bluuebunny/crossref_metadata_2025 huggingface dataset:
Delayed Neurosurgical Intervention in Traumatic Brain Injury Patients Referred From Primary Hospitals Is Not Associated With an Unfavorable Outcome
Authors: Grevfors Niklas , Lindblad Caroline , Nelson David W. , Svensson Mikael , Thelin Eric Peter , Rubenson Wahlin Rebecka
Published: January 2021

Background: Secondary transports of patients suffering from traumatic brain injury (TBI) may result in a delayed management and neurosurgical intervention, which is potentially detrimental. The aim of this study was to study the effect of triaging and delayed transfers on outcome, specifically studying time to diagnostics and neurosurgical management.

Methods: This was a retrospective observational cohort study of TBI patients in need of neurosurgical care, 15 years and older, in the Stockholm Region, Sweden, from 2008 throughout 2014. Data were collected from pre-hospital and in-hospital charts. Known TBI outcome predictors, including the protein biomarker of brain injury S100B, were used to assess injury severity. Characteristics and outcomes of direct trauma center (TC) and those of secondary transfers were evaluated and compared. Functional outcome, using the Glasgow Outcome Scale, was assessed in survivors at 6–12 months after trauma. Regression models, including propensity score balanced models, were used for endpoint assessment.

Results: A total of n = 457 TBI patients were included; n = 320 (70%) patients were direct TC transfers, whereas n = 137 (30%) were secondary referrals. In all, n = 295 required neurosurgery for the first 24 h after trauma (about 75% of each subgroup). Direct TC transfers were more severely injured (median Glasgow Coma Scale 8 vs. 13) and more often suffered a high energy trauma (31 vs. 2.9%) than secondary referrals. Admission S100B was higher in the TC transfer group, though S100B levels 12–36 h after trauma were similar between cohorts. Direct or indirect TC transfer could be predicted using propensity scoring. The secondary referrals had a shorter distance to the primary hospital, but had later radiology and surgery than the TC group (all p < 0.001). In adjusted multivariable analyses with and without propensity matching, direct or secondary transfers were not found to be significantly related to outcome. Time from trauma to surgery did not affect outcome.

Conclusions: TBI patients secondary transported to a TC had surgical intervention performed hours later, though this did not affect outcome, presumably demonstrating that accurate pre-hospital triaging was performed. This indicates that for selected patients, a wait-and-see approach with delayed neurosurgical intervention is not necessarily detrimental, but warrants further research.
An Open Source Classifier for Bed Mattress Signal in Infant Sleep Monitoring
Authors: Ranta Jukka , Airaksinen Manu , Kirjavainen Turkka , Vanhatalo Sampsa , Stevenson Nathan J.
Published: January 2021

Objective

To develop a non-invasive and clinically practical method for a long-term monitoring of infant sleep cycling in the intensive care unit.

Methods

Forty three infant polysomnography recordings were performed at 1–18 weeks of age, including a piezo element bed mattress sensor to record respiratory and gross-body movements. The hypnogram scored from polysomnography signals was used as the ground truth in training sleep classifiers based on 20,022 epochs of movement and/or electrocardiography signals. Three classifier designs were evaluated in the detection of deep sleep (N3 state): support vector machine (SVM), Long Short-Term Memory neural network, and convolutional neural network (CNN).

Results

Deep sleep was accurately identified from other states with all classifier variants. The SVM classifier based on a combination of movement and electrocardiography features had the highest performance (AUC 97.6%). A SVM classifier based on only movement features had comparable accuracy (AUC 95.0%). The feature-independent CNN resulted in roughly comparable accuracy (AUC 93.3%).

Conclusion

Automated non-invasive tracking of sleep state cycling is technically feasible using measurements from a piezo element situated under a bed mattress.

Significance

An open source infant deep sleep detector of this kind allows quantitative, continuous bedside assessment of infant’s sleep cycling.
Power Comparisons and Clinical Meaning of Outcome Measures in Assessing Treatment Effect in Cancer Cachexia: Secondary Analysis From a Randomized Pilot Multimodal Intervention Trial
Authors: Balstad Trude R. , Brunelli Cinzia , Pettersen Caroline H. , Schønberg Svanhild A. , Skorpen Frank , Fallon Marie , Kaasa Stein , Bye Asta , Laird Barry J. A. , Stene Guro B. , Solheim Tora S.
Published: January 2021

Background: New clinical trials in cancer cachexia are essential, and outcome measures with high responsiveness to detect meaningful changes are crucial. This secondary analysis from a multimodal intervention trial estimates sensitivity to change and between treatment effect sizes (ESs) of outcome measures associated with body composition, physical function, metabolism, and trial intervention.

Methods: The study was a multicenter, open-label, randomized pilot study investigating the feasibility of a 6-week multimodal intervention [exercise, non-steroidal anti-inflammatory drugs, and oral nutritional supplements containing polyunsaturated fatty acids (n−3 PUFAs)] vs. standard cancer care in non-operable non-small-cell lung cancer and advanced pancreatic cancer. Body composition measures from computerized tomography scans and circulating biomarkers were analyzed.

Results: Forty-six patients were randomized, and the analysis included 22 and 18 patients in the treatment and control groups, respectively. The between-group ESs were high for body weight (ES = 1.2, p < 0.001), small for body composition and physical function [handgrip strength (HGS)] measures (ES < 0.25), moderate to high for n-3 PUFAs and 25-hydroxyvitamin D (25-OH vitamin D) (ES range 0.64–1.37, p < 0.05 for all), and moderate for serum C-reactive protein (ES = 0.53, p = 0.12). Analysis within the multimodal treatment group showed high sensitivity to change for adiponectin (ES = 0.86, p = 0.001) and n-3 PUFAs (ES > 0.8, p < 0.05 for all) and moderate for 25-OH vitamin D (ES = 0.49, p = 0.03). In the control group, a moderate sensitivity to change for body weight (ES = −0.84, p = 0.002) and muscle mass (ES = −0.67, p = 0.016) and a high sensitivity to change for plasma levels of 25-OH vitamin D (ES = −0.88, p = 0.002) were found.

