bluuebunny/crossref_metadata_2025 huggingface dataset:
Fruitarian Diet and Blood Glucose Control in Type 1 Diabetes: A Case Report
Authors: Vetrani Claudia , Bozzetto Lutgarda , Della Pepa Giuseppe , Rivellese Angela Albarosa , Annuzzi Giovanni
Published: February 2022

Diet is a key determinant of blood glucose control in individuals with type 1 diabetes. Although dietary education is part of their clinical follow-up, many patients show a propensity to self-treatment, adopting dietary changes, often extreme, that do not consider the overall impact on health. Here, we describe the case of a patient with type 1 diabetes who switched to a fruitarian diet because of ideological beliefs. A 25-year-old man with type 1 diabetes on an insulin pump and continuous glucose monitoring on optimal blood glucose control (HbA1c 6.5%, 48 mmol/mol; glucose time-in-range 70–180 mg/dl, TIR, 90%; coefficient of variation, CV, 36%) switched to a fruitarian diet because of ideological beliefs. After 3 months on this diet, blood glucose control was still optimal (TIR 88%, CV 33%), while plasma triglycerides and liver enzymes were above normal values. After 3 more months, blood glucose control had worsened (TIR 72%, CV 37%), plasma triglyceride and liver enzymes were within normal values, and hyperkalemia was detected. In this case report, a strict fruitarian diet was associated with early negative changes in some biochemical parameters, also in presence of optimal blood glucose control. Dietary counseling remains essential in the follow-up of patients with type 1 diabetes to ensure personalized medical nutrition therapy and monitor dietary changes that may affect health but with no major impact on blood glucose control.
Effects of Diosmin on Vascular Leakage and Inflammation in a Mouse Model of Venous Obstruction
Authors: Zou Junjie , Yuan Dongping , Yang Jin , Yu Yun
Published: February 2022

At present, iliac vein compression syndrome (IVCS) plagues countless people, posing a significant economic and social burden. The progress of current IVCS-related research is slow owing to the limitations of animal models. In this study, we generated a mouse model of iliac vein stenosis (IVS) to monitor the effects of IVCS on venous function, such as increased vascular leakage, the expression of adhesion molecules, and elevated inflammation factors. Diosmin, a widely used clinical bioactive ingredient, was administered to confirm its therapeutic effects on the IVS mouse model. The results revealed that diosmin manifested therapeutic improvement in the IVS mouse model. In addition, we verified that the IVS mouse model is a stable and reproducible animal model for pathophysiological studies. High-purity diosmin can be beneficial to venous dysfunction and hence provides a more effective treatment option for venous diseases.
Green Tea Polyphenols Upregulate the Nrf2 Signaling Pathway and Suppress Oxidative Stress and Inflammation Markers in D-Galactose-Induced Liver Aging in Mice
Authors: Wang Dongxu , Wang Taotao , Li Zhanming , Guo Yuanxin , Granato Daniel
Published: February 2022

The beneficial effects of green tea polyphenols (GTPs) on D-galactose (D-Gal)-induced liver aging in male Kunming mice were investigated. For this purpose, 40 adult male Kunming mice were divided into four groups. All animals, except for the normal control and GTPs control, were intraperitoneally injected with D-galactose (D-Gal; 300 mg/kg/day for 5 days a week) for 12 consecutive weeks, and the D-Gal-treated mice were allowed free access to 0.05% GTPs (w/w) diet or normal diet for 12 consecutive weeks. Results showed that GTP administration improved the liver index and decreased transaminases and total bilirubin levels. Furthermore, GTPs significantly increased hepatic glutathione and total antioxidant levels, and the activities of superoxide dismutase, catalase, and glutathione S-transferase (GST). Furthermore, GTPs downregulated 8-hydroxy-2-deoxyguanosine, advanced glycation end products, and hepatic oxidative stress markers, such as malondialdehyde and nitric oxide. Additionally, GTPs abrogated dysregulation in hepatic Kelch-like ECH-associated protein 1 and nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target gene expression [heme oxygenase 1, NAD(P)H:quinone oxidoreductase 1, and GST] and inhibited tumor necrosis factor-α, transforming growth factor-β, and interleukin (IL)-1β and IL-6 in the liver of treated mice. Finally, GTPs effectively attenuated D-Gal-induced edema, vacuole formation, and inflammatory cell infiltration. In conclusion, GTPs showed antioxidant and anti-inflammatory properties in D-Gal-induced aging mice, and may be considered a natural alternative to the effects of hepatic aging.
Associations of Racial and Ethnic Category, Age, Comorbidities, and Socioeconomic Factors on Concordance to NCCN Guidelines for Patients With High-Risk Biliary Tract Cancers After Surgery
Authors: Huang Lauren F. , Hong Augustine , Cioffi Gino , Alahmadi Asrar , Tang Tin-Yun , Ocuin Lee M. , Patil Nirav , Bajor David L. , Saltzman Joel N. , Mohamed Amr , Selfridge Eva , Webb Hooper Monica , Barnholtz-Sloan Jill , Lee Richard T.
Published: February 2022

Background

Biliary tract cancers (BTC) have a limited prognosis even for localized cancers, emphasizing the importance of multidisciplinary management. NCCN guidelines recommend adjuvant chemotherapy (CT) +/- radiotherapy (RT) for high-risk disease. We analyzed the association between racial and ethnic category along with other demographic factors and concordance to NCCN guidelines among patients following surgery for high-risk BTC.

