bluuebunny/crossref_metadata_2025 huggingface dataset:
Insulin-Regulated Aminopeptidase Inhibition Ameliorates Metabolism in Obese Zucker Rats
Authors: Krskova Katarina , Balazova Lucia , Dobrocsyova Viktoria , Olszanecki Rafal , Suski Maciej , Chai Siew Yeen , Zorad Štefan
Published: December 2020

The aim of our study was to determine the influence of inhibition of insulin-regulated aminopeptidase/oxytocinase (IRAP) on glucose tolerance and metabolism of skeletal muscle and visceral adipose tissue in obese Zucker rats. Obese Zucker rats administered with IRAP inhibitor–HFI-419 at a dose of 29 μg/100 g BW/day by osmotic minipumps implanted subcutaneously for 2 weeks. Two-hour intraperitoneal glucose tolerance test (ipGTT) was performed in fasting rats. Plasma oxytocin levels were measured by enzyme immunoassay after plasma extraction. In the musculus quadriceps and epididymal adipose tissue, the expression of factors affecting tissue oxidative status and metabolism was determined by real-time qPCR and/or Western blot analysys. The plasma and tissue enzymatic activities were determined by colorimetric or fluorometric method. Circulated oxytocin levels in obese animals strongly tended to increase after HFI-419 administration. This was accompanied by significantly improved glucose utilization during ipGTT and decreased area under the curve (AUC) for glucose. In skeletal muscle IRAP inhibitor treatment up-regulated enzymes of antioxidant defense system – superoxide dismutase 1 and 2 and improved insulin signal transduction pathway. HFI-419 increased skeletal muscle aminopeptidase A expression and activity and normalized its plasma levels in obese animals. In epididymal adipose tissue, gene expression of markers of inflammation and adipocyte hypertrophy was down-regulated in obese rats after HFI-419 treatment. Our results demonstrate that IRAP inhibition improves whole-body glucose tolerance in insulin-resistant Zucker fatty rats and that this metabolic effect of HFI-419 involves ameliorated redox balance in skeletal muscle.
DNA Damage Induces Dynamic Associations of BRD4/P-TEFb With Chromatin and Modulates Gene Transcription in a BRD4-Dependent and -Independent Manner
Authors: Song Yawei , Hu Gongcheng , Jia Jinping , Yao Mingze , Wang Xiaoshan , Lu Wenliang , Hutchins Andrew P. , Chen Jiekai , Ozato Keiko , Yao Hongjie
Published: December 2020

The bromodomain-containing protein BRD4 has been thought to transmit epigenetic information across cell divisions by binding to both mitotic chromosomes and interphase chromatin. UV-released BRD4 mediates the recruitment of active P-TEFb to the promoter, which enhances transcriptional elongation. However, the dynamic associations between BRD4 and P-TEFb and BRD4-mediated gene regulation after UV stress are largely unknown. In this study, we found that BRD4 dissociates from chromatin within 30 min after UV treatment and thereafter recruits chromatin. However, P-TEFb binds tightly to chromatin right after UV treatment, suggesting that no interactions occur between BRD4 and P-TEFb within 30 min after UV stress.BRD4knockdown changes the distribution of P-TEFb among nuclear soluble and chromatin and downregulates the elongation activity of RNA polymerase II. Inhibition of JNK kinase but not other MAP kinases impedes the interactions between BRD4 and P-TEFb. RNA-seq and ChIP assays indicate that BRD4 both positively and negatively regulates gene transcription in cells treated with UV stress. These results reveal previously unrecognized dynamics of BRD4 and P-TEFb after UV stress and regulation of gene transcription by BRD4 acting as either activator or repressor in a context-dependent manner.
Acupuncture Treatment Reduces Incidence of Parkinson's Disease in Patients With Depression: A Population-Based Retrospective Cohort Study in Taiwan
Authors: Huang Cheng-Hao , Lin Mei-Chen , Hsieh Ching-Liang
Published: December 2020

Depression is a risk factor for subsequent Parkinson's disease (PD). Some patients with depression undergo acupuncture treatment because of other diseases in Taiwan. Therefore, the present study used data from Taiwan's National Health Insurance Research Database (NHIRD) to investigate the incidence of PD in patients having depression with and without acupuncture treatment. We conducted a retrospective study of a matched cohort of 48,981 patients with newly diagnosed depression between 2000 and 2012 who were selected from the NHIRD. The 1:1 propensity score method was utilized to match an equal number of patients (N = 9,189) in the acupuncture and non-acupuncture cohorts. We employed Cox proportional hazard models to evaluate the risk of PD. The cumulative incidence of PD in both cohorts was estimated using the Kaplan–Meier method, and the difference was examined through a log-rank test. Patients with depression who received acupuncture treatment demonstrated a lower risk of PD [adjusted hazard ratio (aHR) = 0.39, 95% confidence interval = 0.31–0.49] than those who did not undergo acupuncture treatment, after adjusting for age, sex, insurance amount, geographic region, urbanization levels, comorbidities, and drugs. The cumulative incidence of PD was significantly lower in the acupuncture cohort than in the non-acupuncture cohort (log-rank test, p < 0.001). The database did not indicate the severity of depression and acupoints. The results suggest that acupuncture treatment significantly reduced the development of PD in patients with depression; however, a future study should be conducted to provide more objective evidence.
Neural Generators Underlying Temporal Envelope Processing Show Altered Responses and Hemispheric Asymmetry Across Age
Authors: Farahani Ehsan Darestani , Wouters Jan , van Wieringen Astrid
Published: December 2020

