bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive Analysis of Expression Regulation for RNA m6A Regulators With Clinical Significance in Human Cancers
Authors: Liu Xiaonan , Wang Pei , Teng Xufei , Zhang Zhang , Song Shuhui
Published: February 2021

Background

N6-methyladenosine (m6A), the most abundant chemical modification on eukaryotic messenger RNA (mRNA), is modulated by three class of regulators namely “writers,” “erasers,” and “readers.” Increasing studies have shown that aberrant expression of m6A regulators plays broad roles in tumorigenesis and progression. However, it is largely unknown regarding the expression regulation for RNA m6A regulators in human cancers.

Results

Here we characterized the expression profiles of RNA m6A regulators in 13 cancer types with The Cancer Genome Atlas (TCGA) data. We showed that METTL14, FTO, and ALKBH5 were down-regulated in most cancers, whereas YTHDF1 and IGF2BP3 were up-regulated in 12 cancer types except for thyroid carcinoma (THCA). Survival analysis further revealed that low expression of several m6A regulators displayed longer overall survival times. Then, we analyzed microRNA (miRNA)-regulated and DNA methylation-regulated expression changes of m6A regulators in pan-cancer. In total, we identified 158 miRNAs and 58 DNA methylation probes (DMPs) involved in expression regulation for RNA m6A regulators. Furthermore, we assessed the survival significance of those regulatory pairs. Among them, 10 miRNAs and 7 DMPs may promote cancer initiation and progression; conversely, 3 miRNA/mRNA pairs in kidney renal clear cell carcinoma (KIRC) may exert tumor-suppressor function. These findings are indicative of their potential prognostic values. Finally, we validated two of those miRNA/mRNA pairs (hsa-miR-1307-3p/METTL14 and hsa-miR-204-5p/IGF2BP3) that could serve a critical role for potential clinical application in KIRC patients.

Conclusions

Our findings highlighted the importance of upstream regulation (miRNA and DNA methylation) governing m6A regulators’ expression in pan-cancer. As a result, we identified several informative regulatory pairs for prognostic stratification. Thus, our study provides new insights into molecular mechanisms of m6A modification in human cancers.
MYCN Drives a Tumor Immunosuppressive Environment Which Impacts Survival in Neuroblastoma
Authors: Raieli Salvatore , Di Renzo Daniele , Lampis Silvia , Amadesi Camilla , Montemurro Luca , Pession Andrea , Hrelia Patrizia , Fischer Matthias , Tonelli Roberto
Published: February 2021

A wide range of malignancies presents MYCN amplification (MNA) or dysregulation. MYCN is associated with poor prognosis and its over-expression leads to several dysregulations including metabolic reprogramming, mitochondria alteration, and cancer stem cell phenotype. Some hints suggest that MYCN overexpression leads to cancer immune-escape. However, this relationship presents various open questions. Our work investigated in details the relationship of MYCN with the immune system, finding a correlated immune-suppressive phenotype in neuroblastoma (NB) and different cancers where MYCN is up-regulated. We found a downregulated Th1-lymphocytes/M1-Macrophages axis and upregulated Th2-lymphocytes/M2-macrophages in MNA NB patients. Moreover, we unveiled a complex immune network orchestrated by N-Myc and we identified 16 genes modules associated to MNA NB. We also identified a MYCN-associated immune signature that has a prognostic value in NB and recapitulates clinical features. Our signature also discriminates patients with poor survival in non-MNA NB patients where MYCN expression is not discriminative. Finally, we showed that targeted inhibition of MYCN by BGA002 (anti-MYCN antigene PNA) is able to restore NK sensibility in MYCN-expressing NB cells. Overall, our study unveils a MYCN-driven immune network in NB and shows a therapeutic option to restore sensibility to immune cells.
Targeting Cytoprotective Autophagy to Enhance Anticancer Therapies
Authors: Xiao Malina , Benoit Alice , Hasmim Meriem , Duhem Caroline , Vogin Guillaume , Berchem Guy , Noman Muhammad Zaeem , Janji Bassam
Published: February 2021

Autophagy is a highly regulated multi-step process that occurs at the basal level in almost all cells. Although the deregulation of the autophagy process has been described in several pathologies, the role of autophagy in cancer as a cytoprotective mechanism is currently well established and supported by experimental and clinical evidence. Our understanding of the molecular mechanism of the autophagy process has largely contributed to defining how we can harness this process to improve the benefit of cancer therapies. While the role of autophagy in tumor resistance to chemotherapy is extensively documented, emerging data point toward autophagy as a mechanism of cancer resistance to radiotherapy, targeted therapy, and immunotherapy. Therefore, manipulating autophagy has emerged as a promising strategy to overcome tumor resistance to various anti-cancer therapies, and autophagy modulators are currently evaluated in combination therapies in several clinical trials. In this review, we will summarize our current knowledge of the impact of genetically and pharmacologically modulating autophagy genes and proteins, involved in the different steps of the autophagy process, on the therapeutic benefit of various cancer therapies. We will also briefly discuss the challenges and limitations to developing potent and selective autophagy inhibitors that could be used in ongoing clinical trials.
The Mevalonate Pathway, a Metabolic Target in Cancer Therapy
Authors: Guerra Borja , Recio Carlota , Aranda-Tavío Haidée , Guerra-Rodríguez Miguel , García-Castellano José M. , Fernández-Pérez Leandro
Published: February 2021

