bluuebunny/crossref_metadata_2025 huggingface dataset:
Autophagy in Viral Development and Progression of Cancer
Authors: Suares Alejandra , Medina María Victoria , Coso Omar
Published: March 2021

Autophagy is a complex degradative process by which eukaryotic cells capture cytoplasmic components for subsequent degradation through lysosomal hydrolases. Although this catabolic process can be triggered by a great variety of stimuli, action in cells varies according to cellular context. Autophagy has been previously linked to disease development modulation, including cancer. Autophagy helps suppress cancer cell advancement in tumor transformation early stages, while promoting proliferation and metastasis in advanced settings. Oncoviruses are a particular type of virus that directly contribute to cell transformation and tumor development. Extensive molecular studies have revealed complex ways in which autophagy can suppress or improve oncovirus fitness while still regulating viral replication and determining host cell fate. This review includes recent advances in autophagic cellular function and emphasizes its antagonistic role in cancer cells.
Human Serum Albumin Decorated Indocyanine Green Improves Fluorescence-Guided Resection of Residual Lesions of Breast Cancer in Mice
Authors: Wang Zun , Chen Min , Liu Jing-Jing , Chen Rong-He , Yu Qian , Wang Gui-Mei , Nie Li-Ming , Huang Wen-He , Zhang Guo-Jun
Published: March 2021

Objective

Achieving negative resection margin is critical but challenging in breast-conserving surgery. Fluorescence-guided surgery allows the surgeon to visualize the tumor bed in real-time and to facilitate complete resection. We envisioned that intraoperative real-time fluorescence imaging with a human serum albumin decorated indocyanine green probe could enable complete surgical removal of breast cancer in a mouse model.

Methods

We prepared the probe by conjugating indocyanine green (ICG) with human serum albumin (HSA). In vitro uptake of the HSA-ICG probe was compared between human breast cancer cell line MDA-MB-231 and normal breast epithelial cell line MCF 10A. In vivo probe selectivity for tumors was examined in nude mice bearing MDA-MB-231-luc xenografts and the FVB/N-Tg (MMTV-PyMT) 634Mul/J mice model with spontaneous breast cancer. A positive-margin resection mice model bearing MDA-MB-231-luc xenograft was established and the performance of the probe in assisting surgical resection of residual lesions was examined.

Results

A significantly stronger fluorescence intensity was detected in MDA-MB-231 cells than MCF 10A cells incubated with HSA-ICG. In vivo fluorescence imaging showed that HSA-ICG had an obvious accumulation at tumor site at 24 h with tumor-to-normal tissue ratio of 8.19 ± 1.30. The same was true in the transgenic mice model. The fluorescence intensity of cancer tissues was higher than that of non-cancer tissues (58.53 ± 18.15 vs 32.88 ± 11.34). During the surgical scenarios, the residual tumors on the surgical bed were invisible with the naked eye, but were detected and resected with negative margin under HSA-ICG guidance in all the mice (8/8). Recurrence rate among mice that underwent resection with HSA-ICG (0/8) was significantly lower than the rates among mice with ICG (4/8), as well as the control group under white light (7/7).

Conclusions

This study suggests that real-time in vivo visualization of breast cancer with an HSA-ICG fluorescent probe facilitates complete surgical resection of breast cancer in a mouse xenograft model.
Bioinformatics-Based Identification of HDAC Inhibitors as Potential Drugs to Target EGFR Wild-Type Non-Small-Cell Lung Cancer
Authors: Wang Yizhe , Zheng Chunlei , Lu Wenqing , Wang Duo , Cheng Yang , Chen Yang , Hou Kezuo , Qi Jianfei , Liu Yunpeng , Che Xiaofang , Hu Xuejun
Published: March 2021

Patients with EGFR-mutant non-small-cell lung cancer (NSCLC) greatly benefit from EGFR-tyrosine kinase inhibitors (EGFR-TKIs) while the prognosis of patients who lack EGFR-sensitive mutations (EGFR wild type, EGFR-WT) remains poor due to a lack of effective therapeutic strategies. There is an urgent need to explore the key genes that affect the prognosis and develop potentially effective drugs in EGFR-WT NSCLC patients. In this study, we clustered functional modules related to the survival traits of EGFR-WT patients using weighted gene co-expression network analysis (WGCNA). We used these data to establish a two-gene prognostic signature based on the expression of CYP11B1 and DNALI1 by combining the least absolute shrinkage and selection operator (LASSO) algorithms and Cox proportional hazards regression analysis. Following the calculation of risk score (RS) based on the two-gene signature, patients with high RSs showed a worse prognosis. We further explored targeted drugs that could be effective in patients with a high RS by the connectivity map (CMap). Surprisingly, multiple HDAC inhibitors (HDACis) such as trichostatin A (TSA) and vorinostat (SAHA) that may have efficacy were identified. Also, we proved that HDACis could inhibit the proliferation and metastasis of NSCLC cells in vitro. Taken together, our study identified prognostic biomarkers for patients with EGFR-WT NSCLC and confirmed a novel potential role for HDACis in the clinical management of EGFR-WT patients.
MR-Guided Radiotherapy for Brain and Spine Tumors
Authors: Maziero Danilo , Straza Michael W. , Ford John C. , Bovi Joseph A. , Diwanji Tejan , Stoyanova Radka , Paulson Eric S. , Mellon Eric A.
Published: March 2021