Speech understanding problems are highly prevalent in the aging population, even when hearing sensitivity is clinically normal. These difficulties are attributed to changes in central temporal processing with age and can potentially be captured by age-related changes in neural generators. The aim of this study is to investigate age-related changes in a wide range of neural generators during temporal processing in middle-aged and older persons with normal audiometric thresholds. A minimum-norm imaging technique is employed to reconstruct cortical and subcortical neural generators of temporal processing for different acoustic modulations. The results indicate that for relatively slow modulations (<50 Hz), the response strength of neural sources is higher in older adults than in younger ones, while the phase-locking does not change. For faster modulations (80 Hz), both the response strength and the phase-locking of neural sources are reduced in older adults compared to younger ones. These age-related changes in temporal envelope processing of slow and fast acoustic modulations are possibly due to loss of functional inhibition, which is accompanied by aging. Both cortical (primary and non-primary) and subcortical neural generators demonstrate similar age-related changes in response strength and phase-locking. Hemispheric asymmetry is also altered in older adults compared to younger ones. Alterations depend on the modulation frequency and side of stimulation. The current findings at source level could have important implications for the understanding of age-related changes in auditory temporal processing and for developing advanced rehabilitation strategies to address speech understanding difficulties in the aging population.
Nanoparticle-Based Sustainable Agriculture and Food Science: Recent Advances and Future Outlook
Authors: Mittal Deepti , Kaur Gurjeet , Singh Parul , Yadav Karmveer , Ali Syed Azmal
Published: December 2020

In the current scenario, it is an urgent requirement to satisfy the nutritional demands of the rapidly growing global population. Using conventional farming, nearly one third of crops get damaged, mainly due to pest infestation, microbial attacks, natural disasters, poor soil quality, and lesser nutrient availability. More innovative technologies are immediately required to overcome these issues. In this regard, nanotechnology has contributed to the agrotechnological revolution that has imminent potential to reform the resilient agricultural system while promising food security. Therefore, nanoparticles are becoming a new-age material to transform modern agricultural practices. The variety of nanoparticle-based formulations, including nano-sized pesticides, herbicides, fungicides, fertilizers, and sensors, have been widely investigated for plant health management and soil improvement. In-depth understanding of plant and nanomaterial interactions opens new avenues toward improving crop practices through increased properties such as disease resistance, crop yield, and nutrient utilization. In this review, we highlight the critical points to address current nanotechnology-based agricultural research that could benefit productivity and food security in future.
Contact-Chemosensory Evolution Underlying Reproductive Isolation in Drosophila Species
Authors: Sato Kosei , Yamamoto Daisuke
Published: December 2020

The main theme of the review is how changes in pheromone biochemistry and the sensory circuits underlying pheromone detection contribute to mate choice and reproductive isolation. The review focuses primarily on gustatory and non-volatile signals in Drosophila. Premating isolation is prevalent among closely related species. In Drosophila, preference for conspecifics against other species in mate choice underlies premating isolation, and such preference relies on contact chemosensory communications between a female and male along with other biological factors. For example, although D. simulans and D. melanogaster are sibling species that yield hybrids, their premating isolation is maintained primarily by the contrasting effects of 7,11-heptacosadiene (7,11-HD), a predominant female pheromone in D. melanogaster, on males of the two species: it attracts D. melanogaster males and repels D. simulans males. The contrasting preference for 7,11-HD in males of these two species is mainly ascribed to opposite effects of 7,11-HD on neural activities in the courtship decision-making neurons in the male brain: 7,11-HD provokes both excitatory and inhibitory inputs in these neurons and differences in the balance between the two counteracting inputs result in the contrasting preference for 7,11-HD, i.e., attraction in D. melanogaster and repulsion in D. simulans. Introduction of two double bonds is a key step in 7,11-HD biosynthesis and is mediated by the desaturase desatF, which is active in D. melanogaster females but transcriptionally inactivated in D. simulans females. Thus, 7,11-HD biosynthesis diversified in females and 7,11-HD perception diversified in males, yet it remains elusive how concordance of the changes in the two sexes was attained in evolution.
Evaluation of Synergy Extrapolation for Predicting Unmeasured Muscle Excitations from Measured Muscle Synergies
Authors: Ao Di , Shourijeh Mohammad S. , Patten Carolynn , Fregly Benjamin J.
Published: December 2020