A hallmark of cancer cells includes a metabolic reprograming that provides energy, the essential building blocks, and signaling required to maintain survival, rapid growth, metastasis, and drug resistance of many cancers. The influence of tumor microenviroment on cancer cells also results an essential driving force for cancer progression and drug resistance. Lipid-related enzymes, lipid-derived metabolites and/or signaling pathways linked to critical regulators of lipid metabolism can influence gene expression and chromatin remodeling, cellular differentiation, stress response pathways, or tumor microenviroment, and, collectively, drive tumor development. Reprograming of lipid metabolism includes a deregulated activity of mevalonate (MVA)/cholesterol biosynthetic pathway in specific cancer cells which, in comparison with normal cell counterparts, are dependent of the continuous availability of MVA/cholesterol-derived metabolites (i.e., sterols and non-sterol intermediates) for tumor development. Accordingly, there are increasing amount of data, from preclinical and epidemiological studies, that support an inverse association between the use of statins, potent inhibitors of MVA biosynthetic pathway, and mortality rate in specific cancers (e.g., colon, prostate, liver, breast, hematological malignances). In contrast, despite the tolerance and therapeutic efficacy shown by statins in cardiovascular disease, cancer treatment demands the use of relatively high doses of single statins for a prolonged period, thereby limiting this therapeutic strategy due to adverse effects. Clinically relevant, synergistic effects of tolerable doses of statins with conventional chemotherapy might enhance efficacy with lower doses of each drug and, probably, reduce adverse effects and resistance. In spite of that, clinical trials to identify combinatory therapies that improve therapeutic window are still a challenge. In the present review, we revisit molecular evidences showing that deregulated activity of MVA biosynthetic pathway has an essential role in oncogenesis and drug resistance, and the potential use of MVA pathway inhibitors to improve therapeutic window in cancer.
The Effectiveness of Different Treatment Modalities of Cutaneous Angiosarcoma: Results From Meta-Analysis and Observational Data From SEER Database
Authors: Bi Siwei , Chen Shanshan , Wu Beiyi , Cen Ying , Chen Junjie
Published: February 2021

Introduction

Cutaneous angiosarcoma (cAS) is an aggressive vascular tumor that originates from vascular or lymphatic epithelial cells. To date, the cAS literature has been limited in a small number with single-center experiences or reports due to its rarity and the optimal treatment strategy is still in dispute. This study aimed to conduct a systematic review and compare the effect of available treatments retrieved from observational studies and Surveillance, Epidemiology, and End Results (SEER) program.

Methods

The authors performed a systematic review in the PubMed, Embase and MEDLINE database identifying the researches assessing the treatment for cAS patients. Clinical and treatment information of patients who had been diagnosed with a primary cAS were also obtained from the SEER program.

Results

Thirty-two studies were eligible but only 5 of which with 276 patients were included in meta-analysis since the unclear or unavailable information. The risk ratio of 5-year death for surgery, surgery with radiotherapy and surgery with chemotherapy were 0.84, 0.96, and 0.69. Meanwhile, in SEER database, there are 291 metastatic and 437 localized patients with cAS. The localized patients receiving surgery showed a significantly worse overall survival result when compared with the surgery combined with RT: hazard ratio: 1.6, 95% confidential interval: 1.05, 2.42, P = 0.03.

Conclusion

In conclusion, our study provided a detailed picture of the effectiveness of present treatments for localized and metastatic cAS patients. The CT could be inappropriate in localized patients. For metastatic patients, the surgery combined RT was recommended compared with surgery alone since its enhanced OS prognosis. Yet, more novel-designed clinical trials with specific targeted populations and rigorous conducting are needed for a solid conclusion on which would be a better treatment strategy.
Contralateral Lower Neck Sparing Radiotherapy in Stage N1 Nasopharyngeal Carcinoma: Long-Term Survival Outcomes and Late Toxicities
Authors: Sun Zhuang , Wang Jingyun , Huang Runda , Wang Xiaohui , Chen Chunyan , Deng Meiling , Zhao Chong , Wang Hanyu , Han Fei
Published: February 2021

Purpose

To explore the feasibility of contralateral lower neck sparing radiotherapy for patients with stage N1 nasopharyngeal carcinoma (NPC) by analyzing long-term survival outcomes and late toxicities.

Methods

Data of patients with stage N1 NPC who were treated with contralateral lower neck sparing radiotherapy between January 2013 and December 2015 were analyzed. These patients were all staged by magnetic resonance imaging (MRI), and all received irradiation to the upper neck (levels II, III, and Va) bilaterally along with ipsilateral levels IV and Vb, without irradiation of the contralateral lower neck. Treatment outcomes, regional failure patterns, and late toxicities were examined.

Results

A total of 275 eligible patients with stage N1 NPC were included in the present study. The median follow-up period was 62 months (range, 3–93 months). The 5-year overall survival (OS), distant metastasis-free survival (DMFS), local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), locoregional recurrence-free survival (LRRFS), and progression-free survival (PFS) rates were 90.5, 91.3, 94.7, 95.3, 91.2, and 81.7%, respectively. A total of 13 patients (4.7%) developed regional recurrence, all of which occurred in the field and not out of the field. Among 254 patients with available data on late toxicities, the most common late toxicity was xerostomia. No late injuries occurred in the carotid arteries, brachial plexus, or spinal cord. In addition to one case (0.4%) of neck fibrosis and three cases (1.2%) of hearing loss, there were no other grade 3–4 late toxicities observed.

