bluuebunny/crossref_metadata_2025 huggingface dataset:
CLASSROOM CLIMATE AND STUDENT SELF-EFFICACY IN E-LEARNING
Authors: Davidovitch Nitza , Yavich Roman
Published: May 2022

The last two decades have seen significant growth in e-Learning in many institutions, with the main growth engine being significant development of technologies providing access to information. These technologies have dramatically changed how societies and individuals communicate. The current study examined whether the paradigm of good teaching dimensions customary in the research literature can predict students’ self-efficacy and social-academic climate in e-Learning. For this purpose, 147 students from different academic institutions were sampled and asked to choose one course they had studied online, completing a questionnaire on their experience of the course. The questionnaire was divided into four sub-topics, where at first the participants were asked to answer several demographic questions and the rest of the questions were divided by the research variables as follows: the first group of questions dealt with perceived self-efficacy; the second group dealt with the teaching dimensions presented in Hativa’s (2015) theory, from which select teaching behaviors were extracted. In the final part, the questionnaire examined the social-academic climate during the course. The research results show correlations between the research variables and some of the demographic variables. The higher the respondent’s age and years of schooling, the higher the lecturer’s evaluation. Furthermore, men were found to rank lecturers on teaching dimensions significantly lower than did women. Respondent self-efficacy rose with age and years of schooling. Moreover, the higher the participants’ age, the more positive the climate reported, and women tended to rank classroom climate higher than did men.
Keywords: classroom climate, e-Learning, self-efficacy, teaching dimensions
Epicardial Adipose Tissue-Derived IL-1β Triggers Postoperative Atrial Fibrillation
Authors: Cabaro Serena , Conte Maddalena , Moschetta Donato , Petraglia Laura , Valerio Vincenza , Romano Serena , Di Tolla Michele Francesco , Campana Pasquale , Comentale Giuseppe , Pilato Emanuele , D’Esposito Vittoria , Di Mauro Annabella , Cantile Monica , Poggio Paolo , Parisi Valentina , Leosco Dario , Formisano Pietro
Published: May 2022

Background and aims: Post-operative atrial fibrillation (POAF), defined as new-onset AF in the immediate period after surgery, is associated with poor adverse cardiovascular events and a higher risk of permanent AF. Mechanisms leading to POAF are not completely understood and epicardial adipose tissue (EAT) inflammation could be a potent trigger. Here, we aim at exploring the link between EAT-secreted interleukin (IL)-1β, atrial remodeling, and POAF in a population of coronary artery disease (CAD) patients.

Methods: We collected EAT and atrial biopsies from 40 CAD patients undergoing cardiac surgery. Serum samples and EAT-conditioned media were screened for IL-1β and IL-1ra. Atrial fibrosis was evaluated at histology. The potential role of NLRP3 inflammasome activation in promoting fibrosis was explored in vitro by exposing human atrial fibroblasts to IL-1β and IL-18.

Results: 40% of patients developed POAF. Patients with and without POAF were homogeneous for clinical and echocardiographic parameters, including left atrial volume and EAT thickness. POAF was not associated with atrial fibrosis at histology. No significant difference was observed in serum IL-1β and IL-1ra levels between POAF and no-POAF patients. EAT-mediated IL-1β secretion and expression were significantly higher in the POAF group compared to the no-POAF group. The in vitro study showed that both IL-1β and IL-18 increase fibroblasts’ proliferation and collagen production. Moreover, the stimulated cells perpetuated inflammation and fibrosis by producing IL-1β and transforming growth factor (TGF)-β.

Conclusion: EAT could exert a relevant role both in POAF occurrence and in atrial fibrotic remodeling.
Carbon Accounting for Enhanced Weathering
Authors: Amann Thorben , Hartmann Jens
Published: May 2022

The inevitable deployment of negative emission technologies requires carbon accounting to incentivise the investment and to foster an active CO2 certificate trading schema. Enhanced Weathering as one of the negative emission technologies is being tested in the field now, but lacks a verifiable and cost-effective carbon accounting approach. Based on results from a lab scale column experiment and field observations, it is hypothesized that the observed stable positive correlation between total alkalinity and electrical conductivity may present a way to easily predict the initial CO2 sequestration at the application site by chemical mineral weathering at low costs. Alkalinity is a measure to track weathering products. It is not difficult to measure, yet continuous and mid- to high-frequency sampling and analyses are expensive and time consuming. The observed strong correlation of alkalinity with electrical conductivity could be harnessed and enable a CO2 uptake monitoring by simple electrical conductivity measurements in soils or any point in the discharge system. For a successful implementation and calibration, data are needed, covering the most likely employment scenarios of soil, climate, hydrology, rock product, application scenario and plant abundance. Incorporated in a growing public database, this could be used as an assessment and benchmark system for future EW deployment.
Sr-Nd-Hf Isotopic Disequilibrium During the Partial Melting of Metasediments: Insight From Himalayan Leucosome
Authors: Yang Lei , Wang Jia-Min , Liu Xiao-Chi , Khanal Gautam P. , Wu Fu-Yuan
Published: May 2022