Electromyography (EMG)-driven musculoskeletal modeling relies on high-quality measurements of muscle electrical activity to estimate muscle forces. However, a critical challenge for practical deployment of this approach is missing EMG data from muscles that contribute substantially to joint moments. This situation may arise due to either the inability to measure deep muscles with surface electrodes or the lack of a sufficient number of EMG channels. Muscle synergy analysis (MSA) is a dimensionality reduction approach that decomposes a large number of muscle excitations into a small number of time-varying synergy excitations along with time-invariant synergy weights that define the contribution of each synergy excitation to all muscle excitations. This study evaluates how well missing muscle excitations can be predicted using synergy excitations extracted from muscles with available EMG data (henceforth called “synergy extrapolation” or SynX). The method was evaluated using a gait data set collected from a stroke survivor walking on an instrumented treadmill at self-selected and fastest-comfortable speeds. The evaluation process started with full calibration of a lower-body EMG-driven model using 16 measured EMG channels (collected using surface and fine wire electrodes) per leg. One fine wire EMG channel (either iliopsoas or adductor longus) was then treated as unmeasured. The synergy weights associated with the unmeasured muscle excitation were predicted by solving a nonlinear optimization problem where the errors between inverse dynamics and EMG-driven joint moments were minimized. The prediction process was performed for different synergy analysis algorithms (principal component analysis and non-negative matrix factorization), EMG normalization methods, and numbers of synergies. SynX performance was most influenced by the choice of synergy analysis algorithm and number of synergies. Principal component analysis with five or six synergies consistently predicted unmeasured muscle excitations the most accurately and with the greatest robustness to EMG normalization method. Furthermore, the associated joint moment matching accuracy was comparable to that produced by initial EMG-driven model calibration using all 16 EMG channels per leg. SynX may facilitate the assessment of human neuromuscular control and biomechanics when important EMG signals are missing.
Sensorimotor vs. Motor Upper Limb Therapy for Patients With Motor and Somatosensory Deficits: A Randomized Controlled Trial in the Early Rehabilitation Phase After Stroke
Authors: De Bruyn Nele , Saenen Leen , Thijs Liselot , Van Gils Annick , Ceulemans Eva , Essers Bea , Lafosse Christophe , Michielsen Marc , Beyens Hilde , Schillebeeckx Fabienne , Alaerts Kaat , Verheyden Geert
Published: December 2020

Background:Somatosensory function plays an important role in motor learning. More than half of the stroke patients have somatosensory impairments in the upper limb, which could hamper recovery.

Question:Is sensorimotor upper limb (UL) therapy of more benefit for motor and somatosensory outcome than motor therapy?

Design:Randomized assessor- blinded multicenter controlled trial with block randomization stratified for neglect, severity of motor impairment, and type of stroke.

Participants:40 first-ever stroke patients with UL sensorimotor impairments admitted to the rehabilitation center.

Intervention:Both groups received 16 h of additional therapy over 4 weeks consisting of sensorimotor (N= 22) or motor (N= 18) UL therapy.

Outcome measures:Action Research Arm test (ARAT) as primary outcome, and other motor and somatosensory measures were assessed at baseline, post-intervention and after 4 weeks follow-up.

Results:No significant between-group differences were found for change scores in ARAT or any somatosensory measure between the three time points. For UL impairment (Fugl-Meyer assessment), a significant greater improvement was found for the motor group compared to the sensorimotor group from baseline to post-intervention [mean (SD) improvement 14.65 (2.19) vs. 5.99 (2.06);p= 0.01] and from baseline to follow-up [17.38 (2.37) vs. 6.75 (2.29);p= 0.003].

Conclusion:UL motor therapy may improve motor impairment more than UL sensorimotor therapy in patients with sensorimotor impairments in the early rehabilitation phase post stroke. For these patients, integrated sensorimotor therapy may not improve somatosensory function and may be less effective for motor recovery.

Clinical Trial Registration:www.ClinicalTrials.gov, identifier NCT03236376.
Optimizing Patient Selection for Interhospital Transfer and Endovascular Therapy in Acute Ischemic Stroke: Real-World Data From a Supraregional, Hub-and-Spoke Neurovascular Network in Germany
Authors: Stefanou Maria-Ioanna , Stadler Vera , Baku Dominik , Hennersdorf Florian , Ernemann Ulrike , Ziemann Ulf , Poli Sven , Mengel Annerose
Published: December 2020

Background: Interhospital transfer for endovascular treatment (EVT) within neurovascular networks might result in transfer of patients who will not undergo EVT (futile transfer). Limited evidence exists on factors associated with the primary patient selection for interhospital transfer from primary stroke centers (PSCs) to comprehensive stroke centers (CSCs), or EVT-workflow parameters that may render a transfer futile.

Methods: A prospective, registry-based study was performed between July 1, 2017 and June 30, 2018, at a hub-and-spoke neurovascular network in southwest Germany, comprising 12 referring PSCs and one designated CSC providing round-the-clock EVT at the University Hospital Tübingen. Patients with acute ischemic stroke due to suspected large artery occlusion (LAO) were included upon emergency interhospital transfer inquiry (ITI).

Results: ITI was made for 154 patients, 91 (59%) of whom were transferred to the CSC. Non-transferred patients (41%) had significantly higher premorbid modified Rankin scale scores (mRS) compared to transferred patients [median (IQR): 2 (1–3) vs. 0 (0–1), p < 0.001]. Interhospital transfer was denied due to: distal vessel occlusion (44.4%), or non-verifiable LAO (33.3%) in computed tomography angiography (CTA) upon teleconsultation by CSC neuroradiologists; limited Stroke-Unit or ventilation capacity (9.5%), or limited neuroradiological capacity at the CSC (12.7%). The CT-to-ITI interval was significantly longer in patients denied interhospital transfer [median (IQR): 43 (29–56) min] compared to transferred patients [29 (15–55), p = 0.029]. No further differences in EVT-workflow, and no differences in the 3-month mRS outcomes were noted between non-transferred and transferred patients [median (IQR): 2 (0–5) vs. 3 (1–4), p = 0.189]. After transfer to the CSC, 44 (48%) patients underwent EVT. The Alberta stroke program early CT score [ORadj (95% CI): 1.786 (1.573–2.028), p < 0.001] and the CT-to-ITI interval [0.994 (0.991–0.998), p = 0.001] were significant predictors of the likelihood of EVT performance.

