bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel humanized Frizzled-7-targeting antibody enhances antitumor effects of Bevacizumab against triple-negative breast cancer via blocking Wnt/β-catenin signaling pathway
Authors: Xie Wei , Zhao Huijie , Wang Fengxian , Wang Yiyun , He Yuan , Wang Tong , Zhang Kunchi , Yang Hao , Zhou Zhaoli , Shi Haibin , Wang Jin , Huang Gang 
Published: January 2021

Abstract
Background
Anti-angiogenic therapy has been widely applied to the clinical treatment of malignant tumors. However, the efficacy of such treatments has been called into question, especially in triple-negative breast cancer (TNBC). Bevacizumab, the first anti-angiogenic agent approved by FDA, actually increases invasive and metastatic properties of TNBC cells, resulting from the activation of Wnt/β-catenin signaling in response to hypoxia. As a critical receptor of Wnt/β-catenin signaling, Frizzled-7 (Fzd7) is aberrantly expressed in TNBC, indicating Fzd7 a potential target for developing drugs to be combined with anti-angiogenic agents.

Methods
Hybridoma technique and antibody humanization technique were utilized to generate a Fzd7-targeting antibody (SHH002-hu1). Biolayer interferometry (BLI) assay and near infrared (NIR) imaging were conducted to detect the affinity and targeting ability of SHH002-hu1. Next, whether SHH002-hu1 could suppress the invasion and migration of TNBC cells induced by Bevacizumab were validated, and the underlying molecular mechanisms were elucidated by luciferase reporter and western blot assays. The nude-mice transplanted TNBC models were established to assess the anti-TNBC activities of SHH002-hu1 when combined with Bevacizumab. Then, the effects on putative TNBC stem-like cells and Wnt/β-catenin signaling were evaluated by immunofluorescence (IF). Further, the tumor-initiating and self-renew capacity of TNBC cells were studied by secondary nude mouse xenograft model and sphere formation assay. In addition, the effects of SHH002-hu1 on the adaptation of TNBC cells to hypoxia were evaluated by the detection of vasculogenic mimicry (VM) and hypoxia-inducible factor-1α (HIF-1α) transcriptional activity.

Results
The novel humanized antibody targeting Fzd7 (SHH002-hu1) exhibited extremely high affinity with Fzd7, and specifically targeted to Fzd7+ cells and tumor tissues. SHH002-hu1 repressed invasion, migration and epithelial-mesenchymal cell transformation (EMT) of TNBC cells induced by Bevacizumab through abating Wnt/β-catenin signaling. SHH002-hu1 significantly enhanced the capacity of Bevacizumab to inhibit the growth of TNBC via reducing the subpopulation of putative TNBC stem-like cells, further attenuating Bevacizumab-enhanced tumor-initiating and self-renew capacity of TNBC cells. Moreover, SHH002-hu1 effectively restrained the adaptation of TNBC cells to hypoxia via disrupting Wnt/β-catenin signaling.

Conclusion
SHH002-hu1 significantly enhances the anti-TNBC capacity of Bevacizumab, and shows the potential of preventing TNBC recurrence, suggesting SHH002-hu1 a good candidate for the synergistic therapy together with Bevacizumab.
Hsa_circ_0005273 facilitates breast cancer tumorigenesis by regulating YAP1-hippo signaling pathway
Authors: Wang Xuehui , Ji Changle , Hu Jiashu , Deng Xiaochong , Zheng Wenfang , Yu Yunhe , Hua Kaiyao , Zhou Xiqian , Fang Lin 
Published: January 2021

Abstract
Background
Circular RNAs (circRNAs), a novel class of endogenous RNAs, have shown to participate in the development of breast cancer (BC). Hsa_circ_0005273 is a circRNA generated from several exons of PTK2. However, the potential functional role of hsa_circ_0005273 in BC remains largely unknown. Here we aim to evaluate the role of hsa_circ_0005273 in BC.

Methods
The expression level of hsa_circ_0005273 and miR-200a-3p were examined by RT-qPCR in BC tissues and cell lines. The effect of knocking down hsa_circ_0005273 in BC cell lines were evaluated by examinations of cell proliferation, migration and cell cycle. In addition, xenografts experiment in nude mice were performed to evaluate the effect of hsa_circ_0005273 in BC. RNA immunoprecipitation assay, RNA probe pull-down assay, luciferase reporter assay and fluorescence in situ hybridization were conducted to confirm the relationship between hsa_circ_0005273, miR-200a-3p and YAP1.

