

Introduction: Pancreatic cancer continues to have a poor outcome. Many patients are diagnosed with advanced disease, and in a considerable proportion, abutment or invasion of visceral arteries is present. Moreover, some patients have anatomical variations or stenosis of major visceral arteries requiring arterial reconstruction upon pancreatic cancer resection to avoid organ ischemia. Simultaneous arterial reconstruction during resection is associated with relevant morbidity and mortality. This trial evaluates the approach of visceral debranching, that is, arterial reconstruction, prior to neoadjuvant chemotherapy and tumor resection in patients with locally advanced, unresectable pancreatic cancer.Methods and Analysis: The trial includes patients with locally advanced, non-metastatic pancreatic cancer with arterial abutment or invasion (deemed primarily unresectable), variations in vascular anatomy, or stenosis of visceral arteries. The participants undergo visceral debranching, followed by current standard neoadjuvant chemotherapy (mFOLFIRINOX, gemcitabine–nab-paclitaxel, or other) and potential subsequent tumor resection. The primary outcome is feasibility, measured as the proportion of patients who start neoadjuvant therapy within 6 weeks of visceral debranching. The trial has an exact single-stage design. The proportion below which the treatment is considered ineffective is set at 0.7 (H0). The proportion above which the treatment warrants further exploration in a phase III trial is set at 0.9 (H1). With a power (1-beta) of 0.8 and a type 1 mistake (alpha) of 0.05, the required sample size is 28 patients. Feasibility of the approach will be assumed if 24 of the enrolled 28 patients proceed to neoadjuvant chemotherapy within 6 weeks from visceral debranching.Discussion: This trial evaluates a new treatment sequence, that is, visceral debranching followed by chemotherapy and resection, for pancreatic cancer with invasion or abutment of visceral arteries. The primary objective of the trial is to evaluate feasibility. Trial results will allow for estimating treatment effects and calculating the sample size of a randomized controlled trial, in which the approach will be tested if the feasibility endpoint is met.Clinical Trial Registration:clinicaltrials.gov, identifier: NCT04136769.
The Relationship Between Fragility Fractures and Pain Experience: A Systematic Review
Authors: Chen Pei-En , Chien Ching-Wen , Tung Tao-Hsin 
Published: May 2021

Purpose: This systematic review is conducted to explore the relationship between fragility fractures and pain experience.Methods: We searched for relevant studies on Pubmed, Embase, Web of Science, and the Cochrane library without restrictions on language from inception until February 4th, 2021. The risk of bias and methodological quality was evaluated using the Newcastle-Ottawa Scale and ROBINS-I tool.Results: Twenty-one studies were included in this systematic review. The so-called study reported participants with continuous post-fracture pain. The included studies showed that post- fractured pain can decrease with time, however, the continual pain can last at least 1 year even longer, and some participants would need to self-manage pain. Moreover, the limited range of motion was considered as a factor that might distress the normal development of daily activities.Conclusions: The current evidence could not fully support that pain continues to influence patients' lives after a fragility fracture. However, it still showed the pain might come with fracture. The findings also could be useful to help health care providers better recognize and manage this clinical consequence of fractures. Nonetheless, future large-scale longitudinal studies will be required to evaluate the long-term effects of pain in fragility fractures.
Noninvasive Ventilation in Patients With COVID-19-Related Acute Hypoxemic Respiratory Failure: A Retrospective Cohort Study
Authors: Fu Yingyun , Guan Lili , Wu Weibo , Yuan Jing , Zha Shanshan , Wen Junmin , Lin Zhenghao , Qiu Chen , Chen Rongchang , Liu Lei 
Published: May 2021

