bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pembrolizumab in FIGO IVB Verrucous Carcinoma of the Vulva: A Case Report
Authors: Wang Yuhan , Lin Rongchun , Zhang Bingzhong , Zhou Hui , Lin Zhongqiu , Yao Tingting 
Published: May 2021

BackgroundVulvar cancer is the fourth most common gynecologic cancer, and prognosis is poor in advanced vulvar cancer patients. Treatment for advanced vulvar cancer has not been satisfactory. In this report, we firstly report a FIGO IVB vulva verrucous carcinoma patient who obtained good prognosis after systemic treatment.Case PresentationA patient was admitted to hospital due to her vulvar lesion persistent for past 14 years. The vulvar mass has widely invaded urethra, part of anus, the lower third of the vagina, bilateral superior and inferior branches of pubis, and bilateral internal and external muscles of obturator. Multiple metastatic lymph nodes were also found in the pelvic cavity. The histopathological studies confirmed vulvar verrucous carcinoma with a PD-L1 overexpression. After six courses of neoadjuvant chemotherapy and pembrolizumab, the patient underwent radical vulvectomy and achieved optimal cytoreduction. Postoperative pathology found no residual tumor. The patient then received one course of postoperative chemotherapy and pembrolizumab, underwent radiation therapy, and was disease free after 6 months follow-up.ConclusionOur individualized treatment strategy is successful. Pembrolizumab is safe and effective in the treatment of advanced vulvar verrucous carcinoma with PD-L1 overexpression.
Radiomic Analysis of Contrast-Enhanced Mammography With Different Image Types: Classification of Breast Lesions
Authors: Wang Simin , Mao Ning , Duan Shaofeng , Li Qin , Li Ruimin , Jiang Tingting , Wang Zhongyi , Xie Haizhu , Gu Yajia 
Published: May 2021

Objective: A limited number of studies have focused on the radiomic analysis of contrast-enhanced mammography (CEM). We aimed to construct several radiomics-based models of CEM for classifying benign and malignant breast lesions.Materials and Methods: The retrospective, double-center study included women who underwent CEM between November 2013 and February 2020. Radiomic analysis was performed using high-energy (HE), low-energy (LE), and dual-energy subtraction (DES) images from CEM. Datasets were randomly divided into the training and testing sets at a ratio of 7:3. The maximum relevance minimum redundancy (mRMR) method and least absolute shrinkage and selection operator (LASSO) logistic regression were used to select the radiomic features and construct the best classification models. The performances of the models were assessed by the area under the receiver operating characteristic curve (AUC) with a 95% confidence interval (CI). Leave-group-out cross-validation (LGOCV) for 100 rounds was performed to obtain the mean AUCs, which were compared by the Wilcoxon rank-sum test and the Kruskal–Wallis rank-sum test.Results: A total of 192 women with 226 breast lesions (101 benign; 125 malignant) were enrolled. The median age was 48 years (range, 22–70 years). For the classification of breast lesions, the AUCs of the best models were 0.931 (95% CI: 0.873–0.989) for HE, 0.897 (95% CI: 0.807–0.981) for LE, 0.882 (95% CI: 0.825–0.987) for DES images and 0.960 (95% CI: 0.910–0.998) for all of the CEM images in the testing set. According to LGOCV, the models constructed with the HE images and all of the CEM images showed the highest mean AUCs for the training (0.931 and 0.938, respectively; P &lt; 0.05 for both) and testing sets (0.892 and 0.889, respectively; P = 0.55 for both), which were significantly higher than those of the two models constructed with the LE and DES images in the training (0.912 and 0.899, respectively; all P &lt; 0.05) and testing sets (0.866 and 0.862, respectively; all P &lt; 0.05).Conclusions: Radiomic analysis of CEM images was valuable for classifying benign and malignant breast lesions. The use of HE images or all three types of CEM images can achieve the best performance.
Comprehensive Analysis of GLUT1 Immune Infiltrates and ceRNA Network in Human Esophageal Carcinoma
Authors: Liu Xu-Sheng , Gao Yan , Wu Li-Bing , Wan Hua-Bing , Yan Peng , Jin Yang , Guo Shi-Bo , Wang Ya-Lan , Chen Xue-Qin , Zhou Lu-Meng , Yang Jian-Wei , Kui Xue-Yan , Liu Xiao-Yu , Pei Zhi-Jun 
Published: May 2021