Conclusion: Our findings show that hub-and-spoke neurovascular network infrastructures efficiently enable access to EVT to patients with AIS due to LAO, who are primarily admitted to PSCs without on-site EVT availability. As in real-world settings optimal allocation of EVT resources is warranted, teleconsultation by experienced endovascular interventionists and prompt interhospital-transfer-inquiries are crucial to reduce the futile transfer rates and optimize patient selection for EVT within neurovascular networks.
Gene Therapy Vector Encoding Neuropeptide Y and Its Receptor Y2 for Future Treatment of Epilepsy: Preclinical Data in Rats
Authors: Szczygieł Julia Alicja , Danielsen Kira Iben , Melin Esbjörn , Rosenkranz Søren Hofman , Pankratova Stanislava , Ericsson Annika , Agerman Karin , Kokaia Merab , Woldbye David Paul Drucker
Published: December 2020

Gene therapy to treat pharmacoresistant temporal lobe epilepsy in humans is now being developed using an AAV vector (CG01) that encodes the combination of neuropeptide Y and its antiepileptic receptor Y2. With this in mind, the present study aimed to provide important preclinical data on the effects of CG01 on the duration of transgene expression, cellular tropism, and potential side effects on body weight and cognitive function. The CG01 vector was administered unilaterally into the dorsal and ventral hippocampus of adult male rats and expression of both transgenes was found to remain elevated without a sign of decline at 6 months post-injection. CG01 appeared to mediate expression selectively in hippocampal neurons, without expression in astrocytes or oligodendrocytes. No effects were seen on body weight as well as on short- or long-term memory as revealed by testing in the Y-maze or Morris water maze tests. Thus these data show that unilateral CG01 vector treatment as future gene therapy in pharmacoresistant temporal lobe epilepsy patients should result in stable and long-term expression predominantly in neurons and be well tolerated without side effects on body weight and cognitive function.
Use of UHPH to Obtain Juices With Better Nutritional Quality and Healthier Wines With Low Levels of SO2
Authors: Morata Antonio , Guamis Buenaventura
Published: December 2020

Ultra-high pressure homogenization (UHPH) is a high pressure technique in which a fluid is pressurized by pumping at higher than 200 MPa and instantaneously depressurized at atmospheric pressure across a special valve. The full process takes <0.2 s and the in-valve time is <0.02 s. In the valve, extremely intense impacts and shear forces produce the nanofragmentation of biological tissue at a range of 100–300 nm. The antimicrobial effect is highly effective, reaching easily inactivation levels higher than 6-log cycles even at low in-valve temperatures. At in-valve temperatures of 140–150°C (0.02 s) the destruction of thermoresistant spores is possible. Even when the temperature in-valve can be elevated (70–150°C), it can be considered a gentle technology because of the tremendously short processing time. It is easy to get outlet temperatures after valve of 20–25°C by the expansion and assisted by heat exchangers. Thermal markers as hydroxymethylfurfural (HMF) are not formed, nor are deleterious effects observed in sensitive compounds as terpenes or anthocyanins, probably because of the low effect in covalent bonds of small molecules of the high-pressure techniques compared with thermal technologies. Additionally, intense inactivation of oxidative enzymes is observed, therefore protecting the sensory and nutritional quality of fruit juices and avoiding or reducing the use of antioxidants as sulphites. UHPH can be consider a powerful and highly effective continuous and sterilizing technology without thermal repercussions, able to keep fresh juices with most of their initial sensory and nutritional quality and allowing high-quality and natural fermented derivatives as wine.
Systematic Analysis of microRNA Biomarkers for Diagnosis, Prognosis, and Therapy in Patients With Clear Cell Renal Cell Carcinoma
Authors: Cheng Guiyun , Li Mengru , Ma Xiaoyu , Nan Fangmei , Zhang Lu , Yan Zhongyi , Li Huimin , Zhang Guosen , Han Yali , Xie Longxiang , Guo Xiangqian
Published: December 2020

The ever-increasing morbidity and mortality of clear cell renal cell carcinoma (ccRCC) urgently demands updated biomarkers. MicroRNAs (miRNAs) are involved in diverse biological processes such as cell proliferation, differentiation, apoptosis by regulating their target genes’ expression. In kidney cancers, miRNAs have been reported to be involved in tumorigenesis and to be the diagnostic, prognostic, and therapeutic response biomarkers. Here, we performed a systematic analysis for ccRCC-related miRNAs as biomarkers by searching keywords in the NCBI PubMed database and found 118 miRNAs as diagnostic biomarkers, 28 miRNAs as prognostic biomarkers, and 80 miRNAs as therapeutic biomarkers in ccRCC. miRNA-21, miRNA-155, miRNA-141, miRNA-126, and miRNA-221, as significantly differentially expressed miRNAs between cancer and normal tissues, play extensive roles in the cell proliferation, differentiation, apoptosis of ccRCC. GO and KEGG enrichment analysis of these miRNAs’ target genes through Metascape showed these target genes are enriched in Protein Domain Specific Binding (GO:0019904). In this paper, we identified highly specific miRNAs in the pathogenesis of ccRCC and explored their potential applications for diagnosis, prognosis, and treatment of ccRCC.
miR-631 Inhibits Intrahepatic Metastasis of Hepatocellular Carcinoma by Targeting PTPRE
Authors: Chen Bingqing , Liao Zhibin , Qi Yongqiang , Zhang Hongwei , Su Chen , Liang Huifang , Zhang Bixiang , Chen Xiaoping
Published: December 2020