Introduction: Noninvasive ventilation (NIV) has been used to alleviate hypoxemia and dyspnea, but there is no consensus on the application of NIV in patients with coronavirus disease 2019 (COVID-19). Some staff use NIV as the rescue therapy which might lead to the adverse outcomes. This study was to identify early factors associated with intubation to help the medical staff select appropriate patients for receiving NIV treatment.Methods: Patients with laboratory-confirmed COVID-19 who were treated with NIV in emergency department or ICU of the Third People's Hospital (the only designated hospital for treating COVID-19 in Shenzhen) between January 1 and August 31, 2020, were retrospectively analyzed.Results: Thirty-nine patients with COVID-19 treated with NIV were included; of them, 16 (41%) received endotracheal intubation and 3 (8%) died. Significant differences were observed between intubated and non-intubated patients in PaO2/FiO2 before NIV initiation, hospitalization duration, NIV as the rescue therapy, and PaO2/FiO2 of ≤200 mmHg after 1–2 h of NIV initiation. Notably, 1–2 h after NIV initiation, a PaO2/FiO2 of ≤200 mmHg (odds ratio [OR], 9.35; 95% confidence interval [CI], 1.84–47.62; P = 0.007) and NIV as the rescue therapy (OR, 5.43; 95% CI, 1.09–27.12; P = 0.039) were the risk factors for intubation.Conclusions: In patients with COVID-19-related acute hypoxemic respiratory failure receiving NIV, close attention should be paid to PaO2/FiO2 after 1–2 h of NIV initiation. Also, using NIV as rescue therapy should draw our awareness that it might delay escalation of respiratory support and lead to adverse outcomes.
Multi-Omics Integrative Analysis Uncovers Molecular Subtypes and mRNAs as Therapeutic Targets for Liver Cancer
Authors: Shen Yi , Xiong Wei , Gu Qi , Zhang Qin , Yue Jia , Liu Changsong , Wang Duan 
Published: May 2021

Objective: This study aimed to systematically analyze molecular subtypes and therapeutic targets of liver cancer using integrated multi-omics analysis.Methods: DNA copy number variations (CNVs), simple nucleotide variations (SNVs), methylation, transcriptome as well as corresponding clinical information for liver carcinoma were retrieved from The Cancer Genome Atlas (TCGA). Multi-omics analysis was performed to identify molecular subtypes of liver cancer via integrating CNV, methylation as well as transcriptome data. Immune scores of two molecular subtypes were estimated using tumor immune estimation resource (TIMER) tool. Key mRNAs were screened and prognosis analysis was performed, which were validated using RT-qPCR. Furthermore, mutation spectra were analyzed in the different subtypes.Results: Two molecular subtypes (iC1 and iC2) were conducted for liver cancer. Compared with the iC2 subtype, the iC1 subtype had a worse prognosis and a higher immune score. Two key mRNAs (ANXA2 and CHAF1B) were significantly related to liver cancer patients' prognosis, which were both up-regulated in liver cancer tissues in comparison to normal tissues. Seventeen genes with p &lt; 0.01 differed significantly for SNV loci between iC1 and iC2 subtypes.Conclusion: Our integrated multi-omics analyses provided new insights into the molecular subtypes of liver cancer, helping to identify novel mRNAs as therapeutic targets and uncover the mechanisms of liver cancer.
Machine Learning Classification of Inflammatory Bowel Disease in Children Based on a Large Real-World Pediatric Cohort CEDATA-GPGE® Registry
Authors: Schneider Nicolas , Sohrabi Keywan , Schneider Henning , Zimmer Klaus-Peter , Fischer Patrick , de Laffolie Jan ,   CEDATA-GPGE Study Group
Published: May 2021

Introduction: The rising incidence of pediatric inflammatory bowel diseases (PIBD) facilitates the need for new methods of improving diagnosis latency, quality of care and documentation. Machine learning models have shown to be applicable to classifying PIBD when using histological data or extensive serology. This study aims to evaluate the performance of algorithms based on promptly available data more suited to clinical applications.Methods: Data of inflammatory locations of the bowels from initial and follow-up visitations is extracted from the CEDATA-GPGE registry and two follow-up sets are split off containing only input from 2017 and 2018. Pre-processing excludes patients in remission and encodes the categorical data numerically. For classification of PIBD diagnosis, a support vector machine (SVM), a random forest algorithm (RF), extreme gradient boosting (XGBoost), a dense neural network (DNN) and a convolutional neural network (CNN) are employed. As best performer, a convolutional neural network is further improved using grid optimization.Results: The achieved accuracy of the optimized neural network reaches up to 90.57% on data inserted into the registry in 2018. Less performant methods reach 88.78% for the DNN down to 83.94% for the XGBoost. The accuracy of prediction for the 2018 follow-up dataset is higher than those for older datasets. Neural networks yield a higher standard deviation with 3.45 for the CNN compared to 0.83–0.86 of the support vector machine and ensemble methods.Discussion: The displayed accuracy of the convolutional neural network proofs the viability of machine learning classification in PIBD diagnostics using only timely available data.
In-Bed Sensorimotor Rehabilitation in Early and Late Subacute Stroke Using a Wearable Elbow Robot: A Pilot Study
Authors: Huang Mei Zhen , Yoon Yong-Soon , Yang Jisu , Yang Chung-Yong , Zhang Li-Qun 
Published: May 2021