BackgroundGlucose transporter 1 (GLUT1) is encoded by the solute carrier family 2A1 (SLC2A1) gene and is one of the glucose transporters with the greatest affinity for glucose. Abnormal expression of GLUT1 is associated with a variety of cancers. However, the biological role of GLUT1 in esophageal carcinoma (ESCA) remains to be determined.MethodsWe analyzed the expression of GLUT1 in pan-cancer and ESCA as well as clinicopathological analysis through multiple databases. Use R and STRING to perform GO/KEGG function enrichment and PPI analysis for GLUT1 co-expression. TIMER and CIBERSORT were used to analyze the relationship between GLUT1 expression and immune infiltration in ESCA. The TCGA ESCA cohort was used to analyze the relationship between GLUT1 expression and m6A modification in ESCA, and to construct a regulatory network in line with the ceRNA hypothesis.ResultsGLUT1 is highly expressed in a variety of tumors including ESCA, and is closely related to histological types and histological grade. GO/KEGG functional enrichment analysis revealed that GLUT1 is closely related to structural constituent of cytoskeleton, intermediate filament binding, cell-cell adheres junction, epidermis development, and P53 signaling pathway. PPI shows that GLUT1 is closely related to TP53, GIPC1 and INS, and these three proteins all play an important role in tumor proliferation. CIBERSORT analysis showed that GLUT1 expression is related to the infiltration of multiple immune cells. When GLUT1 is highly expressed, the number of memory B cells decreases. ESCA cohort analysis found that GLUT1 expression was related to 7 m6A modifier genes. Six possible crRNA networks in ESCA were constructed by correlation analysis, and all these ceRNA networks contained GLUT1.ConclusionGLUT1 can be used as a biomarker for the diagnosis and treatment of ESCA, and is related to tumor immune infiltration, m6A modification and ceRNA network.
Study of an Online Plan Verification Method and the Sensitivity of Plan Delivery Accuracy to Different Beam Parameter Errors in Proton and Carbon Ion Radiotherapy
Authors: Zhao Jun , Chen Zhi , Wu Xianwei , Xing Ying , Li Yongqiang 
Published: May 2021

For scanning beam particle therapy, the plan delivery accuracy is affected by spot size deviation, position deviation and particle number deviation. Until now, all plan verification systems available for particle therapy have been designed for pretreatment verification. The purpose of this study is to introduce a method for online plan delivery accuracy checks and to evaluate the sensitivity of plan delivery accuracy to different beam parameter errors. A program was developed using MATLAB to reconstruct doses from beam parameters recorded in log files and to compare them with the doses calculated by treatment planning system (TPS). Both carbon ion plans and proton plans were evaluated in this study. The dose reconstruction algorithm is verified by comparing the dose from the TPS with the reconstructed dose under the same beam parameters. The sensitivity of plan delivery accuracy to different beam parameter errors was analyzed by comparing the dose reconstructed from the pseudo plans that manually added errors with the original plan dose. For the validation of dose reconstruction algorithm, mean dose difference between the reconstructed dose and the plan dose were 0.70% ± 0.24% and 0.51% ± 0.25% for carbon ion beam and proton beam, respectively. According to our simulation, the delivery accuracy of the carbon ion plan is more sensitive to spot position deviation and particle number deviation, and the delivery accuracy of the proton plan is more sensitive to spot size deviation. To achieve a 90% gamma pass rate with 3 mm/3% criteria, the average spot size deviation, position deviation, particle number deviation should be within 23%, 1.9 mm, and 1.5% and 20%, 2.1 mm, and 1.6% for carbon ion beam and proton beam, respectively. In conclusion, the method that we introduced for online plan delivery verification is feasible and reliable. The sensitivity of plan delivery accuracy to different errors was clarified for our system. The methods used in this study can be easily repeated in other particle therapy centers.
Impact of Total Epinephrine Dose on Long Term Neurological Outcome for Cardiac Arrest Patients: A Cohort Study
Authors: Shi Xiaowei , Yu Jiong , Pan Qiaoling , Lu Yuanqiang , Li Lanjuan , Cao Hongcui 
Published: May 2021

