Publications by authors named "Guan Wang"

444 Publications

Ca-activated Cl channel TMEM16A inhibition by cholesterol promotes angiogenesis in endothelial cells.

J Adv Res 2021 Mar 15;29:23-32. Epub 2020 Sep 15.

Department of Ion Channel Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China.

Introduction: Ca-activated Cl channel TMEM16A is expressed in endothelial cells, and contributes to many diseases such as hypertension, blood-brain barrier dysfunction, and pulmonary hypertension. It remains unclear whether TMEM16A regulates endothelial angiogenesis, which participates in many physiological and pathological processes. Cholesterol regulates many ion channels including TMEM16A, and high cholesterol levels contribute to endothelial dysfunction. It remains to be determined whether cholesterol regulates TMEM16A expression and function in endothelial cells.

Objective: This study aimed to investigate whether cholesterol regulated TMEM16A expression and function in endothelial angiogenesis.

Methods: Whole-cell patch clamp techniques were used to record Ca-activated Cl currents in human aortic endothelial cells (HAECs) and HEK293 cells transfected with TMEM16A-overexpressing plasmids. Western blot was used to examine the expression of TMEM16A and DNA methyltransferase 1 (DNMT1) in HAECs. CCK-8 assay, would healing assay, and tube formation assay were used to test endothelial cell proliferation, migration and angiogenesis, respectively.

Results: TMEM16A mediates the Ca-activated Cl channel in HAECs. Cholesterol treatment inhibited TMEM16A expression via upregulation of DNMT1 in HAECs, and the inhibitory effect of cholesterol on TMEM16A expression was blocked by 5-aza, the DNMT1 inhibitor. In addition, direct application of cholesterol inhibited TMEM16A currents in heterologous HEK293 cells with an IC of 0.1209 μM. Similarly, cholesterol directly inhibited TMEM16A currents in HAECs. Furthermore, TMEM16A knockdown increased tube formation, cell migration and proliferation of HAECs, and TMEM16A overexpression produced the opposite effect.

Conclusion: This study reveals a novel mechanism of cholesterol-mediated TMEM16A inhibition, by which cholesterol reduces TMEM16A expression via DNMT1-mediated methylation and directly inhibits channel activities. TMEM16A channel inhibition promotes endothelial cell angiogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jare.2020.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020148PMC
March 2021

LncRNA H19 secreted by umbilical cord blood mesenchymal stem cells through microRNA-29a-3p/FOS axis for central sensitization of pain in advanced osteoarthritis.

Am J Transl Res 2021 15;13(3):1245-1256. Epub 2021 Mar 15.

Department of Hepatobiliary and Pancreatic Surgery, Cell Transplantation Center, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital Chengdu 610072, China.

Objective: To explore the molecular mechanism of umbilical cord blood mesenchymal stem cells (UCBMSCs) in the treatment of advanced osteoarthritis pain.

Methods: Normal healthy rats were selected to establish advanced osteoarthritis (OA) model, and the rats were randomly divided into control group, intravenous group, intracavitary group and intrathecal group. The intravenous group received intravenous injection of UCBMSCs, intracavitary group received intra-articular injection of UCBMSCs, and intrathecal group received subarachnoid injection of UCBMSCs. The pain behavior and serum pro-inflammatory factor levels were evaluated before and after treatment. microRNA-29a-3p and FOS mRNA in spinal dorsal horn was detected using qPCR, the phosphorylation of c-fos protein and NR1, NR2B, ERK and PKCg was detected using Western blot, and the level of LncRNA H19 was detected using qPCR.

Results: LncRNA H19 was enriched in the exosomes of UCBMSCs. microRNA-29a-3p was the target gene of LncRNA H19, while FOS was the downstream target of microRNA-29a-3p. Pain and inflammation of rats in the intrathecal group improved best, and the phosphorylation levels of c-fos and NR1, NR2B, ERK and PKCg in the spinal dorsal horn of the intrathecal group decreased. LncRNA H19 regulated the central sensitization of astrocytes through microRNA-29a-3p/FOS axis.