Conclusion: Demonstrating high sensitivity to change and between treatment ES and body composition measures, body weight still stands out as a clinical and relevant outcome measure in cancer cachexia. Body composition and physical function measures clearly are important to address but demand large sample sizes to detect treatment group differences.

Trial registration:ClinicalTrials.gov identifier: NCT01419145.
LAT1 Protein Content Increases Following 12 Weeks of Resistance Exercise Training in Human Skeletal Muscle
Authors: Roberson Paul A. , Mobley C. Brooks , Romero Matthew A. , Haun Cody T. , Osburn Shelby C. , Mumford Petey W. , Vann Christopher G. , Greer Rory A. , Ferrando Arny A. , Roberts Michael D.
Published: January 2021

Introduction: Amino acid transporters are essential for cellular amino acid transport and promoting protein synthesis. While previous literature has demonstrated the association of amino acid transporters and protein synthesis following acute resistance exercise and amino acid supplementation, the chronic effect of resistance exercise and supplementation on amino acid transporters is unknown. The purpose herein was to determine if amino acid transporters and amino acid metabolic enzymes were related to skeletal muscle hypertrophy following resistance exercise training with different nutritional supplementation strategies.

Methods: 43 college-aged males were separated into a maltodextrin placebo (PLA, n = 12), leucine (LEU, n = 14), or whey protein concentrate (WPC, n = 17) group and underwent 12 weeks of total-body resistance exercise training. Each group's supplement was standardized for total energy and fat, and LEU and WPC supplements were standardized for total leucine (6 g/d). Skeletal muscle biopsies were obtained prior to training and ~72 h following each subject's last training session.

Results: All groups increased type I and II fiber cross-sectional area (fCSA) following training (p < 0.050). LAT1 protein increased following training (p < 0.001) and increased more in PLA than LEU and WPC (p < 0.050). BCKDHα protein increased and ATF4 protein decreased following training (p < 0.001). Immunohistochemistry indicated total LAT1/fiber, but not membrane LAT1/fiber, increased with training (p = 0.003). Utilizing all groups, the change in ATF4 protein, but no other marker, trended to correlate with the change in fCSA (r = 0.314; p = 0.055); however, when regression analysis was used to delineate groups, the change in ATF4 protein best predicted the change in fCSA only in LEU (r2 = 0.322; p = 0.043). In C2C12 myoblasts, LAT1 protein overexpression caused a paradoxical decrease in protein synthesis levels (p = 0.002) and decrease in BCKDHα protein (p = 0.001).

Conclusions: Amino acid transporters and metabolic enzymes are affected by resistance exercise training, but do not appear to dictate muscle fiber hypertrophy. In fact, overexpression of LAT1 in vitro decreased protein synthesis.
Impact of Inversion Time for FLAIR Acquisition on the T2-FLAIR Mismatch Detectability for IDH-Mutant, Non-CODEL Astrocytomas
Authors: Kinoshita Manabu , Arita Hideyuki , Takahashi Masamichi , Uda Takehiro , Fukai Junya , Ishibashi Kenichi , Kijima Noriyuki , Hirayama Ryuichi , Sakai Mio , Arisawa Atsuko , Takahashi Hiroto , Nakanishi Katsuyuki , Kagawa Naoki , Ichimura Kouichi , Kanemura Yonehiro , Narita Yoshitaka , Kishima Haruhiko
Published: January 2021

The current research tested the hypothesis that inversion time (TI) shorter than 2,400 ms under 3T for FLAIR can improve the diagnostic accuracy of the T2-FLAIR mismatch sign for identifying IDHmt, non-CODEL astrocytomas. We prepared three different cohorts; 94 MRI from 76 IDHmt, non-CODEL Lower-grade gliomas (LrGGs), 33 MRI from 31 LrGG under the restriction of FLAIR being acquired with TI < 2,400 ms for 3T or 2,016 ms for 1.5T, and 112 MRI from 112 patients from the TCIA/TCGA dataset for LrGG. The presence or absence of the “T2-FLAIR mismatch sign” was evaluated, and we compared diagnostic accuracies according to TI used for FLAIR acquisition. The T2-FLAIR mismatch sign was more frequently positive when TI was shorter than 2,400 ms under 3T for FLAIR acquisition (p = 0.0009, Fisher’s exact test). The T2-FLAIR mismatch sign was positive only for IDHmt, non-CODEL astrocytomas even if we confined the cohort with FLAIR acquired with shorter TI (p = 0.0001, Fisher’s exact test). TCIA/TCGA dataset validated that the sensitivity, specificity, PPV, and NPV of the T2-FLAIR mismatch sign to identify IDHmt, non-CODEL astrocytomas improved from 31, 90, 79, and 51% to 67, 94, 92, and 74%, respectively and the area under the curve of ROC improved from 0.63 to 0.87 when FLAIR was acquired with shorter TI. We revealed that TI for FLAIR impacts the T2-FLAIR mismatch sign’s diagnostic accuracy and that FLAIR scanned with TI < 2,400 ms in 3T is necessary for LrGG imaging.
Early Toxicities After High Dose Rate Proton Therapy in Cancer Treatments
Authors: Doyen Jérôme , Sunyach Marie-Pierre , Almairac Fabien , Bourg Véronique , Naghavi Arash O. , Duhil de Bénazé Gwenaëlle , Claren Audrey , Padovani Laetitia , Benezery Karen , Noël Georges , Hannoun-Lévi Jean-Michel , Guedea Ferran , Giralt Jordi , Vidal Marie , Baudin Guillaume , Opitz Lucas , Claude Line , Bondiau Pierre-Yves
Published: January 2021

Background

The conventional dose rate of radiation therapy is 0.01–0.05 Gy per second. According to preclinical studies, an increased dose rate may offer similar anti-tumoral effect while dramatically improving normal tissue protection. This study aims at evaluating the early toxicities for patients irradiated with high dose rate pulsed proton therapy (PT).