Radiogenic isotopes of granitoids are widely applied to fingerprint the source of granitoids and study the magma mingling and assimilation processes, aiming to decipher the planetary differentiation. This weapon is based on the assumption that crustal melts inherit the radiogenic isotopes of protoliths. However, complicated melting processes in the crust would drive the radiogenic isotopes of melt away from the source, thus calling for a clear understanding of the behaviors of radiogenic isotopes during crustal melting. This study investigated the joint behavior of Rb-Sr, Sm-Nd, and Lu-Hf isotope systems during the melting of metasediments. Leucosome, schist, and leucogranite samples were collected from the Nyalam, South Tibet, where the leucosome was produced by muscovite dehydration melting of metapelites. Results show that the leucosome has a broad range of Sr-Nd-Hf isotopes (87Sr/86Sri: 0.763,48–0.875321, εNd(t): 14.6–11.6, εHf(t): 15.0–4.4) that deviate from the metasediments. We attributed it to the non-modal or disequilibrium melting of metapelites. The variation of Sr isotopes of leucosome is formed due to preferential entry into the melt of muscovite relative to plagioclase during melting. The changing 87Sr/86Sri and 87Rb/86Sr of leucosome define an errorchron at ∼ 500 Ma indicating an early Paleozoic tectono-thermal event supported by the U-Pb age of zircon cores (∼460 Ma) in the leucosome. The Nd isotopes of leucosome are mainly controlled by the preferential dissolution of apatite relative to monazite. The inadequate dissolution of zircon caused more depleted initial Hf isotopes compositions in the leucosome than the source. However, the leucosome with a higher crystallization temperature has radiogenic isotopic composition closer to the source. It indicates that the melting temperature greatly affects the isotope equilibrium between source and melt.
Assessing Worldwide Research Activity on ICT in Climate Change Using Scopus Database: A Bibliometric Analysis
Authors: Stefanis Christos , Giorgi Elpida , Kalentzis Konstantinos , Tselemponis Athanasios , Tsigalou Christina , Nena Evangelia , Kontogiorgis Christos , Kourkoutas Yiannis , Voidarou Chrysa , Chatzaki Ekaterini , Dokas Ioannis , Konstantinidis Theodoros , Bezirtzoglou Eugenia
Published: May 2022

Internet and Communication Technology (ICT) tools have been already introduced in every aspect of environmental science. Regarding climate change, research trends and developments on ICT help realize how ICT evolved and its potential future role in climate change. This study aimed to assess ICT solutions in climate change research trends using the Scopus database, bibliometric indicators, and network visualization. After a preliminary application of various combinations, the phrase “ICT and climate change” was used with language selection “English” from 01/01/1999 to 01/12/2021. A collection of 453 articles published in scientific journals and conference proceedings was revealed, which allowed the visualization mapping of the research agenda in the field of ICT and climate change. The most relevant topics are related to Computer Science, Engineering, Environmental and Social sciences. It has been found that a significant amount of documents were published after 2008. The Royal Institute of Technology-KTH was the most productive institution, followed by the Consiglio Nazionale Delle Ricerche and the Universitetet I Oslo. In addition, the dominant countries in the respective research area were the United Kingdom, Italy, United States, India and Sweden. According to citations, most of the published research activity emerged in various journals, like Environment and Planning, Cities and Energies. It was possible to spot past trends and ongoing development, intending to introduce ICT tools in climate change impacts and examine the issues expected to be pertinent in the future.
Case Report: Hereditary Fibrosing Poikiloderma With Tendon Contractures, Myopathy, and Pulmonary Fibrosis (POIKTMP) Presenting With Liver Cirrhosis and Steroid-Responsive Interstitial Pneumonia
Authors: Takimoto-Sato Michiko , Miyauchi Toshinari , Suzuki Masaru , Ujiie Hideyuki , Nomura Toshifumi , Ikari Tomoo , Nakamura Tomohiko , Takahashi Kei , Matsumoto-Sasaki Machiko , Kimura Hirokazu , Kimura Hiroki , Matsui Yuichiro , Kitagataya Takashi , Yamada Ren , Suzuki Kazuharu , Nakamura Akihisa , Nakai Masato , Sho Takuya , Ogawa Koji , Sakamoto Naoya , Yamaguchi Naoko , Otsuka Noriyuki , Tomaru Utano , Konno Satoshi
Published: May 2022

Background: Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) is an extremely rare disease caused by mutations in FAM111B, and only approximately 30 cases have been reported worldwide. Some patients develop interstitial pneumonia, which may lead to progressive pulmonary fibrosis and poor prognosis. However, no effective treatment for interstitial pneumonia associated with POIKTMP has been reported. Here, we report an autopsy case of POIKTMP, wherein interstitial pneumonia was improved by corticosteroids.

Case Presentation: A 44-year-old Japanese man was referred to our hospital due to poikiloderma, hypotrichosis, and interstitial pneumonia. He developed progressive poikiloderma and muscle weakness since infancy. He also had tendon contractures, short stature, liver cirrhosis, and interstitial pneumonia. Mutation analysis of FAM111B revealed a novel and de novo heterozygous missense mutation, c.1886T > G (p(Phe629Cys)), through which we were able to diagnose the patient with POIKTMP. 3 years after the POIKTMP diagnosis, interstitial pneumonia had worsened. After 2 weeks of administrating 40 mg/day of prednisolone, his symptoms and lung shadows improved. However, he subsequently developed severe hepatic encephalopathy and eventually died of respiratory failure due to bacterial pneumonia and pulmonary edema. Autopsy revealed an unclassifiable pattern of interstitial pneumonia, as well as the presence of fibrosis and fatty degeneration in several organs, including the liver, kidney, skeletal muscle, heart, pancreas, and thyroid.

