bluuebunny/crossref_metadata_2025 huggingface dataset:
Nomogram Predicting Cancer-Specific Death in Parotid Carcinoma: a Competing Risk Analysis
Authors: Li Xiancai , Hu Mingbin , Gu Weiguo , Liu Dewu , Mei Jinhong , Chen Shaoqing
Published: October 2021

Purpose

Multiple factors have been shown to be tied to the prognosis of individuals with parotid cancer (PC); however, there are limited numbers of reliable as well as straightforward tools available for clinical estimation of individualized mortality. Here, a competing risk nomogram was established to assess the risk of cancer-specific deaths (CSD) in individuals with PC.

Methods

Data of PC patients analyzed in this work were retrieved from the Surveillance, Epidemiology, and End Results (SEER) data repository and the First Affiliated Hospital of Nanchang University (China). Univariate Lasso regression coupled with multivariate Cox assessments were adopted to explore the predictive factors influencing CSD. The cumulative incidence function (CIF) coupled with the Fine-Gray proportional hazards model was employed to determine the risk indicators tied to CSD as per the univariate, as well as multivariate analyses conducted in the R software. Finally, we created and validated a nomogram to forecast the 3- and 5-year CSD likelihood.

Results

Overall, 1,467 PC patients were identified from the SEER data repository, with the 3- and 5-year CSD CIF after diagnosis being 21.4% and 24.1%, respectively. The univariate along with the Lasso regression data revealed that nine independent risk factors were tied to CSD in the test dataset (n = 1,035) retrieved from the SEER data repository. Additionally, multivariate data of Fine-Gray proportional subdistribution hazards model illustrated that N stage, Age, T stage, Histologic, M stage, grade, surgery, and radiation were independent risk factors influencing CSD in an individual with PC in the test dataset (p < 0.05). Based on optimization performed using the Bayesian information criterion (BIC), six variables were incorporated in the prognostic nomogram. In the internal SEER data repository verification dataset (n = 432) and the external medical center verification dataset (n = 473), our nomogram was well calibrated and exhibited considerable estimation efficiency.

Conclusion

The competing risk nomogram presented here can be used for assessing cancer-specific mortality in PC patients.
Clinical Efficacy and Safety of Proton and Carbon Ion Radiotherapy for Prostate Cancer: A Systematic Review and Meta-Analysis
Authors: Li Meixuan , Li Xiuxia , Yao Liang , Han Xue , Yan Wenlong , Liu Yujun , Fu Yiwen , Wang Yakun , Huang Min , Zhang Qiuning , Wang Xiaohu , Yang Kehu
Published: October 2021

Background

Carbon ion radiotherapy (CIRT) and proton beam therapy (PBT) are promising methods for prostate cancer, however, the consensus of an increasing number of studies has not been reached. We aimed to provide systematic evidence for evaluating the efficacy and safety of CIRT and PBT for prostate cancer by comparing photon radiotherapy.

Materials and Methods

We searched for studies focusing on CIRT and PBT for prostate cancer in four online databases until July 2021. Two independent reviewers assessed the quality of included studies and used the GRADE approach to rate the quality of evidence. R 4.0.2 software was used to conduct the meta-analysis. A meta-regression test was performed based on the study design and tumor stage of each study.

Results

A total of 33 studies including 13 CIRT- and 20 PBT-related publications, involving 54,101, participants were included. The quality of the included studies was found to be either low or moderate quality. Random model single-arm meta-analysis showed that both the CIRT and PBT have favorable efficacy and safety, with similar 5-year overall survival (OS) (94 vs 92%), the incidence of grade 2 or greater acute genitourinary (AGU) toxicity (5 vs 13%), late genitourinary (LGU) toxicity (4 vs 5%), acute gastrointestinal (AGI) toxicity (1 vs 1%), and late gastrointestinal (LGI) toxicity (2 vs 4%). However, compared with CIRT and PBT, photon radiotherapy was associated with lower 5-year OS (72–73%) and a higher incidence of grade 2 or greater AGU (28–29%), LGU (13–14%), AGI (14–19%), and LGI toxicity (8–10%). The meta-analysis showed the 3-, 4-, and 5-year local control rate (LCR) of CIRT for prostate cancer was 98, 97, and 99%; the 3-, 4-, 5-, and 8-year biochemical relapse-free rate (BRF) was 92, 91, 89, and 79%. GRADE assessment results indicated that the certainty of the evidence was very low. Meta-regression results did not show a significant relationship based on the variables studied (P<0.05).

Conclusions

Currently available evidence demonstrated that the efficacy and safety of CIRT and PBT for prostate cancer were similar, and they may significantly improve the OS, LCR, and reduce the incidence of GU and GI toxicity compared with photon radiotherapy. However, the quantity and quality of the available evidence are insufficient. More high-quality controlled studies are needed in the future.
Chemical Synthesis of the PAX Protein Inhibitor EG1 and Its Ability to Slow the Growth of Human Colorectal Carcinoma Cells
Authors: McDougall Lorissa , Kueh Jui Thiang Brian , Ward Jake , Tyndall Joel D. A. , Woolley Adele G. , Mehta Sunali , Stayner Cherie , Larsen David S. , Eccles Michael R.
Published: October 2021