MRI is the standard modality to assess anatomy and response to treatment in brain and spine tumors given its superb anatomic soft tissue contrast (e.g., T1 and T2) and numerous additional intrinsic contrast mechanisms that can be used to investigate physiology (e.g., diffusion, perfusion, spectroscopy). As such, hybrid MRI and radiotherapy (RT) devices hold unique promise for Magnetic Resonance guided Radiation Therapy (MRgRT). In the brain, MRgRT provides daily visualizations of evolving tumors that are not seen with cone beam CT guidance and cannot be fully characterized with occasional standalone MRI scans. Significant evolving anatomic changes during radiotherapy can be observed in patients with glioblastoma during the 6-week fractionated MRIgRT course. In this review, a case of rapidly changing symptomatic tumor is demonstrated for possible therapy adaptation. For stereotactic body RT of the spine, MRgRT acquires clear isotropic images of tumor in relation to spinal cord, cerebral spinal fluid, and nearby moving organs at risk such as bowel. This visualization allows for setup reassurance and the possibility of adaptive radiotherapy based on anatomy in difficult cases. A review of the literature for MR relaxometry, diffusion, perfusion, and spectroscopy during RT is also presented. These techniques are known to correlate with physiologic changes in the tumor such as cellularity, necrosis, and metabolism, and serve as early biomarkers of chemotherapy and RT response correlating with patient survival. While physiologic tumor investigations during RT have been limited by the feasibility and cost of obtaining frequent standalone MRIs, MRIgRT systems have enabled daily and widespread physiologic measurements. We demonstrate an example case of a poorly responding tumor on the 0.35 T MRIgRT system with relaxometry and diffusion measured several times per week. Future studies must elucidate which changes in MR-based physiologic metrics and at which timepoints best predict patient outcomes. This will lead to early treatment intensification for tumors identified to have the worst physiologic responses during RT in efforts to improve glioblastoma survival.
Identification of a Metabolism-Related Signature for the Prediction of Survival in Endometrial Cancer Patients
Authors: Fan Yuan , Li Xingchen , Tian Li , Wang Jianliu
Published: March 2021

Objective

Endometrial cancer (EC) is one of the most common gynecologic malignancies. The present study aims to identify a metabolism-related biosignature for EC and explore the molecular immune-related mechanisms underlying the tumorigenesis of EC.

Methods

Transcriptomics and clinical data of EC were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Common differentially expressed metabolism-related genes were extracted and a risk signature was identified by using the least absolute shrinkage and selection operator (LASSO) regression analysis method. A nomogram integrating the prognostic model and the clinicopathological characteristics was established and validated by a cohort of clinical EC patients. Furthermore, the immune and stromal scores were observed and the infiltration of immune cells in EC cells was analyzed.

Results

Six genes, including CA3, HNMT, PHGDH, CD38, PSAT1, and GPI, were selected for the development of the risk prediction model. The Kaplan-Meier curve indicated that patients in the low-risk group had considerably better overall survival (OS) (P = 7.874e-05). Then a nomogram was constructed and could accurately predict the OS (AUC = 0.827, 0.821, 0.845 at 3-, 5-, and 7-year of OS). External validation with clinical patients showed that patients with low risk scores had a longer OS (p = 0.04). Immune/stromal scores and infiltrating density of six types of immune cells were lower in high-risk group.

Conclusions

In summary, our work provided six potential metabolism-related biomarkers as well as a nomogram for the prognosis of EC patients, and explored the underlying mechanism involved in the progression of EC.
Impact of Multidisciplinary Team Management on the Survival Rate of Head and Neck Cancer Patients: A Cohort Study Meta-analysis
Authors: Shang Changyi , Feng Linfei , Gu Ying , Hong Houlin , Hong Lilin , Hou Jun
Published: March 2021

Background: Head and neck cancer (HNC) is one of the more common malignant tumors that threaten human health worldwide. Multidisciplinary team management (MDTM) in HNC treatment has been introduced in the past several decades to improve patient survival rates. This study reviewed the impact of MDTM on survival rates in patients with HNC compared to conventional treatment methods.

Methods: Only cohort studies were identified for this meta-analysis that included an exposure group that utilized MDTM and a control group. Heterogeneity and sensitivity also were assessed. Survival rate data for HNC patients were analyzed using RevMan 5.2 software.

Results: Five cohort studies (n = 39,070) that examined survival rates among HNC patients were included. Hazard ratios (HR) were calculated using the random effect model. The results revealed that exposure groups treated using MDTM exhibited a higher survival rate [HR = 0.84, 95% CI (0.76–0.92), P = 0.0004] with moderate heterogeneity (I2 = 68%, p = 0.01). For two studies that examined the effect of MDTM on the survival rate for patients specifically with stage IV HNC, MDTM did not produce any statistically significant improvement in survival rates [HR = 0.81, 95% CI (0.59–1.10), p = 0.18].

Conclusions: The application of MDTM based on conventional surgery, radiotherapy, and chemotherapy improved the overall survival rate of patients with HNC. Future research should examine the efficacy of MDTM in patients with cancer at different stages.
Exploration of an Integrative Prognostic Model of Radiogenomics Features With Underlying Gene Expression Patterns in Clear Cell Renal Cell Carcinoma
Authors: Huang Yeqian , Zeng Hao , Chen Linyan , Luo Yuling , Ma Xuelei , Zhao Ye
Published: March 2021

Background

Clear cell renal cell carcinoma (ccRCC) is one of the most common malignancies in urinary system, and radiomics has been adopted in tumor staging and prognostic evaluation in renal carcinomas. This study aimed to integrate image features of contrast-enhanced CT and underlying genomics features to predict the overall survival (OS) of ccRCC patients.