Conclusions: We report a case of POIKTMP in which interstitial pneumonia was improved by corticosteroids, suggesting that corticosteroids could be an option for the treatment of interstitial pneumonia associated with this disease.
Production of Conjoined Transgenic and Edited Barley and Wheat Plants for Nud Genes Using the CRISPR/SpCas9 System
Authors: Zang Yiming , Gong Qiang , Xu Yanhao , Liu Huiyun , Bai Hao , Li Na , Du Lipu , Ye Xingguo , Lan Caixia , Wang Ke
Published: May 2022

The Nudum (Nud) gene controls the caryopsis type of cereal crops by regulating lipid biosynthetic pathways. Based on the HvNud sequence and its homologous gene sequences in wheat, a conserved sgRNA was designed to obtain the mutants from the barley variety “Vlamingh” and the wheat variety “Fielder” via Agrobacterium-mediated transformation. A total of 19 and 118 transgenic plants were obtained, and 11 and 61 mutant plants were identified in T0 transgenic plants in barley and wheat after PCR-RE detection, and the editing efficiencies of the targeted gene were 57.9 and 51.7% in barley and wheat, respectively. The grain shape of the barley mutants was naked. Five different combinations of mutations for wheat TaNud genes were identified in the T0 generation, and their homozygous-edited plants were obtained in the T1 generation. Interestingly, the conjoined plants in which one plant has different genotypes were first identified. The different tillers in an individual T0 plant showed independent transgenic or mutant events in both barley and wheat, and the different genotypes can stably inherit into T1 generation, indicating that the T0 transgenic plants were the conjoined type. In addition, we did not find any off-target mutations in both barley and wheat. A candidate method for detecting putative-edited wheat plants was suggested to avoid losing mutations in this investigation. This study provides not only materials for studying the function of the Nud gene in barley and wheat but also a system for detecting the mutants in wheat.
kngMap: Sensitive and Fast Mapping Algorithm for Noisy Long Reads Based on the K-Mer Neighborhood Graph
Authors: Wei Ze-Gang , Fan Xing-Guo , Zhang Hao , Zhang Xiao-Dan , Liu Fei , Qian Yu , Zhang Shao-Wu
Published: May 2022

With the rapid development of single molecular sequencing (SMS) technologies such as PacBio single-molecule real-time and Oxford Nanopore sequencing, the output read length is continuously increasing, which has dramatical potentials on cutting-edge genomic applications. Mapping these reads to a reference genome is often the most fundamental and computing-intensive step for downstream analysis. However, these long reads contain higher sequencing errors and could more frequently span the breakpoints of structural variants (SVs) than those of shorter reads, leading to many unaligned reads or reads that are partially aligned for most state-of-the-art mappers. As a result, these methods usually focus on producing local mapping results for the query read rather than obtaining the whole end-to-end alignment. We introduce kngMap, a novel k-mer neighborhood graph-based mapper that is specifically designed to align long noisy SMS reads to a reference sequence. By benchmarking exhaustive experiments on both simulated and real-life SMS datasets to assess the performance of kngMap with ten other popular SMS mapping tools (e.g., BLASR, BWA-MEM, and minimap2), we demonstrated that kngMap has higher sensitivity that can align more reads and bases to the reference genome; meanwhile, kngMap can produce consecutive alignments for the whole read and span different categories of SVs in the reads. kngMap is implemented in C++ and supports multi-threading; the source code of kngMap can be downloaded for free at: https://github.com/zhang134/kngMap for academic usage.
Precursors to Systemic Sclerosis and Systemic Lupus Erythematosus: From Undifferentiated Connective Tissue Disease to the Development of Identifiable Connective Tissue Diseases
Authors: Martin Calderon Leonardo , Pope Janet E.
Published: May 2022

The pathogenesis of connective tissue diseases (CTDs), such as systemic lupus erythematosus (SLE) and systemic sclerosis (SSc), is characterized by derangements of the innate and adaptive immune system, and inflammatory pathways leading to autoimmunity, chronic cytokine production, and chronic inflammation. The diagnosis of these diseases is based on meeting established criteria with symptoms, signs and autoantibodies. However, there are pre-clinical states where criteria are not fulfilled but biochemical and autoimmune derangements are present. Understanding the underlying processes responsible for disease pathogenesis in pre-clinical states, which place patients at increased risk for the development of established connective tissue diseases, represents an opportunity for early identification and potentially enables timely treatment with the goal of limiting disease progression and improved prognosis. This scoping review describes the role of the innate and adaptive immune responses in the pre-clinical states of undifferentiated CTD at risk for SSc and prescleroderma, the evolution of antibodies from nonspecific to specific antinuclear antibodies prior to SLE development, and the signaling pathways and inflammatory markers of fibroblast, endothelial, and T cell activation underlying immune dysregulation in these pre-clinical states.
Mechanical and Antibacterial Properties of h-BN-TiO2 Nanocomposite-Modified Glass Ionomer Cement
Authors: Ma Yu , Guo Yan-Zhu , Liu Yan , Wang Yu-Rui , Yang Jiang-Chuan , Kong Xin-Zi , Jia Hong-Lin , Li Rui-Zhi , Han Qi-Ze , Zheng Cheng-Dong , Hu Xin-Jun , Liu Bin
Published: May 2022