Conclusion: Intrathecal injection of umbilical cord blood mesenchymal stem cells can improve the pain and central sensitization of advanced osteoarthritis through LncRNA H19/microRNA-29a-3p/FOS axis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014348PMC
March 2021

Approximate back-projection method for improving lateral resolution in circular-scanning-based photoacoustic tomography.

Med Phys 2021 Apr 10. Epub 2021 Apr 10.

Department of Biomedical Engineering, School of Basic Medical Science, Central South University, Changsha, Hunan, 410083, China.

Purpose: In circular-scanning-based photoacoustic tomography (PAT), the effect of finite transducer aperture has not been effectively resolved. The goal of this paper is to propose a practical reconstruction method that accounts for the finite transducer aperture to improve the lateral resolution.

Methods: We for the first time propose to calculate the spatial temporal response (STR) of the employed finite-sized transducer in a forward model, and then compensate the time delay and the directional sensitivity of the transducer in the framework of the back-projection method. Both simulation and phantom experiments were carried out to evaluate the lateral resolution improvement with the proposed method. The performance of this new method for imaging complicated targets was also assessed by calculating the mean image gradient.

Results: Simulation results showed that with this new method the lateral resolution for off-center targets can be as good as that for the center targets. Phantom experimental results showed that this new method can improve the lateral resolution more than 2 times for a point target about 5 mm far from the rotation center. Phantom experimental results also showed that many blurred fine structures of a piece of leaf veins at the off-center regions were well restored with the new method, and the mean image gradient improved about 1.3 times.

Conclusion: The proposed new method can effectively account for the effect of finite transducer aperture for circular-scanning-based PAT in homogenous acoustic media. This new method also features for its robustness and computational efficiency, so that it is a worthy replacement to the conventional back-projection algorithm in circular-scanning-based PAT. This new method can be of great importance to the design of circular-scanning or spherical-scanning-based PAT systems.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mp.14880DOI Listing
April 2021

Correction to: Integrating Transwomen and Female Athletes with Differences of Sex Development (DSD) into Elite Competition: The FIMS 2021 Consensus Statement.

Sports Med 2021 Apr 9. Epub 2021 Apr 9.

Centre for Exercise Sciences and Sports Medicine, FIMS Collaborating Centre of Sports Medicine, Rome, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40279-021-01467-0DOI Listing
April 2021

Predicting Unexpected Deterioration in COVID-19 Patients using PICTURE Analytic: Validation and Comparison to Existing Methods.

JMIR Med Inform 2021 Apr 3. Epub 2021 Apr 3.

Michigan Center for Integrative Research In Critical Care, Department of Emergency Medicine, University of Michigan, 2800 N. Plymouth RoadNCRC 10-A112, Ann Arbor, US.

Background: The 2019 coronavirus (COVID-19) has led to unprecedented strain on healthcare facilities across the United States. Accurately identifying patients at an increased risk of deterioration may help hospitals manage their resources while improving the quality of patient care. Here we present the results of an analytical model, PICTURE (Predicting Intensive Care Transfers and Other UnfoReseen Events), to identify patients at a high risk for imminent intensive care unit (ICU) transfer, respiratory failure, or death with the intention to improve prediction of deterioration due to COVID-19.

Objective: To validate the PICTURE model's ability to predict unexpected deterioration in general ward and COVID-19 patients, and to compare its performance with the Epic Deterioration Index (EDI), an existing model which has recently been assessed for use in COVID-19 patients.