MicroRNAs (miRNAs) have been reported to play critical roles in the pathological development of hepatocellular carcinoma (HCC), one of the most common cancers in the world. Our study aims to explore the expression, function and mechanism of miR-631 in HCC. Our findings are that expression of miR-631 is significantly down-regulated in HCC tissue compared with that in adjacent non-cancerous tissue, and low expression of miR-631 in HCC tissue is associated with cirrhosis, multiple tumors, incomplete tumor encapsulation, poor tumor differentiation, and high TNM stage. Our test results showed that miR-631 could inhibit migration, invasion, epithelial–mesenchymal transition (EMT) and intrahepatic metastasis of HCC. Receptor-type protein tyrosine phosphatase epsilon (PTPRE) as a downstream target of miR-631 could promote migration, invasion and EMT of HCC cells. Besides, the expression of PTPRE had a negative correlation with the expression of miR-631 both in vivo and in vitro, and increasing expression of PTPRE could reverse inhibitory effects of miR-631 in HCC cells. In sum, our study first demonstrated that miR-631 targeted PTPRE to inhibit intrahepatic metastasis in HCC. We gain insights from these findings into the mechanism of miRNAs regulation in HCC metastasis and further introduce a novel therapeutic target for HCC treatment.
Prophylactic AEDs Treatment for Patients With Supratentorial Meningioma Does Not Reduce the Rate of Perioperative Seizures: A Retrospective Single-Center Cohort Study
Authors: Yang Ming , Cheng Yong-Ran , Zhou Meng-Yun , Wang Ming-Wei , Ye Lan , Xu Zu-Cai , Feng Zhan-Hui , Ma Xun-Tai
Published: December 2020

Meningiomas, the most common brain tumor, inevitably require surgical treatment. However, the efficacy of prophylactic antiepileptic drugs (AEDs), in reducing the frequency of new-onset seizures during the perioperative period remains controversial. To further clarify if prophylactic antiepileptic drug treatment for patients with meningioma had value, we reviewed the medical records of 186 supratentorial meningioma patients who were operated at our hospital between 2016 and 2018. SPSS 24.0 software was used for statistical analysis. The results of univariate analysis showed that factors including age, sex, the course of the disease (years), maximum cross-sectional area of the tumor, location of the tumor, multiple or single tumors, adjacent to the cortex, peritumoral brain edema, World Health Organization classification, and peritumoral adhesion were not associated with perioperative seizures (P >0.05). Furthermore, the results of multivariate analysis revealed hydrocephalus (OR 4.87 P = 0.05) and non-skull base location (OR 1.88 P = 0.04) were significant risk factors for perioperative in-hospital seizures. Prophylactic valproic acid treatment did not contribute to the alleviation of perioperative seizures (OR 1.76 P = 0.04). However, Multivariate logistic regression analyses excluding the patients with seizures before operation confirmed prophylactic valproic acid treatment did not reduce the frequency of seizures during the perioperative period (OR 1.84 P = 0.04). Taken together, the data suggest that prophylactic valproic acid treatment for patients with supratentorial meningioma does not reduce the rate of perioperative seizures.
A Special Report on 2019 International Planning Competition and a Comprehensive Analysis of Its Results
Authors: Chen Jiayun , Dai Jianrong , Nobah Ahmad , Bai Sen , Bi Nan , Lai Youqun , Li Minghui , Tian Yuan , Wang Xuetao , Fu Qi , Liang Bin , Zhang Tao , Xia Wenlong , Xu Yuan , Ren Wenting , Yan Xuena , Zhu Ji , Chen Deqi , Yang Jiming
Published: December 2020

Purpose

The aim of this work is to introduce the 2019 International Planning Competition and to analyze its results.

Methods and materials

A locally advanced non-small cell lung cancer (LA-NSCLC) case using the simultaneous integrated boost approach was selected. The plan quality was evaluated by using a ranking system in accordance with practice guidelines. Planners used their clinical Treatment Planning System (TPS) to generate the best possible plan along with a survey, designed to obtain medical physics aspects information. We investigated the quality of the large population of plans designed by worldwide planners using different planning and delivery systems. The correlations of plan quality with relevant planner characteristics (work experience, department scale, and competition experience) and with technological parameters (TPS and modality) were examined.

Results

The number of the qualified plans was 287 with a wide range of scores (38.61–97.99). The scores showed statistically significant differences by the following factors: 1) department scale: the mean score (89.76 ± 8.36) for planners from the departments treating >2,000 patients annually was the highest of all; 2) competition experience: the mean score for the 107 planners with previous competition experience was 88.92 ± 9.59, statistically significantly from first-time participants (p = .001); 3) techniques: the mean scores for planners using VMAT (89.18 ± 6.43) and TOMO (90.62 ± 7.60) were higher than those using IMRT (82.28 ± 12.47), with statistical differences (p <.001). The plan scores were negligibly correlated with the planner’s years of work experience or the type of TPS used. Regression analysis demonstrated that plan score was associated with dosimetric objectives that were difficult to achieve, which is generally consistent with a clinical practice evaluation. However, 51.2% of the planners abandoned the difficult component of total lung receiving a dose of 5 Gy in their plan design to achieve the optimal plan.