Method

We extracted 107 radiomics features out of 205 patients with available CT images obtained from TCIA database and corresponding clinical and genetic information from TCGA database. LASSO-COX and SVM-RFE were employed independently as machine-learning algorithms to select prognosis-related imaging features (PRIF). Afterwards, we identified prognosis-related gene signature through WGCNA. The random forest (RF) algorithm was then applied to integrate PRIF and the genes into a combined imaging-genomics prognostic factors (IGPF) model. Furthermore, we constructed a nomogram incorporating IGPF and clinical predictors as the integrative prognostic model for ccRCC patients.

Results

A total of four PRIF and four genes were identified as IGPF and were represented by corresponding risk score in RF model. The integrative IGPF model presented a better prediction performance than the PRIF model alone (average AUCs for 1-, 3-, and 5-year were 0.814 vs. 0.837, 0.74 vs. 0.806, and 0.689 vs. 0.751 in test set). Clinical characteristics including gender, TNM stage and IGPF were independent risk factors. The nomogram integrating clinical predictors and IGPF provided the best net benefit among the three models.

Conclusion

In this study we established an integrative prognosis-related nomogram model incorporating imaging-genomic features and clinical indicators. The results indicated that IGPF may contribute to a comprehensive prognosis assessment for ccRCC patients.
Pain Management in a Model of Interstitial Cystitis/Bladder Pain Syndrome by a Vaccinal Strategy
Authors: Augé Céline , Basso Lilian , Blanpied Catherine , Vergnolle Nathalie , Gamé Xavier , Chabot Sophie , Lluel Philippe , Dietrich Gilles
Published: March 2021

Current analgesic treatments for Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) are limited. Here, we propose a novel antinociceptive strategy exploiting the opioid-mediated analgesic properties of T lymphocytes to relieve from bladder pain. In a chronic model of IC/BPS in rats, we show that a secondary T cell response against intravesically administered ovalbumin prevents from visceral pain in OVA-primed animals. The analgesic effect is associated with the recruitment of T lymphocytes within the inflamed mucosa and is reversed by naloxone-methiodide, a peripheral opioid receptor antagonist. Similarly, intravesical instillation of BCG or tetanus toxoid antigens in vaccinated rats protects from pain in the same model. We show opioid-dependent analgesic properties of local vaccine antigen recall in a preclinical rat model of chronic cystitis. Since BCG bladder instillation is regularly used in humans (as anticancer therapy), our results open it as a new therapeutic positioning for a pain management indication for IC/BPS patients.
A Minimal Information Model for Potential Drug-Drug Interactions
Authors: Hochheiser Harry , Jing Xia , Garcia Elizabeth A. , Ayvaz Serkan , Sahay Ratnesh , Dumontier Michel , Banda Juan M. , Beyan Oya , Brochhausen Mathias , Draper Evan , Habiel Sam , Hassanzadeh Oktie , Herrero-Zazo Maria , Hocum Brian , Horn John , LeBaron Brian , Malone Daniel C. , Nytrø Øystein , Reese Thomas , Romagnoli Katrina , Schneider Jodi , Zhang Louisa (Yu) , Boyce Richard D.
Published: March 2021

Despite the significant health impacts of adverse events associated with drug-drug interactions, no standard models exist for managing and sharing evidence describing potential interactions between medications. Minimal information models have been used in other communities to establish community consensus around simple models capable of communicating useful information. This paper reports on a new minimal information model for describing potential drug-drug interactions. A task force of the Semantic Web in Health Care and Life Sciences Community Group of the World-Wide Web consortium engaged informaticians and drug-drug interaction experts in in-depth examination of recent literature and specific potential interactions. A consensus set of information items was identified, along with example descriptions of selected potential drug-drug interactions (PDDIs). User profiles and use cases were developed to demonstrate the applicability of the model. Ten core information items were identified: drugs involved, clinical consequences, seriousness, operational classification statement, recommended action, mechanism of interaction, contextual information/modifying factors, evidence about a suspected drug-drug interaction, frequency of exposure, and frequency of harm to exposed persons. Eight best practice recommendations suggest how PDDI knowledge artifact creators can best use the 10 information items when synthesizing drug interaction evidence into artifacts intended to aid clinicians. This model has been included in a proposed implementation guide developed by the HL7 Clinical Decision Support Workgroup and in PDDIs published in the CDS Connect repository. The complete description of the model can be found at https://w3id.org/hclscg/pddi.
Fisetin Attenuates Myocardial Ischemia-Reperfusion Injury by Activating the Reperfusion Injury Salvage Kinase (RISK) Signaling Pathway
Authors: Shanmugam Karthi , Boovarahan Sri Rahavi , Prem Priyanka , Sivakumar Bhavana , Kurian Gino A
Published: March 2021