Methods

Subjects were identified from the National Cancer Database (NCDB) for BTC patients who underwent surgery and found to have metastatic lymph nodes (LN+) or positive surgical margins (M+) from 2004 to 2015. We defined concordance to NCCN guidelines as receiving surgery + CT +/- RT and non-concordance to the guidelines as surgery +/- RT. Descriptive studies and multivariate logistic regression analysis was performed.

Results

A total of 3,792 patients were identified with approximately half being female (55.4%) and between the ages of 50-69 (52.8%). Most were White (76.3%) followed by Black (10.6%), Hispanic (8.5%), and Asian (5.3%). The BTC included extrahepatic cholangiocarcinoma (CCA) (48.6%), gallbladder cancer (43.5%), and intrahepatic CCA (7.9%). Most patients had an M- resection (71.9%) but also had LN+ disease (88.0%). There were no significant differences between racial groups in disease presentation (histological grade, tumor stage) and surgical outcomes (LN+, M+, hospital readmission, and 90 day post-surgery mortality). Hispanic patients as compared to White patients were less likely to be insured (85.7% vs 96.3%, p<0.001) and less likely to be treated at an academic facility (42.1% vs 52.1%, p=0.008). Overall, almost one-third (29.7%) of patients received non-concordant NCCN guideline care with Hispanic patients having the highest proportion of non-concordance as compared to Whites patients (36.1% vs 28.7%, p=0.029). On multivariate analysis, Hispanic ethnicity (HR=1.51, 95% CI: 1.15-1.99) remained significantly associated with non-concordance to NCCN guidelines.

Conclusion

This study indicates that Hispanic patients with high-risk BTC are significantly less likely to receive NCCN-concordant treatment in comparison to White patients. More research is needed to confirm and understand the observed disparities and guide targeted interventions at the system-level.
Radiomics Analysis of Multiparametric MRI for Prediction of Synchronous Lung Metastases in Osteosarcoma
Authors: Luo Zhendong , Li Jing , Liao YuTing , Liu RengYi , Shen Xinping , Chen Weiguo
Published: February 2022

Purpose

To establish and verify a predictive model involving multiparameter MRI and clinical manifestations for predicting synchronous lung metastases (SLM) in osteosarcoma.

Materials and Methods

Seventy-eight consecutive patients with osteosarcoma (training dataset, n = 54; validation dataset, n = 24) were enrolled in our study. MRI features were extracted from the T1‐weighted image (T1WI), T2‐weighted image (T2WI), and contrast-enhanced T1-weighted image (CE-T1WI) of each patient. Least absolute shrinkage and selection operator (LASSO) regression and multifactor logistic regression were performed to select key features and build radiomics models in conjunction with logistic regression (LR) and support vector machine (SVM) classifiers. Eight individual models based on T1WI, T2WI, CE-T1WI, T1WI+T2WI, T1WI+CE-T1WI, T2WI+CE-T1WI, T1WI+T2WI+CE-T1WI, and clinical features, as well as two combined models, were built. The area under the receiver operating characteristic curve (AUC), sensitivity and specificity were employed to assess the different models.

Results

Tumor size was the most significant univariate clinical indicator (1). The AUC values of the LR predictive model based on T1WI, T2WI, CE-T1WI, T1WI+T2WI, T1WI+CE-T1WI, T2WI+CE-T1WI, and T1WI+T2WI+CE-T1WI were 0.686, 0.85, 0.87, 0.879, 0.736, 0.85, and 0.914, respectively (2). The AUC values of the SVM predictive model based on T1WI, T2WI, CE-T1WI, T1WI+T2WI, T1WI +CE-T1WI, T2WI +CE-T1WI, and T1WI+T2WI+CE-T1WI were 0.629, 0.829, 0.771, 0.879, 0.643, 0.829, and 0.929, respectively (3). The AUC values of the clinical, combined 1 (clinical and LR-radiomics) and combined 2 (clinical and SVM-radiomics) predictive models were 0.779, 0.957, and 0.943, respectively.

Conclusion

The combined model exhibited good performance in predicting osteosarcoma SLM and may be helpful in clinical decision-making.
Preclinical and Clinical Evidence of Lurbinectedin in Ovarian Cancer: Current Status and Future Perspectives
Authors: Musacchio Lucia , Cicala Carlo Maria , Salutari Vanda , Camarda Floriana , Carbone Maria Vittoria , Ghizzoni Viola , Giudice Elena , Nero Camilla , Perri Maria Teresa , Ricci Caterina , Tronconi Francesca , Scambia Giovanni , Lorusso Domenica
Published: February 2022

Lurbinectedin is an antitumor agent belonging to the natural marine-based tetrahydroisoquinoline family which has shown very promising clinical activity with a favorable safety profile in many types of cancer. Preclinical evidence showed that lurbinectedin inhibits active transcription and binds to GC-rich sequences, leading to irreversible degradation of RNA polymerase II and generation of single- and double-strand DNA breaks and, as a consequence, apoptosis of tumor cells. In addition, lurbinectedin has demonstrated modulation of the tumor microenvironment and activity against cancer cells harboring homologous recombination DNA repair deficiency. Although considerable improvements have been made in the treatment of epithelial ovarian cancer, most patients with advanced disease experience recurrence with a dismal prognosis due to chemotherapy (mainly platinum) resistance. Platinum-resistant/refractory ovarian cancer remains a difficult-to-treat setting of disease, and currently, the exploration of new therapeutic approaches represents a main field of interest. Although the CORAIL phase III study did not meet its primary endpoint, the results suggest that lurbinectedin might be a valid alternative for patients that have exhausted therapeutic options. This article will focus on the clinical evidence, the most recent investigations, and the future perspective regarding the use of lurbinectedin in ovarian cancer.
Clinical Evaluation of the Inverse Planning System Utilized in Gamma Knife Lightning
Authors: Cui Taoran , Nie Ke , Zhu Jiahua , Danish Shabbar , Weiner Joseph , Chundury Anupama , Ohri Nisha , Zhang Yin , Vergalasova Irina , Yue Ning , Wang Xiao
Published: February 2022

Objectives

The purpose of this study is to independently compare the performance of the inverse planning algorithm utilized in Gamma Knife (GK) Lightning Treatment Planning System (TPS) to manual forward planning, between experienced and inexperienced users, for different types of targets.