Methods: The PICTURE model was trained and validated on a cohort of hospitalized non-COVID-19 patients using electronic health record data from 2014-2018. It was then applied to two hold-out test sets: non-COVID-19 patients from 2019 and patients testing positive for COVID-19 in 2020. PICTURE results were aligned to EDI and NEWS scores for head-to-head comparison via Area Under the Receiver Operator Curve (AUROC) and Area Under the Precision Recall Curve (AUPRC). We compared the models' ability to predict an adverse event (defined as ICU transfer, mechanical ventilation use, or death). Shapley values were used to provide explanations for PICTURE predictions.

Results: In non-COVID-19 general ward patients, PICTURE achieved an AUROC (95% CI) of 0.819 (0.805 - 0.834) per observation, compared to the EDI's 0.763 (0.746 - 0.781) (n = 21,740, P < 0.001). In patients testing positive for COVID-19, PICTURE again outperformed the EDI with an AUROC (95% CI) of 0.849 (0.820 - 0.878) compared to the EDI's 0.803 (0.772 - 0.838) (n = 607, P < 0.001). The most important variables influencing PICTURE predictions in the COVID-19 cohort were a rapid respiratory rate, a high level of oxygen support, low oxygen saturation, and impaired mental status (Glasgow coma score).

Conclusions: The PICTURE model is more accurate in predicting adverse patient outcomes for both general ward patients and COVID-19 positive patients in our cohorts compared to the EDI. The ability to consistently anticipate these events may be especially valuable when considering potential incipient waves of COVID-19 infections. The generalizability of the model will require testing in other health care systems for validation.

Clinicaltrial:
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2196/25066DOI Listing
April 2021

Design, synthesis and biological evaluation of brain penetrant benzazepine-based histone deacetylase 6 inhibitors for alleviating stroke-induced brain infarction.

Eur J Med Chem 2021 Mar 17;218:113383. Epub 2021 Mar 17.

Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, Shanghai, 201203, China; Shanghai Engineering Research Center of Pharmaceutical Process, Shanghai, 201203, China. Electronic address:

Histone deacetylase 6 (HDAC6) has become a promising therapeutic target for central nervous system diseases due to its more complex protein structure and biological functions. However, low brain penetration of reported HDAC6 inhibitors limits its clinical application in neurological disorders. Therefore, the benzazepine, a brain-penetrant rigid fragment, was utilized to design a series of selective HDAC6 inhibitors to improve brain bioavailability. Various synthetic strategies were applied to assemble the tetrahydro-benzazepine ring, and 22 compounds were synthesized. Among them, compound 5 showed low nanomolar potency and strong isozyme selectivity for the inhibition of HDAC6 (IC = 1.8 nM, 141-fold selectivity over HDAC1) with efficient binding patterns like coordination with the zinc ion and π-π stacking effect. Western blot results showed it could efficiently transport into SH-SY5Y cells and selectively enhance the acetylation level of α-tubulin with a moderate effect on Histone H3. Notably, pharmacokinetic studies demonstrated that compound 5 (brain/plasma ratio of 2.30) had an excellent ability to penetrate the blood-brain barrier of C57 mice. In male rats with transient middle cerebral artery occlusion (MCAO), compound 5 significantly reduced the cerebral infarction from 21.22% to 11.47% and alleviated neurobehavioral deficits in post-ischemic treatment, which provided a strong rationale for pursuing HDAC6-based therapies for ischemic stroke.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2021.113383DOI Listing
March 2021

Synthesis of antibacterial polyether biguanide curing agent and its cured antibacterial epoxy resin.

Des Monomers Polym 2021 Mar 18;24(1):63-72. Epub 2021 Mar 18.

Key Laboratory of Superlight Materials and Surface Technology, Ministry of Education, College of Materials Science and Chemical Engineering, Harbin Engineering University, Harbin, China.

