bluuebunny/crossref_metadata_2025_split huggingface dataset:
Case Report: Pancreatic Neuroendocrine Tumor With Liver Metastasis and Portal Vein Thrombosis
Authors: Tian Yulong , Qi Xingshun , Aljbri Afaf , Xu Ke , Zhong Hongshan 
Published: February 2022

IntroductionPancreatic neuroendocrine neoplasms (PNENs) are rare pancreatic tumors originating from pancreatic neuroendocrine cells. There is no consensus on the treatment for PNENs with unresectable liver metastases. Transcatheter arterial chemoembolization (TACE) is the preferred treatment for unresectable primary liver cancer. But the efficacy of TACE and anticoagulation in PNENs with unresectable liver metastases and portal vein thrombosis has never been reported.Methods and ResultsWe present the case of a 50-year-old male patient with hepatitis C who was found to have a single liver mass during a regular physical examination in 2016. The liver mass was surgically removed. Postoperative pathology suggested a neuroendocrine tumor of the liver, and it was suggested to look for the primary tumor. The patient was followed up until 2020, and the primary pancreatic tumor was found, along with multiple liver metastases and portal vein thrombosis. After transcatheter arterial embolization, anticoagulation, and endocrine therapy, the patient’s tumor load was relieved, and the portal vein was recanalized.ConclusionThe article reports the disease course in a case of a functional pancreatic neuroendocrine tumor with liver metastasis and portal vein thrombosis and reviews previous literature. To our knowledge, we reported for the first time the efficacy of TACE and anticoagulation in PNENs with unresectable liver metastases and portal vein thrombosis.
Integrated Genomic and Transcriptomic Analyses of Diffuse Large B-Cell Lymphoma With Multiple Abnormal Immunologic Markers
Authors: Sheng Lingshuang , Fu Di , Cao Yiwen , Huo Yujia , Wang Shuo , Shen Rong , Xu Pengpeng , Cheng Shu , Wang Li , Zhao Weili 
Published: February 2022

BackgroundDiffuse large B-cell lymphoma (DLBCL) is a highly aggressive subtype of lymphoma and related to autoimmune diseases (AIDs). Primary B-cell receptor-mediated AIDs are associated with poor clinical outcome of DLBCL. To further determine the role of immunological alterations on disease progression, our study integrated genomic and transcriptomic analyses on DLBCL with multiple abnormal immunologic markers.MethodsThe clinical data of 1,792 patients with newly diagnosed DLBCL were collected, with DNA- and RNA-sequencing conducted for 164 and 127 patients, respectively. Frequent gene mutations and the involved dysregulated pathways, along with gene expression pattern and tumor microenvironment alternations, were analyzed and compared based on the immune status of the patients.ResultsDLBCL with multiple abnormal immunologic markers demonstrated a variety of characteristics including elevated serum lactic dehydrogenase level, inferior prognosis, and dysregulated cell cycle and immune response, as well as activated oxidative phosphorylation pathway and increased Th1/Th2 and Th17/Treg ratios, which were highly similar as those that occur in AIDs.ConclusionsWe piloted the description of the clinical and genetic features of DLBCL with multiple abnormal immunologic markers, illustrated possible mechanisms of disease progression, and provided a clinical rationale of mechanism-based targeted therapy in this subset of DLBCL.
Case Report: Complete Response to Antiangiogenesis and Immune Checkpoint Blockade in an Unresectable MMR-Deficient Leiomyosarcoma Harboring Biallelic Loss of PTEN
Authors: Guo Xi , Li Suyao , Tong Hanxing , Zhang Yong , Ji Yuan , Zhuang Rongyuan , Zhang Chenlu , You Yang , Lu Weiqi , Zhou Yuhong 
Published: February 2022