This study investigated the mechanical properties and antibacterial properties of hexagonal boron nitride and titanium dioxide (h-BN-TiO2) nanocomposite modified traditional glass ionomer cement. The mechanism of formation of the h-BN-TiO2 nanocomposite was elucidated by conducting molecular dynamics (MD) simulations using the Material Studio (MS) software. Furthermore, synthesis of h-BN-TiO2 nanocomposite by the original growth method using hexagonal boron nitride nanosheets (h-BNNs) and titanium dioxide nanoparticles (TiO2 Nps) and characterization using TEM and AFM to determine their particle sizes, morphologies, and structures. The mechanical properties and antibacterial efficacies of the glass ionomer cement composites were analyzed based on the different mass fractions (0, 0.3, 0.7, 1.1, and 1.5 wt%) of the h-BN-TiO2 nanocomposite. The results showed when the concentration of the h-BN-TiO2 nanocomposite was 1.1 wt%, the Compressive strength (CS) and Vicker hardness (VHN) were 80.2% and 149.65% higher, respectively, compared to the glass ionomer cement without any h-BN-TiO2 nanocomposite. Also, the increase in the concentration of the h-BN-TiO2 nanocomposite led to a decrease in both the coefficient of friction (COF) and solubility, but a 93.4% increase in the antibacterial properties of the glass ionomer cement composites. The cell survival rate of each group was more than 70% after 48 h, but the difference was not statistically significant (p > 0.05). Therefore, the h-BN-TiO2 nanocomposite served as a reinforcing material for glass ionomer cement, which can be useful in clinical dentistry and provide a new strategy for improving the clinical utility of glass ionomer cement.
Cingulin b Is Required for Zebrafish Lateral Line Development Through Regulation of Mitogen-Activated Protein Kinase and Cellular Senescence Signaling Pathways
Authors: Lu Yitong , Tang Dongmei , Zheng Zhiwei , Wang Xin , Zuo Na , Yan Renchun , Wu Cheng , Ma Jun , Wang Chuanxi , Xu Hongfei , He Yingzi , Liu Dong , Liu Shaofeng
Published: May 2022

Cingulin, a cytoplasmic element of tight junctions (TJs), is involved in maintenance of the integrity of epithelial and endothelial cells. However, the role of cingulin in the development of auditory organs remains unclear. Zebrafish is popular as a model organism for hearing research. Using the whole mount in situ hybridization (WISH) experiment, we detected the expression of cingulin b in the posterior lateral line system (PLLs) of zebrafish. We traced the early development progress of zebrafish PLLs from 36 hpf to 72 hpf, and found that inhibition of cingulin b by target morpholinos resulted in severe developmental obstruction, including decreased number of neuromasts, reduced proliferative cells in the primordium, and repressed hair cell differentiation in the neuromasts. To examine the potential mechanism of cingulin b in the development of zebrafish PLL neuromasts, we performed RNA-seq analysis to compare the differently expressed genes (DEGs) between cingulin b knockdown samples and the controls. The KEGG enrichment analysis revealed that MAPK signaling pathway and cellular senescence were the key pathways with most DEGs in cingulin b-MO morphants compared to the Control-MO embryos. Furthermore, quantitative RT-PCR analysis confirmed the findings by RNA-seq that the transcript levels of cell cycle negative regulators such as tp53 and cdkn1a, were remarkably upregulated after inhibition of cingulin b. Our results therefore indicated an important role of cingulin b in the development of auditory organs, and MAPK signaling pathway was inhibited while cellular senescence pathway was activated after downregulation of cingulin b. We bring forward new insights of cingulin by exploring its function in auditory system.
Neuronal ER-Signalosome Proteins as Early Biomarkers in Prodromal Alzheimer's Disease Independent of Amyloid-β Production and Tau Phosphorylation
Authors: Mesa-Herrera Fátima , Marín Raquel , Torrealba Eduardo , Santos Guido , Díaz Mario
Published: May 2022

There exists considerable interest to unveil preclinical period and prodromal stages of Alzheimer's disease (AD). The mild cognitive impairment (MCI) is characterized by significant memory and/or other cognitive domains impairments, and is often considered the prodromal phase of AD. The cerebrospinal fluid (CSF) levels of β-amyloid (βA), total tau (t-tau), and phosphorylated tau (p-tau) have been used as biomarkers of AD albeit their significance as indicators during early stages of AD remains far from accurate. The new biomarkers are being intensively sought as to allow identification of pathological processes underlying early stages of AD. Fifty-three participants (75.4 ± 8.3 years) were classified in three groups as cognitively normal healthy controls (HC), MCI, and subjective memory complaints (SMC). The subjects were subjected to a battery of neurocognitive tests and underwent lumbar puncture for CSF extraction. The CSF levels of estrogen-receptor (ER)-signalosome proteins, βA, t-tau and p-tau, were submitted to univariate, bivariate, and multivariate statistical analyses. We have found that the components of the ER-signalosome, namely, caveolin-1, flotilin-1, and estrogen receptor alpha (ERα), insulin growth factor-1 receptor β (IGF1Rβ), prion protein (PrP), and plasmalemmal voltage dependent anion channel 1 (VDAC) could be detected in the CSF from all subjects of the HC, MCI, and SMC groups. The six proteins appeared elevated in MCI and slightly increased in SMC subjects compared to HC, suggesting that signalosome proteins undergo very early modifications in nerve cells. Using a multivariate approach, we have found that the combination of ERα, IGF-1Rβ, and VDAC are the main determinants of group segregation with resolution enough to predict the MCI stage. The analyses of bivariate relationships indicated that collinearity of ER-signalosome proteins vary depending on the stage, with some pairs displaying opposed relationships between HC and MCI groups, and the SMC stage showing either no relationships or behaviors similar to either HC or MCI stages. The multinomial logistic regression models of changes in ER-signalosome proteins provide reliable predictive criteria, particularly for the MCI. Notably, most of the statistical analyses revealed no significant relationships or interactions with classical AD biomarkers at either disease stage. Finally, the multivariate functions were highly correlated with outcomes from neurocognitive tests for episodic memory. These results demonstrate that alterations in ER-signalosome might provide useful diagnostic information on preclinical stages of AD, independently from classical biomarkers.
Multi-Omics Characterization of a Glycerolipid Metabolism-Related Gene Enrichment Score in Colon Cancer
Authors: Wang Zhiyu , Zhang Zhuoqi , Zhang Ke , Zhou Qiaoxia , Chen Sidong , Zheng Hao , Wang Guoqiang , Cai Shangli , Wang Fujing , Li Shenglong
Published: May 2022