Ischemia-reperfusion (I/R) injury is an unavoidable injury that occurs during revascularization procedures. In the previous study, we reported that fisetin is a natural flavonoid that attenuates I/R injury by suppressing mitochondrial oxidative stress and mitochondrial dysfunction. Though fisetin is reported as a GSK3β inhibitor, it remains unclear whether it attenuates myocardial ischemia by activating the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway, thereby inhibiting the downstream GSK3β, or by directly interacting with GSK3β while rendering its cardioprotection. In this study, the research team investigates the possible mechanism of action of fisetin while rendering its cardioprotective effect against myocardial I/R injury in rats. For this investigation, the team utilized two myocardial I/R models: Ligation of the left anterior descending artery and Langendorff isolated heart perfusion system. The latter has no neurohormonal influences. The PI3K inhibitor (Wortmannin, 0.015 mg/kg), GSK3β inhibitor (SB216763, 0.7 mg/kg), and fisetin (20 mg/kg) were administered intraperitoneally before inducing myocardial I/R. The result of this study reveals that the administration of fisetin decreases the myocardial infarct size, apoptosis, lactate dehydrogenase, and creatine kinase in serum\perfusate of the rat hearts subjected to I/R. However, the inhibition of PI3K with Wortmannin significantly reduced the cardioprotective effect of fisetin both in the ex vivo and vivo models. The administration of GSK3β inhibitor after the administration of fisetin and Wortmannin, re-establishing the cardioprotection, indicates the major role of PI3K in fisetin action. Changes in myocardial oxidative stress (level) and mitochondrial functional preservation of interfibrillar and subsarcolemmal mitochondria support the above findings. Hence, the team here reports that fisetin conferred its cardioprotection against I/R injury by activating the PI3K/Akt/GSK3β signaling pathway in rat hearts.
Mitochondrial Function, Fatty Acid Metabolism, and Body Composition in the Hyperbilirubinemic Gunn Rat
Authors: Vidimce Josif , Pillay Johara , Shrestha Nirajan , Dong Lan-feng , Neuzil Jiri , Wagner Karl-Heinz , Holland Olivia Jane , Bulmer Andrew Cameron
Published: March 2021

Background: Circulating bilirubin is associated with reduced adiposity in human and animal studies. A possible explanation is provided by in vitro data that demonstrates that bilirubin inhibits mitochondrial function and decreases efficient energy production. However, it remains unclear whether hyperbilirubinemic animals have similar perturbed mitochondrial function and whether this is important for regulation of energy homeostasis.

Aim: To investigate the impact of unconjugated hyperbilirubinemia on body composition, and mitochondrial function in hepatic tissue and skeletal muscle.

Materials and Methods: 1) Food intake and bodyweight gain of 14-week old hyperbilirubinemic Gunn (n = 19) and normobilirubinemic littermate (control; n = 19) rats were measured over a 17-day period. 2) Body composition was determined using dual-energy X-ray absorptiometry and by measuring organ and skeletal muscle masses. 3) Mitochondrial function was assessed using high-resolution respirometry of homogenized liver and intact permeabilized extensor digitorum longus and soleus fibers. 4) Liver tissue was flash frozen for later gene (qPCR), protein (Western Blot and citrate synthase activity) and lipid analysis.

Results: Female hyperbilirubinemic rats had significantly reduced fat mass (Gunn: 9.94 ± 5.35 vs. Control: 16.6 ± 6.90 g, p < 0.05) and hepatic triglyceride concentration (Gunn: 2.39 ± 0.92 vs. Control: 4.65 ± 1.67 mg g−1, p < 0.01) compared to normobilirubinemic controls. Furthermore, hyperbilirubinemic rats consumed fewer calories daily (p < 0.01) and were less energetically efficient (Gunn: 8.09 ± 5.75 vs. Control: 14.9 ± 5.10 g bodyweight kcal−1, p < 0.05). Hepatic mitochondria of hyperbilirubinemic rats demonstrated increased flux control ratio (FCR) via complex I and II (CI+II) (Gunn: 0.78 ± 0.16 vs. Control: 0.62 ± 0.09, p < 0.05). Similarly, exogenous addition of 31.3 or 62.5 μM unconjugated bilirubin to control liver homogenates significantly increased CI+II FCR (p < 0.05). Hepatic PGC-1α gene expression was significantly increased in hyperbilirubinemic females while FGF21 and ACOX1 was significantly greater in male hyperbilirubinemic rats (p < 0.05). Finally, hepatic mitochondrial complex IV subunit 1 protein expression was significantly increased in female hyperbilirubinemic rats (p < 0.01).

Conclusions: This is the first study to comprehensively assess body composition, fat metabolism, and mitochondrial function in hyperbilirubinemic rats. Our findings show that hyperbilirubinemia is associated with reduced fat mass, and increased hepatic mitochondrial biogenesis, specifically in female animals, suggesting a dual role of elevated bilirubin and reduced UGT1A1 function on adiposity and body composition.
The Protective Effects of Shengmai Formula Against Myocardial Injury Induced by Ultrafine Particulate Matter Exposure and Myocardial Ischemia are Mediated by the PI3K/AKT/p38 MAPK/Nrf2 Pathway
Authors: Chen Lina , Guo Yuan , Qu Shuiqing , Li Kai , Yang Ting , Yang Yuanmin , Zheng Zhongyuan , Liu Hui , Wang Xi , Deng Shuoqiu , Zhang Yu , Zhu Xiaoxin , Li Yujie
Published: March 2021

Background and Purpose: Ultrafine particulate matter (UFPM) induces oxidative stress (OS) and is considered to be a risk factor of myocardial ischemia (MI). Shengmai formula (SMF) is a traditional Chinese medicine with antioxidant properties and has been used to treat cardiovascular diseases for a long time. The aim of this study was to explore the protective role of SMF and the mechanism by which it prevents myocardial injury in UFPM-exposed rats with MI.

Methods: An MI rat model was established. Animals were randomly divided into five groups: sham, UFPM + MI, SMF (1.08 mg/kg⋅d) + UFPM + MI, SMF (2.16 mg/kg⋅d) + UFPM + MI, and SMF (4.32 mg/kg⋅d) + UFPM + MI. SMF or saline was administrated 7 days before UFPM instillation (100 μg/kg), followed by 24 h of ischemia. Physiological and biochemical parameters were measured, and histopathological examinations were conducted to evaluate myocardial damage. We also explored the potential mechanism of the protective role of SMF using a system pharmacology approach and an in vitro myoblast cell model with small molecule inhibitors.