Results
Hsa_circ_0005273 is over-expressed in BC tissues and cell lines, whereas miR-200a-3p expression is repressed. Depletion of hsa_circ_0005273 inhibited the progression of BC cells in vitro and in vivo, while overexpression of hsa_circ_0005273 exhibited the opposite effect. Importantly, hsa_circ_0005273 upregulated YAP1 expression and inactivated Hippo pathway via sponging miR-200a-3p to promote BC progression.

Conclusions
Hsa_circ_0005273 regulates the miR-200a-3p/YAP1 axis and inactivates Hippo signaling pathway to promote BC progression, which may become a potential biomarker and therapeutic target.
Leg muscle cross‐sectional area measured by ultrasound is highly correlated with MRI
Authors: Sponbeck Joshua K. , Frandsen Clint R. , Ridge Sarah T. , Swanson Derek A. , Swanson Dallin C. , Johnson A. Wayne 
Published: January 2021

AbstractBackgroundThe leg muscles are important for balance, posture, and movement during static and dynamic activity. Obtaining cross‐sectional area measurements (CSA) of the leg muscles helps researchers understand the health and force production capability of individual leg muscles. Therefore, having an easy to use and readily available method to assess leg muscle CSA is needed. Thus, the purpose of this study was to compare the magnitude, repeatability, and validity of CSA measurements of select leg muscles from ultrasound (US) and the current gold standard, magnetic resonance imaging (MRI).Methods20 healthy volunteers participated in this study. Each participant was imaged via US and MRI. The muscles of interest obtained on each participant consisted of the tibialis anterior at both 30 and 50% of the shank length, tibialis posterior at both 30 and 50% of the shank length, the flexor digitorum longus, the fibularis (peroneus) longus, and the fibularis (peroneus) brevis.ResultsStrong Pearson correlations were seen for all of the muscles when comparing US to MRI with a range from. 7840 to. 9676. For all measurements, standard error of the measurement ranged from. 003 to 0.260 cm2. Minimum detectable difference for muscle measurements ranged from. 008 cm2 for MRI fibularis longus and fibularis brevis to. 693 cm2 for MRI of tibialis anterior at 30%. US minimum detectable difference ranged from. 125 cm2 for the tibialis posterior muscle at 30% to. 449 cm2 for the tibialis anterior muscle at 50%.ConclusionsBased on these results ultrasound is a valid method to obtain CSA of muscles of the leg when compared with MRI.
Comparison of the predictive value of progesterone‐related indicators for pregnancy outcomes of women undergoing the short‐acting GnRH agonist long protocol: a retrospective study
Authors: Zhang Yangyang , Xu Yang , Wang Yuqiong , Xue Qing , Shang Jing , Yang Xiuli , Shan Xuemin 
Published: January 2021

Abstract
Background
There are many progesterone (P) elevation-related indicators for predicting pregnancy outcomes, including the serum P, P-to-oestradiol ratio (P/E2), P-to-follicle index (PFI), and P-to-mature oocyte index (PMOI); however, due to inconsistencies in study populations and controlled ovarian hyperstimulation (COH) protocols among studies, these indicators are controversial. Moreover, no researchers have included these four commonly used indicators in one study to compare their predictive efficacies. The objective of this study was to compare the predictive value of P-related indicators for pregnancy outcomes of women undergoing the short-acting GnRH agonist long protocol.

Methods
A total of 612 infertile women undergoing IVF/ICSI were recruited for this study. Serum samples were obtained on the morning of HCG injection for serum P and E2 measurements. Transvaginal ultrasound was performed to determine the follicle count (≥ 14 mm in diameter). The number of mature oocytes was observed in the embryo laboratory after oocyte retrieval.

Results
In cases of P < 2.5 ng/ml, there was no significant difference in the serum P level or P/E2 between the pregnant group and the non-pregnant group. The PFI and PMOI of the pregnant group were significantly lower than those of the non-pregnant group. According to the stratified analysis of the ovarian response, only the PMI and PMOI of the pregnant women in the normal ovarian response group were lower than those of the non-pregnant women. To compare the predictive value of the PFI and PMOI in IVF/ICSI outcomes, the patients were divided into four groups. The good-quality embryo rate and clinical pregnancy rate were highest in Group A (low PFI and low PMOI) and lowest in Group D (high PFI and high PMOI). In the two groups with discordant PFI and PMOI, namely Group B (low PFI and high PMOI) and Group C (high PFI and low PMOI), the good-quality embryo rate and clinical pregnancy rate were not significantly different.