Materials and Methods

Forty patients treated with GK stereotactic radiosurgery (SRS) for pituitary adenoma (PA), vestibular schwannoma (VS), post-operative brain metastases (pBM), and intact brain metastases (iBM) were randomly selected, ten for each site. Three inversely optimized plans were generated for each case by two experienced planners (OptExp1 and OptExp2) and a novice planner (OptNov) using GK Lightning TPS. For each treatment site, the Gradient Index (GI), the Paddick Conformity Index (PCI), the prescription percentage, the scaled beam-on time (sBOT), the number of shots used, and dosimetric metrics to OARs were compared first between the inversely optimized plans and the manually generated clinical plans, and then among the inversely optimized plans. Statistical analyses were performed using the Student’s t-test and the ANOVA followed by the post-hoc Tukey tests.

Results

The GI for the inversely optimized plans significantly outperformed the clinical plans for all sites. PCIs were similar between the inversely optimized and clinical plans for PA and VS, but were significantly improved in the inversely optimized plans for iBM and pBM. There were no significant differences in the sBOT between the inversely optimized and clinical plans, except for the PA cases. No significant differences were observed in dosimetric metrics, except for lower brain V12Gy and PTV D98% in the inversely optimized plans for iBM. There were no noticeable differences in plan qualities among the inversely optimized plans created by the novice and experienced planners.

Conclusion

Inverse planning in GK Lightning TPS produces GK SRS plans at least equivalent in plan quality and similar in sBOT compared to manual forward planning in this independent validation study. The automatic workflow of inversed planning ensures a consistent plan quality regardless of a planner’s experience.
An Integrated Pan-Cancer Analysis of ADAMTS12 and Its Potential Implications in Pancreatic Adenocarcinoma
Authors: Song Caiyun , Chen Jionghuang , Zhang Chaolei , Dong Dapeng
Published: February 2022

Background

A Disintegrin and Metallopeptidase with Thrombospondin Type 1 Motif 12 (ADAMTS12), a member of the ADAMTS family of multidomain extracellular protease enzymes, is involved in the progression of many tumors. However, a pan-cancer analysis of this gene has not yet been performed. Its role in pancreatic adenocarcinoma (PAAD) also remains unclear.

Methods

The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression data (GTEx) databases were used to analyze ADAMTS12 expression in pan-cancer. We assessed the expression, clinical characteristics, prognostic significance, copy number alteration, methylation, and mutation of ADAMTS12 and its correlation with the tumor immune microenvironment. qRT-PCR and immunohistochemistry assays were also performed to validate the expression of ADAMTS12 in PAAD.

Results

Through bioinformatics analysis and preliminary experimental verification, ADAMTS12 was found to be substantially overexpressed in PAAD. High expression level of ADAMTS12 was correlated with worse survival rates in patients with PAAD and high infiltration levels of tumor-associated macrophages, cancer-associated fibroblasts, immune checkpoint proteins, and immunosuppressive genes.

Conclusion

Our findings suggest ADAMTS12 as a potential prognostic biomarker in PAAD. Elevated ADAMTS12 expression may also indicate an immunosuppressive microenvironment.
Application of Proteomics in the Discovery of Radiosensitive Cancer Biomarkers
Authors: Luo Hui , Ge Hong
Published: February 2022

Radiation therapy remains an important component of cancer treatment. Gene-encoded proteins were the actual executors of cellular functions. Proteomic was a novel technology that can systematically analysis protein composition and measure their levels of change, this was a high throughput method, and were the import tools in the post genomic era. In recent years, rapid progress of proteomic have been made in the study of cancer mechanism, diagnosis, and treatment. This article elaborates current advances and future directions of proteomics in the discovery of radiosensitive cancer biomarkers.
Case Report: Atypical HUS Presenting With Acute Rhabdomyolysis Highlights the Need for Individualized Eculizumab Dosing
Authors: Benoit Stefanie W. , Fukuda Tsuyoshi , VandenHeuvel Katherine , Witte David , Fuller Christine , Willis Jennifer , Dixon Bradley P. , Drake Keri A.
Published: February 2022

Background

Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare orphan disease caused by dysregulated complement activation resulting in thrombotic microangiopathy. Although complement-mediated endothelial injury predominantly affects the renal microvasculature, extra-renal manifestations are present in a significant proportion of patients. While eculizumab has significantly improved the morbidity and mortality of this rare disease, optimizing therapeutic regimens of this highly expensive drug remains an active area of research in the treatment of aHUS.