Background

Glycerolipid metabolism is involved in the genesis and progression of colon cancer. The current study aims at exploring the prognostic value and potential molecular mechanism of glycerolipid metabolism-related genes in colon cancer from the perspective of multi-omics.

Methods

Clinical information and mRNA expression data of patients with colon cancer were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Single-sample gene set enrichment analysis (ssGSEA) was applied to calculate the glycerolipid metabolism-related gene enrichment score (GLMS). Univariable and multivariable Cox regression analyses were used to study the prognostic value of GLMS in TCGA-COAD and GSE39582 cohorts. The molecular mechanism of the prognostic factor was investigated via immune cell infiltration estimation and correlation analysis of cancer hallmark pathways. Single-cell transcriptomic dataset GSE146771 was used to identify the cell populations which glycerolipid metabolism targeted on.

Results

The GLMS was found to be associated with tumor location and consensus molecular types (CMSs) of colon cancer in TCGA-COAD cohort (P < 0.05). Patients in the low-GLMS group exhibited poorer overall survival (OS) in TCGA cohort (P = 0.03; HR, 0.63; 95% CI, 0.42–0.94), which was further validated in the GSE39582 dataset (P < 0.001; HR, 0.57; 95% CI, 0.43–0.76). The association between the GLMS and OS remained significant in the multivariable analysis (TCGA cohort: P = 0.04; HR, 0.64; 95% CI, 0.42–0.98; GSE39582 cohort: P < 0.001; HR, 0.60; 95% CI, 0.45–0.80). The GLMS was positively correlated with cancer hallmark pathways including bile acid metabolism, xenobiotic metabolism, and peroxisome and negatively correlated with pathways such as interferon gamma response, allograft rejection, apoptosis, and inflammatory response (P < 0.05). Increased immune infiltration and upregulated expression of immune checkpoints were observed in patients with lower GLMS (P < 0.05). Single-cell datasets verified the different distribution of GLMS in cell subsets, with significant enrichment of GLMS in malignant cells and Tprolif cells.

Conclusion

We demonstrated that GLMS was a potential independent prognostic factor for colon cancer. The GLMS was also correlated with several cancer hallmark pathways, as well as immune microenvironment.
Neoadjuvant Chemoradiotherapy With Simultaneous Integrated Boost in Locally Advanced Cervical Cancer: Long Term Results of a Single-Center Experience
Authors: Nardangeli Alessia , Autorino Rosa , Boldrini Luca , Campitelli Maura , Reina Sara , Ferrandina Gabriella , Bizzarri Nicolò , Tagliaferri Luca , Macchia Gabriella , Valentini Vincenzo , Gambacorta Maria Antonietta
Published: May 2022

Aim of this study was to analyze the efficacy and tolerability of simultaneous integrated boost volumetric modulated arc therapy (SIB-VMAT) associated with cisplatin-based chemotherapy in preoperative setting of patients with locally advanced cervical cancer (LACC). From June 2013 to September 2019, we analyzed patients with LACC who had undergone neoadjuvant chemoradiation (CRT). A radiation dose of 39.6 Gy, 1.8 Gy/fraction was delivered to the pelvis plus a radiation dose to the primary tumor delivered with SIB-VMAT strategy for a total of 50.6Gy, 2.3Gy/fraction in 25 fractions. Cisplatin-based chemotherapy was delivered combined with radiotherapy. Radical hysterectomy plus pelvic with or without aortic lymphadenectomy was performed within 7 to 8 weeks from CRT. One hundred forty-eight patients (median age: 49.5 years; FIGO stage IB2: 7, IIA: 8, IIB: 106, IIIA: 5; IIIB: 16; IVA: 5, IVB: 1; N0: 56, N1: 92) were analyzed. The treatment was well tolerated with good compliance: no grade 3/4 gastrointestinal or genitourinary toxicity was reported; grade 3 neutropenia was described in five cases. Pathological complete response (pCR) was documented in 68 cases (46%) and 32 patients (21.6%) had microscopic residual disease. Pathological nodal involvement was observed in 23 patients (15.5%). At median follow-up of 59 months (range: 27-100), the 3-year local control was 78.5%, whereas the 3-year metastasis-free survival was 70.5%. The 3-year overall survival rate was 89.0%. Neoadjuvant CRT with SIB-VMAT followed by radical surgery results in a high rate of pathologically assessed complete response and a very encouraging local control rate, with acceptable toxicity.
Evidence of Chinese Herbal Medicine Use From an Economic Perspective: A Systematic Review of Pharmacoeconomics Studies Over Two Decades
Authors: Xiong Xiaomo , Jiang Xiangxiang , Lv Gang , Yuan Jing , Li Minghui , Lu Z. Kevin
Published: May 2022

Objectives:Pharmacoeconomics evaluation (PE) is increasingly used in the healthcare decision-making process in China. Little is known about PE conducted in Chinese Herbal Medicines (CHMs). We aimed to systematically review trends, characteristics, and quality of PE of CHMS.