Introduction: Although epinephrine is universally acknowledged to increase return of spontaneous circulation (ROSC) after cardiac arrest, its balanced effects on later outcomes remain uncertain, causing potential harm during post-resuscitation phase. Recent studies have questioned the efficacy and potential deleterious effects of epinephrine on long-term survival and neurological outcomes, despite that the adverse relationship between epinephrine dose and outcome can be partially biased by longer CPR duration and underlying comorbidities. This study explored the long-term effect of epinephrine when used in a cohort of patients that underwent cardiac arrest during cardiopulmonary resuscitation.Methods: The data were originally collected from a retrospective institutional database from January 2007 to December 2015 and are now available on Dryad (via: https://doi.org/10.5061/dryad.qv6fp83). Use of epinephrine was coded by dose (&lt;2 mg, 2 mg, 3–4 mg, ≥5 mg). A favorable neurological outcome was defined using a Cerebral Performance Category (CPC) 1 or 2. The association between epinephrine dosing and 3-months neurological outcome was analyzed by univariate analysis and multivariate logistic regression.Results: Univariate and multivariate analysis demonstrated a negative association between total epinephrine dose and neurological outcome. Of the 373 eligible patients, 92 received less than 2 mg of epinephrine, 60 received 2 mg, 97 received 3–4 mg and 124 received more than 5 mg. Compared to patients who received less than 2 mg of epinephrine, the adjusted odds ratio (OR) of a favorable neurological outcome was 0.8 (95% confidence interval [CI]: 0.38–1.68) for 2 mg of epinephrine, 0.43 (95% confidence interval [CI]: 0.21–0.89) for 3–4 mg of epinephrine and 0.40 (95% confidence interval [CI]: 0.17–0.96) for more than 5 mg of epinephrine.Conclusion: In this cohort of patients who achieved ROSC, total epinephrine dosing during resuscitation was associated with a worse neurological outcome three months after cardiac arrest, after adjusting other confounding factors. Further researches are needed to investigate the long-term effect of epinephrine on cardiac arrest patients.
Benefits and Harms of Low-Dose Rivaroxaban in Asian Patients With Atrial Fibrillation: A Systematic Review and Meta-analysis of Real-World Studies
Authors: Qian Jun , Yan Yi-Dan , Yang Sheng-Yan , Zhang Chi , Li Wen-Yan , Gu Zhi-Chun 
Published: May 2021

Background: Low-dose prescription of rivaroxaban was common among patients with atrial fibrillation (AF) in Asia. However, the benefits and harms of rivaroxaban at a low dosage in Asian patients with AF remains unclear. Accordingly, we aimed to collect and summarize all available evidence to fill this important knowledge gap.Methods: In this systematic review and meta-analysis, we systematically searched databases of MEDLINE, EMBASE, and Cochrane Library for relevant studies from inception until February 23, 2021. Eligible retrospective nationwide or health insurance database studies or prospective registration studies that reported efficacy (stroke/systemic embolism), safety (major bleeding, intracranial hemorrhage, gastrointestinal bleeding), or other outcomes (myocardial infarction, death) of low-dose rivaroxaban in comparison with warfarin in AF patients were enrolled. Data extraction and study quality assessment were conducted by two authors independently. Low dosing of rivaroxaban (15/10 mg) was defined as the received dose lower than the recommended dose (20 mg) approved in most districts. Hazard ratio (HR) with 95% confidence intervals (95% CIs) was pooled using a random-effect model. Subgroup analyses were conducted according to different dose regimens. Sensitivity analyses were conducted by sequential elimination of each study from the pool. Since potential effect modifiers (patient demographics, differences of each study, and others) may lead to bias in primacy outcomes, we performed a meta-regression analysis to explore the influence of these factors on the primary efficacy and safety outcomes.Results: Totally, 12 studies involving 292,815 Asian patients with AF were included. All studies were detected as low to moderate risk bias. Low-dose rivaroxaban treatment in Asian AF patients was associated with a reduced risk of stroke/systemic embolism (HR: 0.76, 95% CI: 0.70–0.84, I2: 57.8%), major bleeding (HR: 0.72, 95% CI: 0.62–0.84, I2: 81.5%), and all-cause death (HR: 0.65, 95% CI: 0.58–0.73, I2: 81.7%) when compared with warfarin. Furthermore, consistent results were observed among different dose regimens (10/15/20 mg) in all the clinical outcomes (Pinteraction &gt; 0.05 for each outcome). Meta-regression analysis failed to detect any potential confounding to impact the primacy outcomes.Conclusion: Insights from the present meta-analysis, we found that low-dose rivaroxaban, even at a dosage of 10 mg daily, was associated with a reduced risk of stroke/SE and bleeding than warfarin in Asian AF patients. However, owing to considerable heterogeneity among included studies, further prospective studies are required to confirm these findings.
MicroRNAs Regulating Mitochondrial Function in Cardiac Diseases
Authors: Zhang Guang-Qiong , Wang Sheng-Quan , Chen Yan , Fu Ling-Yun , Xu Yi-Ni , Li Ling , Tao Ling , Shen Xiang-Chun 
Published: May 2021