Case Presentation

This report describes the case of a previously healthy 4 year-old male who presented with rhabdomyolysis preceding the development of aHUS with anuric kidney injury requiring dialysis. Clinical stabilization required increased and more frequent eculizumab doses compared with the standardized weight-based guidelines. In the maintenance phase of his disease, pharmacokinetic analysis indicated adequate eculizumab levels could be maintained with an individualized dosing regimen every 3 weeks, as opposed to standard 2 week dosing, confirmed in this patient over a 4 year follow up period. Cost analyses show that weight-based maintenance dosing costs $312,000 per year, while extending the dosing interval to every 3 weeks would cost $208,000, a savings of $104,000 per year, relative to the cost of $72,000 from more frequent eculizumab dosing during his initial hospitalization to suppress his acute disease.

Conclusion

This case exemplifies the potential of severe, multisystem involvement of aHUS presenting with extra-renal manifestations, including rhabdomyolysis as in this case, and highlights the possibility for improved clinical outcomes and higher value care with individualized eculizumab dosing in patients over the course of their disease.
Eluxadoline Versus Antispasmodics in the Treatment of Irritable Bowel Syndrome: An Adjusted Indirect Treatment Comparison Meta-analysis
Authors: Qin Di , Tao Qing-Feng , Huang Shi-Le , Chen Min , Zheng Hui
Published: February 2022

Objective: Eluxadoline is a newly approved drug for irritable bowel syndrome (IBS), but it has rarely been compared with positive controls. We aimed to compare eluxadoline with antispasmodics in the treatment of IBS.

Methods: We searched the OVID Medline, Embase, and the Cochrane Central Register of Controlled Trials databases for randomized controlled trials (RCTs) comparing eluxadoline or antispasmodics with placebo. The search was conducted from 1 January 1980, to 1 September 2020, without any language restrictions. The primary efficacy outcome was the relief of abdominal pain, defined by a reduction of pain scores of at least 30% from baseline. The secondary efficacy outcome was the relief of global IBS symptoms, defined by a composite response of a decrease in abdominal pain and improvement in stool consistency on the same day for at least 50% of the days assessed. The data were pooled using a random-effects model. Outcome estimates were pooled by using Risk Ratios (RRs) and P-scores.

Results: Forty-two trials with 8,457 participants were included from 45 articles. Compared with placebo, each of drotaverine, pinaverium, alverine combined with simethicone (ACS) and eluxadoline 100 mg was highly effective in the relief of abdominal pain, with drotaverine [RR, 2.71 (95% CI, 1.70 to 4.32), P-score = 0.95] ranking first. Drotaverine, otilonium, cimetropium, pinaverium, and eluxadoline 100 mg had significantly high the relief of global IBS symptomss, for which drotaverine [RR, 2.45 (95% CI, 1.42 to 4.22), P-score = 0.95] was ranked first. No significant difference was found between these interventions. Pinaverium had a significantly higher the relief of global IBS symptoms than eluxadoline [RR, 1.72 (95% CI, 1.33 to 2.21)] on sensitivity analysis. However, no significant difference was found in the number of adverse events between each intervention and the placebo.

Conclusion: Our network meta-analysis showed that eluxadoline 100 mg was at least as effective as antispasmodics in relieving abdominal pain in IBS. But eluxadoline had more reported adverse events. Antispasmodics are still the first choice for the treatment of IBS.
Diabetic Corneal Neuropathy: Pathogenic Mechanisms and Therapeutic Strategies
Authors: Zhou Ting , Lee Allie , Lo Amy Cheuk Yin , Kwok Jeremy Sze Wai John
Published: February 2022

Diabetes mellitus (DM) is a major global public health problem that can cause complications such as diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy. Besides the reporting of reduction in corneal nerve density and decrease in corneal sensitivity in diabetic patients, there may be a subsequent result in delayed corneal wound healing and increased corneal infections. Despite being a potential cause of blindness, these corneal nerve changes have not gained enough attention. It has been proposed that corneal nerve changes may be an indicator for diabetic neuropathy, which can provide a window for early diagnosis and treatment. In this review, the authors aimed to give an overview of the relationship between corneal nerves and diabetic neuropathy as well as the underlying pathophysiological mechanisms of corneal nerve fiber changes caused by DM for improved prediction and prevention of diabetic neuropathy. In addition, the authors summarized current and novel therapeutic methods for delayed corneal wound healing, nerve protection and regeneration in the diabetic cornea.
Use of a Baculovirus-Mammalian Cell Expression-System for Expression of Drug-Metabolizing Enzymes: Optimization of Infection With a Focus on Cytochrome P450 3A4
Authors: Miyauchi Yuu , Kimura Akane , Sawai Madoka , Fujimoto Keiko , Hirota Yuko , Tanaka Yoshitaka , Takechi Shinji , Mackenzie Peter I. , Ishii Yuji
Published: February 2022