Methods:We systematically searched both Chinese (CNKI, WanFang, and VIP) and English (Pubmed) databases. Studies were included if they were PE studies comparing both costs and outcomes between two or more interventions published in Chinese or English. Assessment of the quality of studies was conducted using the Quality of Health Economic Analyses (QHES) instrument.T-test and Chi-square tests were used to compare the studies before and after the first edition ofChina Guidelines for PEpublished in 2011, and between studies published in Chinese and English.

Results:A total of 201 articles were included. There was an increasing trend of PE studies on CHMs during the study period. The top three studied diseases were central nervous system (CNS), mental, and behavioral disorders; cardiovascular diseases; and blood, immune and endocrine diseases. The average QHES score for the included studies was 63.37. Cost-effectiveness analysis (CEA) accounted for the majority (76.6%) of the included studies. Only a quarter of the articles (27.4%) were funded, and there were significantly more studies funded after the publication ofChina guidelines for PE. About 96.5% of studies did not specify evaluation perspectives and 89.6% of studies had a sample size of less than 300. Around half of the studies (55%) used incremental analysis, but only a few of them considered using a threshold. Half of the studies lacked sensitivity analysis. There was no significant improvement in the quality of studies published after the publication ofChina Guidelines for PE, and English articles had significantly higher quality than Chinese articles.

Conclusion:This study identified several problems in PE studies on CHMs, including having small sample sizes, lacking necessary research elements, and using single evaluation methods. The quality of PE studies on CHMs was not sufficient. Researchers need to understand the standardized way to conduct PE studies and improve the quality and level of PE studies on CHMs.
Crosstalk of Histone and RNA Modifications Identified a Stromal-Activated Subtype with Poor Survival and Resistance to Immunotherapy in Gastric Cancer
Authors: Yuan Cheng , Zhang Junchang , Deng Cuncan , Xia Yujian , Li Bo , Meng Sijun , Jin Xinghan , Cheng Lvjia , Li Huafu , Zhang Changhua , He Yulong
Published: May 2022

Emerging evidence has revealed the pivotal role of epigenetic modifications in shaping the tumor microenvironment (TME). However, crosstalk between different modification types and their clinical relevance in cancers remain largely unexplored. In this study, using ChIP/MeRIP-seq data of seven human gastric cell lines, we systematically characterized the crosstalk of four epigenetic modification types including H3K4me1, H3K4me3, H3K27ac, and N6-methyladenosine (m6A) and identified a recurrent subtype with high FTO expression and low HDAC1 expression across three independent gastric cancer (GC) cohorts, which we named the epigenetic-modification-dysregulated (EMD) subtype. Patients of the EMD subtype were featured with poor survival, stromal activation, and immune suppression. Extensive relevance to clinical characteristics was observed in the EMD subtype, including the Lauren classification, MSI status, histological grade, TNM stage, the Asian Cancer Research Group classification, and the immune/fibrotic classification. An EMD score was then constructed using WGCNA and ssGSEA algorithms, to precisely recognize the EMD subtype and indicate prognosis and response to immunotherapy in multiple independent GC cohorts. Correlations of the EMD score with tumor mutation burden, tumor purity, aneuploidy score, tumorigenic pathways, TME characteristics, and FTO/HDAC1 ratio were measured. In vitro experiments were performed to demonstrate the correlation between FTO and the epithelial–mesenchymal transition pathway, which suggested FTO as a targetable vulnerability for GC patients with a high EMD score. Altogether, by comprehensively analyzing the epigenetic modification patterns of 1518 GC patients, we identified a novel stromal-activated subtype with poor survival and resistance to immunotherapy, which might benefit from the combined immune checkpoint inhibition therapy with FTO inhibition.
Salvia miltiorrhiza in Breast Cancer Treatment: A Review of Its Phytochemistry, Derivatives, Nanoparticles, and Potential Mechanisms
Authors: Zhao Huan , Han Bing , Li Xuan , Sun Chengtao , Zhai Yufei , Li Man , Jiang Mi , Zhang Weiping , Liang Yi , Kai Guoyin
Published: May 2022

Breast cancer is one of the most deadly malignancies in women worldwide. Salvia miltiorrhiza, a perennial plant that belongs to the genus Salvia, has long been used in the management of cardiovascular and cerebrovascular diseases. The main anti-breast cancer constituents in S. miltiorrhiza are liposoluble tanshinones including dihydrotanshinone I, tanshinone I, tanshinone IIA, and cryptotanshinone, and water-soluble phenolic acids represented by salvianolic acid A, salvianolic acid B, salvianolic acid C, and rosmarinic acid. These active components have potent efficacy on breast cancer in vitro and in vivo. The mechanisms mainly include induction of apoptosis, autophagy and cell cycle arrest, anti-metastasis, formation of cancer stem cells, and potentiation of antitumor immunity. This review summarized the main bioactive constituents of S. miltiorrhiza and their derivatives or nanoparticles that possess anti-breast cancer activity. Besides, the synergistic combination with other drugs and the underlying molecular mechanisms were also summarized to provide a reference for future research on S. miltiorrhiza for breast cancer treatment.
Investigation of the Anti-Inflammatory Activity of Fusaproliferin Analogues Guided by Transcriptome Analysis
Authors: Kuang Qi-Xuan , Lei Li-Rong , Li Qing-Zhou , Peng Wan , Wang Yu-Mei , Dai Yi-Fei , Wang Dong , Gu Yu-Cheng , Deng Yun , Guo Da-Le
Published: May 2022

Background: Excessive inflammation results in severe tissue damage as well as serious acute or chronic disorders, and extensive research has focused on finding new anti-inflammatory hit compounds with safety and efficacy profiles from natural products. As promising therapeutic entities for the treatment of inflammation-related diseases, fusaproliferin and its analogs have attracted great interest. However, the underlying anti-inflammatory mechanism is still poorly understood and deserves to be further investigated.