Conclusions

Contralateral lower neck sparing radiotherapy would be safe and feasible for patients with stage N1 NPC, with the potential to improve the long-term quality of life of patients.
Identification and Validation of Ubiquitin-Specific Proteases as a Novel Prognostic Signature for Hepatocellular Carcinoma
Authors: Ni Wenkai , Bian Saiyan , Zhu Mengqi , Song Qianqian , Zhang Jianping , Xiao Mingbing , Zheng Wenjie
Published: February 2021

Purpose

Ubiquitin-specific proteases (USPs), as a sub-family of deubiquitinating enzymes (DUBs), are responsible for the elimination of ubiquitin-triggered modification. USPs are recently correlated with various malignancies. However, the expression features and clinical significance of USPs have not been systematically investigated in hepatocellular carcinoma (HCC).

Methods

Genomic alterations and expression profiles of USPs were investigated in CbioPortal and The Cancer Genome Atlas (TCGA) Liver hepatocellular carcinoma (LIHC) dataset. Cox regression and least absolute shrinkage and selection operator (LASSO) analyses were conducted to establish a risk signature for HCC prognosis in TCGA LIHC cohort. Subsequently, Kaplan-Meier analysis, receiver operating characteristic (ROC) curves and univariate/multivariate analyses were performed to evaluate the prognostic significance of the risk signature in TCGA LIHC and international cancer genome consortium (ICGC) cohorts. Furthermore, we explored the alterations of the signature genes during hepatocarcinogenesis and HCC progression in GSE89377. In addition, the expression feature of USP39 was further explored in HCC tissues by performing western blotting and immunohistochemistry.

Results

Genomic alterations and overexpression of USPs were observed in HCC tissues. The consensus analysis indicated that the USPs-overexpressed sub-Cluster was correlated with aggressive characteristics and poor prognosis. Cox regression with LASSO algorithm identified a risk signature formed by eight USPs for HCC prognosis. High-risk group stratified by the signature score was correlated with advanced tumor stage and poor survival HCC patients in TCGA LIHC cohort. In addition, the 8-USPs based signature could also robustly predict overall survival of HCC patients in ICGC(LIRI-JP) cohort. Furthermore, gene sets enrichment analysis (GSEA) showed that the high-risk score was associated with tumor-related pathways. According to the observation in GSE89377, USP39 expression was dynamically increased with hepatocarcinogenesis and HCC progression. The overexpression of USP39 was further determined in a local HCC cohort and correlated with poor prognosis. The co-concurrence analysis suggested that USP39 might promote HCC by regulating cell-cycle- and proliferation- related genes.

Conclusion

The current study provided a USPs-based signature, highlighting its robust prognostic significance and targeted value for HCC treatment.
The Impact of Epstein-Barr Virus Infection on Epigenetic Regulation of Host Cell Gene Expression in Epithelial and Lymphocytic Malignancies
Authors: Leong Merrin Man Long , Lung Maria Li
Published: February 2021

Epstein-Barr virus (EBV) infection is associated with a variety of malignancies including Burkitt’s lymphoma (BL), Hodgkin’s disease, T cell lymphoma, nasopharyngeal carcinoma (NPC), and ∼10% of cases of gastric cancer (EBVaGC). Disruption of epigenetic regulation in the expression of tumor suppressor genes or oncogenes has been considered as one of the important mechanisms for carcinogenesis. Global hypermethylation is a distinct feature in NPC and EBVaGC, whereas global reduction of H3K27me3 is more prevalent in EBVaGC and EBV-transformed lymphoblastoid cells. In BL, EBV may even usurp the host factors to epigenetically regulate its own viral gene expression to restrict latency and lytic switch, resulting in evasion of immunosurveillance. Furthermore, in BL and EBVaGC, the interaction between the EBV episome and the host genome is evident with respectively unique epigenetic features. While the interaction is associated with suppression of gene expression in BL, the corresponding activity in EBVaGC is linked to activation of gene expression. As EBV establishes a unique latency program in these cancer types, it is possible that EBV utilizes different latency proteins to hijack the epigenetic modulators in the host cells for pathogenesis. Since epigenetic regulation of gene expression is reversible, understanding the precise mechanisms about how EBV dysregulates the epigenetic mechanisms enables us to identify the potential targets for epigenetic therapies. This review summarizes the currently available epigenetic profiles of several well-studied EBV-associated cancers and the relevant distinct mechanisms leading to aberrant epigenetic signatures due to EBV.
Advances in Optical Aptasensors for Early Detection and Diagnosis of Various Cancer Types
Authors: Zahra Qurat ul ain , Khan Qaiser Ali , Luo Zhaofeng
Published: February 2021

Cancer is a life-threatening concern worldwide. Sensitive and early-stage diagnostics of different cancer types can make it possible for patients to get through the best available treatment options to combat this menace. Among several new detection methods, aptamer-based biosensors (aptasensors) have recently shown promising results in terms of sensitivity, identification, or detection of either cancerous cells or the associated biomarkers. In this mini-review, we have summarized the most recent (2016–2020) developments in different approaches belonging to optical aptasensor technologies being widely employed for their simple operation, sensitivity, and early cancer diagnostics. Finally, we shed some light on limitations, advantages, and current challenges of aptasensors in clinical diagnostics, and we elaborated on some future perspectives.
Overexpression of ABCC1 Confers Drug Resistance to Betulin
Authors: Chen Xuan-Yu , Yang Yuqi , Wang Jing-Quan , Wu Zhuo-Xun , Li Jing , Chen Zhe-Sheng
Published: February 2021