Colorectal cancer is primarily a disease of the developed world. The incidence rate has continued to increase over time, reflecting both demographic and lifestyle changes, which have resulted in genomic and epigenomic modifications. Many of the epigenetic modifications occur in genes known to be closely associated with embryonic development and cellular growth. In particular, the paired box (PAX) transcription factors are crucial for correct tissue development during embryogenesis due to their role in regulating genes involved in proliferation and cellular maintenance. In a number of cancers, including colorectal cancer, the PAX transcription factors are aberrantly expressed, driving proliferation and thus increased tumour growth. Here we have synthesized and used a small molecule PAX inhibitor, EG1, to inhibit PAX transcription factors in HCT116 colorectal cell cultures which resulted in reduced proliferation after three days of treatment. These results highlight PAX transcription factors as playing an important role in the proliferation of HCT116 colorectal cancer cells, suggesting there may be a potential therapeutic role for inhibition of PAX in limiting cancer cell growth.
Runt-Related Transcription Factor 3 Promotes Acute Myeloid Leukemia Progression
Authors: Zhang Wenwen , Ma Qian , Long Bing , Sun Zhangyi , Liu Lingling , Lin Dongjun , Zhao Minyi
Published: October 2021

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with high relapse/refractory rate. Genetic and epigenetic abnormalities are driving factors for leukemogenesis. RUNX1 and RUNX2 from the Runt-related transcription factor (RUNX) family played important roles in AML pathogenesis. However, the relationship between RUNX3 and AML remains unclear. Here, we found that RUNX3 was a super-enhancer-associated gene and highly expressed in AML cells. The Cancer Genome Atlas (TCGA) database showed high expression of RUNX3 correlated with poor prognosis of AML patients. We observed that Runx3 knockdown significantly inhibited leukemia progression by inducing DNA damage to enhance apoptosis in murine AML cells. By chromatin immunoprecipitation sequencing (ChIP-seq) analysis, we discovered that RUNX3 in AML cells mainly bound more genes involved in DNA-damage repair and antiapoptosis pathways compared to that in normal bone marrow cells. Runx3 knockdown obviously inhibited the expression of these genes in AML cells. Overall, we identified RUNX3 as an oncogene overexpressed in AML cells, and Runx3 knockdown suppressed AML progression by inducing DNA damage and apoptosis.
NK Cells in the Tumor Microenvironment as New Potential Players Mediating Chemotherapy Effects in Metastatic Melanoma
Authors: Garofalo Cinzia , De Marco Carmela , Cristiani Costanza Maria
Published: October 2021

Until the last decade, chemotherapy was the standard treatment for metastatic cutaneous melanoma, even with poor results. The introduction of immune checkpoints inhibitors (ICIs) radically changed the outcome, increasing 5-year survival from 5% to 60%. However, there is still a large portion of unresponsive patients that would need further therapies. NK cells are skin-resident innate cytotoxic lymphocytes that recognize and kill virus-infected as well as cancer cells thanks to a balance between inhibitory and activating signals delivered by surface molecules expressed by the target. Since NK cells are equipped with cytotoxic machinery but lack of antigen restriction and needing to be primed, they are nowadays gaining attention as an alternative to T cells to be exploited in immunotherapy. However, their usage suffers of the same limitations reported for T cells, that is the loss of immunogenicity by target cells and the difficulty to penetrate and be activated in the suppressive tumor microenvironment (TME). Several evidence showed that chemotherapy used in metastatic melanoma therapy possess immunomodulatory properties that may restore NK cells functions within TME. Here, we will discuss the capability of such chemotherapeutics to: i) up-regulate melanoma cells susceptibility to NK cell-mediated killing, ii) promote NK cells infiltration within TME, iii) target other immune cell subsets that affect NK cells activities. Alongside traditional systemic melanoma chemotherapy, a new pharmacological strategy based on nanocarriers loaded with chemotherapeutics is developing. The use of nanotechnologies represents a very promising approach to improve drug tolerability and effectiveness thanks to the targeted delivery of the therapeutic molecules. Here, we will also discuss the recent developments in using nanocarriers to deliver anti-cancer drugs within the melanoma microenvironment in order to improve chemotherapeutics effects. Overall, we highlight the possibility to use standard chemotherapeutics, possibly delivered by nanosystems, to enhance NK cells anti-tumor cytotoxicity. Combined with immunotherapies targeting NK cells, this may represent a valuable alternative approach to treat those patients that do not respond to current ICIs.
Cabozantinib for HCC Treatment, From Clinical Back to Experimental Models
Authors: Deng Shanshan , Solinas Antonio , Calvisi Diego F.
Published: October 2021

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related mortality worldwide. Patients with early-stage HCC can be treated successfully with surgical resection or liver transplantation. However, the usual late diagnosis of HCC precludes curative treatments, and systemic therapies are the only viable option for inoperable patients. Sorafenib, an orally available multikinase inhibitor, is a systemic therapy approved for treating patients with advanced HCC yet providing limited benefits. Consequently, new drugs have been developed to overcome sorafenib resistance and improve patients’ prognoses. A new promising strategy is using c-MET inhibitors, such as cabozantinib, as activation of c-MET occurs in up to 40% of HCC patients. In particular, cabozantinib, in combination with the checkpoint inhibitor atezolizumab, is currently in phase 3 clinical trial for HCC, and the results are eagerly awaited. Herein, we summarize and review the drugs approved for the treatment of advanced HCC, mainly focusing on the clinical and preclinical efficacy evaluation of cabozantinib. Also, we report the available preclinical data on cabozantinib-based combination therapies for HCC, current obstacles for cabozantinib therapy, and the future directions for cabozantinib-based treatment for HCC.
Does My Neck Make Me Clumsy? A Systematic Review of Clinical and Neurophysiological Studies in Humans
Authors: Harman Samantha C. , Zheng Zhen , Kendall Julie C. , Vindigni Dein , Polus Barbara I.
Published: October 2021

Introduction:Clumsiness has been described as a symptom associated with neck pain and injury. However, the actuality of this symptom in clinical practice is unclear. The aim of this investigation was to collect definitions and frequency of reports of clumsiness in clinical studies of neck pain/injury, identify objective measures of clumsiness and investigate the association between the neck and objective measures of clumsiness.