Materials and Methods

A single institution retrospective chart review was performed for patients treated with high dose rate (10 Gy per second) pulsed proton therapy, from September 2016 to April 2020. This included both benign and malignant tumors with ≥3 months follow-up, evaluated for acute (≤2 months) and subacute (>2 months) toxicity after the completion of PT.

Results

There were 127 patients identified, with a median follow up of 14.8 months (3–42.9 months). The median age was 55 years (1.6–89). The cohort most commonly consisted of benign disease (55.1%), cranial targets (95.1%), and were treated with surgery prior to PT (56.7%). There was a median total PT dose of 56 Gy (30–74 Gy), dose per fraction of 2 Gy (1–3 Gy), and CTV size of 47.6 ml (5.6–2,106.1 ml). Maximum acute grade ≥2 toxicity were observed in 49 (38.6%) patients, of which 8 (6.3%) experienced grade 3 toxicity. No acute grade 4 or 5 toxicity was observed. Maximum subacute grade 2, 3, and 4 toxicity were discovered in 25 (19.7%), 12 (9.4%), and 1 (0.8%) patient(s), respectively.

Conclusion

In this cohort, utilizing high dose rate proton therapy (10 Gy per second) did not result in a major decrease in acute and subacute toxicity. Longer follow-up and comparative studies with conventional dose rate are required to evaluate whether this approach offers a toxicity benefit.
Case Report: Management Approach and Use of Extracorporeal Membrane Oxygenation for Diffuse Alveolar Hemorrhage After Pediatric Hematopoietic Cell Transplant
Authors: Fan Kimberly , Hurley Caitlin , McNeil Michael J. , Agulnik Asya , Federico Sara , Qudeimat Amr , Saini Arun , McArthur Jennifer , Morrison Ronald Ray , Sandhu Hitesh , Shah Samir , Ghafoor Saad
Published: January 2021

Introduction:Diffuse alveolar hemorrhage (DAH) is an early pulmonary complication of hematopoietic cell transplantation (HCT) associated with severe hypoxemic respiratory failure and mortality. Extracorporeal membrane oxygenation (ECMO) support is often used for respiratory failure refractory to conventional interventions; however, its use has been limited in HCT patients with DAH due to potential for worsening alveolar hemorrhage and reported high mortality.

Case Presentation:We report two cases of DAH following HCT who developed refractory hypoxemic respiratory failure despite cessation of bleeding and were successfully supported with ECMO.

Conclusion:DAH after HCT should not automatically preclude ECMO support; rather, these patients must be evaluated individually for ECMO within the context of their overall clinical picture.
Therapeutic Drug Monitoring and Outcome of Infliximab Therapy in Pediatric Onset Inflammatory Bowel Disease
Authors: Kolho Kaija-Leena
Published: January 2021

Inflammatory bowel disease (IBD) with pediatric onset has become more prevalent during past decades. Thus, the number of patients with moderate to severe disease subtype treated with antagonists to tumor necrosis factor alpha (TNFα) has concurrently risen. Most pediatric patients initially respond to these drugs but will need dose escalation during the first year of therapy. As pediatric data regarding therapeutic drug monitoring during therapy with TNFα-blocker adalimumab are sparse, this review focuses on the literature on therapeutic drug monitoring of infliximab and how it may guide management.
Dihydropyridine Calcium Channel Blockers Suppress the Transcription of PD-L1 by Inhibiting the Activation of STAT1
Authors: Pan Xiaohui , Li Run , Guo Hongjie , Zhang Wenxin , Xu Xiaqing , Chen Xi , Ding Ling
Published: January 2021

Programmed death ligand 1 (PD-L1) which is upregulated in various epithelial tumors, plays a central role in the evasion of the immune system. In addition to monoclonal antibodies that blocking PD1/PD-L1 axis, finding small molecule compounds that can suppress PD-L1 expression might be another substitutable strategy for PD1/PD-L1 based therapy. Here, we found that dihydropyridine calcium channel blockers dose-dependently reduced the expression of PD-L1, both in the cytoplasm and cell surface. IFNγ induced PD-L1 transcription was consistently suppressed by Lercanidipine in 24 h, whereas, the half-life of PD-L1 protein was not significantly affected. IFNγ trigged significant STAT1 phosphorylation, which was eliminated by Lercanidipine. Similarly, STAT1 phosphorylation could also be abolished by extracellular calcium chelating agent EGTA and intracellular calcium chelator BAPTA-AM. Furthermore, Lercanidipine enhanced killing ability of T cells by down-regulating PD-L1. Taken together, our studies suggest that calcium signal is a crucial factor that mediates the transcription of PD-L1 and regulation of calcium can be used as a potential strategy for PD-L1 inhibition.
Combination Effect of Three Main Constituents From Sarcandra glabra Inhibits Oxidative Stress in the Mice Following Acute Lung Injury: A Role of MAPK-NF-κB Pathway
Authors: Liu Chun-Ping , Liu Jian-Xing , Gu Jiangyong , Liu Fang , Li Jin-Hua , Bin-Yang  , Yuan-Zheng  , Jie-Li  , Wu Shou-hai , Wu Qing-he , Xian-Zhang  , Li Long-Mei , Yang Hai-Long , Wang Lei , Li Xiong
Published: January 2021