At present, bacteria continue to threaten human health, and the resistance of bacteria to antibiotics continues to increase, so the development of new antibacterial agents and antibacterial materials is increasingly important to ensure human health. In this paper, three polyether biguanide compounds with high antibacterial properties were synthesized by reacting polyetheramine T403 with o-tolylbiguanide, m-tolylbiguanide and p-tolylbiguanide (o-TTB, m-TTB and p-TTB), respectively. The antimicrobial performance of polyether biguanide against E. coli and S. aureus was evaluated using a minimum inhibitory concentration method, and the results showed that the synthesized polyether biguanide exhibited efficient and broad-spectrum antimicrobial effects. Among them, o-tolyl biguanide derivative o-TTB showed the best antimicrobial performance, with minimum inhibitory concentrations of 20 and 15 μg/mL against E. coli and S. aureus, respectively. Then, epoxy resin E51 was cured using the obtained TTB as a curing agent to prepare an epoxy resin with antibacterial properties. The inhibition of the growth of S. aureus by the cured o-TTB/E51 resin was investigated by incubating the cured epoxy resin with bacteria, and the results showed that the cured resin had a significant inhibitory effect on the growth of bacteria. The non-isothermal curing kinetics of the o-TTB/E51 system were investigated by differential scanning calorimetry (DSC) to determine the optimized curing reaction temperature, curing kinetic parameters and curing kinetics equation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15685551.2021.1900025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993382PMC
March 2021

[New opportunities and challenges for hybrid data and model driven bioprocess optimization and scale-up].

Sheng Wu Gong Cheng Xue Bao 2021 Mar;37(3):1004-1016

State Key Laboratory of Bioreactor Engineering, Shanghai 200237, China.

Currently, biomanufacturing technology and industry are receiving worldwide attention. However, there are still great challenges on bioprocess optimization and scale-up, including: lacing the process detection methods, which makes it difficult to meet the requirement of monitoring of key indicators and parameters; poor understanding of cell metabolism, which arouses problems to rationally achieve process optimization and regulation; the reactor environment is very different across the scales, resulting in low efficiency of stepwise scale-up. Considering the above key issues that need to be resolved, here we summarize the key technological innovations of the whole chain of fermentation process, i.e., real-time detection-dynamic regulation-rational scale-up, through case analysis. In the future, bioprocess design will be guided by a full lifecycle in-silico model integrating cellular physiology (spatiotemporal multiscale metabolic models) and fluid dynamics (CFD models). This will promote computer-aided design and development, accelerate the realization of large-scale intelligent production and serve to open a new era of green biomanufacturing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.13345/j.cjb.200634DOI Listing
March 2021

BiVO/FeO@polydopamine superparticles for tumor multimodal imaging and synergistic therapy.

J Nanobiotechnology 2021 Mar 29;19(1):90. Epub 2021 Mar 29.

State Key Laboratory of Supramolecular Structure and Materials, Jilin University, Changchun, 130012, People's Republic of China.

Background: Despite tremendous progress has been achieved in tumor theranostic over the past decade, accurate identification and complete eradication of tumor cells remain a great challenge owing to the limitation of single imaging modality and therapeutic strategy.

Results: Herein, we successfully design and construct BiVO/FeO@polydopamine (PDA) superparticles (SPs) for computed tomography (CT)/photoacoustic (PA)/magnetic resonance (MR) multimodal imaging and radiotherapy (RT)/photothermal therapy (PTT) synergistic therapy toward oral epithelial carcinoma. On the one hand, BiVO NPs endow BiVO/FeO@PDA SPs with impressive X-ray absorption capability due to the high X-ray attenuation coefficient of Bi, which is beneficial for their utilization as radiosensitizers for CT imaging and RT. On the other hand, FeO NPs impart BiVO/FeO@PDA SPs with the superparamagnetic property as a T-weighted contrast agent for MR imaging. Importantly, the aggregation of FeO NPs in SPs and the presence of PDA shell greatly improve the photothermal conversion capability of SPs, making BiVO/FeO@PDA SPs as an ideal photothermal transducer for PA imaging and PTT. By integrating advantages of various imaging modalities (CT/PA/MR) and therapeutic strategies (RT/PTT), our BiVO/FeO@PDA SPs exhibit the sensitive multimodal imaging feature and superior synergistic therapeutic efficacy on tumors.