Conclusion

The 2019 international planning competition was carried out successfully, and its results were analyzed. Plan quality was not correlated with work experiences or the TPS used, but it was correlated with department scale, modality, and competition experience. These findings differed from those reported in previous studies.
Transient Receptor Potential Melastatin 8 (TRPM8) Channel Regulates Proliferation and Migration of Breast Cancer Cells by Activating the AMPK-ULK1 Pathway to Enhance Basal Autophagy
Authors: Huang Yuan , Li Shi , Jia Zhenhua , Zhao Weiwei , Zhou Cefan , Zhang Rui , Ali Declan William , Michalak Marek , Chen Xing-Zhen , Tang Jingfeng
Published: December 2020

The calcium-permeable cation channel TRPM8 (transient receptor potential melastatin 8) is a member of the TRP superfamily of cation channels that is upregulated in various types of cancer with high levels of autophagy, including prostate, pancreatic, breast, lung, and colon cancers. Autophagy is closely regulated by AMP-activated protein kinase (AMPK) and plays an important role in tumor growth by generating nutrients through degradation of intracellular structures. Additionally, AMPK activity is regulated by intracellular Ca2+ concentration. Considering that TRPM8 is a non-selective Ca2+-permeable cation channel and plays a key role in calcium homoeostasis, we hypothesized that TRPM8 may control AMPK activity thus modulating cellular autophagy to regulate the proliferation and migration of breast cancer cells. In this study, overexpression of TRPM8 enhanced the level of basal autophagy, whereas TRPM8 knockdown reduced the level of basal autophagy in several types of mammalian cancer cells. Moreover, the activity of the TRPM8 channel modulated the level of basal autophagy. The mechanism of regulation of autophagy by TRPM8 involves autophagy-associated signaling pathways for activation of AMPK and ULK1 and phagophore formation. Impaired AMPK abolished TRPM8-dependent regulation of autophagy. TRPM8 interacts with AMPK in a protein complex, and cytoplasmic C-terminus of TRPM8 mediates the TRPM8–AMPK interaction. Finally, basal autophagy mediates the regulatory effects of TRPM8 on the proliferation and migration of breast cancer cells. Thus, this study identifies TRPM8 as a novel regulator of basal autophagy in cancer cells acting by interacting with AMPK, which in turn activates AMPK to activate ULK1 in a coordinated cascade of TRPM8-mediated breast cancer progression.
Duration of FOLFOX Adjuvant Chemotherapy in High-Risk Stage II and Stage III Colon Cancer With Deficient Mismatch Repair
Authors: Hu Huabin , Wu Zehua , Wang Chao , Huang Yan , Zhang Jianwei , Cai Yue , Xie Xiaoyu , Li Jianxia , Shen Cailu , Li Weiwei , Ling Jiayu , Xu Xuehu , Deng Yanhong
Published: December 2020

Background

We evaluated the impact of 3 months of mFOLFOX6 adjuvant chemotherapy or surgery alone in comparison with 6 months of mFOLFOX6 on disease-free survival (DFS) in deficient mismatch repair (dMMR) colon cancer (CC) patients.

Methods

This retrospective study identified a cohort of patients with high-risk stage II and III dMMR CC who underwent curative surgery between May 2011 and July 2019. DFS was compared using the Kaplan-Meier survival methods and Cox proportional hazards models. Propensity-score matching was performed to reduce imbalance in baseline characteristics.

Results

A total of 242 dMMR CC patients were identified; 66 patients received 6 months of mFOLFOX6, 87 patients received 3 months of mFOLFOX6, and 89 patients were treated with surgery alone. The 3-year DFS rate was 72.8% in 3-month therapy group and 86.1% in 6-month therapy group, with a hazard ratio (HR) of 2.78 (95CI%, 1.18 to 6.47; P= 0.019). The difference in DFS between surgery alone group and 6-month therapy group was also observed but was nonsignificant (HR= 2.30, 95%CI, 0.99 to 5.38; P=0.054). The benefit of 6-month therapy in DFS compared with 3-month therapy group was pronounced for patients with stage III (HR=2.81, 95%CI, 1.03 to 7.67; P=0.044) but not for high-risk stage II patients. Propensity score matched analysis confirmed a DFS benefit in the 6-month therapy group.

Conclusion

This study suggested that a 6-month duration of mFOLFOX6 adjuvant chemotherapy in dMMR CC patients may be associated with improved DFS compared with 3-month therapy, particularly in patients with stage III. The observational nature of the study implies caution should be taken in the interpretation of these results.
Iron Supplementation Interferes With Immune Therapy of Murine Mammary Carcinoma by Inhibiting Anti-Tumor T Cell Function
Authors: Tymoszuk Piotr , Nairz Manfred , Brigo Natascha , Petzer Verena , Heeke Simon , Kircher Brigitte , Hermann-Kleiter Natascha , Klepsch Victoria , Theurl Igor , Weiss Günter , Pfeifhofer-Obermair Christa
Published: December 2020