BackgroundLeiomyosarcoma (LMS) is a malignant smooth muscle neoplasm, in which the efficacy of immune checkpoint blockade (ICB) is very limited. What is worse, loss of PTEN, known as a negative factor for ICB, frequently occurred in LMS. Seeking new strategies for LMS patients harboring loss of PTEN is important and challenging.Case PresentationA 42-year-old Chinese male was diagnosed as having unresectable LMS of the iliopsoas. After the failure of two prior chemotherapy regimens, whole-exome sequencing revealed that tumor tissue had high tumor mutation burden (689 Muts), high microsatellite instability, and some somatic mutations, including PTEN (copy number loss and p.N323fs), MSH6 (p.F1088fs), TP53 p.R273C, ASXL1 p.G645fs, ATR p.S1843P, and CDKN2A p.A118P. Then, antiangiogenic agent (pazopanib or anlotinib) plus pembrolizumab was administered from January 2 to August 6, 2018. However, pazopanib was stopped on June 18 due to the grade 2/3 adverse effect of hand–foot skin reaction, and anlotinib was administered. Considering that the tumor shrunk after immunotherapy, he underwent radical resection on September 6, 2018. The final pathological diagnosis confirmed pathologic complete response (CR). Until the latest follow-up (September 15, 2021), no progressive disease was observed and total disease-free survival has exceeded 36 months.ConclusionWe presented a patient with an unresectable mismatch repair (MMR)-deficient LMS harboring biallelic loss of PTEN who achieved CR from a combination strategy of antiangiogenesis plus pembrolizumab. Such a strategy might be a promising strategy to overcome the ICB resistance caused by the loss of PTEN. Such conclusions need to be further confirmed in further investigations.
Network Pharmacology Study and Experimental Validation of Yiqi Huayu Decoction Inducing Ferroptosis in Gastric Cancer
Authors: Song Siyuan , Wen Fang , Gu Suping , Gu Peixin , Huang Wenjie , Ruan Shuai , Chen Xiaoxue , Zhou Jiayu , Li Ye , Liu Jiatong , Shu Peng 
Published: February 2022

ObjectiveThis study aimed to identify the mechanism of Yiqi Huayu Decoction (YQHY) induced ferroptosis in gastric cancer (GC) by using network pharmacology and experimental validation.MethodsThe targets of YQHY, ferroptosis-related targets, and targets related to GC were derived from databases. Following the protein–protein interaction (PPI) network, the hub targets for YQHY induced ferroptosis in GC were identified. Furthermore, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were used to analyze the hub targets from a macro perspective. We verified the hub targets by molecular docking, GEPIA, HPA, and the cBioPortal database. Finally, we performed cell viability assays, quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, lipid peroxidation, and GSH assays to explore the mechanism of YQHY induced ferroptosis in GC.ResultsWe identified the main active compounds and hub targets: Quercetin, DIBP, DBP, Mipax, Phaseol and TP53, ATM, SMAD4, PTGS2, and ACSL4. KEGG enrichment analyses indicated that the JAK2-STAT3 signaling pathway may be a significant pathway. Molecular docking results showed that the main active compounds had a good binding activity with the hub targets. The experimental results proved that YQHY could induce ferroptosis in AGS by increasing the MDA content and reducing the GSH content. qRT–PCR and Western blot results showed that YQHY can induce ferroptosis in GC by affecting the JAK2-STAT3 pathway and the expression of ACSL4.ConclusionsThis study indicated that YQHY can induce ferroptosis in GC by affecting the JAK2–STAT3 pathway and the expression of ACSL4, and induction of ferroptosis may be one of the possible mechanisms of YQHY’s anti-recurrence and metastasis of GC.
The Causal Relationships Between Extrinsic Exposures and Risk of Prostate Cancer: A Phenome-Wide Mendelian Randomization Study
Authors: Gu Dongqing , Tang Mingshuang , Wang Yutong , Cui Huijie , Zhang Min , Bai Ye , Zeng Ziqian , Tan Yunhua , Wang Xin , Zhang Ben 
Published: February 2022

BackgroundProstate cancer is the second most common cancer in males worldwide, and multitudes of factors have been reported to be associated with prostate cancer risk.ObjectivesWe aim to conduct the phenome-wide exposed-omics analysis of the risk factors for prostate cancer and verify the causal associations between them.MethodsWe comprehensively searched published systematic reviews and meta-analyses of cohort studies and conducted another systematic review and meta-analysis of the Mendelian randomization studies investigating the associations between extrinsic exposures and prostate cancer, thus to find all of the potential risk factors for prostate cancer. Then, we launched a phenome-wide two-sample Mendelian randomization analysis to validate the potentially causal relationships using the PRACTICAL consortium and UK Biobank.ResultsWe found a total of 55 extrinsic exposures for prostate cancer risk. The causal effect of 30 potential extrinsic exposures on prostate cancer were assessed, and the results showed docosahexaenoic acid (DHA) [odds ratio (OR)=0.806, 95% confidence interval (CI): 0.661-0.984, p=0.034], insulin-like growth factor binding protein 3 (IGFBP-3) (OR=1.0002, 95%CI: 1.00004-1.0004, p=0.016), systemic lupus erythematosus (SLE) (OR=0.9993, 95%CI: 0.9986-0.99997, p=0.039), and body mass index (BMI) (OR=0.995, 95%CI: 0.990-0.9999, p=0.046) were associated with prostate cancer risk. However, no association was found between the other 26 factors and prostate cancer risk.ConclusionsOur study discovered the phenome-wide exposed-omics risk factors profile of prostate cancer, and verified that the IGFBP-3, DHA, BMI, and SLE were causally related to prostate cancer risk. The results may provide new insight into the study of the pathogenesis of prostate cancer.
Transcriptome and Lipid Metabolomics-Based Discovery: Glycyrrhizic Acid Alleviates Tripterygium Glycoside Tablet-Induced Acute Liver Injury by Regulating the Activities of CYP and the Metabolism of Phosphoglycerides
Authors: Shi Qiaoli , Wang Qixin , Chen Jiayun , Xia Fei , Qiu Chong , Li Min , Zhao Minghong , Zhang Qian , Luo Piao , Lu Tianming , Zhang Ying , Xu Liting , He Xueling , Zhong Tianyu , Lin Na , Guo Qiuyan 
Published: February 2022