Mitochondria are the key organelles that supply cellular energy. As the most active organ in the body, the energy required to maintain the mechanical function of the heart requires a high quantity of high-quality mitochondria in cardiomyocytes. MicroRNAs (miRNAs) are single-stranded noncoding RNAs, approximately 22 nt in length, which play key roles in mediating post-transcriptional gene silencing. Numerous studies have confirmed that miRNAs can participate in the occurrence and development of cardiac diseases by regulating mitochondrial function-related genes and signaling pathways. Therefore, elucidating the crosstalk that occurs between miRNAs and mitochondria is important for the prevention and treatment of cardiac diseases. In this review, we discuss the biogenesis of miRNAs, the miRNA-mediated regulation of major genes involved in the maintenance of mitochondrial function, and the effects of miRNAs on mitochondrial function in cardiac diseases in order to provide a theoretical basis for the clinical prevention and treatment of cardiac disease and the development of new drugs.
Pharmacokinetic Study of Oral 14C-Radiolabeled Hyzetimibe, A New Cholesterol Absorption Inhibitor
Authors: Liao Jianwei , Wang Xin , Li Zhenyu , Ouyang Dongsheng 
Published: May 2021

Background and objectives: Hyzetimibe is a candidate drug being investigated as the second-in-class cholesterol absorption inhibitor; it lowers plasma levels of low-density lipoprotein cholesterol (LDL-C) by blocking the Niemann-Pick C1-like 1 protein, a transporter mainly expressed in the intestine that allows dietary cholesterol to enter the body from the intestinal lumen. Previous studies on the metabolism of hyzetimibe in healthy volunteers were not enough to show the biotransformation and excretion pathway; in particular, whether hyzetimibe maintains pharmacological action for duration sufficient to pass through the hepatic-intestinal circulation remains unknown. Furthermore, it remains unclear whether the differences between the chemical structures of ezetimibe and hyzetimibe would result in different pharmacokinetic characteristics. Given that the molecular target is in the intestine and the substantial hepatic-intestinal circulation is a metabolic characteristic of the drug, a study of hyzetimibe as an oral 14C-radiolabeled drug, compared with routinely metabolized drugs, would play an important role in uncovering pharmacokinetic details.Methods: After an overnight fast and before taking medication, six healthy male volunteers swallowed an investigational product suspension containing 20 mg/∼100 μCi of 14C-labeled hyzetimibe as a single dose. Whole-blood, plasma, urine, and fecal samples were collected, and hyzetimibe and its metabolites were measured. Pharmacokinetic variables of hyzetimibe and its metabolites were calculated and statistically analyzed according to obtained concentration data. Safety data were collected throughout the study.Results: The major metabolite detected in plasma was hyzetimibe-glucuronide, which accounted for 97.2% of the total plasma radioactivity. The mean cumulative excretion of total radioactivity of the dose was 16.39% in urine and 76.90% in feces. Unchanged drug and hyzetimibe-glucuronide were identified as the major components in the feces and the urine, respectively. The main metabolic conversions of hyzetimibe were glucuronidation (M1), mono-oxidation (M4), and mono-oxidation with additional sulfonation (M7). Hyzetimibe was considered generally safe and well tolerated.Conclusion: This study of 14C-radiolabeled hyzetimibe provides a full profile of the biotransformation and excretion routes of hyzetimibe to improve the understanding of the pharmacokinetic characteristics of hyzetimibe. The changed hydroxyl group in the hyzetimibe structure made it easier for that drug, compared with ezetimibe, to combine with glucuronic acid and subsequently increased the urinary excretion of hyzetimibe vs. ezetimibe. These differences highlight the need to investigate in more detail the different pharmacokinetic impacts on the efficacy and safety of hyzetimibe and ezetimibe.
ShenLian Extract Enhances TGF-β Functions in the Macrophage-SMC Unit and Stabilizes Atherosclerotic Plaques
Authors: Liu Li , Li Qi , Yin Jie , Zhao Zheng , Sun Lidong , Ran Qingsen , Du Xinke , Wang Yajie , Li Yujie , Yang Qing , Chen Ying , Weng Xiaogang , Cai Weiyan , Zhu Xiaoxin 
Published: May 2021