Objects: To evaluate the feasibility and effectiveness of in-bed wearable elbow robot training for motor recovery in patients with early and late subacute stroke.Methods: Eleven in-patient stroke survivors (male/female: 7/4, age: 50.7 ± 10.6 years, post-stroke duration: 2.6 ± 1.9 months) received 15 sessions of training over about 4 weeks of hospital stay. During each hourly training, participants received passive stretching and active movement training with motivating games using a wearable elbow rehabilitation robot. Isometric maximum muscle strength (MVC) of elbow flexors and extensors was evaluated using the robot at the beginning and end of each training session. Clinical measures including Fugl-Meyer Assessment of upper extremity (FMA-UE), Motricity Index (MI) for upper extremities, Modified Ashworth Scale (MAS) were measured at baseline, after the 4-week training program, and at a 1-month follow-up. The muscle strength recovery curve over the training period was characterized as a logarithmic learning curve with three parameters (i.e., initial muscle strength, rate of improvement, and number of the training session).Results: At the baseline, participants had moderate to severe upper limb motor impairment {FMA-UE [median (interquartile range)]: 28 (18–45)} and mild spasticity in elbow flexors {MAS [median (interquartile range)]: 0 (0–1)}. After about 4 weeks of training, significant improvements were observed in FMA-UE (p = 0.003) and MI (p = 0.005), and the improvements were sustained at the follow-up. The elbow flexors MVC significantly increased by 1.93 Nm (95% CI: 0.93 to 2.93 Nm, p = 0.017) and the elbow extensor MVC increased by 0.68 Nm (95% CI: 0.05 to 1.98 Nm, p = 0.036). Muscle strength recovery curve showed that patients with severe upper limb motor impairment had a greater improvement rate in elbow flexor strength than those with moderate motor impairment.Conclusion: In-bed wearable elbow robotic rehabilitation is feasible and effective in improving biomechanical and clinical outcomes for early and late subacute stroke in-patients. Results from the pilot study suggested that patients with severe upper limb motor impairment may benefit more from the robot training compared to those with moderate impairment.
Current Evidence of the Efficacy and Safety of Neoadjuvant EGFR-TKIs for Patients With Non-small Cell Lung Cancer
Authors: Shi Xiaoshun , Dong Xiaoying , Zhai Jianxue , Liu Xiguang , Lu Di , Ni Zhen , Wu Hua , Cai Kaican 
Published: May 2021

PurposeEpidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been indicated to be an effective treatment for advanced EGFR-mutant NSCLC. However, the neoadjuvant application of EGFR-TKIs in resectable NSCLC needs further investigation. Here, we aimed to evaluate the efficacy and safety of neoadjuvant EGFR-TKIs for lung cancer.MethodsPublished studies on neoadjuvant EGFR-TKIs in NSCLC were identified in PubMed, Web of Science, and EMBASE until June 1, 2020. Data on surgical rates, objective response rates (ORRs), pathologic responses, and adverse event (AE) rates were retrieved for proportional meta-analysis.ResultsIn total, 7 enrolled studies involving 129 EGFR-TKI-sensitive NSCLC patients were included in this analysis. The overall surgical rate in these studies was 95% (95% CI: 83% to 100%), with an ORR of 48% (95% CI: 39% to 57%) in the population with EGFR-TKI-sensitive mutations, whereas the ORR including wild-type EGFR patients was 28% (95% CI: 14% to 44%). The rate of grade 1-2 AEs was 69% (95% CI: 41% to 91%) but with an acceptable rate of grade 3-4 AEs of 0% (95% CI: 0% to 5%). The pooled rates of rash and diarrhea were 56% (95% CI: 31% to 79%) and 25% (95% CI: 6% to 51%), respectively. The impact of neoadjuvant EGFR-TKIs on survival remains inconclusive.ConclusionsNeoadjuvant EGFR-TKIs showed objective responses in approximately half of EGFR-sensitive NSCLC patients with a tolerable adverse effect profile. The favorable impact of neoadjuvant EGFR-TKIs on NSCLC needs more evidence for validation, such as the comparison of survival improvement between EGFR-TKIs and chemotherapy. The efficacy of neoadjuvant next-generation EGFR-TKIs in clinical trials remains unclear.
Molecular Identification and Genetic Characterization of Early-Stage Multiple Primary Lung Cancer by Large-Panel Next-Generation Sequencing Analysis
Authors: Pei Guotian , Li Mingwei , Min Xianjun , Liu Qiang , Li Dasheng , Yang Yingshun , Wang Shuai , Wang Xiaoyu , Wang Huina , Cheng Huanqing , Cao Shanbo , Huang Yuqing 
Published: May 2021