Background: Glycyrrhizic acid (GA) has been reported to be liver protective; however, the characters and underlying mechanisms of GA against tripterygium glycoside tablet (TGT)-induced acute liver injury remain unelucidated.Hypothesis/Purpose: We assumed that GA could relieve TGT-induced acute liver injury by regulating liver function-related genes and lipid metabolites.Study Design: TGT-induced acute liver injury models were constructed in vivo and in vitro. Then the liver protective effect and mechanisms of GA were investigated by a combination of transcriptome, lipid metabolomics, and experimental validation.Methods: Intraperitoneal injection of GA was given in advance for six successive days. Then, the TGT-induced acute liver injury model was constructed by a single oral administration of TGT at 270 mg/kg, except for the normal group. All animals were sacrificed 18 h later. The serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin (TBIL), glutathione peroxidase (GSH-PX), and superoxide dismutase (SOD) were quantified. Liver tissues were used to observe pathological changes through hematoxylin–eosin (HE) staining and selected for transcriptome and metabolome sequencing. The underlying mechanisms were analyzed and further validated both in vivo and in vitro.Results: Pre-administration of GA markedly decreased the serum concentrations of AST, ALT, ALP, and TBIL but increased those of SOD and GSH-Px, improving the liver morphology of mice with TGT-induced acute liver injury. In addition, GA significantly increased the gene levels of Cyp2b13, Cyp2c69, Cyp3a16, Cyp3a44, Fmo3, and Nipal1. Differentially accumulated metabolites were screened and classified as phosphatidylcholine (PC) and phosphatidylethanolamine (PE). The in vitro results indicated that pre-administration of GA markedly alleviated the inhibitory effect of TGT on BRL-3A activity.Conclusion: This study combined transcriptome, lipid metabolomics, and experimental validation to offer convincing evidence that GA alleviates TGT-induced acute liver injury partially by regulating the activities of CYP and the metabolism of PC and PE.
Antibiotic Use in China’s Public Healthcare Institutions During the COVID-19 Pandemic: An Analysis of Nationwide Procurement Data, 2018–2020
Authors: Yang Ying , Geng Xin , Liu Xiaojun , Wen Xiaotong , Wu Ruonan , Cui Dan , Mao Zongfu 
Published: February 2022

Background: The overuse of antibiotics is a serious public health problem and a major challenge in China, and China lacks up-to-date evidence on the nationwide antibiotic use in different healthcare settings. The changes of China’s antibiotic use under the COVID-19 pandemic are still unknown.Objective: This study aimed to investigate the use of antibiotics in China’s public medical institutions based on a three-year nationwide surveillance and to examine the impact of the COVID-19 pandemic on China’s antibiotic consumption.Methods: This study used nationwide drug procurement data from the China Drug Supply Information Platform (CDSIP). We retrospectively analyzed antibiotic procurement data of 9,176 hospitals and 39,029 primary healthcare centers (PHCs) from 31 provinces in mainland China from January 2018 to December 2020. Antibiotic utilization was measured by defined daily doses (DDDs) and DDD per 1,000 inhabitants per day (DID). Generalized linear regression models were established to quantify the impact of the COVID-19 pandemic on antibiotic use.Results: The total antibiotic consumption among all healthcare settings increased from 12.94 DID in 2018 to 14.45 DID in 2019, and then dropped to 10.51 DID in 2020. More than half of antibiotics were consumed in PHCs, especially in central regions (59%–68%). The use of penicillins (J01C) and cephalosporins (J01D) accounted for 32.02% and 28.86% of total antibiotic consumption in 2020. During 2018–2020, parenteral antibiotics accounted for 31%–36% of total antibiotic consumption; the proportion is more prominent in central and western regions and the setting of hospitals. Access category antibiotics comprised 40%–42% of the total utilization. Affected by COVID-19, the antibiotic consumption was significantly dropped both in hospitals (β = −.11, p &lt; .001) and PHCs (β = −.17, p &lt; .001), as well as in total (β = −.14, p &lt; .001). Significant increments were observed in the proportion of total antibiotics (β = .02, p = .024) consumed in hospitals (against the consumption in all healthcare settings), as well as parenteral antibiotics (β = 1.73, p = .001).Conclusion: The consistent preferred use of penicillin and cephalosporin, as well as injections, among China’s public healthcare institutions should draw concern. China’s antibiotic consumption significantly declined during the COVID-19 pandemic, which brings opportunities for antibiotic use management in China.
Metabolomic Profiling of Brain Protective Effect of Edaravone on Cerebral Ischemia-Reperfusion Injury in Mice
Authors: Ma Hui-fen , Zheng Fan , Su Lin-jie , Zhang Da-wei , Liu Yi-ning , Li Fang , Zhang Yuan-yuan , Gong Shuai-shuai , Kou Jun-ping 
Published: February 2022