Results: UFPM produced myocardial injuries on myocardial infarct size; serum levels of LDH, CK-MB, and cardiac troponin; and OS responses in the rats with MI. Pretreatment with SMF significantly attenuated these damages via reversing the biomarkers. SMF also improved histopathology induced by UFPM and significantly altered the PI3K/AKT/MAPK and OS signaling pathways. The expression patterns of Cat, Gstk1, and Cyba in the UFPM model group were reversed in the SMF-treated group. In in vitro studies, SMF attenuated UFPM-induced reactive oxygen species production, mitochondrial damage, and OS responses. The PI3K/AKT/p38 MAPK/Nrf2 pathway was significantly changed in the SMF group compared with that in the UFPM group, whereas opposite results were obtained for pathway inhibition.

Conclusion: These findings indicate that SMF prevents OS responses and exerts beneficial effects against myocardial injury induced by UFPM + MI in rats. Furthermore, the PI3K/AKT/p38 MAPK/Nrf2 signaling pathway might be involved in the protective effects of SMF.
Inhibition of Autophagy Prevents Panax Notoginseng Saponins (PNS) Protection on Cardiac Myocytes Against Endoplasmic Reticulum (ER) Stress-Induced Mitochondrial Injury, Ca2+ Homeostasis and Associated Apoptosis
Authors: Chen Jun , Li Li , Bai Xueyang , Xiao Lili , Shangguan Jiahong , Zhang Wenjing , Zhang Xiangqin , Wang Shen , Liu Gangqiong
Published: March 2021

Endoplasmic reticulum (ER) stress is often closely linked to autophagy, hypoxia signaling, mitochondrial biogenesis and reactive oxygen species (ROS) responses. Understanding the interaction between ER stress, mitochondrial function and autophagy is of great importance to provide new mechanisms for the pathology, prevention and treatment of cardiovascular diseases. Our previous study has reported that Panax notoginseng saponins (PNS) protection against thapsigargin (TG)-induced ER stress response and associated cell apoptosis in cardiac myocytes is calcium dependent and mediated by ER Ca2+ release through RyR2. However, whether its protection upon ER stress and associated apoptosis is related to mitochondrial function and autophagy remains largely unknown. Here, we investigated the roles of PNS played in TG-induced mitochondrial function, ROS accumulation and autophagy. We also assessed its effects on Ca2+ homeostasis, ER stress response and associated cell death in the presence of autophagy inhibition. PNS-pretreated primary cultured neonatal rat cardiomyocytes were stimulated with TG to induce ER stress response. Mitochondrial potential (Δψm) was measured by JC-1. The general and mitochondrial ROS were measured by DCFH-DA and MitoSOX Red, respectively. Autophagy was evaluated by immunofluorescence of LC3, and immunoblots of LC3, p62, ATG7 and PINK1. In addition, mRFP-GFP-LC3 labeling was used to assess the autophagic influx. SiATG7 transfected H9c2 cells were generated to inhibit autophagy. Cytosolic and ER Ca2+ dynamics were investigated by calcium imaging. RyR2 oxidation was tested by oxyblot. Cell viability was examined by TUNEL assay. ER stress response and cell apoptosis were detected by immunoblots of BiP, CHOP, Cleaved Caspase-3 and Caspase-12. The results demonstrated that firstly, PNS protects against TG-induced mitochondrial injury and ROS accumulation. Secondly, PNS enhances autophagy in TG-induced cardiac myocytes. Thirdly, inhibition of autophagy diminishes PNS prevention of TG-induced mitochondrial injury, ROS accumulation and disruption of Ca2+ homeostasis. Last but not least, inhibition of autophagy abolishes PNS protection against TG-induced ER stress response and associated apoptosis. In summary, PNS protection against ER stress response and associated apoptosis is related to the regulation of mitochondrial injury and ROS overproduction via modulation of autophagy. These data provide new insights for molecular mechanisms of PNS as a potential preventive approach to the management of cardiovascular diseases.
A Prospective Study of Vitamin D Supplement in Thyroidectomy Patients Based on Relative Decline of Parathyroid Hormone
Authors: Hao Qing , Qin Yun , Zhao Wanjun , Zhang Lingyun , Luo Han
Published: March 2021

Background: In postthyroidectomy patients, hypocalcemia is the most common complication to prolong hospital stay and decrease patients’ satisfaction. Based on current evidence, it is recommended to supply vitamin D to patients with high risk of developing hypocalcemia. However, how to stratify the risk of patients remains challenging.

Aim: We conducted a prospective study to evaluate the effect of vitamin D supplement (calcitriol) on high-risk hypocalcemia patients based on relative decline of parathyroid hormone (RDP).

Method: RDP was calculated by the difference between preoperative and postoperative first-day PTH divided by preoperative PTH and presented as percentage. Patients who underwent total thyroidectomy in addition to bilateral central compartment dissection were enrolled prospectively and were divided into two cohorts: Cohort I: patients with RDP ≤70% and Cohort II: patients with RDP >70%. Patients in Cohort I were then randomly assigned to Group A or B, and patients in Cohort II were randomly assigned to Group C or D. All groups received oral calcium, and patients in Groups B and D also received calcitriol. All patients were followed for one year. In the study, standard procedure dictates that only oral calcium is given to patients whose RDP ≤70% and that oral calcium and calcitriol are given to patients whose RDP >70%. Therefore, Cohort I Group A and Cohort II Group D are controls in this study.