Conclusions
The PFI and PMOI had equal value in predicting clinical pregnancy outcomes in the normal ovarian response group undergoing the short-acting GnRH agonist long protocol. Each clinical centre can choose one of the indicators according to their actual situation in clinical practice and establish individual cut-off values for PFI and PMOI based on their own hormonal measurements.
The accuracy of initial diagnoses in coma: an observational study in 835 patients with non-traumatic disorder of consciousness
Authors: Lutz Maximilian , Möckel Martin , Lindner Tobias , Ploner Christoph J. , Braun Mischa , Schmidt Wolf Ulrich 
Published: January 2021

Abstract
Background
Management of patients with coma of unknown etiology (CUE) is a major challenge in most emergency departments (EDs). CUE is associated with a high mortality and a wide variety of pathologies that require differential therapies. A suspected diagnosis issued by pre-hospital emergency care providers often drives the first approach to these patients. We aim to determine the accuracy and value of the initial diagnostic hypothesis in patients with CUE.

Methods
Consecutive ED patients presenting with CUE were prospectively enrolled. We obtained the suspected diagnoses or working hypotheses from standardized reports given by prehospital emergency care providers, both paramedics and emergency physicians. Suspected and final diagnoses were classified into I) acute primary brain lesions, II) primary brain pathologies without acute lesions and III) pathologies that affected the brain secondarily. We compared suspected and final diagnosis with percent agreement and Cohen’s Kappa including sub-group analyses for paramedics and physicians. Furthermore, we tested the value of suspected and final diagnoses as predictors for mortality with binary logistic regression models.

Results
Overall, suspected and final diagnoses matched in 62% of 835 enrolled patients. Cohen’s Kappa showed a value of κ = .415 (95% CI .361–.469, p < .005). There was no relevant difference in diagnostic accuracy between paramedics and physicians. Suspected diagnoses did not significantly interact with in-hospital mortality (e.g., suspected class I: OR .982, 95% CI .518–1.836) while final diagnoses interacted strongly (e.g., final class I: OR 5.425, 95% CI 3.409–8.633).

Conclusion
In cases of CUE, the suspected diagnosis is unreliable, regardless of different pre-hospital care providers’ qualifications. It is not an appropriate decision-making tool as it neither sufficiently predicts the final diagnosis nor detects the especially critical comatose patient. To avoid the risk of mistriage and unnecessarily delayed therapy, we advocate for a standardized diagnostic work-up for all CUE patients that should be triggered by the emergency symptom alone and not by any suspected diagnosis.
Incidence, prognostic factors, and outcomes of venous thromboembolism in critically ill patients: data from two prospective cohort studies
Authors: Eck Ruben J. , Hulshof Lisa , Wiersema Renske , Thio Chris H. L. , Hiemstra Bart , van den Oever Niels C. Gritters , Gans Reinold O. B. , van der Horst Iwan C. C. , Meijer Karina , Keus Frederik 
Published: January 2021

Abstract
Background
The objective of this study was to describe the prevalence, incidence, prognostic factors, and outcomes of venous thromboembolism in critically ill patients receiving contemporary thrombosis prophylaxis.

Methods
We conducted a pooled analysis of two prospective cohort studies. The outcomes of interest were in-hospital pulmonary embolism or lower extremity deep vein thrombosis (PE-LDVT), in-hospital nonleg deep vein thrombosis (NLDVT), and 90-day mortality. Multivariable logistic regression analysis was used to evaluate the association between predefined baseline prognostic factors and PE-LDVT or NLDVT. Cox regression analysis was used to evaluate the association between PE-LDVT or NLDVT and 90-day mortality.

Results
A total of 2208 patients were included. The prevalence of any venous thromboembolism during 3 months before ICU admission was 3.6% (95% CI 2.8–4.4%). Out of 2166 patients, 47 (2.2%; 95% CI 1.6–2.9%) developed PE-LDVT and 38 patients (1.8%; 95% CI 1.2–2.4%) developed NLDVT. Renal replacement therapy (OR 3.5 95% CI 1.4–8.6), respiratory failure (OR 2.0; 95% CI 1.1–3.8), and previous VTE (OR 3.6; 95% CI 1.7–7.7) were associated with PE-LDVT. Central venous catheters (OR 5.4; 95% CI 1.7–17.8) and infection (OR 2.2; 95% CI 1.1–4.3) were associated with NLDVT. Occurrence of PE-LDVT but not NLDVT was associated with increased 90-day mortality (HR 2.7; 95% CI 1.6–4.6, respectively, 0.92; 95% CI 0.41–2.1).