Edaravone (EDA) injection has been extensively applied in clinics for treating stroke. Nevertheless, the metabolite signatures and underlying mechanisms associated with EDA remain unclear, which deserve further elucidation for improving the accurate usage of EDA. Ischemia stroke was simulated by intraluminal occlusion of the right middle cerebral artery for 1 h, followed by reperfusion for 24 h in mice. Brain infarct size, neurological deficits, and lactate dehydrogenase (LDH) levels were improved by EDA. Significantly differential metabolites were screened with untargeted metabolomics by cross-comparisons with pre- and posttreatment of EDA under cerebral ischemia/reperfusion (I/R) injury. The possibly involved pathways, such as valine, leucine, and isoleucine biosynthesis, and phenylalanine, taurine, and hypotaurine metabolisms, were enriched with differential metabolites and relevant regulatory enzymes, respectively. The network of differential metabolites was constructed for the integral exhibition of metabolic characteristics. Targeted analysis of taurine, an important metabolic marker, was performed for further validation. The level of taurine decreased in the MCAO/R group and increased in the EDA group. The inhibition of EDA on cerebral endothelial cell apoptosis was confirmed by TdT-mediated dUTP nick-end labeling (TUNEL) stain. Cysteine sulfinic acid decarboxylase (CSAD), the rate-limiting enzyme of taurine generation, significantly increased along with inhibiting endothelial cell apoptosis after treatment of EDA. Thus, CSAD, as the possible new therapeutic target of EDA, was selected and validated by Western blot and immunofluorescence. Together, this study provided the metabolite signatures and identified CSAD as an unrecognized therapeutic intervention for EDA in the treatment of ischemic stroke via inhibiting brain endothelial cell apoptosis.
Intranasal Delivery of Galanin 2 and Neuropeptide Y1 Agonists Enhanced Spatial Memory Performance and Neuronal Precursor Cells Proliferation in the Dorsal Hippocampus in Rats
Authors: Borroto-Escuela Dasiel O. , Fores Ramón , Pita Mariana , Barbancho Miguel A. , Zamorano‐Gonzalez Pablo , Casares Natalia García , Fuxe Kjell , Narváez Manuel 
Published: February 2022

A need for new therapeutic approaches are necessary for dementia conditions and memory deficits of different origins, such as Alzheimer's disease. There is complex pathophysiological mechanisms involved, affecting adult hippocampal neurogenesis, in which neuropeptides and its neurogenesis regulation seem to participate. Neuropeptide Y(NPY) Y1 receptor (Y1R) and galanin (GAL) receptor 2 (GALR2) interact in brain regions responsible for learning and memory processes, emphasizing the hippocampus. Moreover, a significant challenge for treatments involving peptide drugs is bypassing the blood-brain barrier. The current study assesses the sustained memory performance induced by GALR2 and NPYY1R agonists intranasal coadministration and their neurochemical hippocampal correlates. Memory retrieval was conducted in the object-in-place task together with in situ proximity ligation assay (PLA) to manifest the formation of GALR2/Y1R heteroreceptor complexes and their dynamics under the different treatments. We evaluated cell proliferation through a 5-Bromo-2’-deoxyuridine (BrdU) expression study within the dentate gyrus of the dorsal hippocampus. The GalR2 agonist M1145 was demonstrated to act with the Y1R agonist to improve memory retrieval at 24 hours in the object-in-place task. Our data show that the intranasal administration is a feasible technique for directly delivering Galanin or Neuropeptide Y compounds into CNS. Moreover, we observed the ability of the co-agonist treatment to enhance the cell proliferation in the DG of the dorsal hippocampus through 5- Bromo-2’-deoxyuridine (BrdU) expression analysis at 24 hours. The understanding of the cellular mechanisms was achieved by analyzing the GALR2/Y1R heteroreceptor complexes upon agonist coactivation of their two types of receptor protomers in Doublecortin-expressing neuroblasts. Our results may provide the basis for developing heterobivalent agonist pharmacophores, targeting GALR2-Y1R heterocomplexes. It involves especially the neuronal precursor cells of the dentate gyrus in the dorsal hippocampus for the novel treatment of neurodegenerative pathologies as in the Alzheimer’s disease.
Mothers’ and Fathers’ Science-Related Talk With Daughters and Sons While Reading Life and Physical Science Books
Authors: Shirefley Tess A. , Leaper Campbell 
Published: February 2022