Iron is both, an essential compound for many metabolic processes, and iron deficiency can impact on the proliferation of cells including lymphocytes but also tumor cells. On the other hand, excess iron-catalyzed radical formation can induce cellular toxicity which has been previously demonstrated for T cells in hereditary iron overload. Despite these interconnections, little is known on the effects of clinically approved intravenous iron supplements for curing cancer-related anemia, on T cell differentiation, tumor proliferation, anti-tumor T cell responses and, of clinical importance, on efficacy of cancer immunotherapies. Herein, we analyzed the effects of intravenous iron supplementation on T cell function and on the effectiveness of anti-cancer chemotherapy with IL-2/doxorubicin or immunotherapy with checkpoint-inhibitor anti-PD-L1 in C57Bl/6N female mice with implanted E0771 mammary carcinomas. We found that iron application resulted to an increased availability of iron in the tumor microenvironment and stimulation of tumor growth. In parallel, iron application inhibited the activation, expansion and survival of cytotoxic CD8+ T cells and of CD4+ T helper cells type 1 and significantly reduced the efficacy of the investigated anti-cancer treatments. Our results indicate that iron administration has a tumor growth promoting effect and impairs anti-cancer responses of tumor infiltrating T lymphocytes along with a reduced efficacy of anti-cancer therapies. Iron supplementation in cancer patients, especially in those treated with immunotherapies in a curative setting, may be thus used cautiously and prospective studies have to clarify the impact of such intervention on the outcome of patients.
Intraoperative Confocal Laser Endomicroscopy Ex Vivo Examination of Tissue Microstructure During Fluorescence-Guided Brain Tumor Surgery
Authors: Belykh Evgenii , Zhao Xiaochun , Ngo Brandon , Farhadi Dara S. , Byvaltsev Vadim A. , Eschbacher Jennifer M. , Nakaji Peter , Preul Mark C.
Published: December 2020

Background

Noninvasive intraoperative optical biopsy that provides real-time imaging of histoarchitectural (cell resolution) features of brain tumors, especially at the margin of invasive tumors, would be of great value. To assess clinical-grade confocal laser endomicroscopy (CLE) and to prepare for its use intraoperatively in vivo, we performed an assessment of CLE ex vivo imaging in brain lesions.

Methods

Tissue samples from patients who underwent intracranial surgeries with fluorescein sodium (FNa)–based wide-field fluorescence guidance were acquired for immediate intraoperative ex vivo optical biopsies with CLE. Hematoxylin-eosin–stained frozen section analysis of the same specimens served as the gold standard for blinded neuropathology comparison. FNa 2 to 5 mg/kg was administered upon induction of anesthesia, and FNa 5 mg/kg was injected for CLE contrast improvement. Histologic features were identified, and the diagnostic accuracy of CLE was assessed.

Results

Of 77 eligible patients, 47 patients with 122 biopsies were enrolled, including 32 patients with gliomas and 15 patients with other intracranial lesions. The positive predictive value of CLE optical biopsies was 97% for all specimens and 98% for gliomas. The specificity of CLE was 90% for all specimens and 94% for gliomas. The second FNa injection in seven patients, a mean of 2.6 h after the first injection, improved image quality and increased the percentage of accurately diagnosed images from 67% to 93%. Diagnostic CLE features of lesional glioma biopsies and normal brain were identified. Seventeen histologic features were identified.

Conclusions

Results demonstrated high specificity and positive predictive value of ex vivo intraoperative CLE optical biopsies and justify an in vivo intraoperative trial. This new portable, noninvasive intraoperative imaging technique provides diagnostic features to discriminate lesional tissue with high specificity and is feasible for incorporation into the fluorescence-guided surgery workflow, particularly for patients with invasive brain tumors.
Impact of Time to Castration Resistance on Cytoreductive Radiotherapy in Metastatic Castration-Resistant Prostate Cancer
Authors: Mai Lixin , Zhang Zitong , Li Yonghong , Liu Ruiqi , Li Jibin , Huang Sijuan , Lin Maosheng , Liu Boji , Cao Wufei , Wu Jianhua , Liu Mengzhong , Zhou Fangjian , Liu Yang , He Liru
Published: December 2020

Background

The role of local radiotherapy in metastatic castration-resistant prostate cancer (mCRPC) remains undefined. This study aimed to identify the value of local radiotherapy and potential candidates for mCRPC.

Methods

A total of 215 patients with mCRPC treated with or without cytoreductive radiotherapy (CRT) between June 2011 and February 2019 were analyzed. Overall survival (OS) was calculated from the onset of mCRPC. The receiver-operating characteristic (ROC) curve was used to find the cutoff point for time to castration resistance (TCR).

Results

One-hundred and fifty-five (72.1%) patients received abiraterone after mCRPC, and 54 (25.1%) patients received CRT. The median TCR was 14.9 months. After a median follow-up of 31.7 months, the median OS was 33.3 months. The Eastern Cooperative Oncology Group (ECOG) performance scores 0–1, oligometastases, abiraterone after mCRPC, CRT, and TCR ≥9 months were independent prognostic factors for better OS. Stratified analyses showed improved survival when CRT was applied to patients treated with abiraterone (HR 0.44; 95% CI 0.23–0.83; P = 0.012) and TCR ≥9 months (HR 0.39; 95% CI 0.21–0.74; P = 0.004). The percentage of PSA response after radiotherapy was higher in patients with TCR ≥9 months compared to those with TCR <9 months. No grade 3 or worse adverse events after radiotherapy were reported.

Conclusions

ECOG performance score, oligometastases, abiraterone application, TCR and CRT were independent prognostic factors for OS in patients with mCRPC. Patients with a short duration of response to primary androgen deprivation therapy were less likely to benefit from CRT.
Pediatric Inflammatory Multisystem Syndrome and Rheumatic Diseases During SARS-CoV-2 Pandemic
Authors: Schvartz Adrien , Belot Alexandre , Kone-Paut Isabelle
Published: December 2020