Conclusion
Thrombotic events are common in critically ill patients, both before and after ICU admittance. Development of PE-LDVT but not NLDVT was associated with increased mortality. Prognostic factors for developing PE-LDVT or NLDVT despite prophylaxis can be identified at ICU admission and may be used to select patients at higher risk in future randomized clinical trials.

Trial registration

NCT03773939.
Eubacterium rectale contributes to colorectal cancer initiation via promoting colitis
Authors: Wang Yijia , Wan Xuehua , Wu Xiaojing , Zhang Chunze , Liu Jun , Hou Shaobin 
Published: January 2021

AbstractBackgroundInflammatory bowel disease caused by microbial dysbiosis is an important factor contributing to colorectal cancer (CRC) initiation. The ‘driver-passenger’ model in human gut microbial dysbiosis suggests that ‘driver’ bacteria may colonize with low relative abundance on tumor site but persistently induce chronic change in normal intestinal epithelium and initiate CRC. They are gradually replaced by ‘passenger’ bacteria later on, due to their low adaptability to the on-tumor site niche.ResultsTo reveal site-specific bacterial taxon markers in CRC patients, we analyzed the gut mucosal microbiome of 75 paired samples of on-tumor and tumor-adjacent sites, 75 off-tumor sites, and 26 healthy controls. Linear discriminant analysis of relative abundance profiles revealed unique bacterial taxon distribution correlated with specific tumor sites, withEubacteriumhaving the distribution characteristic of potential driver bacteria. We further show thatEubacterium rectaleendotoxin activates the transcription factor NF-κΒ, which regulates multiple aspects of innate and adaptive immune responses in normal colon epithelial cells. Unlike the ‘passenger’ bacteriumFusobacterium nucleatum,E. rectalepromotes dextran sodium sulfate-induced colitis in Balb/c mice.ConclusionsOur findings reveal thatE. rectalefunctions as a ‘driver’ bacterium and contributes to cancer initiation via promoting inflammation.
High genetic diversity in Campylobacter concisus isolates from patients with microscopic colitis
Authors: Aagaard Marta Emilie Yde , Kirk Karina Frahm , Nielsen Henrik , Nielsen Hans Linde 
Published: January 2021

AbstractThe emerging intestinal pathogen Campylobacter concisus has been associated with prolonged diarrhoea and classic inflammatory bowel diseases (IBD) and was recently also linked with microscopic colitis (MC). Previous reports have observed a high genetic diversity within isolates from diarrhoeic and IBD patients and from healthy controls (HC), and division of isolates into two major genomospecies (GS1 and GS2). The aim of this study was to describe genetic diversity in 80 recently cultivated MC biopsy and faecal isolates of C. concisus by multi-locus sequence typing (MLST); and to compare the phylogenetic relatedness to 102 isolates from diarrhoeic and IBD patients and HCs by k-mer-based distance estimation. MLST revealed high genetic diversity in MC isolates with 72 novel sequence types. K-mer divided MC isolates into two distinct clusters (cluster 1 n = 21, cluster 2 n = 49), with a significantly higher prevalence of cluster 2 isolates in biopsies than in faeces, p = 0.009. K-mer divided the 182 isolates into two major phylogenetic clusters: cluster 1 (GS1 isolates) and cluster 2 (GS2 isolates), which further differentiated into three subgroups. Cluster 1 and the three cluster 2 subgroups were each distinctive in mean genome size and GC count. Isolates from all disease phenotypes were present in cluster 1 and cluster 2 subgroup 2 and 3, whereas cluster 2 subgroup 1 only contained isolates restricted to patients with ulcerative colitis (n = 10) and HC (n = 4).
Morphological study of embryonic Chd8+/− mouse brains using light-sheet microscopy
Authors: Gómez Harold F. , Hodel Leonie , Michos Odyssé , Iber Dagmar 
Published: January 2021

Abstract
Objective
Autism spectrum disorder (ASD) encompasses a group of neurodevelopmental conditions that remain poorly understood due to their genetic complexity. CHD8 is a risk allele strongly associated with ASD, and heterozygous Chd8 loss-of-function mice have been reported to exhibit macrocephaly in early postnatal stages. In this work, we sought to identify measurable brain alterations in early embryonic development.