Caffeoylquinic acids, coumarins and dicaffeoyl derivatives are considered to be three kinds of the most abundant bioactive components in Sarcandra glabra, an anti-inflammatory herb mainly found in Southern Asia. The combined anti-inflammatory effect of three typical constituents C + R + I (chlorogenic acid + rosmarinic acid + isofraxidin) from this plant has been investigated. The result implies that targeting the MAPK-NF-κB pathway would be one of the major mechanisms involved, using LPS stimulated RAW 264.7 cells as in vitro model and LPS-induced acute lung injury in mice as in vivo model. C + R + I can significantly suppress the levels of nitric oxide (NO), pro-inflammatory cytokines, and inhibit iNOS and COX-2 expression in LPS-treated RAW264.7 macrophage cells. Western blot analysis showed that C + R + I suppressed phosphorylation of NF-κB and MAPK, including phosphorylation of p65-NF-κB, IKB, ERK, JNK and P38. Besides, C + R + I suppressed MPO protein expression, but promoted SOD and HO-1 expression, and the related targets for C, R, and I were also predicted by molecular docking. This indicated that C + R + I could alleviate oxidative stress induced by LPS, which were further verified in the in vivo model of mice with acute lung injury through the measurement of corresponding inflammatory mediators and the analysis of immunehistochemistry.
The Ginsenoside Exhibits Antiosteoporosis Effects in Ketogenic-Diet-Induced Osteoporosis via Rebalancing Bone Turnover
Authors: Liu Qi , Zhou Jian , Yang Zhou , Xie Chuhai , Huang Yan , Ling Long , Cao Yanming , Hu Hailan , Hua Yue
Published: January 2021

Ginsenoside is widely used in China for therapeutic and healthcare practice. Ginsenoside-Rb2 shows the antiosteoporosis effects in ovariectomized rodents. However, the protective effects on osteoporosis induced by ketogenic diet (KD) remain unknown. Therefore, this study aimed at evaluating the effects of ginsenoside-Rb2 on KD-induced osteoporosis. Thirty mice were randomly divided into three groups: sham, KD, and KD + Rb2. Bone microstructures, biomechanical properties, concentrations of serum bone alkaline phosphatase (BALP) and tartrate-resistant acid phosphatase (TRACP), and protein expression of osteocalcin (OCN), peroxisome proliferation-activated receptor γ (PPAR-γ), cathepsin K, and TRAP were evaluated after a 12-week intervention. The results show that KD induced significant bone loss and biomechanical impairment. Ginsenoside-Rb2 attenuated significant bone loss and maintained biomechanics in cancellous bone. The bone volume fraction increased from 2.3 to 6.0% in the KD + Rb2 group than that in the KD group. Meanwhile, ginsenoside-Rb2 effectively maintained biomechanical strengths in cancellous bone, increased serum BALP and decreased TRACP, and upregulated OCN and downregulated TRAP, PPAR-γ, and cathepsin K in the KD mice. This study demonstrated that ginsenoside-Rb2 retards bone loss and maintains biomechanics with KD. The underlying mechanism might be that ginsenoside-Rb2 inhibits bone resorption process and induces osteogenic differentiation, providing evidence for ginsenoside as being an alternative option for osteoporosis induced by KD.
Heavy Metal Contaminations in Herbal Medicines: Determination, Comprehensive Risk Assessments, and Solutions
Authors: Luo Lu , Wang Bo , Jiang Jingwen , Fitzgerald Martin , Huang Qin , Yu Zheng , Li Hui , Zhang Jiqing , Wei Jianhe , Yang Chenyuyan , Zhang Hui , Dong Linlin , Chen Shilin
Published: January 2021

Heavy metal contamination in herbal medicines is a global threat to human beings especially at levels above known threshold concentrations. The concentrations of five heavy metals cadmium (Cd), lead (Pb), arsenic (As), mercury (Hg) and copper (Cu) were investigated using Inductively Coupled Plasma Optical Mass Spectrometry (ICP-MS) with 1773 samples around the world. According to Chinese Pharmacopoeia, 30.51% (541) samples were detected with at least one over-limit metal. The over-limit ratio for Pb was 5.75% (102), Cd at 4.96% (88), As at 4.17% (74), Hg at 3.78% (67), and of Cu, 1.75% (31). For exposure assessment, Pb, Cd, As, and Hg have resulted in higher than acceptable risks in 25 kinds of herbs. The maximal Estimated Daily Intake of Pb in seven herbs, of Cd in five, of Hg in four, and As in three exceeded their corresponding Provisional Tolerable Daily Intakes. In total 25 kinds of herbs present an unacceptable risk as assessed with the Hazard Quotient or Hazard Index. Additionally, the carcinogenic risks were all under acceptable limits. Notably, As posed the highest risk in all indicators including Estimated Daily Intake, Hazard Index, and carcinogenic risks. Therefore further study on enrichment effect of different states of As and special attention to monitoring shall be placed on As related contamination.
Sacubitril/Valsartan Reduces Fibrosis and Alleviates High-Salt Diet-Induced HFpEF in Rats
Authors: Zhang Wenchao , Liu Jianwei , Fu Yang , Ji Huifang , Fang Zheyan , Zhou Wanming , Fan Huimin , Zhang Yingxuan , Liao Yan , Yang Ting , Wang Xiaolin , Yuan Wanwan , Chen Xiaoshu , Dong Yi-fei
Published: January 2021