Heterologous expression systems are important for analyzing the effects of genetic factors including single nucleotide polymorphisms on the functions of drug-metabolizing enzymes. In this study, we focused on a baculovirus-mammalian cell (Bac-Mam) expression system as a safer and more efficient approach for this purpose. The baculovirus-insect cell expression system is widely utilized in large-scale protein expression. Baculovirus has been shown to also infect certain mammalian cells, although the virus only replicates in insect cells. With this knowledge, baculovirus is now being applied in a mammalian expression system called the Bac-Mam system wherein a gene-modified baculovirus is used whose promotor is replaced with one that can function in mammalian cells. We subcloned open-reading frames of cytochrome P450 3A4 (CYP3A4), UDP-glucuronosyltransferase (UGT) 1A1, and UGT2B7 into a transfer plasmid for the Bac-Mam system, and prepared recombinant Bac-Mam virus. The obtained virus was amplified in insect Sf9 cells and used to infect mammalian COS-1 cells. Expression of CYP3A4, UGT1A1, and UGT2B7 in COS-1 cell homogenates were confirmed by immunoblotting. Optimum infection conditions including the amount of Bac-Mam virus, culture days before collection, and concentration of sodium butyrate, an enhancer of viral-transduction were determined by monitoring CYP3A4 expression. Expressed CYP3A4 showed appropriate activity without supplying hemin/5-aminolevulinic acid or co-expressing with NADPH-cytochrome P450 reductase. Further, we compared gene transfer efficiency between the Bac-Mam system and an established method using recombinant plasmid and transfection reagent. Our results indicate that the Bac-Mam system can be applied to introduce drug-metabolizing enzyme genes into mammalian cells that are widely used in drug metabolism research. The expressed enzymes are expected to undergo appropriate post-translational modification as they are in mammalian bodies. The Bac-Mam system may thus accelerate pharmacogenetics and pharmacogenomics research.
Screening and Verification of Differentially Expressed Long Non-coding RNAs in the Peripheral Blood of Patients With asthma
Authors: Ma Cheng , Wang Shiyuan , Cao Yuxue , Tang Weifeng , Wuniqiemu Tulake , Teng Fangzhou , Zhu Xueyi , Wei Ying , Dong Jingcheng
Published: February 2022

Growing evidence suggests that long non-coding RNAs (lncRNAs) play a key role in the pathogenesis of asthma. Although some differentially expressed lncRNAs have been identified in asthmatic patients, many asthma-related lncRNAs have not been annotated. In the present study, six patients and three healthy subjects were randomly selected from 34 asthmatic patients and 17 healthy subjects. Second-generation high-throughput sequencing was performed on their peripheral blood samples. There were 1,137 differentially expressed lncRNAs in the asthma patients compared to in the healthy controls, of which 485 were upregulated and 652 were downregulated. The top 30 enriched GO and KEGG terms were identified, and the cytosolic ribosome (GO:0022626) and ribosome (hsa03010) were associated with the most differentially expressed lncRNAs. The top 10 differentially expressed lncRNAs associated with asthma were verified by an lncRNA-mRNA co-expression network and RT-qPCR. Seven of the these (NONHSAT015495.2, MSTRG.71212.2, NONHSAT163272.1, NONHSAT181891.1, NONHSAT190964.1, ENST00000564809, and NONHSAT076890.2) were down-regulated in the peripheral blood of asthmatic patients, which was consistent with the sequencing results. Three patients and three healthy subjects were randomly selected from the remaining subjects to verify these seven lncRNAs by RT-qPCR, which further confirmed the sequencing results. Public database GSE106230 was also in agreement with the FPKM (Fragments Per kilobase of exon model per Million mapped reads) trends of ENST00000564809, NONHSAT015495.2, NONHSAT181891.1, and NONHSAT190964.1. In conclusion, the present study identified seven lncRNAs that may serve as potential biological markers for asthma.
Revealing Calcium Signaling Pathway as Novel Mechanism of Danhong Injection for Treating Acute Myocardial Infarction by Systems Pharmacology and Experiment Validation
Authors: Guo Siyu , Tan Yingying , Huang Zhihong , Li Yikui , Liu Weiyu , Fan Xiaotian , Zhang Jingyuan , Stalin Antony , Fu Changgeng , Wu Zhishan , Wang Penglong , Zhou Wei , Liu Xinkui , Wu Chao , Jia Shanshan , Zhang Jinyan , Duan Xiaoxia , Wu Jiarui
Published: February 2022

Introduction: Danhong injection (DHI) is a traditional Chinese medicine preparation commonly used in the clinical treatment of acute myocardial infarction (AMI). In this study, the active components of DHI and its mechanism in the treatment of AMI were investigated.

Methods: The chemical components of DHI were detected by the ultra-high-performance liquid chromatography-linear trap quadrupole-orbitrap-tandem mass spectrometry (UHPLC-LTQ-Orbitrap-MS/MS), and the targets and pathways of DHI in the treatment of AMI were analyzed by systems pharmacology, which was verified by molecular docking and animal experiments.

Results: A total of 12 active components of DHI were obtained, and 158 common targets of component and disease were identified by systems pharmacology. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis results showed that DHI is closely related to the calcium signaling pathway in the treatment of AMI. Molecular docking showed that the key target protein has good binding affinity to related compounds. The experimental results showed that compared with the model group, LVAWs, EF, and FS significantly (p < 0.05) increased in the DHI group. The percentage of myocardial infarction significantly (p < 0.01) decreased, both in the ventricular and total cardiac regions, and the pathological damage of myocardial tissue also decreased. In addition, the expression of the protein CaMK II decreased (p < 0.01) and the expression of SERCA significantly increased (p < 0.01).

Conclusion: This study revealed that ferulic acid, caffeic acid and rosmarinic acid could inhibit AMI by regulating PLB, CaMK II, SERCA, etc. And mechanistically, calcium signaling pathway was critically involved. Combination of systems pharmacology prediction with experimental validation may provide a scientific basis for in-depth clinical investigation of the material basis of DHI.
Development of a Definition for Medical Affairs Using the Jandhyala Method for Observing Consensus Opinion Among Medical Affairs Pharmaceutical Physicians
Authors: Jandhyala Ravi
Published: February 2022

Background: There is currently no standard definition of medical affairs, despite its increasing importance to the pharmaceutical industry. The evolution of medical affairs necessitated the development of a standardised definition to guide policy and practice to ensure that patients’ interests remain central amid shifts that have, in the past, created fertile ground for ethical violations.