Methods: For the estimation of the anti-inflammatory activity of fusaproliferin (1) and its analogs (2-4)in vitro and in vivo, lipopolysaccharide (LPS)-induced RAW264.7 macrophages and zebrafish embryos were employed. Then, transcriptome analysis was applied to guide subsequent western blot analysis of critical proteins in related signaling pathways. Surface plasmon resonance assays (SPR) combined with molecular docking analyses were finally applied to evaluate the affinity interactions between 1-4 and TLR4 and provide a possible interpretation of the downregulation of related signaling pathways.

Results: 1-4 significantly attenuated the production of inflammatory messengers, including nitric oxide (NO), reactive oxygen species (ROS), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β), as well as nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), in LPS-induced RAW264.7 macrophages. Transcriptome analyses based on RNA-seq indicated the ability of compound 1 to reverse LPS stimulation and the nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPKs) signaling pathways contribute to the anti-inflammatory process. Experimental verification at the protein level revealed that 1 can inhibit the activation of inhibitor of NF-κB kinase (IKK), degradation of inhibitor of NF-κB (IκB), and phosphorylation of NF-κB and reduce nuclear translocation of NF-κB. 1 also decreased the phosphorylation of MAPKs, including p38, extracellular regulated protein kinases (ERK), and c-Jun N-terminal kinase (JNK). SPR assays and molecular docking results indicated that 1-4 exhibited affinity for the TLR4 protein with KD values of 23.5–29.3 μM.

Conclusion: Fusaproliferin and its analogs can be hit compounds for the treatment of inflammation-associated diseases.
Immunoadjuvant Nanoparticles as Trojan Horses for Enhanced Photo-Immunotherapy in the Treatment of Triple-Negative Breast Cancer
Authors: Wu Jinxian , Wang Shanyong , Liu Shanshan , Liu Fang , Zhou Feifan
Published: May 2022

Treatment of triple-negative breast cancer (TNBC) faces great challenges due to high invasiveness and poor prognosis. Therefore, effective treatment methods are urgently needed to control primary tumors and suppress distant tumors. Herein, we employed glycated chitosan (GC), a polysaccharide macromolecular immunoadjuvant, to construct a self-assembly GC@ICG nanoparticle which is accessible to tumor cells for synergistic cancer treatment based on the combination of phototherapy and immunotherapy. In this strategy, the self-associated synthesis of spherical GC@ICG significantly improved the stability of ICG and endowed GC with Trojan Horses in tumor cells to enhance tumor immunogenicity. A bilateral 4T1 tumor-bearing mouse model was established to evaluate the therapeutic outcomes and specific host antitumor immune response. Finally, GC@ICG-based phototherapy can directly eliminate primary tumors and resist the progression of untreated distant tumors. In addition, compared to the treatment of L + GC + ICG, GC@ICG-based phototherapy was evidenced to suppress lung metastasis and enhance infiltration of CD8+ T cells in untreated distant tumors. Therefore, this design shows promise in addressing the challenges of the treatment of TNBC.
Neutral Polysaccharides From Hohenbuehelia serotina With Hypoglycemic Effects in a Type 2 Diabetic Mouse Model
Authors: Liu Qinghong , Wu Jing , Wang Peng , Lu Yuxiao , Ban Xinhe
Published: May 2022

Neutral polysaccharides (NHSPs) from the mushroom Hohenbueheliaserotina were purified by D301/D152 resin ion-exchange chromatography and DEAE-cellulose anion exchange chromatography. The weight-average molecular weight (MW) and number-average molecular weight (Mn) of NHSP were 1,821 and 820.55 kDa, respectively. A monosaccharide component analysis showed that NHSP was composed of glucose, galactose, and mannose in molar ratio 2.6:2.1:1.0. FT-IR and NMR (1H and HSQC) spectroscopic analyses revealed that NHSP contained mainly 1,3-linked β-D-glucose, 1,4-linked β-D-glucose, 1,6-linked β-D-mannose, 1,6-linked α-D-mannose, and 1,6-linked β-D-galactose. The thermogravimetric analysis (TGA) showed that NHSP has good thermal stability below 250°C. NHSP notably reduced the blood glucose level (hypoglycemic effect) at dose 200 mg/kg for 21 days in a type 2 diabetic mouse model. NHSP reduced the liver index significantly, suggesting that it may help prevent hepatic steatosis or hepatomegaly.
Analgesic Effects and Safety of Dexmedetomidine Added to Nalbuphine or Sufentanil Patient-Controlled Intravenous Analgesia for Children After Tonsillectomy Adenoidectomy
Authors: Jia Yingping , Zhou Rui , Li Zhengchen , Wang Yuanyuan , Chen Sandong , Zhao Liyuan , Shao Yi , Qi Jinlian
Published: May 2022