Conclusions: Since there are many kinds of building blocks with unique properties appropriating for self-assembly, our work may largely enrich the library of nanomateirals for tumor diagnosis and treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12951-021-00802-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008624PMC
March 2021

[Astragaloside II inhibits the proliferation of rat pulmonary artery smooth muscle cells induced by hypoxia via blocking NOX/ROS/AKT/mTOR signaling pathway].

Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2021 Mar;37(3):219-224

Basic Discipline of Integrated Chinese and Western Medicine, Heilongjiang University of Chinese Medicine, Harbin 150000, China. *Corresponding authors, E-mail:

Objective To investigate the inhibitory effect of astragaloside II (AS-II) on the proliferation of pulmonary artery smooth muscle cells (PASMCs) induced by hypoxia and its relevant mechanism. Methods Rat primary PASMCs were divided into normoxia group, hypoxia group, hypoxia combined with 20, 40, 80 μmol/L AS-II treated groups, hypoxia combined with nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) inhibitor VAS2870 treated group, and then cultured either in normoxic (210 mL/L O) or hypoxic (20 mL/L O) condition for 24 hours. The proliferation of PASMCs was detected by CCK-8 assay. The level of intracellular reactive oxygen species (ROS) was detected by DCFH-DA staining. Protein kinase B (AKT), phospho-AKT (p-AKT), mammalian target of rapamycin (mTOR), phospho-mTOR (p-mTOR), proliferating cell nuclear antigen (PCNA), NOX1 and NOX4 protein expression were assessed by Western blotting. Results In the hypoxia group, the proliferation of PASMCs, level of intracellular ROS, protein expression of PCNA, p-AKT, p-mTOR, NOX1 and NOX4 increased significantly compared with those in the normoxia group. However, AS-II treatment inhibited hypoxia-induced PASMCs proliferation, decreased the level of intracellular ROS, and suppressed protein expression of PCNA, p-AKT, p-mTOR, NOX1 and NOX4. Moreover, VAS2870 treatment lead to similar changes. Conclusion AS-II can inhibit the proliferation of PASMCs induced by hypoxia, which may be associated with the blocking of NOX/ROS/AKT/mTOR signaling pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
March 2021

Targeting Lysosomal Degradation Pathways: New Strategies and Techniques for Drug Discovery.

J Med Chem 2021 Apr 25;64(7):3493-3507. Epub 2021 Mar 25.

State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China.

A series of tools for targeted protein degradation are inspiring scientists to develop new drugs with advantages over traditional small-molecule drugs. Among these tools, proteolysis-targeting chimeras (PROTACs) are most representative of the technology based on proteasomes. However, the proteasome has little degradation effect on certain macromolecular proteins or aggregates, extracellular proteins, and organelles, which limits the application of PROTACs. Additionally, lysosomes play an important role in protein degradation. Therefore, lysosome-induced protein degradation drugs can directly regulate protein levels , achieve the goal of treating diseases, and provide new strategies for drug discovery. Lysosome-based degradation technology has the potential for clinical translation. In this review, strategies targeting lysosomal pathways and lysosome-based degradation techniques are summarized. In addition, lysosome-based degrading drugs are described, and the advantages and challenges are listed. Our efforts will certainly promote the design, discovery, and clinical application of drugs associated with this technology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.0c01689DOI Listing
April 2021

Integrating Transwomen and Female Athletes with Differences of Sex Development (DSD) into Elite Competition: The FIMS 2021 Consensus Statement.

Sports Med 2021 Mar 24. Epub 2021 Mar 24.

Centre for Exercise Sciences and Sports Medicine, FIMS Collaborating Centre of Sports Medicine, Rome, Italy.