Objectives: The aim of this study was to use an empirical method to observe a consensus of expert opinion on the definition of medical affairs to guide policy and practice within this function.

Methods: In total, 11 medical affairs pharmaceutical physicians (MAPPs) completed a qualitative online survey to identify a list of key items to define medical affairs using the Jandhyala method for generating a consensus of expert opinion. Responses were coded and scored, and aggregated responses were presented to participants in a consensus round. Participants rated their agreement with each item on a 5-point Likert scale from strongly agree to strongly disagree. Indicators that reached a consensus index of >50% (CI > = 0.51) were retained. Items were categorised per previously defined medical affairs functions to determine the scope of the definition. A comparative content analysis using a previous definition identified in the literature was conducted to determine the utility of the definition generated here.

Results: In total, 11 MAPPs generated 15 unique items to define medical affairs. Item awareness indices ranged from 0.24 (‘communication/education’) to 1.00 (‘design/strategy’). All items had a CI of more than 0.5 and were included in the final definition. All items could be categorised per previously defined medical affairs functions. Comparative content analysis showed that our definition varied in four ways: the designation of medical affairs as a medical specialty (and its primary aim, therefore, is to protect patients), the leadership of medical affairs in medicine adoption, the generation of real-world evidence and the specification of distinct stakeholders who benefit from medical affairs.

Conclusion: A standard definition of medical affairs that incorporates the key principles of medical affairs as a medical specialty that leads medicine adoption and generates real-world evidence for specific stakeholders may protect and further the interests of patients by governing practice and policy.
Overexpression of ABCB1 Associated With the Resistance to the KRAS-G12C Specific Inhibitor ARS-1620 in Cancer Cells
Authors: Dong Xing-Duo , Zhang Meng , Cai Chao-Yun , Teng Qiu-Xu , Wang Jing-Quan , Fu Yi-Ge , Cui Qingbin , Patel Ketankumar , Wang Dong-Tao , Chen Zhe-Sheng
Published: February 2022

The KRAS-G12C inhibitor ARS-1620, is a novel specific covalent inhibitor of KRAS-G12C, possessing a strong targeting inhibitory effect on KRAS-G12C mutant tumors. Overexpression of ATP-binding cassette super-family B member 1 (ABCB1/P-gp) is one of the pivotal factors contributing to multidrug resistance (MDR), and its association with KRAS mutations has been extensively studied. However, the investigations about the connection between the inhibitors of mutant KRAS and the level of ABC transporters are still missing. In this study, we investigated the potential drug resistance mechanism of ARS-1620 associated with ABCB1. The desensitization effect of ARS-1620 was remarkably intensified in both drug-induced ABCB1-overexpressing cancer cells and ABCB1-transfected cells as confirmed by cell viability assay results. This desensitization of ARS-1620 could be completely reversed when co-treated with an ABCB1 reversal agent. In mechanism-based studies, [3H] -paclitaxel accumulation assay revealed that ARS-1620 could be competitively pumped out by ABCB1. Additionally, it was found that ARS-1620 remarkably stimulated ATPase activity of ABCB1, and the HPLC drug accumulation assay displayed that ARS-1620 was actively transported out of ABCB1-overexpressing cancer cells. ARS-1620 acquired a high docking score in computer molecular docking analysis, implying ARS-1620 could intensely interact with ABCB1 transporters. Taken all together, these data indicated that ARS-1620 is a substrate for ABCB1, and the potential influence of ARS-1620-related cancer therapy on ABCB1-overexpressing cancer cells should be considered in future clinical applications.
Dynamic Influence Maximization via Network Representation Learning
Authors: Sheng Wei , Song Wenbo , Li Dong , Yang Fei , Zhang Yatao
Published: February 2022

Influence maximization is a hot research topic in the social computing field and has gained tremendous studies motivated by its wild application scenarios. As the structures of social networks change over time, how to seek seed node sets from dynamic networks has attracted some attention. However, all of the existing studies were based on network topology structure data which have the limitations of high dimensionality and low efficiency. Aiming at this drawback, we first convert each node in the network to a low-dimensional vector representation by network representation learning and then solve the problem of dynamic influence maximization in the low-dimensional latent space. Comprehensive experiments on NetHEPT, Twitter, UCI, and Wikipedia datasets show that our method can achieve influence diffusion performance similar to state-of-the-art approaches in much less time.
A New Cooperative Recourse Strategy for Emergency Material Allocation in Uncertain Environments
Authors: Liu Yuxin , Wang Songxin , Li Xianghua
Published: February 2022

Emergency material allocation is an important issue in the urgent handling of public health emergencies. This article models the relief allocation and transportation route planning as an uncertain capacitated arc routing problem, which is a classic combinatorial optimization problem that considers stochastic factors such as uncertain demand and travel time in the service. The stochastic of demand leads to the route failure that the vehicle cannot serve the tasks successfully unexpected. Most existing research uses the independent recourse strategy. That is, each vehicle takes a back-and-forth trip separately when its remaining capacity cannot meet the actual demand of the task. This leads to a considerable recourse cost. However, a few studies have considered vehicular cooperation to deal with route failure, which is beneficial for pooling the capacity of multiple vehicles. In this paper, we propose a new recourse strategy called OneFAll that lets one vehicle take charge of all the failed tasks. In this case, other vehicles can finish the service once they are full. We develop the genetic programming hyper-heuristic with the OneFAll recourse strategy for solving the uncertain capacitated arc routing problem. The experimental studies show that our proposed method outperforms the existing genetic programming hyper-heuristic with the independent recourse strategy to the uncertain capacitated arc routing problem for the ugdb and uval benchmark instances. Moreover, our strategy outperforms the recourse strategy that failed tasks are returned to the unassigned task set for any vehicle to complete. This reflects that there exists resource waste if all vehicles are involved to repair the failed routes.
Impact of 12-Week Moderate-Intensity Aerobic Training on Inflammasome Complex Activation in Elderly Women
Authors: Gomarasca Marta , Micielska Katarzyna , Faraldi Martina , Flis Marta , Perego Silvia , Banfi Giuseppe , Ziemann Ewa , Lombardi Giovanni
Published: February 2022