Tonsillectomy is a frequently performed surgical procedure in children, requiring post-operative analgesia. This study evaluated the efficacy and safety of nalbuphine or sufentanil combined with dexmedetomidine for patient-controlled intravenous analgesia (PCIA) after pediatric tonsillectomy adenoidectomy. A total of 400 patients undergoing tonsillectomy with and without adenoidectomy were included in the study. Patients received a PCIA pump (0.5 mg/kg nalbuphine, 2 μg/kg dexmedetomidine and 0.9% sodium chloride to a total volume of 100 ml) for postoperative pain management were classified into Group ND (n = 200). Patients received a PCIA pump (2 μg/kg sufentanil, 2 μg/kg dexmedetomidine and 0.9% sodium chloride to a total volume of 100 ml) for postoperative pain management were classified into Group SD (n = 200). More stable hemodynamic changes were noted in Group ND than Group SD from 1 h to 48 h after operation. At 6, 12, 24, and 48 h after operation, the children in Group ND had higher Ramsay sedation scores than those in Group SD. The times to push the PCIA button in Group ND and Group SD were 2.44 ± 0.74 and 2.62 ± 1.00, showing significant differences (p = 0.041). The VASR scores of children in Group ND were significantly lower within 6, 12, and 24 h than those in Group SD (p < 0.05). The VASC scores of children in Group ND were significantly lower within four time points (2, 6, 12, and 24 h) than those in Group SD (p < 0.05). At 1st day after surgery, the children in Group ND had lower levels of serum ACTH, IL-6, and COR levels than those in Group SD (p < 0.001). The incidence rates of nausea and vomiting, and pruritus were significantly higher in Group SD than Group ND (5.00% vs. 11.00%, p = 0.028; 1.00% vs. 4.50%, p = 0.032). The total incidence rate of adverse reactions was significantly higher in Group SD than Group ND (15.00% vs. 31.00%, p = 0.0001). The study demonstrated that dexmedetomidine added to nalbuphine PCIA enhanced the analgesic effects, attenuated the postoperative pain, and reduced the stress response after pediatric tonsillectomy adenoidectomy.
Seasonality in Biological Rhythms in Scandinavian brown Bears
Authors: Thiel Alexandra , Giroud Sylvain , Hertel Anne G. , Friebe Andrea , Devineau Olivier , Fuchs Boris , Blanc Stephane , Støen Ole-Gunnar , Laske Timothy G. , Arnemo Jon M. , Evans Alina L.
Published: May 2022

Biological rhythms, such as rhythms in activity and body temperature, are usually highly synchronized and entrained by environmental conditions, such as photoperiod. However, how the expression of these rhythms changes during hibernation, when the perception of environmental cues is limited, has not yet been fully understood for all hibernators, especially in the wild. The brown bear (Ursus arctos) in Scandinavia lives in a highly seasonal environment and adapts to harsh winter conditions by exhibiting hibernation, characterized by reduced metabolism and activity. In this study, we aimed to explore the expression of biological rhythms in activity, body temperature and heart rate of free-ranging brown bears over the annual cycle, including active, hibernation and the transition states around den entry and exit. We found that rhythms in physiology and activity are mostly synchronized and entrained by the light-dark cycle during the bears’ active state with predominantly diel and ultradian rhythms for body temperature, activity and heart rate. However, during hibernation, rhythms in body temperature and heart rate were considerably slowed down to infradian rhythms, influenced by the amount of snow in the denning area, whereas rhythms in activity remained diel. Rhythms in the transition states when bears prepared for entering or coming out of hibernation state displayed a combination of infradian and diel rhythms, indicating the preparation of the body for the change in environmental conditions. These results reveal that brown bears adjust their biological rhythms to the seasonal environment they inhabit. Rhythms in physiology and activity show simultaneity during the active state but are partly disconnected from each other during hibernation, when bears are most sheltered from the environment.
Ephaptic Coupling Is a Mechanism of Conduction Reserve During Reduced Gap Junction Coupling
Authors: Lin Joyce , Abraham Anand , George Sharon A. , Greer-Short Amara , Blair Grace A. , Moreno Angel , Alber Bridget R. , Kay Matthew W. , Poelzing Steven
Published: May 2022

Many cardiac pathologies are associated with reduced gap junction (GJ) coupling, an important modulator of cardiac conduction velocity (CV). However, the relationship between phenotype and functional expression of the connexin GJ family of proteins is controversial. For example, a 50% reduction of GJ coupling has been shown to have little impact on myocardial CV due to a concept known as conduction reserve. This can be explained by the ephaptic coupling (EpC) theory whereby conduction is maintained by a combination of low GJ coupling and increased electrical fields generated in the sodium channel rich clefts between neighboring myocytes. At the same time, low GJ coupling may also increase intracellular charge accumulation within myocytes, resulting in a faster transmembrane potential rate of change during depolarization (dV/dt_max) that maintains macroscopic conduction. To provide insight into the prevalence of these two phenomena during pathological conditions, we investigated the relationship between EpC and charge accumulation within the setting of GJ remodeling using multicellular simulations and companion perfused mouse heart experiments. Conduction along a fiber of myocardial cells was simulated for a range of GJ conditions. The model incorporated intercellular variations, including GJ coupling conductance and distribution, cell-to-cell separation in the intercalated disc (perinexal width—WP), and variations in sodium channel distribution. Perfused heart studies having conditions analogous to those of the simulations were performed using wild type mice and mice heterozygous null for the connexin gene Gja1. With insight from simulations, the relative contributions of EpC and charge accumulation on action potential parameters and conduction velocities were analyzed. Both simulation and experimental results support a common conclusion that low GJ coupling decreases and narrowing WP increases the rate of the AP upstroke when sodium channels are densely expressed at the ends of myocytes, indicating that conduction reserve is more dependent on EpC than charge accumulation during GJ uncoupling.