Sport is historically designated by the binary categorization of male and female that conflicts with modern society. Sport's governing bodies should consider reviewing rules determining the eligibility of athletes in the female category as there may be lasting advantages of previously high testosterone concentrations for transwomen athletes and currently high testosterone concentrations in differences in sex development (DSD) athletes. The use of serum testosterone concentrations to regulate the inclusion of such athletes into the elite female category is currently the objective biomarker that is supported by most available scientific literature, but it has limitations due to the lack of sports performance data before, during or after testosterone suppression. Innovative research studies are needed to identify other biomarkers of testosterone sensitivity/responsiveness, including molecular tools to determine the functional status of androgen receptors. The scientific community also needs to conduct longitudinal studies with specific control groups to generate the biological and sports performance data for individual sports to inform the fair inclusion or exclusion of these athletes. Eligibility of each athlete to a sport-specific policy needs to be based on peer-reviewed scientific evidence made available to policymakers from all scientific communities. However, even the most evidence-based regulations are unlikely to eliminate all differences in performance between cisgender women with and without DSD and transwomen athletes. Any remaining advantage held by transwomen or DSD women could be considered as part of the athlete's unique makeup.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40279-021-01451-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988249PMC
March 2021

The effect of consecutive ambient air pollution on the hospital admission from chronic obstructive pulmonary disease in the Chengdu region, China.

Air Qual Atmos Health 2021 Mar 18:1-13. Epub 2021 Mar 18.

The Biomedical Engineering School, University of Technology Sydney, Ultimo, NSW 2007 Australia.

Hospitalisation risks for chronic obstructive pulmonary disease (COPD) have been attributed to ambient air pollution worldwide. However, a rise in COPD hospitalisations may indicate a considerable increase in fatality rate in public health. The current study focuses on the association between consecutive ambient air pollution (CAAP) and COPD hospitalisation to offer predictable early guidance towards estimates of COPD hospital admissions in the event of consecutive exposure to air pollution. Big data analytics were collected from 3-year time series recordings (from 2015 to 2017) of both air data and COPD hospitalisation data in the Chengdu region in China. Based on the combined effects of CAAP and unit increase in air pollutant concentrations, a quasi-Poisson regression model was established, which revealed the association between CAAP and estimated COPD admissions. The results show the dynamics and outbreaks in the variations in COPD admissions in response to CAAP. Cross-validation and mean squared error (MSE) are applied to validate the goodness of fit. In both short-term and long-term air pollution exposures, test outcomes show that the COPD hospitalisation risk is greater for men than for women; similarly, the occurrence of COPD hospital admissions in the group of elderly people (> 65 years old) is significantly larger than that in lower age groups. The time lag between the air quality and COPD hospitalisation is also investigated, and a peak of COPD hospitalisation risk is found to lag 2 days for air quality index (AQI) and PM, and 1 day for PM. The big data-based predictive paradigm would be a measure for the early detection of a public health event in post-COVID-19. The study findings can also provide guidance for COPD admissions in the event of consecutive exposure to air pollution in the Chengdu region.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11869-021-00998-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971392PMC
March 2021

Broadband terahertz absorber with tunable frequency and bandwidth by using Dirac semimetal and strontium titanate.

Opt Express 2021 Mar;29(5):7713-7723

A bifunctional broadband absorber in the terahertz band based on patterned bulk Dirac semimetal (BDS) and strontium titanate (STO) is proposed. The properties of the absorber are investigated using the finite-difference time-domain (FDTD) method. The results show that the width of absorption can be modulated from 0.59 THz to 0.7 THz when the Fermi energy of the BDS is independently shifted from 40 meV to 50 meV. By tuning the temperature from 250 K to 400K, the center frequency of the broadband absorption spectrum can be changed from 1.311 THz to 1.505 THz, and the absorption bandwidth broadens from 0.66 THz to 0.81 THz. In addition, the simulation results show that the absorber is insensitive to electromagnetic wave polarization, and can still maintain a stable broadband absorption effect when the oblique incidence is within 40° for TE and TM modes. Based on the impedance matching theory, the physical mechanism of the broadband absorption is analyzed theoretically. This work can provide an alternative way to design high-performance multifunctional tunable terahertz devices.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1364/OE.418679DOI Listing
March 2021

Noise analysis of the fiber-based vibration detection system.