Previous studies have confirmed the clinical efficacy of sacubitril/valsartan (Sac/Val) for the treatment of heart failure with reduced ejection fraction (HFrEF). However, the role of Sac/Val in heart failure with preserved ejection fraction (HFpEF) remains unclear. Sac/Val is a combination therapeutic medicine comprising sacubitril and valsartan that acts as a first angiotensin receptor blocker and neprilysin inhibitor (angiotensin-receptor neprilysin inhibitor (ARNI)). Here, we investigated the role of Sac/Val in high-salt diet-induced HFpEF coupled with vascular injury as well as the underlying mechanism. Rats were fed with high-salt feed, followed by intragastric administration of Sac/Val (68 mg/kg; i.g.). The results of functional tests revealed that a high-salt diet caused pathological injuries in the heart and vascular endothelium, which were significantly reversed by treatment with Sac/Val. Moreover, Sac/Val significantly decreased the levels of fibrotic factors, including type I collagen and type Ⅲ collagen, thus, reducing the ratio of MMP2/TIMP2 while increasing Smad7 levels. Further investigation suggested that Sac/Val probably reversed the effects of high-salt diet-induced HFpEF by inhibiting the activation of the TGF-β1/Smad3 signaling pathway. Thus, treatment with Sac/Val effectively alleviated the symptoms of high-salt diet-induced HFpEF, probably by inhibiting fibrosis via the TGF-β1/Smad3 signaling pathway, supporting the therapeutic potential of Sac/Val for the treatment of HFpEF.
CPEB4-Promoted Paclitaxel Resistance in Ovarian Cancer In Vitro Relies on Translational Regulation of CSAG2
Authors: Zhang Yaqing , Gan Hongyun , Zhao Fei , Ma Xiaomei , Xie Xiaofeng , Huang Rui , Zhao Jin
Published: January 2021

Background: Drug resistance is a major obstacle in chemotherapy for ovarian cancer, wherein the up regulation of drug-resistant genes plays an important role. The cytoplasmic polyadenylation element binding protein 4 (CPEB4) is an RNA binding protein that controls mRNA cytoplasmic polyadenylation and translation.

Methods: The expression of CPEB4 in paclitaxel-resistant ovarian cancer cell lines and recurrent ovarian tumors relative to counterparts was determined by qRT-PCR, Western blotting and immunohistochemistry. The response to paclitaxel treatment was evaluated by cellular viability test and colony formation assay. RNA immunoprecipitation and poly(A) tail test were applied to examine the levels of RNA binding and cytoplasmic polyadenylation.

Results: CPEB4 is elevated in paclitaxel-resistant ovarian cancer cells and recurrent ovarian tumors treated with paclitaxel-based chemotherapy. In addition, CPEB4 overexpression promotes paclitaxel resistance in ovarian cancer cells in vitro, and vice versa, CPEB4 knockdown restores paclitaxel sensitivity, indicating that CPEB4 confers paclitaxel resistance in ovarian cancer cells. Mechanistically, CPEB4 binds with the taxol (paclitaxel)-resistance-associated gene-3 (TRAG-3/CSAG2) mRNAs and induces its expression at a translational level. Moreover, CSAG2 expression is upregulated in paclitaxel-resistant ovarian carcinoma and cancer cell lines, and more importantly, siRNA-mediated CSAG2 knockdown overtly attenuates CPEB4-mediated paclitaxel resistance.

Conclusion: This study suggests that the drug-resistant protein CSAG2 is translationally induced by CPEB4, which underlies CPEB4-promoted paclitaxel resistance in ovarian cancer in vitro. Thus, interfering CPEB4/CSAG2 axis might be of benefit to overcome paclitaxel-resistant ovarian cancer.
Time-Dependent Distribution of Hydroxychloroquine in Cynomolgus Macaques Using Population Pharmacokinetic Modeling Method
Authors: Liu Qi , Bi Guofang , Chen Guiying , Guo Xuan , Tu Siqi , Tong Xiaolin , Xu Man , Liu Mengjie , Wang Bei , Jiang Hongliang , Wang Jufeng , Li Haiyan , Wang Kun , Liu Dongyang , Song Chunli
Published: January 2021

To evaluate the biodistribution of hydroxychloroquine (HCQ) in cynomolgus macaques and receive dynamic quantitative relationship between plasma, blood, and lung tissue concentration using the population pharmacokinetic modeling method, seventeen cynomolgus macaques were divided into six groups according to different HCQ dosing regimens over 5 days. The monkeys were euthanized, and blood, plasma, urine, feces and ten tissues were collected. All the samples were prepared by protein precipitation and analyzed by HPLC-MS/MS detection. The population pharmacokinetics of HCQ in the plasma, red blood cells, and lung tissue was conducted and simulated via ADAPT program. Results demonstrated that the maximum concentration (Cmax) of HCQ was 292.33 ng/mL in blood and 36.90 ng/mL in plasma after single dose of 3 mg/kg. The value of area under curve (AUC0–∞) was determined as 5,978.94 and 363.31 h* ng/mL for the blood and plasma, respectively. The descending order of the tissue-to-plasma concentration ratio was liver > spleen > kidney > lung > heart > subcutaneous fat > brain. The tissue-to-plasma concentration ratio and the tissue-to-blood concentration ratio for lung were found to be time-dependent with 267.38 and 5.55 at 120 h postdose, respectively. A five-compartment model with first-order oral absorption and elimination best described the plasma, blood, and lung tissue pharmacokinetics. The estimated elimination rate constant (ke) for a typical monkey was 0.236 h−1. The volume of distribution in central (Vc/F) and other two peripheral compartments (Vb/F and Vl/F) were 114, 2.68, and 5.55 L, respectively. Model-based simulation with PK parameters from cynomolgus macaques showed that the ratio of the blood or plasma to lung tissue was a dynamic change course, which suggested that the rate of HCQ concentration decrease in the blood or plasma was faster than that in the lung tissue. HCQ was found to be accumulated in tissues, especially in the liver, kidney, lung, and spleen. Also, the tissue-to-plasma concentration ratio increased over time. The population pharmacokinetic model developed could allow for the assessment of pharmacokinetics–pharmacodynamics relationships, especially relevant tissue concentration-response for HCQ. Determining appropriate treatment regimens in animals allows translation of these to clinical studies.
Tanshinone IIA: A Review of its Anticancer Effects
Authors: Fang Zhong‐ying , Zhang Miao , Liu Jia-ning , Zhao Xue , Zhang Yong-qing , Fang Lei
Published: January 2021