Results
We performed light-sheet fluorescence microscopy imaging of N-cadherin stained and optically cleared Chd8+/− and wild-type mouse brains at embryonic day 12.5 (E12.5). We report a detailed morphometric characterization of embryonic brain shapes and cortical neuroepithelial apical architecture. While Chd8+/− characteristic expansion of the forebrain and midbrain was not observed this early in embryogenesis, a tendency for a decreased lateral ventricular sphericity and an increased intraocular distance in Chd8+/− brains was found compared to controls. This study advocates the use of high-resolution microscopy technologies and multi-scale morphometric analyses of target brain regions to explore the etiology and cellular basis of Chd8 haploinsufficiency.
An MRI-based strategy for differentiation of frontotemporal dementia and Alzheimer’s disease
Authors:   the National Alzheimer’s Coordinating Center, the Alzheimer’s Disease Neuroimaging Initiative, Yu Qun ,   the Frontotemporal Lobar Degeneration Neuroimaging Initiative, Mai Yingren , Ruan Yuting , Luo Yishan , Zhao Lei , Fang Wenli , Cao Zhiyu , Li Yi , Liao Wang , Xiao Songhua , Mok Vincent C. T. , Shi Lin , Liu Jun 
Published: January 2021

Abstract
Background
The differential diagnosis of frontotemporal dementia (FTD) and Alzheimer’s disease (AD) is difficult due to the overlaps of clinical symptoms. Structural magnetic resonance imaging (sMRI) presents distinct brain atrophy and potentially helps in their differentiation. In this study, we aim at deriving a novel integrated index by leveraging the volumetric measures in brain regions with significant difference between AD and FTD and developing an MRI-based strategy for the differentiation of FTD and AD.

Methods
In this study, the data were acquired from three different databases, including 47 subjects with FTD, 47 subjects with AD, and 47 normal controls in the NACC database; 50 subjects with AD in the ADNI database; and 50 subjects with FTD in the FTLDNI database. The MR images of all subjects were automatically segmented, and the brain atrophy, including the AD resemblance atrophy index (AD-RAI), was quantified using AccuBrain®. A novel MRI index, named the frontotemporal dementia index (FTDI), was derived as the ratio between the weighted sum of the volumetric indexes in “FTD dominant” structures over that obtained from “AD dominant” structures. The weights and the identification of “FTD/AD dominant” structures were acquired from the statistical analysis of NACC data. The differentiation performance of FTDI was validated using independent data from ADNI and FTLDNI databases.

Results
AD-RAI is a proven imaging biomarker to identify AD and FTD from NC with significantly higher values (p < 0.001 and AUC = 0.88) as we reported before, while no significant difference was found between AD and FTD (p = 0.647). FTDI showed excellent accuracy in identifying FTD from AD (AUC = 0.90; SEN = 89%, SPE = 75% with threshold value = 1.08). The validation using independent data from ADNI and FTLDNI datasets also confirmed the efficacy of FTDI (AUC = 0.93; SEN = 96%, SPE = 70% with threshold value = 1.08).

Conclusions
Brain atrophy in AD, FTD, and normal elderly shows distinct patterns. In addition to AD-RAI that is designed to detect abnormal brain atrophy in dementia, a novel index specific to FTD is proposed and validated. By combining AD-RAI and FTDI, an MRI-based decision strategy was further proposed as a promising solution for the differential diagnosis of AD and FTD in clinical practice.
Spectrum of liver lesions hyperintense on hepatobiliary phase: an approach by clinical setting
Authors: Vernuccio Federica , Gagliano Domenico Salvatore , Cannella Roberto , Ba-Ssalamah Ahmed , Tang An , Brancatelli Giuseppe 
Published: January 2021

AbstractHepatobiliary MRI contrast agents are increasingly being used for liver imaging. In clinical practice, most focal liver lesions do not uptake hepatobiliary contrast agents. Less commonly, hepatic lesions may show variable signal characteristics on hepatobiliary phase. This pictorial essay reviews a broad spectrum of benign and malignant focal hepatic observations that may show hyperintensity on hepatobiliary phase in various clinical settings. In non-cirrhotic patients, focal hepatic observations that show hyperintensity in the hepatobiliary phase are usually benign and typically include focal nodular hyperplasia. In patients with primary or secondary vascular disorders, focal nodular hyperplasia-like lesions arise as a local hyperplastic response to vascular alterations and tend to be iso- or hyperintense in the hepatobiliary phase. In oncologic patients, metastases and cholangiocarcinoma are hypointense lesions in the hepatobiliary phase; however, occasionally they may show a diffuse, central and inhomogeneous hepatobiliary paradoxical uptake with peripheral rim hypointensity. Post-chemotherapy focal nodular hyperplasia-like lesions may be tricky, and their typical hyperintense rim in the hepatobiliary phase is very helpful for the differential diagnosis with metastases. In cirrhotic patients, hepatocellular carcinoma may occasionally appear hyperintense on hepatobiliary phase.