ObjectiveThe incidence of early stage multiple primary lung cancer (MPLC) has been increasing in recent years, while the ideal strategy for its diagnosis and treatment remains controversial. The present study conducted genomic analysis to identify a new molecular classification method for accurately predicting the diagnosis and therapy for patients with early stage MPLC.MethodsA total of 240 tissue samples from 203 patients with multiple-non-small-cell lung cancers (NSCLCs) (n = 30), early stage single-NSCLC (Group A, n = 94), and advanced-stage NSCLC (Group B, n = 79) were subjected to targeted multigene panel sequencing.ResultsThirty patients for whom next-generation sequencing was performed on &gt;1 tumor were identified, yielding 45 tumor pairs. The frequencies of EGFR, TP53, RBM10, ERBB2, and CDKN2A mutations exhibited significant differences between early and advanced-stage NSCLCs. The prevalence of the EGFR L858R mutation in early stage NSCLC was remarkably higher than that in advanced-stage NSCLC (P = 0.047). The molecular method classified tumor pairs into 26 definite MPLC tumors and four intrapulmonary metastasis (IM) tumors. A high rate of discordance in driver genetic alterations was found in the different tumor lesions of MPLC patients. The prospective Martini histologic prediction of MPLC was discordant with the molecular method for three patients (16.7%), particularly in the prediction of IM (91.7% discordant).ConclusionsComprehensive molecular evaluation allows the unambiguous delineation of clonal relationships among tumors. In comparison, the Martini and Melamed criteria have notable limitations in the recognition of IM. Our results support the adoption of a large panel to supplement histology for strongly discriminating NSCLC clonal relationships in clinical practice.
Increased CDC6 Expression Associates With Poor Prognosis in Patients With Clear Cell Renal Cell Carcinoma
Authors: Yicong Yao , Wang Yi , Denglong Wu , Baoying Hu 
Published: May 2021

BackgroundCDC6 (Cell division control protein 6), located at chromosome 17q21.3, plays an important role in the early stage of DNA replication and has unique functions in various malignant tumors. Here, we evaluate the relationship between CDC6 expression and oncology outcomes in patients with clear cell renal cell carcinoma (ccRCC).MethodsA retrospective analysis of 118 ccRCC patients in Affiliated Hospital of Nantong University from 2015 to 2017 was performed. Triplicate tissue microarrays (TMA) were prepared from formalin-fixed and paraffin-embedded specimens. Immunohistochemistry (IHC) was conducted to evaluate the relationship between CDC6 expression and standard pathological features and prognosis. The RNA sequencing data and corresponding clinical information were acquired from the TCGA database. GSEA was used to identify signal pathways related to CDC6. Cox regression analysis was used to assess independent prognostic factors. In addition, the relationship between CDC6 and immunity was also investigated.ResultsThe results of Kaplan–Meier curve indicated that the OS of the patients with high expression of CDC6 was shorter than that of the patients with low CDC6 expression. Integrating the TCGA database and IHC staining, the results showed that CDC6 in ccRCC tissue was obviously up-regulated compared with adjacent normal kidney tissue. The results of Logistic regression analysis demonstrated that ccRCC patients with high expression of CDC6 are more likely to develop advanced disease than ccRCC patients with low CDC6 expression. The results of GSEA showed that the high expression of CDC6 was related to multiple signaling pathways. As for immunity, it was also related to TMB, immune checkpoint molecules, tumor microenvironment and immune infiltration. There were significantly correlations with CDC6 and immune cell infiltration levels and tumor microenvironment. The results of further results of the TCGA database showed that CDC6 was obviously related to immune checkpoint molecules and immune cells.ConclusionsIncreased expression of CDC6 is a potentially prognostic factor of poor prognosis in ccRCC patients.