Results: The incidence of clinical hypocalcemia in Groups A and D (the controls) was 11.0% (10/91), and 17.6% (16/91) required additional intravenous calcium. Of note, no patients developed permanent hypocalcemia. Furthermore, calcitriol supplement did not have significant impact on clinical outcomes between Group A and B in Cohort I. By contrast, calcitriol supplement distinctly improved clinical outcome by comparing Groups C and D (Cohort II), as marked by clinical hypocalcemia, need of requiring intravenous calcium, and long-termed decreased levels of PTH.

Conclusion: Supplying calcitriol based on RDP cutoff of 70% may be a wise practice in thyroidectomy patients, and RDP 70% may be a useful predictor to stratify high-risk patients.
Burn Ointment Promotes Cutaneous Wound Healing by Modulating the PI3K/AKT/mTOR Signaling Pathway
Authors: Gan Dali , Su Qiyuan , Su Hanwen , Wu Li , Chen Jun , Han Bing , Xiang Meixian
Published: March 2021

Burn ointment (BO) is a clinically useful medicine for the treatment of burns and scalds. However, there is no enough scientific evidence to report the effect of BO on wound healing and its analgesic and anti-inflammatory efficacy. The aim of this work was to evaluate the anti-inflammatory and analgesic efficacy of BO and to reveal the potential wound healing properties and related mechanisms of BO. In this work, the content of active ingredients of BO was determined by high-performance liquid chromatography (HPLC). Two animal models of inflammation were used to study its anti-inflammatory activity, and a hot plate method was used to evaluate its analgesic effect. In addition, mouse incision and rat burn models were used to investigate the effect of BO on the anti-inflammatory and wound healing mechanisms. The results showed that BO was safe for topical application, and BO could significantly inhibit auricular swelling in mice and paw swelling in rats and significantly prolong the latency period of paw licking in the hot plate experiment in mice. It can also accelerate wound healing and repair scars by promoting the formation of new epithelial tissues in rat burn models. In addition, BO significantly downregulated the serum level of TNF-α and significantly increased the serum levels of VEGF and TGF-β1. Also, BO promoted the expression of collagen I and increased the ratio in p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR pathways. Our results demonstrate the safety and efficacy of BO and suggest that activation of the PI3K/AKT/mTOR signaling pathway may play an important role in the promotion of wound healing by BO.
LINC01116 Promotes Doxorubicin Resistance in Osteosarcoma by Epigenetically Silencing miR-424-5p and Inducing Epithelial-Mesenchymal Transition
Authors: Li Ran , Ruan Qing , Zheng Jia , Zhang Butian , Yang Hongliang
Published: March 2021

Background: Development of resistance to doxorubicin-based chemotherapy limits its curative effect in osteosarcoma. In the current study, we focused on investigating the mechanisms underlying the development of doxorubicin resistance in osteosarcoma.

Methods: The human osteosarcoma cell line MG-63 and doxorubicin-resistant MG-63/Dox cells were used in this study. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of the long non-coding RNA LINC01116 in the two cell lines. Then, the specific shRNA for LINC01116 was employed to suppress LINC01116 expression in MG-63/Dox cells. Cell viability was assessed by the CCK-8 and colony formation assays. Cell migration and invasion were evaluated by the transwell assay. Moreover, the epithelial-mesenchymal transition (EMT)-related proteins, E-cadherin, vimentin, and N-cadherin were evaluated by Western blotting. The regulation of LINC01116 on miR-424-5p expression was examined using methylation-specific PCR, RNA immunoprecipitation, and Western blotting assay. The potential targeting of HMGA2 by miR-424-5p was predicted using the bioinformatics databases TargetScan and miRanda and verified by a dual-luciferase reporter assay.

Results: LINC01116 was more highly expressed in MG-63/Dox cells than in MG-63 cells. Inhibition of LINC01116 suppressed cell viability, migration, and invasion, along with upregulating the expression of E-cadherin, downregulating vimentin, and attenuating doxorubicin resistance in MG-63/Dox cells. Further mechanism-related investigations indicated that LINC01116 regulated HMGA2 expression via the EZH2-associated silencing of miR-424-5p.

Conclusion: LINC01116 exerts regulatory effects on doxorubicin resistance through the miR-424-5p axis, providing a potential approach to overcoming chemoresistance in osteosarcoma.
Influence of YES1 Kinase and Tyrosine Phosphorylation on the Activity of OCT1
Authors: Uddin Muhammad Erfan , Garrison Dominique A. , Kim Kyeongmin , Jin Yan , Eisenmann Eric D. , Huang Kevin M. , Gibson Alice A. , Hu Zeping , Sparreboom Alex , Hu Shuiying
Published: March 2021

Organic cation transporter 1 (OCT1) is a transporter that regulates the hepatic uptake and subsequent elimination of diverse cationic compounds. Although OCT1 has been involved in drug-drug interactions and causes pharmacokinetic variability of many prescription drugs, details of the molecular mechanisms that regulate the activity of OCT1 remain incompletely understood. Based on an unbiased phospho-proteomics screen, we identified OCT1 as a tyrosine-phosphorylated transporter, and functional validation studies using genetic and pharmacological approaches revealed that OCT1 is highly sensitive to small molecules that target the protein kinase YES1, such as dasatinib. In addition, we found that dasatinib can inhibit hepatic OCT1 function in mice as evidenced from its ability to modulate levels of isobutyryl L-carnitine, a hepatic OCT1 biomarker identified from a targeted metabolomics analysis. These findings provide novel insight into the post-translational regulation of OCT1 and suggest that caution is warranted with polypharmacy regimes involving the combined use of OCT1 substrates and kinase inhibitors that target YES1.
3D-FV-FE Aeroacoustic Larynx Model for Investigation of Functional Based Voice Disorders
Authors: Falk Sebastian , Kniesburges Stefan , Schoder Stefan , Jakubaß Bernhard , Maurerlehner Paul , Echternach Matthias , Kaltenbacher Manfred , Döllinger Michael
Published: March 2021