Betulin is a lupane-type pentacyclic triterpene, which is isolated from birch bark. It has a broad spectrum of biological and pharmacological properties, such as anti-inflammatory, anti-tumor, anti-viral, and anti-bacterial activity. Herein, we explored the factors that may result in betulin resistance, especially with respect to its interaction with ATP-binding cassette subfamily C member 1 (ABCC1). ABCC1 is an important member of the ATP-binding cassette (ABC) transporter family, which is central to mediating multidrug resistance (MDR) in naturally derived anticancer agents. An MTT-based cell viability assay showed that ABCC1 overexpression has the ability to desensitize both cancer cell line and gene-transfected cell line to betulin and that this betulin-induced resistance can be antagonized by a known ABCC1 inhibitor MK571 at 25 μM. Additionally, betulin upregulates the ABCC1 protein expression level in both concentration-dependent and time-dependent manners, also blocks the transport function mediated by ABCC1. Subsequently, a high affinity score of betulin was achieved in a computational docking analysis, demonstrating a strong interaction of betulin with ABCC1.
Hyperdense Pancreatic Ductal Adenocarcinoma: Clinical Characteristics and Proteomic Landscape
Authors: Xu He , Hua Jie , Meng Qingcai , Wang Xiaohong , Xu Jin , Wang Wei , Zhang Bo , Liu Jiang , Liang Chen , Yu Xianjun , Shi Si
Published: February 2021

Purpose

Hypodensity of pancreatic ductal adenocarcinoma (PDAC) during contrast-enhanced computed tomography (CECT) examination is common, but a minority of PDAC patients exhibit hyperdense images. The present study examined the clinical characteristics and protein landscape of PDAC with hyperdensity.

Materials and Methods

A total of 844 pathologically confirmed PDAC patients who underwent CECT before surgery were included. During the parenchymal phase of CECT, patients were assigned to the hyperdense or hypodense group based on CT values. Clinical and CT characteristics for predicting relapse-free survival (RFS) and overall survival (OS) were analyzed using the Kaplan–Meier method and Cox proportional hazards model. The expression of the tumor angiogenesis marker CD31 and stroma-related protein CTHRC1 were analyzed using immunohistochemistry (IHC) assay to evaluate differences between the two groups. Proteomics was performed to compare the possible mechanisms underlying the differential enhancement on CT scans.

Results

Based on CECT, 43 and 801 PDAC patients had hyperdense and hypodense lesions, respectively. All 43 patients presented a hyperdense lesion in the parenchymal phase. The mean CECT values of the hyperdense group were higher than the hypodense group (102.5 ± 17.4 and 53.7 ± 18.7, respectively, P< 0.001). The hyperdense group had a better prognosis than the hypodense group (median RFS, 19.97 vs. 12.34 months, P = 0.0176; median OS, 33.6 vs. 20.3 months, P = 0.047). Multivariate analysis showed that age, higher CA19-9 levels (> 300 U/ml), tumor stage, tumor differentiation, tumor CT density, and adjuvant chemotherapy were significant independent prognostic factors for OS. CD31 immunohistochemical staining showed that the hyperdense PDACs had a higher microvessel density than the hypodense group (P< 0.001). CTHRC1 expression was higher in the hypodense group (P = 0.019). Sixty-eight differentially expressed proteins were found using the tandem mass tag labeling-based quantification of the proteomes of PDAC tissue samples, and 7 proteins (POFUT1, PKP2, P0DOX4, ITPR1, HBG2, IGLC3, SAA2) were related to angiogenesis.

Conclusion

Patients who presented with a hyperdense mass on CECT had a higher microvessel density and better prognosis. Anti-angiogenic therapy may be suitable for these patients.
The Emerging Landscape of Long Non-Coding RNAs in Colorectal Cancer Metastasis
Authors: Liao Zhiming , Nie Hui , Wang Yutong , Luo Jingjing , Zhou Jianhua , Ou Chunlin
Published: February 2021

Colorectal cancer (CRC) is one of the most common gastrointestinal cancers, with extremely high rates of morbidity and mortality. The main cause of death in CRC is distant metastasis; it affects patient prognosis and survival and is one of the key challenges in the treatment of CRC. Long non-coding RNAs (lncRNAs) are a group of non-coding RNA molecules with more than 200 nucleotides. Abnormal lncRNA expression is closely related to the occurrence and progression of several diseases, including cancer. Recent studies have shown that numerous lncRNAs play pivotal roles in the CRC metastasis, and reversing the expression of these lncRNAs through artificial means can reduce the malignant phenotype of metastatic CRC to some extent. This review summarizes the major mechanisms of lncRNAs in CRC metastasis and proposes lncRNAs as potential therapeutic targets for CRC and molecular markers for early diagnosis.
Conservative Management of Patent Ductus Arteriosus in Preterm Infants—A Systematic Review and Meta-Analyses Assessing Differences in Outcome Measures Between Randomized Controlled Trials and Cohort Studies
Authors: Hundscheid Tim , Jansen Esther J. S. , Onland Wes , Kooi Elisabeth M. W. , Andriessen Peter , de Boode Willem P.
Published: February 2021

Objective: This study aims to evaluate outcome after conservative management (no pharmacological/surgical intervention other than fluid restriction, diuretics, or ventilator adjustments) compared with active (pharmacological and/or surgical) treatment for patent ductus arteriosus (PDA) in preterm infants and analyze differences in outcome between randomized controlled trials (RCTs) and cohort studies.

Study Design: This is a systematic literature review using PubMed, EMBASE, and Cochrane library. RCTs and cohort studies comparing conservative management with active treatment were included. Meta-analysis was used to compare conservative management with any active (pharmacological and/or surgical), any pharmacological (non-prophylactic and prophylactic), and/or surgical treatment for mortality as primary and major neonatal morbidity as secondary outcome measure. Fixed-effect analysis was used, unless heterogeneity (I2) was >50%. Outcome is presented as relative risk (RR) with 95% confidence interval.