Background/Aim: Macrophage polarization and phenotypic switching of smooth muscle cells (SMCs) are multi-faceted events dominating atherosclerosis (AS) progression. TGF-β was proved to been one of the bridge on the crosstalk between macrophage and SMC. ShenLian (SL) was extracted from a potent anti-atherosclerotic formula. However, its exact mechanism rebalancing inflammatory microenvironment of AS remain largely unknown. Within the entirety of macrophage and SMC, this study investigated the pharmacological effects of SL on stabilizing atherosclerotic plaques.Methods: The main components of SL were examined by high performance liquid chromatography. Co-culture and conditioned medium models of macrophage/SMC interactions were designed to identify the relationship between macrophage polarization and switching of SMC phenotypes. Flow cytometry, immunofluorescent staining, RT-PCR, western blotting, and ELISA were used to determine the expression of molecules relating to AS progression. An atherosclerosis animal model, established by placing a perivascular collar on the right common carotid artery in ApoE−/− mice, was used to investigate whether TGF-β is the key molecular mediator of SL in crosstalk between macrophage and SMC. Plaque size was defined by nuclear magnetic resonance imaging. Key markers related to phenotypic transformation of macrophage and SMC were determined by immunohistochemical staining.Results: Results revealed that, accompanied by rebalanced M2 macrophage polarization, SL supported SMC phenotypic transformation and functionally reconstruct the ECM of plaques specifically in macrophage-SMC co-cultural model. Molecularly, such activity of SL closely related to the activation of STAT3/SOCS3 pathway. Furthermore, in co-culture system, up-regulation of α-SMA induced by SL could neutralized by 1D11, a TGF-β neutralizing antibody, indicating that SL mediated Macrophage-SMC communication by enhancing TGF-β. In the AS model constructed by ApoE−/− mice, effects of SL on phenotypic transformation of macrophage and SMC has been well verified. Specific blocking of TGF-β largely attenuated the aforementioned effects of SL.Conclusion: Our findings highlighted that TGF-β might be the responsive factor of SL within macrophage and SMC communication. This study revealed that crosstalk between macrophage and SMC forms a holistic entirety promoting atherosclerotic plaque stability.
Persistently Increased Systemic ACE2 Activity Is Associated With an Increased Inflammatory Response in Smokers With COVID-19
Authors: Kaur Gagandeep , Yogeswaran Shaiesh , Muthumalage Thivanka , Rahman Irfan 
Published: May 2021

Background: Tobacco smoking is known to be involved in the pathogenesis of several cardiopulmonary diseases. Additionally, smokers are highly susceptible to infectious agents due to weakened immunity. However, the progression of lung injury based on SARS-CoV-2-mediated COVID-19 pathogenesis amongst smokers and those with pre-existing pulmonary diseases is not known. We determined the systemic levels and activity of COVID-19 associated proteins, cytokine/chemokines, and lipid mediators (lipidomics) amongst COVID-19 patients with and without a history of smoking to understand the underlying susceptible factor in the pathogenesis of COVID-19.Methods: We obtained serum from healthy (CoV−), COVID-19 positive (CoV+), and COVID-19 recovered (CoV Rec) subjects with and without a history of smoking. We conducted a Luminex multiplex assay (cytokine levels), LC/MS (eicosanoids or oxylipin panel), and ACE2 enzymatic activity assays on the serum samples to determine the systemic changes in COVID-19 patients.Results: On comparing the levels of serum ACE2 amongst COVID-19 (positive and recovered) patients and healthy controls, we found a pronounced increase in serum ACE2 levels in patients with COVID-19 infection. Furthermore, ACE2 enzyme activity was significantly increased amongst COVID-19 patients with a smoking history. Also, we analyzed the levels of Angiotensin 1–7 (Ang1–7) peptide, the product of enzymatic action of ACE2, in the serum samples. We found significantly high levels of Ang1–7 in the serum of both CoV+ and CoV Rec patients. Our data further demonstrated a smoking-induced increase in serum furin and inflammatory cytokine [IFNγ(p = 0.0836), Eotaxin (p &lt; 0.05), MCP-1 (p &lt; 0.05), and IL-9 (p = 0.0991)] levels in COVID-19 patients as compared to non-smoking controls. Overall, our results show that smoking adversely affects the levels of systemic inflammatory markers and COVID-19 associated proteins, thus suggesting that COVID-19 infection may have severe outcomes amongst smokers.