Methods:Six electronic databases were systematically searched, records identified and assessed including a risk of bias. Heterogeneity in designs of studies prevented pooling of data, so qualitative analysis was undertaken.

Results:Eighteen studies were retrieved and assessed; the overall quality of evidence was moderate to high. Eight were prospective cross-sectional studies comparing upper limb sensorimotor task performance and ten were case series involving a healthy cohort only. Clumsiness was defined as a deficit in coordination or impairment of upper limb kinesthesia. All but one of 18 studies found a deterioration in performing upper limb kinesthetic tasks including a healthy cohort where participants were exposed to a natural neck intervention that required the neck to function toward extreme limits.

Conclusion:Alterations in neck sensory input occurring as a result of requiring the neck to operate near the end of its functional range in healthy people and in patients with neck pain/injury are associated with reductions in acuity of upper limb kinesthetic sense and deterioration in sensorimotor performance. Understanding the association between the neck and decreased accuracy of upper limb kinesthetic tasks provide pathways for treatment and rehabilitation strategies in managing clumsiness.
Roles of Surgery in the Treatment of Patients With High-Risk Neuroblastoma in the Children Oncology Group Study: A Systematic Review and Meta-Analysis
Authors: Qi Yingyi , Zhan Jianghua
Published: October 2021

Purpose: Neuroblastoma is the most common extracranial solid tumor in children, and most patients are at high risk when they are initially diagnosed. The roles of surgery and induction chemotherapy in patients with high-risk neuroblastoma have been a subject of much controversy and debate. The objective of the current study was to assess the roles of surgery in high-risk neuroblastoma.

Method: The review protocol was prospectively registered (PROSPEROID: CRD42021253961). The PubMed, Embase, Cochrane, and CNKI databases were searched from inception to January 2020 with no restrictions on language or publication date. Clinical studies comparing the outcomes of different surgical ranges for the treatment of high-risk neuroblastoma were analyzed. The Mantel–Haenszel method and a random effects model was utilized to calculate the hazard ratio (95% CI).

Results: Fourteen studies that assessed 1,915 subjects met the full inclusion criteria. Compared with the gross tumor resection (GTR) group, complete tumor resection (CTR) did not significantly improve the 5-year EFS [p = 1.0; HR = 0.95 (95% CI, 0.87–1.05); I2 = 0%], and the 5-year OS [p = 0.76; HR = 1.08 (95% CI, 0.80–1.46); I2 = 0%] of patients. GTR or CTR resection had significantly better 5-year OS [p = 0.45; HR = 0.56 (95% CI, 0.43–0.72); I2 = 0%] and 5-year EFS [p = 0.15; HR = 0.80 (95% CI, 0.71–0.90); I2 = 31%] than subtotal tumor resection (STR) or biopsy only; however, both CTR or GTR showed a trend for more intra and post-operative complications compared with the STR or biopsy only [p = 0.37; OR = 1.54 (95% CI, 1.08–2.20); I2 = 0%]. The EFS of the patients who underwent GTR or CTR at the time of diagnosis and after induction chemotherapy were similar [p = 0.24; HR = 1.53 (95% CI, 0.84–2.77); I2 = 29%].

Conclusion: For patients with high-risk neuroblastoma, complete tumor resection and gross tumor resection of the primary tumor were related to improved survival, with very limited effects on reducing intraoperative and postoperative complications. It is necessary to design strong chemotherapy regimens to improve the survival rate of advanced patients.

Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/, PROSPEROID [CRD42021253961].
Cardiotoxicity in Biological Agent-Targeted Therapy for Rheumatoid Arthritis: ADR Signal Mining and Analysis of Food and Drug Administration Adverse Event Reporting System Database
Authors: Tang Xiaoyan , Xu Xiaolin , Li Ji , Zhao Bin
Published: October 2021

Purpose: Biologic agent-induced cardiotoxicity is markedly concerning. Rheumatoid arthritis (RA) treated with biologic agents is known to have the potential for cardiotoxicity; however, existing clinical evidence is not adequate to explain real-world patterns of cardiotoxicity. In this study, we quantify the risk of cardiotoxicity in patients with rheumatoid arthritis treated with biological agents.

Methods: Cardiotoxicity reports induced by four types of biologic agents, abatacept, adalimumab, tocilizumab, and etanercept were used to mine data from the FDA's adverse event reporting system (FAERS) database from January 1, 2004 through September 30, 2020. Reports of cardiotoxic events were analyzed using a reporting odds ratio (ROR) algorithm, the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), the multi-item gamma Poisson shrinker (MGPS), and logistic regression methods. We use the preferred term of the Medical Dictionary of Regulatory Activities to identify such events.

Results: A total of 3,969 reports of cardiotoxic events were identified involving biologic agents used for RA as the suspect drugs in this study, 317 reports of abatacept, 2,137 reports of adalimumab, 273 reports of tocilizumab, and 1,242 reports of etanercept. Adalimumab was the most reported, followed by etanercept. The proportion of death and disability outcomes reported for each targeted treatment represents approximately 20–25% of the total reported severe adverse events. In addition, relatively low cardiotoxicity reporting rates were found with abatacept.