IntroductionIn prior studies conducted in the United States, parents’ gender-differentiated encouragement of science predicted children’s later science motivation. Most of this research has focused on older children or teens and only looked at the impact of mothers. However, accumulating evidence suggests that gender-differentiated encouragement of science interest may begin in early childhood. Moreover, fathers may be more likely than mothers to treat sons and daughters differently in science-learning contexts.MethodsWe examined 50 United States families with both a mother and a father (82% White; 98% with at least some college education) and either a daughter or a son (48–83 months; M = 62, SD = 9). On separate visits, each parent reads two books with their child. One was about life science and the other was about physical science. We coded parents’ science-related talk during these interactions.Results and ConclusionIn contrast to our predictions, parents used higher proportions of science talk with daughters than sons, including higher average rates of overall science talk and specific types of science talk (e.g., science explanations, science-related personal connections, and science-learning talk). Moreover, most of the child gender effects occurred while reading the physical science books. Book topic and parent gender moderated some additional patterns. Book reading is discussed as a potential context for mitigating socialization experiences that traditionally disfavor girls’ interest in physical science.
The Measurement Properties and Acceptability of a New Parent–Infant Bonding Tool (‘Me and My Baby’) for Use in United Kingdom Universal Healthcare Settings: A Psychometric, Cross-Sectional Study
Authors: Bywater Tracey , Dunn Abigail , Endacott Charlotte , Smith Karen , Tiffin Paul A. , Price Matthew , Blower Sarah 
Published: February 2022

IntroductionThe National Institute for Health and Care Excellence (NICE) guidelines acknowledge the importance of the parent–infant relationship for child development but highlight the need for further research to establish reliable tools for assessment, particularly for parents of children under 1 year. This study explores the acceptability and psychometric properties of a co-developed tool, ‘Me and My Baby’ (MaMB).Study designA cross-sectional design was applied. The MaMB was administered universally (in two sites) with mothers during routine 6–8-week Health Visitor contacts. The sample comprised 467 mothers (434 MaMB completers and 33 ‘non-completers’). Dimensionality of instrument responses were evaluated via exploratory and confirmatory ordinal factor analyses. Item response modeling was conducted via a Rasch calibration to evaluate how the tool conformed to principles of ‘fundamental measurement’. Tool acceptability was evaluated via completion rates and comparing ‘completers’ and ‘non-completers’ demographic differences on age, parity, ethnicity, and English as an additional language. Free-text comments were summarized. Data sharing agreements and data management were compliant with the General Data Protection Regulation, and University of York data management policies.ResultsHigh completion rates suggested the MaMB was acceptable. Psychometric analyses showed the response data to be an excellent fit to a unidimensional confirmatory factor analytic model. All items loaded statistically significantly and substantially (&gt;0.4) on a single underlying factor (latent variable). The item response modeling showed that most MaMB items fitted the Rasch model. (Rasch) item reliability was high (0.94) yet the test yielded little information on each respondent, as highlighted by the relatively low ‘person separation index’ of 0.1.Conclusion and next stepsMaMB reliably measures a single construct, likely to be infant bonding. However, further validation work is needed, preferably with ‘enriched population samples’ to include higher-need/risk families. The MaMB tool may benefit from reduced response categories (from four to three) and some modest item wording amendments. Following further validation and reliability appraisal the MaMB may ultimately be used with fathers/other primary caregivers and be potentially useful in research, universal health settings as part of a referral pathway, and clinical practice, to identify dyads in need of additional support/interventions.