For the clinical analysis of underlying mechanisms of voice disorders, we developed a numerical aeroacoustic larynx model, calledsimVoice, that mimics commonly observed functional laryngeal disorders as glottal insufficiency and vibrational left-right asymmetries. The model is a combination of the Finite Volume (FV) CFD solver Star-CCM+ and the Finite Element (FE) aeroacoustic solver CFS++.simVoicemodels turbulence using Large Eddy Simulations (LES) and the acoustic wave propagation with the perturbed convective wave equation (PCWE). Its geometry corresponds to a simplified larynx and a vocal tract model representing the vowel /a/. The oscillations of the vocal folds are externally driven. In total, 10 configurations with different degrees of functional-based disorders were simulated and analyzed. The energy transfer between the glottal airflow and the vocal folds decreases with an increasing glottal insufficiency and potentially reflects the higher effort during speech for patients being concerned. This loss of energy transfer may also have an essential influence on the quality of the sound signal as expressed by decreasing sound pressure level (SPL), Cepstral Peak Prominence (CPP), and Vocal Efficiency (VE). Asymmetry in the vocal fold oscillations also reduces the quality of the sound signal. However,simVoiceconfirmed previous clinical and experimental observations that a high level of glottal insufficiency worsens the acoustic signal quality more than oscillatory left-right asymmetry. Both symptoms in combination will further reduce the quality of the sound signal. In summary,simVoiceallows for detailed analysis of the origins of disordered voice production and hence fosters the further understanding of laryngeal physiology, including occurring dependencies. A current walltime of 10 h/cycle is, with a prospective increase in computing power, auspicious for a future clinical use ofsimVoice.
Assessment of Secular Trends and Health Risk in Pediatric Cardiorespiratory Fitness From the Republic of Slovenia
Authors: Morrison Shawnda A. , Sember Vedrana , Leskošek Bojan , Kovač Marjeta , Jurak Gregor , Starc Gregor
Published: March 2021

Objectives

Determine the temporal trends in cardiorespiratory fitness (CRF) and health risk of Slovenian schoolchildren across a 20-year span, assessed via 20-m shuttle run (20mSRT), including defining centile ranges and possible health risk(s) for each generation.

Methods

Nationally representative data from 9,426 healthy schoolchildren (6–14 years old) were used to determine changes in CRF across three generations, in 1993 (n = 3,174), 2003 (n = 3,457) and 2013 (n = 2,795) from a multistage, stratified, decennial study.

Results

20mSRT performance declined ∼2.8% from 1993 to 2003, independent of age or sex of the child. This trend was reversed in 2013, increasing by ∼8.2% across all age groups, for both girls and boys, for a net increase of 5.4%. The magnitude of improvement was similar for both sexes. Moreover, girls in the 2013 generation (for ages 10–13 year) completed more stages than their 2003 male counterparts. Across all generations, children achieved CRF values corresponding to low cardiovascular risk for future health outcomes. Centile values ranged from “low” to “very high” depending on age, sex, and generation of the sample.

Conclusion

Negative trends in CRF from Slovenian schoolchildren were reversed by 2013, indicating that Slovenia should continue implementing progressive national physical fitness strategies introduced between sampling periods (i.e., 2003–2013). Additionally, due to the universal nature of Slovenian schoolchildren achieving “healthy cut-off values” for 20mSRT (generation-inclusive), it is suggested that more specific cut-off criteria are developed, especially for younger children, and girls, so that future CRF results can be more accurately applied for both clinical and pedagogical users.
A Composite Analysis of Flowering Time Regulation in Lettuce
Authors: Han Rongkui , Truco Maria José , Lavelle Dean O. , Michelmore Richard W.
Published: March 2021

Plants undergo profound physiological changes when transitioning from vegetative to reproductive growth. These changes affect crop production, as in the case of leafy vegetables. Lettuce is one of the most valuable leafy vegetable crops in the world. Past genetic studies have identified multiple quantitative trait loci (QTLs) that affect the timing of the floral transition in lettuce. Extensive functional molecular studies in the model organism Arabidopsis provide the opportunity to transfer knowledge to lettuce to explore the mechanisms through which genetic variations translate into changes in flowering time. In this review, we integrated results from past genetic and molecular studies for flowering time in lettuce with orthology and functional inference from Arabidopsis. This summarizes the basis for all known genetic variation underlying the phenotypic diversity of flowering time in lettuce and how the genetics of flowering time in lettuce projects onto the established pathways controlling flowering time in plants. This comprehensive overview reveals patterns across experiments as well as areas in need of further study. Our review also represents a resource for developing cultivars with delayed flowering time.
Optimal Time Intervals in Two-Stage Takeover Warning Systems With Insight Into the Drivers’ Neuroticism Personality
Authors: Zhang Wei , Zeng Yilin , Yang Zhen , Kang Chunyan , Wu Changxu , Shi Jinlei , Ma Shu , Li Hongting
Published: March 2021