Aging often associates with a chronic low-grade inflammatory status that can be consequent to the activation of Toll-like receptors (TLRs) and the downstream NLR family pyrin domain containing 3 (NLRP3) inflammasome and causes a chronic secretion of pro-inflammatory cytokines. Since exercise has known anti-inflammatory effects, we investigated the effect of Nordic walking training on inflammasome activation and downstream effectors in elderly women. A population of elderly women was divided into EXP (n = 29) that completed 12 weeks of the moderate-intensity aerobic training program and CTRL (n = 29), performing no activity. Blood samples were taken before and after the first (T1-pre and T1-post, respectively) and last (T2-pre and T2-post, respectively) exercise unit. Inflammasome activation status was assessed by whole blood NLRP3 and TLR4 expression by RT-qPCR. Serum levels of IL-1β, IL-6, TNFα, and IL-18 cytokines were assayed by multiplex fluorescent beads-based immunoassays or ELISA. NLRP3 and TLR4 levels were reduced 2 folds between T1-pre and T2-pre and induced at T2-post, compared to T2-pre, by 2.6- and 2.9-fold, respectively. A single exercise bout elicited a 1. 38-, 1. 5-, and 1.36-fold rise of IL-1β, TNFα, and IL-6 concentration, respectively, although not significant, at the beginning of the training (T1-pre vs. T1-post), a 1.4-fold decrease for IL-1β and TNFα at the end of the training (T1-pre vs. T2-pre), and a 2-, 1.8- and 1.26-fold increase after the last exercise session (T2-pre vs. T2-post) for the three cytokines. When stratifying the population based on BMI in normal weight (NW) and overweight (OW), NLRP3 and TLR4 expression was affected only in NW. As for inflammatory cytokines, IL-1β was modulated in NW at the beginning of the training, whereas in OW at the end of the training; for TNFα, this time-dependent modulation was significant only in OW. Applied aerobic training affected the resting expression of inflammasome constituents (NLRP3 and TLR4) and levels of downstream effectors (IL-1β, TNFα, and IL-6). However, at the end of the program, participants acquire an acute inflammatory response to exercise that was absent at baseline. Future studies would have to define the molecular mechanisms associated with, and how to potentiate, the exercise-associated inflammatory response.
Hypoxia During the Consolidation Phase of Distraction Osteogenesis Promotes Bone Regeneration
Authors: Liu Yanshi , Liu Jialin , Cai Feiyu , Liu Kai , Zhang Xiaoxu , Yusufu Aihemaitijiang
Published: February 2022

Background

Hypoxia is the critical driving force for angiogenesis and can trigger the osteogenic-angiogenic coupling followed by the enhancement of bone regeneration. While lots of studies showed that hypoxia administration can accelerate bone formation during distraction osteogenesis (DO), the therapeutic timing for the osteogenic purpose was concentrated on the distraction phase. The outcomes of hypoxia administration in the consolidation phase stay uncertain. The purpose of this study was to determine the osteogenic effectiveness of hypoxia therapy during the consolidation phase, if any, to enhance bone regeneration in a rat femoral DO model.

Methods

A total of 42 adult male Sprague-Dawley rats underwent right femoral mid-diaphysis transverse osteotomy and were randomly divided into Control (NS administration, n = 21) and Group1 (deferoxamine therapy, n = 21) after distraction. During the consolidation phase, Group1 was treated with local deferoxamine (DFO) injection into the distraction zone, while the Control underwent the same dosage of NS. Animals were sacrificed after 2, 4, and 6 weeks of consolidation. The process of bone formation and remodeling was monitored by digital radiographs, and the regenerated bone was evaluated by micro-computed tomography (micro-CT), biomechanical test, and histological analysis. The serum content of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) were measured by enzyme linked immunosorbent assay (ELISA) for further analysis.

Results

Bone regeneration was significantly enhanced after hypoxia therapy during the consolidation phase. The digital radiograph, micro-CT, and biomechanical evaluation showed better effects regarding volume, continuity, and mechanical properties of the regenerated bone in Group1. The histomorphological evaluation also revealed the hypoxia treatment contributed to accelerate bone formation and remodeling during DO. The higher positive expression of angiogenic and osteogenic markers were observed in Group1 after hypoxia administration according to the immunohistochemical analysis. The serum content of HIF-1α and VEGF was also increased after hypoxia therapy as evidenced from ELISA.