Globally, the coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), appeared to have a milder clinical course in children compared to adults. As severe forms of COVID-19 in adults included an aberrant systemic immune response, children with chronic systemic inflammatory diseases were cautiously followed. No evidence for a specific susceptibility was identified in this pediatric population. European and US Pediatricians started to notice cases of myocarditis, sharing some features with toxic shock syndrome, Kawasaki disease, and macrophage activation syndrome in otherwise healthy patients. Multisystem Inflammatory Syndrome in Children (MIS-C) and Pediatric Inflammatory Multisystem Syndrome (PIMS) have designated this new entity in the US and Europe, respectively. The spectrum of severity ranged from standard hospitalization to pediatric intensive care unit management. Most patients had a clinical history of exposure to COVID-19 patients and/or SARS-COV2 biological diagnosis. Clinical presentations include fever, cardiac involvement, gastro-intestinal symptoms, mucocutaneous manifestations, hematological features, or other organ dysfunctions. The temporal association between the pandemic peaks and outbreaks of PIMS seems to be in favor of a post-infectious, immune-mediated mechanism. Thus, SARS-CoV2 can rarely be associated with severe systemic inflammatory manifestations in previously healthy children differently from adults highlighting the specific need for COVID-19 research in the pediatric population.
Quality Control of Radix Astragali (The Root of Astragalus membranaceus var. mongholicus) Along Its Value Chains
Authors: Bi Yaqiong , Bao Haiying , Zhang Chunhong , Yao Ruyu , Li Minhui
Published: December 2020

Radix Astragali (RA), the root of Astragalus membranaceus var. mongholicus (Bunge) P.K. Hsiao, known as “Huangqi” in Chinese, has been used as a traditional herbal medicine or food in China for more than 2,000 years and is now consumed globally. Unfortunately, the increasing demand for RA has led to the overexploitation of its wild stock, as well as quality problems, including adulteration and contamination. Therefore, the sustainable cultivation of RA is urgently needed. In the present research, semi-structured interviews and key informant interviews were conducted, over a 2-year period, to collect data from stakeholders in the main production areas; moreover, a targeted chemical analysis-based quality assessment strategy was applied to understand the quality of RA. Accordingly, 10 different types of value chains (VCs) were identified in RA production; meanwhile, the contents of the main active ingredients (astragaloside and calycosin-7-O-β-D-glucoside) were analyzed by HPLC-ELSD-UV and the yield of medicinal material was demined and further analyzed using k-means clustering analysis. The results show that the tight relationship between quality of the RA and stakeholders’ revenues among the VCs, which reflects a more general trend in the production system. Over the past few decades, vertical coordination has emerged increasingly in VCs of RA, which leads to a more coherent traceability system and rigorous regulations in the supply chains. Daodi herbs can be considered to be a standard that is distinctive with good quality characteristics that emphasize the origins of the medicinal plants. We find that the suitability of geographical areas and vertical integration can improve the VCs of RA, which further contributes to its quality control, as well as its sustainable production.
Grape Seed Proanthocyanidin Extract Ameliorates Cardiac Remodelling After Myocardial Infarction Through PI3K/AKT Pathway in Mice
Authors: Ruan Yongxue , Jin Qike , Zeng Jingjing , Ren Fangfang , Xie Zuoyi , Ji Kangting , Wu Lianpin , Wu Jingguo , Li Lei
Published: December 2020

Myocardial infarction is one of the most serious fatal diseases in the world, which is due to acute occlusion of coronary arteries. Grape seed proanthocyanidin extract (GSPE) is an active compound extracted from grape seeds that has anti-oxidative, anti-inflammatory and anti-tumor pharmacological effects. Natural products are cheap, easy to obtain, widely used and effective. It has been used to treat numerous diseases, such as cancer, brain injury and diabetes complications. However, there are limited studies on its role and associated mechanisms in myocardial infarction in mice. This study showed that GSPE treatment in mice significantly reduced cardiac dysfunction and improved the pathological changes due to MI injury.In vitro, GSPE inhibited the apoptosis of H9C2 cells after hypoxia culture, resulting in the expression of Bax decreased and the expression of Bcl-2 increased. The high expression of p-PI3K and p-AKT was detected in MI modelin vivoandin vitro. The use of the specific PI3K/AKT pathway inhibitor LY294002 regressed the cardio-protection of GSPE. Our results showed that GSPE could improve the cardiac dysfunction and remodeling induced by MI and inhibit cardiomyocytes apoptosis in hypoxic conditions through the PI3K/AKT signaling pathway.
Therapeutic Potential of Exosomes in Pulmonary Fibrosis
Authors: Xie Linshen , Zeng Ye
Published: December 2020

Pulmonary fibrosis is closely associated with the recruitment of fibroblasts from capillary vessels with damaged endothelial cells, the epithelial mesenchymal transition (EMT) of type II alveolar epithelial cells, and the transformation of fibroblasts to myofibroblasts. Recent studies suggest that EMT is a key factor in the pathogenesis of pulmonary fibrosis, as the disruption of EMT-related effector molecules can inhibit the occurrence and development of PF. With the numerous advancements made in molecular biology in recent years, researchers have discovered that exosomes and their cargos, such as miRNAs, lncRNAs, and proteins, can promote or inhibit the EMT, modulate the transformation of fibroblasts into myofibroblasts, contribute to the proliferation of fibroblasts and promote immunoregulatory and mitochondrial damage during pulmonary fibrosis. Exosomes are key factors regulating the differentiation of bone marrow mesenchymal stem cells (BMSCs) into myofibroblasts. Interestingly, exosomes derived from BMSCs under pathological and physiological conditions may promote or inhibit the EMT of type II alveolar epithelial cells and the transformation of fibroblasts into myofibroblasts to regulate pulmonary fibrosis. Thus, exosomes may become a new direction in the study of drugs for the treatment of pulmonary fibrosis.