Conclusion: Analysis of FAERS data offers a more precise profile on the characteristics and occurrences of cardiotoxic events. The findings are a clinical reminder to physicians that an increased vigilance concerning the cardiotoxic effects of biological agents needs to be implemented. Also, more comparative studies are required in the future to explain the mechanisms that cause these cardiac phenomena.
The Physical Fitness Level of College Students Before and After Web-Based Physical Education During the COVID-19 Pandemic
Authors: Xia Wei , Huang Cai-hong , Guo Yu , Guo Min-gang , Hu Ming , Dai Jian , Deng Cheng-hu
Published: October 2021

Background: The COVID-19 pandemic has been an emergency worldwide. Web-based physical education is a choice for college students to keep on their study. The aim of this study was to compare the data of physical fitness of college students before and after web-based physical education.

Methods: All the students of 2018 and 2019 in Wuhan University of Technology who had taken the web-based physical education class in 2020 were included in this study. The records of annual physical fitness tests of all the subjects in 2019 and 2020 which were carried out in September were reviewed, including weight, height, body mass index (BMI), vital capacity (VC), 50-m dash, sit-and-reach, standing long jump, male-specific pull-ups and 1,000-m race, and female-specific sit-ups and 800-m race.

Results: There were 24,112 male and 9,690 female records of physical fitness tests included in our study. The results of 11,219 male and 4,651 female students who completed both physical fitness tests in 2019 and 2020 were employed for Wilcoxon signed-rank test. Declined performance was observed on male 50-m dash by 0.1 s, male 1,000-m race by 14 s, and female 800-m race by 11 s. Notably, the percentage of male obesity, based on BMI, rose from 10.6 to 15.2% and 17.1 to 21.8% for male overweight; correspondingly, the percentage of male normal weight declined from 55.9 to 51.9% and 16.4 to 11.1% for male thinness. The trend of increasing BMI in males should be paid attention to. Improved results on vital capacity, sit-and-reach, standing long jump for both males and females, female 50-m dash, female sit-ups, and male pull-ups were observed in 2020. All the results of physical fitness tests were significantly different between 2019 and 2020 (p < 0.01) by Wilcoxon signed-rank test.

Conclusions: The changes of physical fitness tests before and after web-based physical education suggested that the focus should be placed on improvement for running tests through appropriate alternatives, such as fast running in place and shuttle run. In addition, the simple, convenient, and practical sport that require available equipment and little field should be considered for web-based physical education.
Diagnosis and Treatment of Small Vessel Childhood Primary Angiitis of the Central Nervous System (sv-cPACNS): An International Survey
Authors: Keenan Paul , Brunner Jürgen , Quan Angela S. , Smitka Martin , Hahn Gabriele , Pain Clare E. , Häfner Renate , Speth Fabian , Gerstl Lucia , Hedrich Christian M.
Published: October 2021

Childhood primary angiitis of the Central Nervous System (cPACNS) is a rare autoimmune and inflammatory disease. It can result in significant neuronal damage, neurodevelopmental delay and potentially death. Childhood PACNS is divided into subcategories: angiography-positive p-cPACNS that affects medium and large vessels, and angiography-negative small vessel sv-cPACNS. Due to its rarity, variable clinical representation, and the lack of a diagnostic criteria and therapeutic plans, diagnosis and treatment of cPACNS is challenging and approaches vary. This survey collected information on diagnostic and therapeutic approaches to sv-PACNS. It was shared with international clinician networks, including the German Society for Paediatric Rheumatology, the Paediatric Rheumatology European Society, the “Network Paediatric Stroke,” and members of the American College of Rheumatology/CARRA Paediatric Rheumatology list server. This project has shown consensus in numerous diagnostic and therapeutic treatment approaches, highlighting key areas which will be utilised to develop statements in the use of expert consensus meetings to standardise diagnostic and therapeutic approaches in this rare inflammatory disease.
The Extent and Impact of Variation in ADME Genes in Sub-Saharan African Populations
Authors: da Rocha Jorge E. B. , Othman Houcemeddine , Botha Gerrit , Cottino Laura , Twesigomwe David , Ahmed Samah , Drögemöller Britt I. , Fadlelmola Faisal M. , Machanick Philip , Mbiyavanga Mamana , Panji Sumir , Wright Galen E. B. , Adebamowo Clement , Matshaba Mogomotsi , Ramsay Michéle , Simo Gustave , Simuunza Martin C. , Tiemessen Caroline T. , Baldwin Sandra , Chiano Mathias , Cox Charles , Gross Annette S. , Thomas Pamela , Gamo Francisco-Javier , Hazelhurst Scott
Published: October 2021

Introduction: Investigating variation in genes involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs are key to characterizing pharmacogenomic (PGx) relationships. ADME gene variation is relatively well characterized in European and Asian populations, but data from African populations are under-studied—which has implications for drug safety and effective use in Africa.

Results: We identified significant ADME gene variation in African populations using data from 458 high-coverage whole genome sequences, 412 of which are novel, and from previously available African sequences from the 1,000 Genomes Project. ADME variation was not uniform across African populations, particularly within high impact coding variation. Copy number variation was detected in 116 ADME genes, with equal ratios of duplications/deletions. We identified 930 potential high impact coding variants, of which most are discrete to a single African population cluster. Large frequency differences (i.e., >10%) were seen in common high impact variants between clusters. Several novel variants are predicted to have a significant impact on protein structure, but additional functional work is needed to confirm the outcome of these for PGx use. Most variants of known clinical outcome are rare in Africa compared to European populations, potentially reflecting a clinical PGx research bias to European populations.