Conclusion

Hypoxia administration during the consolidation phase of distraction osteogenesis has benefits in enhancing bone regeneration, including accelerates the bone formation and remodeling.
Spatial Distribution of the Pepper Blight (Phytophthora capsici) Suppressive Microbiome in the Rhizosphere
Authors: Li Huixiu , Wang Ning , Ding Jia , Liu Yingjie , Ding Xiaoyan , Wei Yuquan , Li Ji , Ding Guo-chun
Published: February 2022

The properties of plant rhizosphere are dynamic and heterogeneous, serving as different habitat filters for or against certain microorganisms. Herein, we studied the spatial distribution of bacterial communities in the rhizosphere of pepper plants treated with a disease-suppressive or non-suppressive soil. The bacterial richness was significantly (p < 0.05) higher in plants treated with the disease-suppressive soil than in those treated with the non-suppressive soil. Bacterial richness and evenness greatly differed between root parts, with decrease from the upper taproot to the upper fibrous root, the lower taproot, and the lower fibrous root. As expected, the bacterial community in the rhizosphere differed between suppressive and non-suppressive soil. However, the spatial variation (36%) of the bacterial community in the rhizosphere was much greater than that explained by soils (10%). Taxa such as subgroups of Acidobacteria, Nitrosospira, and Nitrospira were known to be selectively enriched in the upper taproot. In vitro Bacillus antagonists against Phytophthora capsici were also preferentially colonized in the taproot, while the genera such as Clostridium, Rhizobium, Azotobacter, Hydrogenophaga, and Magnetospirillum were enriched in the lower taproot or fibrous root. In conclusion, the spatial distribution of bacterial taxa and antagonists in the rhizosphere of pepper sheds light on our understanding of microbial ecology in the rhizosphere.
Transcriptomics Analysis of Wheat Tassel Response to Tilletia laevis Kühn, Which Causes Common Bunt of Wheat
Authors: He Ting , Ren Zhaoyu , Muhae-Ud-Din Ghulam , Guo Qingyun , Liu Taiguo , Chen Wanquan , Gao Li
Published: February 2022

Tilletia laevis Kühn [synonym T. foetida (Wallr.) Liro] can lead to a wheat common bunt, which is one of the most serious diseases affecting kernels, a serious reduction in grain yield, and losses can reach up to 80% in favorable environments. To understand how wheat tassels respond to T. laevis, based on an RNA-Seq technology, we analyzed a host transcript accumulation on healthy wheat tassels and on tassels infected by the pathogen. Our results showed that 7,767 out of 15,658 genes were upregulated and 7,891 out of 15,658 genes were downregulated in wheat tassels. Subsequent gene ontology (GO) showed that differentially expressed genes (DEGs) are predominantly involved in biological processes, cellular components, and molecular functions. Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that 20 pathways were expressed significantly during the infection of wheat with T. laevis, while biosynthesis of amino acids, carbon metabolism, and starch and sucrose metabolism pathways were more highly expressed. Our findings also demonstrated that genes involved in defense mechanisms and myeloblastosis (MYB) transcription factor families were mostly upregulated, and the RNA-seq results were validated by quantitative real-time polymerase chain reaction (qRT-PCR). This is the first report on transcriptomics analysis of wheat tassels in response to T. laevis, which will contribute to understanding the interaction of T. laevis and wheat, and may provide higher efficiency control strategies, including developing new methods to increase the resistance of wheat crops to T. laevis-caused wheat common bunt.
Overview of Witloof Chicory (Cichorium intybus L.) Discolorations and Their Underlying Physiological and Biochemical Causes
Authors: De Jaegere Isabel , Cornelis Yannah , De Clercq Tim , Goossens Alain , Van de Poel Bram
Published: February 2022

Many fruits and vegetables suffer from unwanted discolorations that reduce product quality, leading to substantial losses along the supply chain. Witloof chicory (Cichorium intybusL. var.foliosum), a specialty crop characterized by its unique bitter taste and crunchiness, is particularly sensitive to various types of red and brown discolorations. The etiolated vegetable suffers from three predominant color disorders, i.e., core browning, internal leaf reddening, and leaf edge browning. Additionally, several less frequently observed color disorders such as hollow pith, external red, andpoint noircan also negatively affect crop quality. In this article, we bring together fragmented literature and present a comprehensive overview of the different discoloration types in chicory, and discuss their potential underlying physiological causes, including laticifer rupture, calcium deficiency, and a disturbed water distribution. We also describe the role of environmental cues that influence discoloration incidence, including cultivation and postharvest storage conditions such as forcing and storage temperature, root ripeness and the duration of the forcing process. Finally, we zoom in on the underlying biochemical pathways that govern color disorders in witloof chicory, with a strong emphasis on polyphenol oxidase.
Political Potentials, Deep-Seated Nativism and the Success of the German AfD
Authors: Schulte-Cloos Julia
Published: February 2022

The German populist radical right party “Alternative for Germany” (AfD) was founded amid various economic and political crises. This article argues that the electoral success of this political challenger, however, is rooted in more than the upsurge of populist resentments born out of these crises. Integrating theories about the activation of attitudes with arguments about the effects of exposure to local political contexts, I contend that the electoral success of the AfD reflects the mobilization of deep-seated nativist sentiments. To test these propositions, I draw on a large panel dataset of the AfD’s electoral returns at the municipal level (N = 10,694) which I link to pre-crises data on the marginal success of extreme-right parties. Exploiting variation between municipalities located within the same county (N = 294), I estimate a series of spatial simultaneous autoregressive error models by maximum likelihood estimation. The results show that the success of the AfD is rooted in the local prevalence of nativist sentiments that date prior to the crises that fomented the formation of the challenger party–an effect that becomes stronger in the course of the radicalization of the AfD. I further demonstrate that the populist right AfD is best able to broaden its electoral appeal among local communities with an extreme-right sub-culture, particularly in Eastern Germany. This suggests that even small extreme-right networks can act as a breeding ground for the populist right and help spread xenophobic and nativist sentiments among citizens.