Results: Twelve cohort studies and four RCTs were included, encompassing 41,804 and 720 patients, respectively. In cohort studies, conservative management for PDA was associated with a significantly higher risk for mortality (RR, 1.34 [1.12–1.62]) but a significantly lower risk for bronchopulmonary dysplasia (RR, 0.55 [0.46–0.65]), necrotizing enterocolitis (RR, 0.85 [0.77–0.93]), intraventricular hemorrhage (RR, 0.88 [0.83–0.95]), and retinopathy of prematurity (RR, 0.47 [0.28–0.79]) compared with any active PDA treatment. Meta-analysis of the RCTs revealed no significant differences in outcome between conservative management and active treatment.

Conclusion: No differences in mortality or morbidity for conservative management compared with active treatment regimens were observed in RCTs. Findings from cohort studies mainly highlight the lack of high-quality evidence for conservative management for PDA in preterm infants.
Pharmacological Prevention of Neonatal Opioid Withdrawal in a Pregnant Guinea Pig Model
Authors: Safa Alireza , Lau Allison R. , Aten Sydney , Schilling Karl , Bales Karen L. , Miller Victoria A. , Fitzgerald Julie , Chen Min , Hill Kasey , Dzwigalski Kyle , Obrietan Karl , Phelps Mitch A. , Sadee Wolfgang , Oberdick John
Published: February 2021

Newborns exposed to prenatal opioids often experience intense postnatal withdrawal after cessation of the opioid, called neonatal opioid withdrawal syndrome (NOWS), with limited pre- and postnatal therapeutic options available. In a prior study in pregnant mice we demonstrated that the peripherally selective opioid antagonist, 6β-naltrexol (6BN), is a promising drug candidate for preventive prenatal treatment of NOWS, and a therapeutic mechanism was proposed based on preferential delivery of 6BN to fetal brain with relative exclusion from maternal brain. Here, we have developed methadone (MTD) treated pregnant guinea pigs as a physiologically more suitable model, enabling detection of robust spontaneous neonatal withdrawal. Prenatal MTD significantly aggravates two classic maternal separation stress behaviors in newborn guinea pigs: calling (vocalizing) and searching (locomotion) - natural attachment behaviors thought to be controlled by the endogenous opioid system. In addition, prenatal MTD significantly increases the levels of plasma cortisol in newborns, showing that cessation of MTD at birth engages the hypothalamic-pituitary-adrenal (HPA) axis. We find that co-administration of 6BN with MTD prevents these withdrawal symptoms in newborn pups with extreme potency (ID50 ∼0.02 mg/kg), at doses unlikely to induce maternal or fetal withdrawal or to interfere with opioid antinociception based on many prior studies in rodents and non-human primates. Furthermore, we demonstrate a similarly high potency of 6BN in preventing opioid withdrawal in adult guinea pigs (ID50 = 0.01 mg/kg). This high potency appears to run counter to our pharmacokinetic studies showing slow 6BN transit of both the placenta and maternal blood brain barrier in guinea pigs, and calls into question the preferential delivery mechanism. Rather, it suggests a novel receptor mechanism to account for the selectively high potency of 6BN to suppress opioid dependence at all developmental stages, even in adults, as compared to its well-established low potency as a classical opioid antagonist. In conclusion, 6BN is an attractive compound for development of a preventive therapy for NOWS.
Results from a Meta-analysis of Combination of PD-1/PD-L1 and CTLA-4 Inhibitors in Malignant Cancer Patients: Does PD-L1 Matter?
Authors: Feng Yuqian , Jin Huimin , Guo Kaibo , Xiang Yuying , Zhang Yiting , Du Wurong , Shen Minhe , Ruan Shanming
Published: February 2021

Background: Combination therapy with immune checkpoint inhibitors (ICIs) has been widely used for clinical treatment in recent years, which has a better survival benefit. However, not all patients can derive clinical benefit from combination immunotherapy. Therefore, it is necessary to explore the biomarkers of combination immunotherapy.

Methods: We retrieved articles from electronic databases including PubMed, EMBASE and Cochrane. The statistical analysis was performed using RevMan software. Progression free survival (PFS), overall survival (OS) and objective response rate (ORR) were the outcome indicators. In the unselect population, we compared combination therapy with other treatments. In addition, we also conducted subgroup analysis on PFS, OS and ORR according to PD-L1 status.

Results: Seven studies were included in the analysis for a total of 3,515 cases. In the unselected population, we found that combination therapy has longer PFS, OS, and better ORR than other treatments for cancer patients. The longer PFS was showed in PD-L1 ≥ 5% cases (HR = 0.64, 95% CI: 0.56–0.76; p < 0.001) than PD-L1 ≥ 1% cases (HR = 0.72, 95% CI: 0.66–0.79; p < 0.001), while ORR and OS have not related to the status of PD-L1.