Tanshinone IIA (Tan IIA) is a pharmacologically lipophilic active constituent isolated from the roots and rhizomes of the Chinese medicinal herb Salvia miltiorrhiza Bunge (Danshen). Tan IIA is currently used in China and other neighboring countries to treat patients with cardiovascular system, diabetes, apoplexy, arthritis, sepsis, and other diseases. Recently, it was reported that tan IIA could have a wide range of antitumor effects on several human tumor cell lines, but the research of the mechanism of tan IIA is relatively scattered in cancer. This review aimed to summarize the recent advances in the anticancer effects of tan IIA and to provide a novel perspective on clinical use of tan IIA.
Determination and Pharmacokinetic Profiles of Four Active Components From Scrophularia ningpoensis Hemsl. in Rats
Authors: Luo Shunbin , Xie Lingping , Chen Jingjing , Tang Congrong , Xu Ren-ai
Published: January 2021

Acteoside, angoroside C, harpagoside, and cinnamic acid, which are the main bioactive ingredients of Scrophularia ningpoensis Hemsl., have wide clinical use with various biological effects. A new and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was established with taxifolin as the internal standard (IS) in this study and was successfully used to study the pharmacokinetic profiles of four active components from S. ningpoensis Hemsl. in rats after sublingual intravenous administration. After protein precipitation with acetonitrile, the mobile phase (consisting of acetonitrile and 0.1% formic acid) was used to separate the analytes on an Acquity UPLC BEH C18 chromatography column (2.1 × 50 mm, 1.7 μm) under gradient elution. The precursor-to-product ion transitions of 623.4 → 161.3 m/z for acteoside, 783.5 → 175.0 m/z for angoroside C, 493.3 → 345.2 m/z for harpagoside and 147.2 → 103.4 m/z for cinnamic acid were monitored by mass spectrometry with negative electrospray ionization in the multiple reaction monitoring (MRM) mode. The concentration range of 10–1,000 ng/ml could be detected by this method with a lower limit of quantification (LLOQ) of 10 ng/ml for each analyte. The intra- and inter-day precision (RSD%) of the method ranged from 2.6 to 9.9% and 2.7–11.5%, respectively. Meanwhile, the accuracy (RE%) was −9.6–10.7% in this developed method. The mean recoveries of four active components from S. ningpoensis Hemsl. were more than 76.7% with negligible matrix effects. The four active components from S. ningpoensis Hemsl. were stable under multiple storage and process conditions. A new, sensitive and simple analytical method had been established and was successfully applied to the pharmacokinetic profiles of four active components from S. ningpoensis Hemsl. in rats after sublingual intravenous administration.
Creation of Silicon-Vacancy Color Centers in Diamond by Ion Implantation
Authors: Lagomarsino S. , Flatae A. M. , Kambalathmana H. , Sledz F. , Hunold L. , Soltani N. , Reuschel P. , Sciortino S. , Gelli N. , Massi M. , Czelusniak C. , Giuntini L. , Agio M.
Published: January 2021

Silicon-vacancy (SiV) centers in diamond are gaining an increased interest for application, such as in quantum technologies and sensing. Due to the strong luminescence concentrated in its sharp zero-phonon line at room temperature, SiV centers are being investigated as single-photon sources for quantum communication, and also as temperature probes for sensing. Here, we discussed strategies for the fabrication of SiV centers in diamond based on Si-ion implantation followed by thermal activation. SiV color centers in high-quality single crystals have the best optical properties, but polycrystalline micro and nanostructures are interesting for applications in nano-optics. Moreover, we discuss the photoluminescence properties of SiV centers in phosphorous-doped diamond, which are relevant for the creation of electroluminescent devices, and nanophotonics strategies to improve the emission characteristics of the SiV centers. Finally, the optical properties of such centers at room and high temperatures show the robustness of the center and give perspectives for temperature-sensing applications.
Deep Learning Assisted Zonal Adaptive Aberration Correction
Authors: Zhang Biwei , Zhu Jiazhu , Si Ke , Gong Wei
Published: January 2021

Deep learning (DL) has been recently applied to adaptive optics (AO) to correct optical aberrations rapidly in biomedical imaging. Here we propose a DL assisted zonal adaptive correction method to perform corrections of high degrees of freedom while maintaining the fast speed. With a trained DL neural network, the pattern on the correction device which is divided into multiple zone phase elements can be directly inferred from the aberration distorted point-spread function image in this method. The inference can be completed in 12.6 ms with the average mean square error 0.88 when 224 zones are used. The results show a good performance on aberrations of different complexities. Since no extra device is required, this method has potentials in deep tissue imaging and large volume imaging.
Mild Attenuation of the Pulmonary Inflammatory Response in a Mouse Model of Hereditary Hemochromatosis Type 4
Authors: Marques Oriana , Neves Joana , Horvat Natalie K. , Altamura Sandro , Muckenthaler Martina U.
Published: January 2021