Discussion: The genetic diversity of ADME genes across sub-Saharan African populations is large. The Southern African population cluster is most distinct from that of far West Africa. PGx strategies based on European variants will be of limited use in African populations. Although established variants are important, PGx must take into account the full range of African variation. This work urges further characterization of variants in African populations including in vitro and in silico studies, and to consider the unique African ADME landscape when developing precision medicine guidelines and tools for African populations.
Anti-Inflammatory and Antimicrobial Volatile Oils: Fennel and Cumin Inhibit Neutrophilic Inflammation via Regulating Calcium and MAPKs
Authors: Korinek Michal , Handoussa Heba , Tsai Yi-Hong , Chen You-Ying , Chen Meng-Hua , Chiou Zan-Wei , Fang Yu , Chang Fang-Rong , Yen Chia-Hung , Hsieh Chung-Fan , Chen Bing-Hung , El-Shazly Mohamed , Hwang Tsong-Long
Published: October 2021

Neutrophilic inflammatory diseases, such as chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), or psoriasis, exert a huge burden on the global health system due to the lack of safe and effective treatments. Volatile oils from terrestrial plants showed impressive therapeutic effects against disorders of the skin, digestive system, lungs, liver, metabolism, and nervous system. However, their effect on the immune system and neutrophil function is still elusive. Fennel, cumin, marjoram, lavender, caraway, and anise are the common nutraceuticals that are widely used in the Mediterranean diet. The volatile oils of these herbs were screened for various biological activities, including anti-inflammatory, anti-allergic, antimicrobial, and antiviral effects. Several oils showed anti-inflammatory and antimicrobial potential. Fennel (Foeniculum vulgare) and cumin (Cuminum cyminum) fruits' volatile oils significantly suppressed the activation of human neutrophils, including respiratory burst and the degranulation induced by formyl peptide receptor agonists fMLF/CB and MMK1 in the human neutrophils (IC50, 3.8–17.2 µg/ml). The cytotoxic effect and free-radical scavenging effects (ABTS, DPPH) of these oils did not account for the observed effects. Both fennel and cumin volatile oils significantly shortened calcium influx recovery time and inhibited phosphorylation of mitogen-activated protein kinases (p38, JNK, and ERK) expression. The gas chromatography–mass spectrometry analysis of these oils revealed the presence of estragole and cuminaldehyde as the major components of fennel and cumin volatile oils, respectively. Our findings suggested that cumin and fennel, common in the Mediterranean diet, hold the potential to be applied for the treatment of neutrophilic inflammatory diseases.
Blood Immune Cell Composition Associated with Obesity and Drug Repositioning Revealed by Epigenetic and Transcriptomic Conjoint Analysis
Authors: Liu Jia-Chen , Liu Sheng-Hua , Fu Guang , Qiu Xiao-Rui , Jiang Run-Dong , Huang Sheng-Yuan , Zhu Li-Yong , Li Wei-Zheng
Published: October 2021

This research was designed to analyze the composition of immune cells in obesity and identify novel and potent drugs for obesity management by epigenetic and transcriptomic conjoint analysis. DNA methylation data set (GSE166611) and mRNA expression microarray (GSE18897) were obtained from the Gene Expression Omnibus database. A total of 72 objects (35 obese samples and 37 controls) were included in the study. Immune cell composition analysis, drug repositioning, and gene set enrichment analysis (GSEA) were performed using CIBERSORT, connectivity map (CMap), and GSEA tools. Besides, we performed a single-cell RNA-seq of the immune cells from whole blood samples obtained from one obese patient and one healthy control. mRNA levels of drug target genes were analyzed by qPCR assay in blood samples from six patients and six healthy controls. Immune cell composition analysis found that CD8 + T cells and NK cells were significantly lower in the obese group. 11 drugs/compounds are considered to possess obesity-control potential, such as atorvastatin. Moreover, the expression of drug targets (STAT3, MCL1, PMAIP1, SOD2, FOX O 3, FOS, FKBP5) in obese patients were higher than those in controls. In conclusion, immune cells are potential therapeutic targets for obesity. Our results also contribute to accelerate research on drug development of obesity.
Riclinoctaose Attenuates Renal Ischemia-Reperfusion Injury by the Regulation of Macrophage Polarization
Authors: Zhao Yang , Ding Zhao , Ge Wenhao , Liu Junhao , Xu Xi , Cheng Rui , Zhang Jianfa
Published: October 2021

Renal ischemia-reperfusion injury is a major trigger of acute kidney injury and leads to permanent renal impairment, and effective therapies remain unresolved. Riclinoctaose is an immunomodulatory octasaccharide composed of glucose and galactose monomers. Here we investigated whether riclinoctaose protects against renal ischemia-reperfusion injury. In mice, pretreatment with riclinoctaose significantly improved renal function, structure, and the inflammatory response after renal ischemia-reperfusion. Flow cytometry analysis revealed that riclinoctaose inhibited ischemia-reperfusion-induced M1 macrophage polarization and facilitated M2 macrophage recruitment into the kidneys. In isolated mouse bone marrow-derived macrophages, pretreatment with riclinoctaose promoted the macrophage polarization toward M2-like phenotype. The inhibitor of Nrf-2/HO-1 brusatol diminished the effects of riclinoctaose on macrophage polarization. In mice, intravenous injection with riclinoctaose-pretreated bone marrow-derived macrophages also protected against renal ischemia-reperfusion injury. Fluorescence-labeled riclinoctaose specifically bound to the membrane of macrophages. Interfering with mDC-SIGN blocked the riclinoctaose function on M2 polarization of macrophages, consequently impairing the renoprotective effect of riclinoctaose. Our results revealed that riclinoctaose is a potential therapeutic agent in preventing renal ischemia-reperfusion injury.
Ginsenoside Rb1 Ameliorates Diabetic Arterial Stiffening via AMPK Pathway
Authors: Zhang Xinyu , Wang Lei , Guo Rong , Xiao Jie , Liu Xiaoling , Dong Mei , Luan Xiaorong , Ji Xiaoping , Lu Huixia
Published: October 2021