Conclusion: This study supported the efficacy of combination therapy with immune checkpoint inhibitors (ICIs), and also showed that PFS in patients with malignant tumors is positively correlated with PD-L1 expression. Due to the limited number of trials included, more high-quality clinical randomized controlled trials should be conducted to confirm the review findings.
Sodium Houttuyfonate Inhibits Bleomycin Induced Pulmonary Fibrosis in Mice
Authors: Shen Yun-hui , Cheng Ming-han , Liu Xin-yu , Zhu De-wei , Gao Jian
Published: February 2021

Pulmonary fibrosis (PF) could severely disrupt the normal lung architecture and function with fatal consequences. Currently, there is no effective treatment for PF or idiopathic pulmonary fibrosis (IPF). The aim of this study was to investigate the effects of Sodium Houttuyfonate (SH) on bleomycin (BLM) induced PF mice model. Our results indicated that SH could attenuate BLM induced lung injury by reducing the inflammation, fibrogenesis and lung/body weight ratio. The proposed mechanisms for the protective effects of SH include: 1) improvement of pulmonary function in BLM mice, for instance, it can elevate the vital capacity (VC), increase the forced expiratory flow at 50% of forced vital capacity (FEF50) and improve other pulmonary function indices; 2) inhibition of collagen formation in BLM mice; 3) attenuation of the elevation of inflammatory cytokines, such as interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α), which are triggered by BLM administration; 4) reduction of the mRNA level and protein production of transforming growth factor-β1 (TGF-β1) in BLM mice. Furthermore, it was found that the protective effects of SH against BLM induced PF in mice was comparable to that of prednisone acetate (PA) tablets, a widely used drug for immunological diseases. Although Houttuynia Cordata Thunb has been widely used in China for lung infection and inflammation, the mechanism has not yet been fully elucidated. Our study provides the evidence that SH is an effective compound against pulmonary injury, irritation and fibrogenesis.
Renormalization of Group Field Theories for Quantum Gravity: New Computations and Some Suggestions
Authors: Finocchiaro Marco , Oriti Daniele
Published: February 2021

We discuss motivation and goals of renormalization analyses of group field theory models of simplicial 4d quantum gravity, and review briefly the status of this research area. We present some new computations of perturbative Group field theories amplitudes, concerning in particular their scaling behavior, and the numerical techniques employed to obtain them. Finally, we suggest a number of research directions for further progress.
Secondary Radiation in Ion Therapy and Theranostics: A Review
Authors: Nandy Maitreyee
Published: February 2021

Ion therapy has emerged as one of the preferred treatment procedures in some selective indication of cancer. The actual dose delivered to the target volume may differ from the planned dose due to wrong positioning of the patient and organ movement during beam delivery. On the other hand, some healthy tissues outside the planned volume may be exposed to radiation dose. It is necessary to determine the primary particle range and the actual exposed volume during irradiation. Many proposed techniques use secondary radiation for the purpose. The secondary radiation consists mainly of neutrons, charged fragments, annihilation photons, among others, and prompt gammas. These are produced through nuclear interaction of the primary beam with the beam line and the patient’s body tissue. Besides its usefulness in characterizing the primary beam, the secondary radiation contributes to the risk of exposure of different tissues. Secondary radiation has significant contribution in theranostics, a comparatively new branch of medicine, which combines diagnosis and therapy. Many authors have made detailed study of the dose delivered to the patient by the secondary radiation and its effects. They have also studied the correlation of secondary charged particles with the beam range and the delivered dose. While these studies have been carried out in great detail in the case of proton and carbon therapy, there are fewer analyses for theranostics. In the present review, a brief account of the studies carried out so far on secondary radiation in ion therapy, its effect, and the role of nuclear reactions is given.
Impact of Ischemic Intra-Conditioning on Power Output and Bar Velocity of the Upper Limbs
Authors: Wilk Michal , Krzysztofik Michal , Jarosz Jakub , Krol Pawel , Leznicka Katarzyna , Zajac Adam , Stastny Petr , Bogdanis Gregory C.
Published: February 2021

This study evaluated the effects of ischemic conditioning on power output and bar velocity in the bench press exercise. Ten healthy males (age: 25 ± 2 years; body mass: 92 ± 8 kg; bench press one repetition maximum −1RM: 145 ± 13 kg), took part in two experimental sessions (with and without ischemia), 1 week apart in random and counterbalanced order. In the ischemic condition, cuffs placed around the upper part of the arms were inflated to 80% of arterial occlusion pressure before each set, while in the control condition there was no blood flow restriction. The exercise protocol included 5 sets of three repetitions each, against a resistance equal to 60% 1RM, with 5 min recovery intervals between sets. There was a main effect of condition for mean power output (MP) and mean bar velocity (MV) (p = 0.01), with overall MP being higher in ischemia than in control by 5.6 ± 4.1% (mean ± 90% compatibility limits), a standardized effect size (ES) of 0.51. Overall MV was also higher by 5.5 ± 4.0%, ES = 0.63. Peak power output (PP) and peak bar velocity (PV) were similar in set 1 of the control and ischemia condition (1039 ± 105 vs. 1054 ± 82 W; 684 ± 74 vs. 696 ± 53 W; 1.09 ± 0.07 vs. 1.12 ± 0.09 m/s; 0.81 ± 0.05 vs. 0.82 ± 0.05 m/s, p = 0.67 to 0.99, mean ± standard deviation). However, from set 3 onward (p = 0.03 to 0.001), PP and PV were higher in ischemia compared with control, with the highest difference observed in set 5 (10.9 ± 5.9%, ES = 0.73 for PP and 8.6 ± 4.6%; ES = 0.89 for PV). These results indicate that ischemia used before each set of the bench press exercise increases power output and bar velocity and this may be used as performance-enhancing stimulus during explosive resistance training.
Vessel Enlargement in Development and Pathophysiology
Authors: Gifre-Renom Laia , Jones Elizabeth A. V.
Published: February 2021