Conditional automated driving [level 3, Society of Automotive Engineers (SAE)] requires drivers to take over the vehicle when an automated system’s failure occurs or is about to leave its operational design domain. Two-stage warning systems, which warn drivers in two steps, can be a promising method to guide drivers in preparing for the takeover. However, the proper time intervals of two-stage warning systems that allow drivers with different personalities to prepare for the takeover remain unclear. This study explored the optimal time intervals of two-stage warning systems with insights into the drivers’ neuroticism personality. A total of 32 drivers were distributed into two groups according to their self-ratings in neuroticism (high vs. low). Each driver experienced takeover under the two-stage warning systems with four time intervals (i.e., 3, 5, 7, and 9 s). The takeover performance (i.e., hands-on-steering-wheel time, takeover time, and maximum resulting acceleration) and subjective opinions (i.e., appropriateness and usefulness) for time intervals and situation awareness (SA) were recorded. The results showed that drivers in the 5-s time interval had the best takeover preparation (fast hands-on steering wheel responses and sufficient SA). Furthermore, both the 5- and 7-s time intervals resulted in more rapid takeover reactions and were rated more appropriate and useful than the 3- and 9-s time intervals. In terms of personality, drivers with high neuroticism tended to take over immediately after receiving takeover messages, at the cost of SA deficiency. In contrast, drivers with low neuroticism responded safely by judging whether they gained enough SA. We concluded that the 5-s time interval was optimal for drivers in two-stage takeover warning systems. When considering personality, drivers with low neuroticism had no strict requirements for time intervals. However, the extended time intervals were favorable for drivers with high neuroticism in developing SA. The present findings have reference implications for designers and engineers to set the time intervals of two-stage warning systems according to the neuroticism personality of drivers.
Daily Challenge/Hindrance Demands and Cognitive Wellbeing: A Multilevel Moderated Mediation Model
Authors: Chen Huangen , Wang Hongyan , Yuan Mengsha , Xu Shan
Published: March 2021

Based on the challenge-hindrance stressor model, this study explored the mechanism of how challenge/hindrance demands affect cognitive wellbeing on a daily basis. Specifically, we examined the mediating effect of work–family enrichment on the relationship between challenge/hindrance demands and cognitive wellbeing. In addition, we tested the moderating effect of overqualification on the relationship between challenge/hindrance demands and work–family enrichment on a daily basis. Finally, we examined the moderated mediation effect of perceived overqualification in a multilevel model. To capture changes in work–family enrichment and cognitive wellbeing that individuals perceived daily, the experience sampling method was adopted to test our theoretical models. A total of 99 participants from China were involved in this investigation. The results showed that daily challenge demands had a significant positive effect on daily cognitive wellbeing, and daily hindrance demands had a significant negative effect on wellbeing. In addition, daily work–family enrichment mediated the positive relationship between daily challenge demands and daily cognitive wellbeing. Moreover, perceived overqualification moderated the relationship between daily challenge demands and daily cognitive wellbeing in the multilevel model. Finally, a significant moderated mediating effect of this overqualification on the indirect effect of daily work–family enrichment on the relationship between daily challenge demands and daily cognitive wellbeing was observed.
An Epistemological Perspective of Integrated Multidisciplinary Treatment When Dealing With Infertile Women With a Parenthood Goal: The Importance of Matterpsychic Perspective
Authors: Vasta Francesca Natascia , Girelli Raffaella
Published: March 2021

This article proposes a multidisciplinary work perspective on couples who undergo assisted reproductive technology (ART) treatments, with particular attention paid to the treatment of women. The epistemological references underlying a vision of infertility and sterility that respect the psyche–soma unity of the person are illustrated: the biopsychosocial model and the psychoneuroimmunology and psychosomatic contemporary models of health and illness. Based on clinical experience in a private and institutional setting, different steps in the course of treatment are described with the related areas of psychological work: from the search for pregnancy to the choice of adhering to an ART treatment, to conception, up to delivery and beyond. The implications of the work are targeted at a better qualification of psychological interventions in this specific multidisciplinary area.
Protocol for a Phase Two, Parallel Three-Armed Non-inferiority Randomized Controlled Trial of Acceptance and Commitment Therapy (ACT-Adjust) Comparing Face-to-Face and Video Conferencing Delivery to Individuals With Traumatic Brain Injury Experiencing Psychological Distress
Authors: Whiting Diane L. , Simpson Grahame K. , Deane Frank P. , Chuah Sarah L. , Maitz Michelle , Weaver Jerre
Published: March 2021

Background: People with traumatic brain injury (TBI) face a range of mental health challenges during the adjustment process post-injury, but access to treatment can be difficult, particularly for those who live in regional and remote regions. eHealth provides the potential to improve access to evidence-based psychological therapy for people with a severe TBI. The aim of the current study is to assess the efficacy of a psychological intervention delivered via video consulting to reduce psychological distress in people with TBI.

Methods: This paper outlines the protocol for a multi-center, three-arm, parallel, non-inferiority randomized controlled trial (RCT) of an evidence-based manualized psychological intervention, ACT-Adjust. ACT-Adjust provides nine sessions for adults with a moderate to severe TBI experiencing clinical levels of psychological distress. Fifty-six participants referred from Brain Injury Rehabilitation Units across New South Wales (NSW) and the NSW icare scheme will be randomly allocated to three conditions; (1) video consulting (VC), (2) face-to-face (FtF) and, (3) a waitlist control (WL).

Discussion: This is the first RCT to evaluate the efficacy of a psychological therapy (ACT-Adjust) delivered via video consulting for individuals with a moderate to severe TBI.

Trial Registration:www.anzctr.org.au, Australian New Zealand Clinical Trials Registry ANZCTRN2619001602112.