Opt Express 2021 Feb;29(4):5588-5597

Detecting seismic events using a fiber-based CW laser interferometer attracts wide attention. To make the detection more effective, we analyze the system's noise level by setting up two vibration detection systems. By changing the fiber length (0∼100 km) and laser noise level, respectively, we detect the minor phase change caused by a 160 µm-fiber-length vibration. Furthermore, we use three indicators, Power Spectral Density, Background Noise Level, and Signal-to-Noise Ratio to analyze the noise level of the whole system. The relation between the system's background noise and corresponding detection result is carried out. This quantitative research can serve as a reference and help people to realize the most efficient vibration detection system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1364/OE.416615DOI Listing
February 2021

Noise-assisted Multivariate Empirical Mode Decomposition based Causal Decomposition for brain-physiological network in bivariate and multiscale time series.

J Neural Eng 2021 Mar 9. Epub 2021 Mar 9.

Key Laboratory for Neuro Information of Ministry of Education, School of Life Science and Technology, University of Electronic Science and Technology of China, No.2006, Xiyuan Ave, West Hi-Tech Zone, Chengdu, 610054, CHINA.

Noise-assisted Multivariate Empirical Mode Decomposition (NA-MEMD) based Causal Decomposition depicts a cause and effect relationship that is not based on the term of prediction, but rather on the phase dependence of time series. Here, we present the NA-MEMD based Causal Decomposition approach according to the covariation and power views traced to Hume and Kant: a priori cause-effect interaction is first acquired, and the presence of a candidate cause and of the effect is then computed from the sensory input somehow.Based on the definition of NA-MEMD based Causal Decomposition, we show such causal relation is a phase relation where the candidate causes are not merely followed by effects, but rather produce effects.The predominant methods used in neuroscience (Granger causality, EMD-based Causal Decomposition) are validated, showing the applicability of NA-MEMD based Causal Decomposition, particular to brain physiological processes in bivariate and multiscale time series.We point to the potential use in the causality inference analysis in a complex dynamic process.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1088/1741-2552/abecf2DOI Listing
March 2021

Small-Molecule Drug Discovery in Triple Negative Breast Cancer: Current Situation and Future Directions.

J Med Chem 2021 Mar 2;64(5):2382-2418. Epub 2021 Mar 2.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.

Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, but an effective targeted therapy has not been well-established so far. Considering the lack of effective targets, where do we go next in the current TNBC drug development? A promising intervention for TNBC might lie in small-molecule drugs that precisely target different molecular characteristics of TNBC. However, an ideal single-target drug discovery still faces a huge challenge. Alternatively, other new emerging strategies, such as dual-target drug, drug repurposing, and combination strategies, may provide new insight into the improvement of TNBC therapeutics. In this review, we focus on summarizing the current situation of a series of candidate small-molecule drugs in TNBC therapy, including single-target drugs, dual-target drugs, as well as drug repurposing and combination strategies that will together shed new light on the future directions targeting TNBC vulnerabilities with small-molecule drugs for future therapeutic purposes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.0c01180DOI Listing
March 2021

Development of small-molecule tropomyosin receptor kinase (TRK) inhibitors for fusion cancers.

Acta Pharm Sin B 2021 Feb 23;11(2):355-372. Epub 2020 May 23.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China.