From developmental stages until adulthood, the circulatory system remodels in response to changes in blood flow in order to maintain vascular homeostasis. Remodeling processes can be driven by de novo formation of vessels or angiogenesis, and by the restructuration of already existing vessels, such as vessel enlargement and regression. Notably, vessel enlargement can occur as fast as in few hours in response to changes in flow and pressure. The high plasticity and responsiveness of blood vessels rely on endothelial cells. Changes within the bloodstream, such as increasing shear stress in a narrowing vessel or lowering blood flow in redundant vessels, are sensed by endothelial cells and activate downstream signaling cascades, promoting behavioral changes in the involved cells. This way, endothelial cells can reorganize themselves to restore normal circulation levels within the vessel. However, the dysregulation of such processes can entail severe pathological circumstances with disturbances affecting diverse organs, such as human hereditary telangiectasias. There are different pathways through which endothelial cells react to promote vessel enlargement and mechanisms may differ depending on whether remodeling occurs in the adult or in developmental models. Understanding the molecular mechanisms involved in the fast-adapting processes governing vessel enlargement can open the door to a new set of therapeutical approaches to be applied in occlusive vascular diseases. Therefore, we have outlined here the latest advances in the study of vessel enlargement in physiology and pathology, with a special insight in the pathways involved in its regulation.
Comprehensive Quantitative Proteome Analysis of Aedes aegypti Identifies Proteins and Pathways Involved in Wolbachia pipientis and Zika Virus Interference Phenomenon
Authors: Martins Michele , Ramos Luis Felipe Costa , Murillo Jimmy Rodriguez , Torres André , de Carvalho Stephanie Serafim , Domont Gilberto Barbosa , de Oliveira Danielle Maria Perpétua , Mesquita Rafael Dias , Nogueira Fábio César Sousa , Maciel-de-Freitas Rafael , Junqueira Magno
Published: February 2021

Zika virus (ZIKV) is a global public health emergency due to its association with microcephaly, Guillain-Barré syndrome, neuropathy, and myelitis in children and adults. A total of 87 countries have had evidence of autochthonous mosquito-borne transmission of ZIKV, distributed across four continents, and no antivirus therapy or vaccines are available. Therefore, several strategies have been developed to target the main mosquito vector, Aedes aegypti, to reduce the burden of different arboviruses. Among such strategies, the use of the maternally-inherited endosymbiont Wolbachia pipientis has been applied successfully to reduce virus susceptibility and decrease transmission. However, the mechanisms by which Wolbachia orchestrate resistance to ZIKV infection remain to be elucidated. In this study, we apply isobaric labeling quantitative mass spectrometry (MS)-based proteomics to quantify proteins and identify pathways altered during ZIKV infection; Wolbachia infection; co-infection with Wolbachia/ZIKV in the A. aegypti heads and salivary glands. We show that Wolbachia regulates proteins involved in reactive oxygen species production, regulates humoral immune response, and antioxidant production. The reduction of ZIKV polyprotein in the presence of Wolbachia in mosquitoes was determined by MS and corroborates the idea that Wolbachia helps to block ZIKV infections in A. aegypti. The present study offers a rich resource of data that may help to elucidate mechanisms by which Wolbachia orchestrate resistance to ZIKV infection in A. aegypti, and represents a step further on the development of new targeted methods to detect and quantify ZIKV and Wolbachia directly in complex tissues.
Identification and Characterization of Chalcone Isomerase Genes Involved in Flavonoid Production in Dracaena cambodiana
Authors: Zhu Jiahong , Zhao Wan , Li Rongshuang , Guo Dong , Li Huiliang , Wang Ying , Mei Wenli , Peng Shiqing
Published: February 2021

Dragon’s blood is a traditional medicine in which flavonoids are the main bioactive compounds; however, the underlying formation mechanism of dragon’s blood remains largely poorly understood. Chalcone isomerase (CHI) is the key enzyme in the flavonoid biosynthesis pathway. However, CHI family genes are not well understood in Dracaena cambodiana Pierre ex Gagnep, an important source plant of dragon’s blood. In this study, 11 CHI family genes were identified from D. cambodiana, and they were classified into three types. Evolutionary and transcriptional profiling analysis revealed that DcCHI1 and DcCHI4 might be involved in flavonoid production. Both DcCHI1 and DcCHI4 displayed low expression levels in stem under normal growth conditions and were induced by methyl jasmonate (MeJA), 6-benzyl aminopurine (6-BA, synthetic cytokinin), ultraviolet-B (UV-B), and wounding. The recombinant proteins DcCHI1 and DcCHI4 were expressed in Escherichia coli and purified by His-Bind resin chromatography. Enzyme activity assay indicated that DcCHI1 catalyzed the formation of naringenin from naringenin chalcone, while DcCHI4 lacked this catalytic activity. Overexpression of DcCHI1 or DcCHI4 enhanced the flavonoid production in D. cambodiana and tobacco. These findings implied that DcCHI1 and DcCHI4 play important roles in flavonoid production. Thus, our study will not only contribute to better understand the function and expression regulation of CHI family genes involved in flavonoid production in D. cambodiana but also lay the foundation for developing the effective inducer of dragon’s blood.
The Epigenetic Faces of ULTRAPETALA1
Authors: Ornelas-Ayala Diego , Garay-Arroyo Adriana , García-Ponce Berenice , R. Álvarez-Buylla Elena , Sanchez María de la Paz
Published: February 2021