Background and Purpose: Macrovascular complication of diabetes mellitus, characterized by increased aortic stiffness, is a major cause leading to many adverse clinical outcomes. It has been reported that ginsenoside Rb1 (Rb1) can improve glucose tolerance, enhance insulin activity, and restore the impaired endothelial functions in animal models. The aim of this study was to explore whether Rb1 could alleviate the pathophysiological process of arterial stiffening in diabetes and its potential mechanisms.

Experimental Approach: Diabetes was induced in male C57BL/6 mice by administration of streptozotocin. These mice were randomly selected for treatment with Rb1 (10−60 mg/kg, i. p.) once daily for 8 weeks. Aortic stiffness was assessed using ultrasound and measurement of blood pressure and relaxant responses in the aortic rings. Mechanisms of Rb1 treatment were studied in MOVAS-1 VSMCs cultured in a high-glucose medium.

Key Results: Rb1 improved DM-induced arterial stiffening and the impaired aortic compliance and endothelium-dependent vasodilation. Rb1 ameliorated DM-induced aortic remodeling characterized by collagen deposition and elastic fibers disorder. MMP2, MMP9, and TGFβ1/Smad2/3 pathways were involved in this process. In addition, Rb1-mediated improvement of arterial stiffness was partly achieved via inhibiting oxidative stress in DM mice, involving regulating NADPH oxidase. Finally, Rb1 could blunt the inhibition effects of DM on AMPK phosphorylation.

Conclusion and Implications: Rb1 may represent a novel prevention strategy to alleviate collagen deposition and degradation to prevent diabetic macroangiopathy and diabetes-related complications.
Betulin Alleviates the Inflammatory Response in Mouse Chondrocytes and Ameliorates Osteoarthritis via AKT/Nrf2/HO-1/NF-κB Axis
Authors: Ren Chenghao , Jin Jie , Hu Wei , Chen Qi , Yang Jian , Wu Yaosen , Zhou Yifei , Sun Liaojun , Gao Weiyang , Zhang Xiaolei , Tian Naifeng
Published: October 2021

Osteoarthritis (OA) is a common degenerative joint disease featuring the degeneration, destruction, and ossification of cartilage. Inflammation which may facilitate OA occurrence and development is considered as the main pathological factor. Betulin, a natural product extracted from birch bark, has been commonly used for inflammation treatment; however, its role in OA remains unclear. This study is aimed to explore whether betulin can suppress IL-1β–induced inflammation in chondrocytes and alleviate OA in vitro and in vivo. In in vitro studies, the generation of pro-inflammatory factors, such as interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), prostaglandin E2 (PGE2), and nitric oxide (NO), was assessed using the enzyme-linked immunosorbent assay (ELISA) and Griess reaction. As revealed by results, betulin inhibited the expression of pro-inflammatory mediators. In addition, the protein expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), matrix metalloproteinase (MMP-13), thrombospondin motifs 5 (ADAMTS5), Collagen II, and Aggrecan were quantified using Western blot analysis. We found that betulin could inhibit the generation of COX-2 and iNOS induced by IL-1β, indicating that betulin has anti-inflammatory effects in chondrocytes. Furthermore, betulin downregulates the expression of MMP-13 and ADAMTS-5 and upregulates the expression of Collagen II and Aggrecan, indicating that it can inhibit the degradation of the extracellular matrix. In mechanism, betulin activated the AKT/Nrf2 pathway and inhibited the phosphorylation of p65. In in vivo studies, administration of betulin in vivo could inhibit cartilage destruction and inflammatory progression. Therefore, these findings suggest that betulin may alleviate IL-1β–induced OA via the AKT/Nrf2/HO-1/NF-κB signal axis, and betulin may be a potential drug for the treatment of OA.
Clinical Efficacy and Safety of Shashen Maidong Decoction in the Treatment of Pediatric Mycoplasma Pneumonia: A Systematic Review and Meta-Analysis
Authors: Wang Jiawei , Ma Xiao , Wei Shizhang , Yang Tao , Tong Yuling , Jing Manyi , Wen Jianxia , Zhao Yanling
Published: October 2021

Objective: This study was intended to provide data to support the effect of Shashen Maidong Decoction in improving mycoplasma pneumonia in pediatric patients through systematic evaluation.

Methods: PubMed, the Web of Science, EMbase, CNKI, CQVIP, Wan-Fang, and CBM databases were comprehensively searched from established in June 2021. Randomized controlled trials of TRQI were selected by screening the literature and extracting information. The Cochrane RCT Evaluation Manual was used to evaluate the methodological quality of all included studies, and Meta-analysis was performed using Stata 14.0 and Review Manager 5.4 software.

Results: A total of 1,127 patients from 12 clinical studies met the inclusion criteria. Meta-analysis results showed that the treatment group of Shashen Maidong Decoction was able to significantly increase the overall efficiency level and significantly reduce the incidence of adverse reactions, time for disappearance of cough, time for relief of cough, time for defervescence, time for disappearance of lung rales, time for return to normal of chest X-ray, T lymphocyte subpopulation (CD3+) and tumor necrosis factor-α (TNF-α) and other index levels (p < 0.05).