The respiratory tract is constantly exposed to pathogens that require iron for proliferation and virulence. Pulmonary iron levels are increased in several lung diseases and associated with increased susceptibility to infections. However, regulation of lung iron homeostasis and its cross talk to pulmonary immune responses are largely unexplored. Here we investigated how increased lung iron levels affect the early pulmonary inflammatory response. We induced acute local pulmonary inflammation via aerosolized LPS in a mouse model of hereditary hemochromatosis type 4 (Slc40a1C326S/C326S), which is hallmarked by systemic and pulmonary iron accumulation, specifically in alveolar macrophages. We show that Slc40a1C326S/C326S mice display a mild attenuation in the LPS-induced pulmonary inflammatory response, with a reduced upregulation of some pro-inflammatory cytokines and chemokines. Despite mildly reduced cytokine levels, there is no short-term impairment in the recruitment of neutrophils into the bronchoalveolar space. These data suggest that increased pulmonary iron levels do not strongly alter the acute inflammatory response of the lung.
RETRACTED: Protective Effect of Xinmailong Injection on Rats With Myocardial Infarction
Authors: Zhang Wei , Li Kailiang , Ding Yu , Ren Jiefeng , Wang Haijun , Si Quanjin
Published: January 2021

This study aimed to investigate the protective effect of Xinmailong injection on rats with myocardial infarction. Thirty-six rats were induced myocardial infarction by operation, and six underwent sham operation. The myocardial infarction rats were randomly divided into three groups, 12 in each, and administered intraperitoneal injection of Xinmailong 5 mg/(kg·d), sodium creatine phosphate 80 mg/(kg·d), or normal saline as control respectively for 14 days. When the treatments were completed, the hemodynamic parameters of the rats were observed, and blood samples were taken to examine blood routine, blood coagulation index, liver and kidney function, inflammatory index, myocardial marker, thrombo-elastography, and other indicators. The morphology of cardiomyocytes was observed through light microscopy, and the microstructure of the myocardial cells was observed under electron microscope. No significant difference was found in blood routine, liver and kidney function, and blood coagulation index between the Xinmailong and sodium creatine phosphate groups compared with the saline control group. However, the inflammatory index and levels of myocardial markers were significantly decreased, and cardiac function was significantly improved. In terms of the morphology of myocardial cells, the Xinmailong group was similar to the sodium creatine phosphate group, the myocardial cell membrane was protected, and myocardial cell damage was reduced. In conclusion, Xinmailong is safe and had anti-inflammatory, heart-improving, and myocardial-protective effects. Its effectiveness is not inferior to that of sodium creatine phosphate.
Relationships Between Circulating Irisin Response to Ice Swimming and Body Composition in People With Regular Exercise Experience
Authors: Mu Shuai , Ding Ding , Ji Chao , Wu Qijun , Xia Yang , Zhou Long , Yang Liyu , Ba Gen , Chang Qing , Fu Qin , Zhao Yuhong
Published: January 2021

Severe cold exercise involves the irisin response, and may be related to body composition. We aimed to investigate changes in circulating irisin after ice swimming (IS), as well as to evaluate the correlation between body composition and the change in irisin caused by IS (Δirisin). 81 ice swimmers were recruited to perform IS activities. Blood samples were drawn 30 min before and 30 min after IS, and the serum levels of irisin and the ice swimmers’ body composition were measured. As results, circulating irisin declined significantly during the recovery period following IS exercise (P < 0.001). The afternoon baseline circulating irisin level and Δirisin in response to IS were correlated with body fat characteristics rather than muscle parameters in ice swimmers. Δirisin subgroup analyses showed that the Δirisin ascending group (Δirisin+) subjects had a higher fat composition and higher basal irisin levels than the Δirisin descending group (Δirisin−). Furthermore, the decrease in irisin was negatively correlated with fat components in Δirisin− subjects, whereas no correlation was observed between the increase in irisin and body composition in Δirisin + subjects. Finally, a non-linear association analysis suggested that body fat indicators had obvious curvilinear relationships with Δirisin. In conclusion, IS caused a significant decrease in irisin. Statistical and curvilinear associations suggested that the correlation between fat tissue and Δirisin caused by IS is dimorphic and the underlying mechanisms may be due to the different metabolic states of subjects.
Red Blood Cell Morphodynamics: A New Potential Marker in High-Risk Patients
Authors: Porro Benedetta , Conte Edoardo , Zaninoni Anna , Bianchi Paola , Veglia Fabrizio , Barbieri Simone , Fiorelli Susanna , Eligini Sonia , Di Minno Alessandro , Mushtaq Saima , Tremoli Elena , Cavalca Viviana , Andreini Daniele
Published: January 2021

In the last years, a substantial contribution of red blood cells (RBCs) in cardiovascular homeostasis has been evidenced, as these cells are able to regulate cardiovascular function by the export of adenosine triphosphate and nitric oxide as well as to maintain redox balance through a well-developed antioxidant system. Recently a link between high-risk plaque (HRP) features and myocardial ischemia, in the absence of severe lumen stenosis, has been evidenced. Nonobstructive coronary artery disease (nonob CAD) has been associated in fact with a greater 1-year risk of myocardial infarction and all-cause mortality compared with no apparent CAD. This new evidence increases interest in searching new triggers to identify these high-risk patients, in the absence/or on top of traditional hazard markers. In this study, we investigated the existence of any association between RBC morphodynamics and HRP features in individuals with different grades of coronary stenosis detected by coronary computed tomography angiography (CCTA). Ninety-one consecutive individuals who underwent CCTA [33 no CAD; 26 nonobstructive (nonob), and 32 obstructive (ob) CAD] were enrolled. RBC morphodynamic features, i.e., RBC aggregability and deformability, were analyzed by means of Laser Assisted Optical Rotation Cell Analyzer (LoRRca MaxSis). The putative global RBC morphodynamic (RMD) score and the related risk chart, associating the extent of HRP (e.g., the non-calcified plaque volume) with both the RMD score and the max % stenosis were computed. In nonob CAD group only positive correlations between RBC rigidity, osmotic fragility or aggregability and HRP features (plaque necrotic core, fibro-fatty and fibro-fatty plus necrotic core plaque volumes) were highlighted. Interestingly, in this patient cohort three of these RBC morphodynamic features result to be independent predictors of the presence of non-calcified plaque volume in this patients group. The risk chart created shows that only in nonob CAD plaque vulnerability increases according to the score quartile. Findings of this work, by evidencing the association between erythrocyte morphodynamic characteristics assessed by LoRRca and plaque instability in a high-risk cohort of nonob CAD, suggest the use of these blood cell features in the identification of high-risk patients, in the absence of severe coronary stenosis.
Inflammation in Periodontal Disease: Possible Link to Vascular Disease
Authors: Paul Oindrila , Arora Payal , Mayer Michael , Chatterjee Shampa
Published: January 2021