ULTRAPETALA1 (ULT1) is a versatile plant-exclusive protein, initially described as a trithorax group (TrxG) factor that regulates transcriptional activation and counteracts polycomb group (PcG) repressor function. As part of TrxG, ULT1 interacts with ARABIDOPSIS TRITHORAX1 (ATX1) to regulate H3K4me3 activation mark deposition. However, our recent studies indicate that ULT1 can also act independently of ATX1. Moreover, the ULT1 ability to interact with transcription factors (TFs) and PcG proteins indicates that it is a versatile protein with other roles. Therefore, in this work we revised recent information about the function of Arabidopsis ULT1 to understand the roles of ULT1 in plant development. Furthermore, we discuss the molecular mechanisms of ULT1, highlighting its epigenetic role, in which ULT1 seems to have characteristics of an epigenetic molecular switch that regulates repression and activation processes via TrxG and PcG complexes.
A Practice-Inspired Mindset for Researching the Psychophysiological and Medical Health Effects of Recreational Dance (Dance Sport)
Authors: Christensen Julia F. , Vartanian Meghedi , Sancho-Escanero Luisa , Khorsandi Shahrzad , Yazdi S. H. N. , Farahi Fahimeh , Borhani Khatereh , Gomila Antoni
Published: February 2021

“Dance” has been associated with many psychophysiological and medical health effects. However, varying definitions of what constitute “dance” have led to a rather heterogenous body of evidence about such potential effects, leaving the picture piecemeal at best. It remains unclear what exact parameters may be driving positive effects. We believe that this heterogeneity of evidence is partly due to a lack of a clear definition of dance for such empirical purposes. A differentiation is needed between (a) the effects on the individual when the activity of “dancing” is enjoyedas a dancerwithindifferent dance domains(e.g.,professional/”high-art”type of dance,eroticdance,religiousdance,clubdancing,Dance Movement Therapy(DMT), and what is commonly known ashobby, recreationalorsocialdance), and (b) the effects on the individual within these different domains, as a dancer of thedifferent dance styles(solo dance, partnering dance, group dance; and all the different styles within these). Another separate category of dance engagement is, not as a dancer, but as a spectator of all of the above. “Watching dance” as part of an audience has its own set of psychophysiological and neurocognitive effects on the individual, and depends on the context where dance is witnessed. With the help of dance professionals, we first outline some different dance domains and dance styles, and outline aspects that differentiate them, and that may, therefore, cause differential empirical findings when compared regardless (e.g., amount of interpersonal contact, physical exertion, context, cognitive demand, type of movements, complexity of technique and ratio of choreography/improvisation). Then, we outline commonalities between all dance styles. We identify six basic components that are part of any dance practice, as part of a continuum, and review and discuss available research for each of them concerning the possible health and wellbeing effects of each of these components, and how they may relate to the psychophysiological and health effects that are reported for “dancing”: (1) rhythm and music, (2) sociality, (3) technique and fitness, (4) connection and connectedness (self-intimation), (5) flow and mindfulness, (6) aesthetic emotions and imagination. Future research efforts might take into account the important differences between types of dance activities, as well as the six components, for a more targeted assessment of how “dancing” affects the human body.
The Co-occurrence of Self-Harm and Aggression: A Cognitive-Emotional Model of Dual-Harm
Authors: Shafti Matina , Taylor Peter James , Forrester Andrew , Pratt Daniel
Published: February 2021

There is growing evidence that some individuals engage in both self-harm and aggression during the course of their lifetime. The co-occurrence of self-harm and aggression is termed dual-harm. Individuals who engage in dual-harm may represent a high-risk group with unique characteristics and pattern of harmful behaviours. Nevertheless, there is an absence of clinical guidelines for the treatment and prevention of dual-harm and a lack of agreed theoretical framework that accounts for why people may engage in this behaviour. The present work aimed to address this gap in the literature by providing a narrative review of previous research of self-harm, aggression and dual-harm, and through doing so, presenting an evidence-based theory of dual-harm – the cognitive-emotional model of dual-harm. This model draws from previous studies and theories, including the General Aggression Model, diathesis-stress models and emotional dysregulation theories. The cognitive-emotional model highlights the potential distal, proximal and feedback processes of dual-harm, the role of personality style and the possible emotional regulation and interpersonal functions of this behaviour. In line with our theory, various clinical and research implications for dual-harm are suggested, including hypotheses to be tested by future studies.
Traditional Games as Cultural Heritage: The Case of Canary Islands (Spain) From an Ethnomotor Perspective
Authors: Luchoro-Parrilla Rafael , Lavega-Burgués Pere , Damian-Silva Sabrine , Prat Queralt , Sáez de Ocáriz Unai , Ormo-Ribes Enric , Pic Miguel
Published: February 2021

UNESCO in the 2030 agenda for sustainable development establishes respect for the environment and sustainability education as key elements for the challenges of society in the coming years. In the educational context, physical education can have a vital role in sustainability education, through Traditional Sporting Games (TSG). The aim of this research was to study from an ethnomotor perspective the different characteristics of two different groups of TSG (with and without objects) in the Canary Islands, Spain. The corpus of this investigation was made up of 513 TSG, identified by two analysis techniques and collected in a database. The categories corresponding to the variables of the internal logic of the game were the type of motor interaction, related to space, relationships with time (competition), and relationships with objects. The study also examined the variables of external logic or sociocultural conditions such as the protagonists, playing areas, and game moments. The data analysis was carried out using descriptive and inferential statistics: cross-tables, effect sizes, classification trees (CHAID), and the identification of frequency areas. Of the total number of playful activities identified (n = 664), most were physical activities (n = 513/664; 77.26%) (non-physical activities: n = 151/664; 22.74%). These activities were Quasi-games without rules (n = 87) and TSG (n = 426) as well as activities with Objects (n = 299) and without material (n = 214). This research confirms that the TSG in the Canary Islands is a mirror of traditional culture and, from a pedagogical approach, shows great potential for material and social sustainability.