Conclusion: Shashen Maidong Decoction has a significant improvement in the levels of relevant indexes in pediatric mycoplasma pneumonia, which provides a basis for the safety and efficacy of pediatric mycoplasma pneumonia. However, due to the small sample size included in the study, the study quality was not high, and more randomized controlled trials of high quality are required for further validation.
Light Sheet Fluorescence Microscopy Illuminating Soft Matter
Authors: You Ruilin , McGorty Ryan
Published: October 2021

Volumetric microscopic imaging data acquired at high speeds is often needed in studies of soft matter. Several microscopy techniques exist for this purpose, but a relative newcomer is light sheet fluorescence microscopy (LSFM). This microscopy method has seen spectacular growth in the biological sciences over the past two decades. In this perspective, we highlight how LSFM may also apply to the field of soft matter. We review the principles and recent advances of LSFM and discuss how it has been used in prior soft matter studies. We demonstrate how a recent implementation of LSFM can be used to study capillary wave fluctuations and droplet coalescence in a colloidal fluid system.
Toward a New Paradigm for Targeted Natriuretic Peptide Enhancement in Heart Failure
Authors: Gidlöf Olof
Published: October 2021

The natriuretic peptide system (NPS) plays a fundamental role in maintaining cardiorenal homeostasis, and its potent filling pressure-regulated diuretic and vasodilatory effects constitute a beneficial compensatory mechanism in heart failure (HF). Leveraging the NPS for therapeutic benefit in HF has been the subject of intense investigation during the last three decades and has ultimately reached widespread clinical use in the form of angiotensin receptor-neprilysin inhibition (ARNi). NPS enhancement via ARNi confers beneficial effects on mortality and hospitalization in HF, but inhibition of neprilysin leads to the accumulation of a number of other vasoactive peptides in the circulation, often resulting in hypotension and raising potential concerns over long-term adverse effects. Moreover, ARNi is less effective in the large group of HF patients with preserved ejection fraction. Alternative approaches for therapeutic augmentation of the NPS with increased specificity and efficacy are therefore warranted, and are now becoming feasible particularly with recent development of RNA therapeutics. In this review, the current state-of-the-art in terms of experimental and clinical strategies for NPS augmentation and their implementation will be reviewed and discussed.
Soluble Interleukin-6 Receptor Regulates Interleukin-6-Dependent Vascular Remodeling in Long-Distance Runners
Authors: Villar-Fincheira Paulina , Paredes Aaron J. , Hernández-Díaz Tomás , Norambuena-Soto Ignacio , Cancino-Arenas Nicole , Sanhueza-Olivares Fernanda , Contreras-Briceño Felipe , Mandiola Jorge , Bruneau Nicole , García Lorena , Ocaranza María Paz , Troncoso Rodrigo , Gabrielli Luigi , Chiong Mario
Published: October 2021

Little is known about the effects of training load on exercise-induced plasma increase of interleukin-6 (IL-6) and soluble IL-6 receptor (sIL-6R) and their relationship with vascular remodeling. We sought to evaluate the role of sIL 6R as a regulator of IL-6-induced vascular remodeling. Forty-four male marathon runners were recruited and allocated into two groups: low-training (LT, <100 km/week) and high-training (HT, ≥100 km/week), 22 athletes per group. Twenty-one sedentary participants were used as reference. IL-6, sIL-6R and sgp130 levels were measured in plasma samples obtained before and immediately after finishing a marathon (42.2-km). Aortic diameter was measured by echocardiography. The inhibitory effect of sIL-6R on IL-6-induced VSMC migration was assessed using cultured A7r5 VSMCs. Basal plasma IL-6 and sIL-6R levels were similar among sedentary and athlete groups. Plasma IL-6 and sIL-6R levels were elevated after the marathon, and HT athletes had higher post-race plasma sIL-6R, but not IL-6, level than LT athletes. No changes in sgp130 plasma levels were found in LT and HT groups before and after running the marathon. Athletes had a more dilated ascending aorta and aortic root than sedentary participants with no differences between HT and LT athletes. However, a positive correlation between ascending aorta diameter and plasma IL-6 levels corrected by training load and years of training was observed. IL-6 could be responsible for aorta dilation because IL-6 stimulated VSMC migration in vitro, an effect that is inhibited by sIL-6R. However, IL-6 did not modify cell proliferation, collagen type I and contractile protein of VSMC. Our results suggest that exercise induces vascular remodeling. A possible association with IL-6 is proposed. Because sIL-6R inhibits IL-6-induced VSMC migration, a possible mechanism to regulate IL-6-dependent VSMC migration is also proposed.
Physiological and Biomechanical Responses to Cross-Country Skiing in Varying Terrain: Low- vs. High-Intensity
Authors: Seeberg Trine M. , Kocbach Jan , Danielsen Jørgen , Noordhof Dionne A. , Skovereng Knut , Meyer Frédéric , Sandbakk Øyvind
Published: October 2021