Inflammation is a well-organized protective response to pathogens and consists of immune cell recruitment into areas of infection. Inflammation either clears pathogens and gets resolved leading to tissue healing or remains predominantly unresolved triggering pathological processes in organs. Periodontal disease (PD) that is initiated by specific bacteria also triggers production of inflammatory mediators. These processes lead to loss of tissue structure and function. Reactive oxygen species and oxidative stress play a role in susceptibility to periodontal pathogenic bacterial infections. Periodontal inflammation is a risk factor for systemic inflammation and eventually cardiovascular disease (CVD). This review discusses the role of inflammation in PD and its two way association with other health conditions such as diabetes and CVD. Some of the mechanisms underpinning the links between inflammation, diabetes, CVD and PD are also discussed. Finally, we review available epidemiological data and other reports to assess possible links between oral health and CVD.
A 1-Minute Re-warm Up at High-Intensity Improves Sprint Performance During the Loughborough Intermittent Shuttle Test
Authors: Yanaoka Takuma , Iwata Risa , Yoshimura Akane , Hirose Norikazu
Published: January 2021

Although a 3- to 7-min re-warm up (RW) elicits performance and physiological benefits after half-time (HT), a time-efficient and feasible RW protocol is required for the use of an RW in the athletic setting. This study aimed to investigate the effect of a 1-min RW at high-intensity on the performance and physiological responses during the Loughborough Intermittent Shuttle Test (LIST). In a randomized and counterbalanced cross-over design, 12 male amateur intermittent team sports players (soccer, basketball, handball, and lacrosse; age, 22 ± 2 years; height, 1.70 ± 0.08 m; body mass, 65.1 ± 8.3 kg; body mass index, 22.4 ± 1.9 kg m−2; VO2max, 53.5 ± 4.5 ml kg−1 min−1) performed the LIST. The LIST comprised two 45-min halves separated by a 15-min HT. Each half comprised repetitions of exercise cycles consisting of 3 × 20-m walking, 1 × 20-m maximal sprint, 3 × 20-m jogging, and 3 × 20-m running. During the HT, the participants were assigned to a control trial (CON; 15-min seated rest) or an RW trial (1-min running at 90% of the maximal oxygen uptake after a 14-min seated rest). Compared to the CON, the RW prevents reductions in sprint performance at the fourth and sixth periods of the LIST (fourth: 2.4%, p = 0.002, d = 1.68, sixth: 3.6%, p = 0.012, d = 1.74) and a decrement of gastrointestinal temperature during HT (0.5°C, p = 0.010, d = 1.41). Moreover, the RW decreased the electromyogram amplitude of maximal voluntary contraction (MVC) after HT (12%, p = 0.017, d = 1.12) without a decrease of maximal voluntary contraction force, suggesting an increased neuromuscular efficiency (9%, p = 0.048, d = 0.58). The RW also increased the mean heart rate in the initial part of the second half (4 bpm, p = 0.016, d = 0.38). In conclusion, the RW improved sprint performance, core temperature, muscle activation, and heart rate in the second half of the LIST. The findings suggest that the RW should be recommended for intermittent team sports players when longer RWs are not possible.
A Pathogenesis-Related Protein-Like Gene Is Involved in the Panax notoginseng Defense Response to the Root Rot Pathogen
Authors: Li Shan , Wang Zie , Tang Bifeng , Zheng Lilei , Chen Hongjun , Cui Xiuming , Ge Feng , Liu Diqiu
Published: January 2021

Pathogenesis-related proteins (PRs) are a class of proteins that accumulate in response to biotic and abiotic stresses to protect plants from damage. In this study, a gene encoding a PR-like protein (PnPR-like) was isolated from Panax notoginseng, which is used in traditional Chinese herbal medicines. An analysis of gene expression in P. notoginseng indicated that PnPR-like was responsive to an infection by the root rot pathogen Fusarium solani. The expression of this gene was induced by several signaling molecules, including methyl jasmonate, ethephon, hydrogen peroxide, and salicylic acid. The PnPR-like-GFP fusion gene was transiently expressed in onion (Allium cepa) epidermal cells, which revealed that PnPR-like is a cytoplasmic protein. The purified recombinant PnPR-like protein expressed in Escherichia coli had antifungal effects on F. solani and Colletotrichum gloeosporioides as well as inhibited the spore germination of F. solani. Additionally, the in vitro ribonuclease (RNase) activity of the recombinant PnPR-like protein was revealed. The PnPR-like gene was inserted into tobacco (Nicotiana tabacum) to verify its function. The gene was stably expressed in T2 transgenic tobacco plants, which exhibited more RNase activity and greater disease resistance than the wild-type tobacco. Moreover, the transient expression of hairpin RNA targeting PnPR-like in P. notoginseng leaves increased the susceptibility to F. solani and decreased the PnPR-like expression level. In conclusion, the cytoplasmic protein PnPR-like, which has RNase activity, is involved in the P. notoginseng defense response to F. solani.