The purposes of our study were to investigate the physiological and biomechanical responses to low-intensity (LI) and high-intensity (HI) roller ski skating on varying terrain and compare these responses between training intensities. Nine elite male skiers performed treadmill roller skiing consisting of two 21 min sessions (7 × 3 min laps) at LI and HI with the same set inclines and intensity-dependent speeds (LI/HI: distance: 5.8/7.5 km, average speed: 16.7/21.3 km/h). Physiological and biomechanical variables were measured continuously, and each movement cycle and sub-technique employed were detected and classified with a machine learning model. Both the LI and HI sessions induced large terrain-dependent fluctuations (relative to the maximal levels) in heart rate (HR, 17.7 vs. 12.2%-points), oxygen uptake (V.O2, 33.0 vs. 31.7%-points), and muscle oxygen saturation in the triceps brachii (23.9 vs. 33.4%-points) and vastus lateralis (12.6 vs. 24.3%-points). A sub-technique dependency in relative power contribution from poles and skis exhibited a time-dependent shift from Lap 1 to Lap 7 toward gradually more ski power (6.6 vs. 7.8%-points, both p < 0.01). The terrain-dependent fluctuations did not differ between LI and HI for V.O2 (p = 0.50), whereas HR fluctuated less (p < 0.01) and displayed a time-dependent increase from Lap 2 to Lap 7 (7.8%-points, p > 0.01) during HI. Oxygen saturation shifted 2.4% points more for legs than arms from LI to HI (p > 0.05) and regarding sub-technique, 14.7% points more G3 on behalf of G2 was employed on the steepest uphill during HI (p < 0.05). Within all sub-techniques, cycle length increased two to three times more than cycle rate from LI to HI in the same terrains, while the corresponding poling time decreased more than ski contact time (all p > 0.05). In sum, both LI and HI cross-country (XC) skiing on varying terrain induce large terrain-dependent physiological and biomechanical fluctuations, similar to the patterns found during XC skiing competitions. The primary differences between training intensities were the time-dependent increase in HR, reduced relative oxygen saturation in the legs compared to the arms, and greater use of G3 on steep uphill terrain during HI training, whereas sub-technique selection, cycle rate, and pole vs. ski power distribution were similar across intensities on flat and moderately uphill terrain.
LKB1 Regulates Goat Intramuscular Adipogenesis Through Focal Adhesion Pathway
Authors: Xiong Yan , Wang Yuxue , Xu Qing , Li An , Yue Yongqi , Ma Yan , Lin Yaqiu
Published: October 2021

Intramuscular fat (IMF) deposition is one of the most important factors to affect meat quality in livestock and induce insulin resistance and adverse metabolic phenotypes for humans. However, the key regulators involved in this process remain largely unknown. Although liver kinase B1 (LKB1) was reported to participate in the development of skeletal muscles and classical adipose tissues. Due to the specific autonomic location of intramuscular adipocytes, deposited between or within muscle bundles, the exact roles of LKB1 in IMF deposition need further verified. Here, we cloned the goat LKB1 coding sequence with 1,317 bp, encoding a 438 amino acid peptide. LKB1 was extensively expressed in detected tissues and displayed a trend from decline to rise during intramuscular adipogenesis. Functionally, knockdown of LKB1 by two individual siRNAs enhanced the intramuscular preadipocytes differentiation, accompanied by promoting lipid accumulation and inducing adipogenic transcriptional factors and triglyceride synthesis-related genes expression. Conversely, overexpression of LKB1 restrained these biological signatures. To further explore the mechanisms, the RNA-seq technique was performed to compare the difference between siLKB1 and the control group. There were 1,043 differential expression genes (DEGs) were screened, i.e., 425 upregulated genes and 618 downregulated genes in the siLKB1 group. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis predicted that the DEGs were mainly enriched in the focal adhesion pathway and its classical downstream signal, the PI3K-Akt signaling pathway. Specifically, knockdown of LKB1 increased the mRNA level of focal adhesion kinase (FAK) and vice versa in LKB1-overexpressed cells, a key component of the activated focal adhesion pathway. Convincingly, blocking this pathway by a specific FAK inhibitor (PF573228) rescued the observed phenotypes in LKB1 knockdown adipocytes. In conclusion, LKB1 inhibited goat intramuscular adipogenesis through the focal adhesion pathway. This work expanded the genetic regulator networks of IMF deposition and provided theoretical support for improving human health and meat quality from the aspect of IMF deposition.
Sedentary Conditions Promote Subregionally Specific Changes in Brain-Derived Neurotrophic Factor in the Rostral Ventrolateral Medulla
Authors: Fyk-Kolodziej Bozena E. , Mueller Patrick J.
Published: October 2021

A sedentary lifestyle is the top preventable cause of death and accounts for substantial socioeconomic costs to society. The rostral ventrolateral medulla regulates blood pressure under normal and pathophysiological states, and demonstrates inactivity-related structural and functional neuroplasticity, which is subregionally specific. The purpose of this study was to examine pro- and mature forms of brain-derived neurotrophic factor (BDNF) and their respective receptors in the male rat rostral ventrolateral medulla (RVLM) and its rostral extension following sedentary vs. active (running wheels) conditions (10–12weeks). We used subregionally specific Western blotting to determine that the mature form of BDNF and its ratio to its pro-form were lower in more caudal subregions of the rostral ventrolateral medulla of sedentary rats but higher in the rostral extension when both were compared to active rats. The full-length form of the tropomyosin receptor kinase B receptor and the non-glycosylated form of the 75 kilodalton neurotrophin receptor were lower in sedentary compared to active rats. The rostrocaudal patterns of expression of the mature form of BDNF and the full-length form of the tropomyosin receptor kinase B receptor were remarkably similar to the subregionally specific patterns of enhanced dendritic branching, neuronal activity, and glutamate-mediated increases in sympathetic nerve activity observed in previous studies performed in sedentary rats. Our studies suggest signaling pathways related to BDNF within subregions of both the rostral ventrolateral medulla and its rostral extension contribute to cardiovascular disease and premature death related to a sedentary lifestyle.