Tropomyosin receptor kinase A, B and C (TRKA, TRKB and TRKC), which are well-known members of the cell surface receptor tyrosine kinase (RTK) family, are encoded by the neurotrophic receptor tyrosine kinase 1, 2 and 3 ( and ) genes, respectively. TRKs can regulate cell proliferation, differentiation and even apoptosis through the RAS/MAPKs, PI3K/AKT and PLC pathways. Gene fusions involving act as oncogenic drivers of a broad diversity of adult and pediatric tumors, and TRKs have become promising antitumor targets. Therefore, achieving a comprehensive understanding of TRKs and relevant TRK inhibitors should be urgently pursued for the further development of novel TRK inhibitors for potential clinical applications. This review focuses on summarizing the biological functions of TRKs and fusion proteins, the development of small-molecule TRK inhibitors with different chemotypes and their activity and selectivity, and the potential therapeutic applications of these inhibitors for future cancer drug discovery efforts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.apsb.2020.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893124PMC
February 2021

The prognosis of radiofrequency ablation versus hepatic resection for patients with colorectal liver metastases: A systematic review and meta-analysis based on 22 studies.

Int J Surg 2021 Mar 12;87:105896. Epub 2021 Feb 12.

Jinan University, No. 601 Huangpu Avenue West, Guangzhou, 510632, China; Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China; Institute of Hepato-Biliary-Pancreatic-Intestinal Disease, North Sichuan Medical College, Nanchong, 637000, China. Electronic address:

Background: Though hepatic resection (HR) is the standard local therapy for patients with colorectal cancer liver metastases (CRLMs), currently, radiofrequency ablation (RFA) may play an alternative role for elderly and vulnerable patients with various organ dysfunctions. This study aims to compare the prognosis of RFA and HR in treatment of CRLMs.

Methods: A systematic search of PubMed, Embase, Cochrane Library and Web of Science up to October 1, 2020 was conducted for relevant studies that compared the prognosis of RFA with HR in the treatment of CRLMs. The primary outcomes were 30-day mortality, long-term recurrence, overall survival (OS) and disease-free survival (DFS). The secondary outcomes were various factors of OS, recurrence-free survival (RFS), survival, recurrence and complication.

Results: A total of 22 studies including 4385 CRLM patients were identified. There was no significant difference between RFA and HR in 30-day mortality, with a pooled OR of 0.88 (95% CI 0.34-2.29; P = 0.80). CRLM patients undergoing RFA experienced significantly higher incidences of marginal and intrahepatic recurrence than HR, with pooled ORs of 7.09 (95% CI 4.56-11.2; 1251 pts) and 2.02 (95% CI 1.24-3.28; 1038 pts). In addition, RFA showed lower 1-, 3- and 5-yr OS rate than HR with pooled ORs of 0.39, 0.40 and 0.60 respectively. A lower 5-yr DFS rate was also found in RFA than HR group, with a pooled OR of 0.74 (95% CI 0.56-0.97; P = 0.03; 1231 pts). Multivariable analysis showed that tumor size, multiple tumors, age, primary node positive and metachronous metastasis were independent factors of OS, and multiple tumors was also an independent factor of RFS.

Conclusions: Though the 30-day mortality of RFA was equal to HR, RFA showed a higher recurrence rate and poor long-term survival outcomes for CRLM patients. Tumor size, multiple tumors, age, primary node positive and metachronous metastasis were independent factors of survival. However, the results were limited because of the inequality baseline characteristics between the comparative groups. Randomized or propensity score matching studies should be performed to clarify the effectiveness of RFA and to determine target populations that benefit most from RFA in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijsu.2021.105896DOI Listing
March 2021

A Rationale for Drug Design Provided by Co-Crystal Structure of IC261 in Complex with Tubulin.

Molecules 2021 Feb 10;26(4). Epub 2021 Feb 10.

Department of Clinical Research Management, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China.

Microtubules composed of α/β tubulin heterodimers are an essential part of the cytoskeleton of eukaryotic cells and are widely regarded as targets for cancer chemotherapy. IC261, which is discovered as an ATP-competitive inhibitor of serine/threonine-specific casein kinase 1 (CK1), has shown its inhibitory activity on microtubule polymerization in recent studies. However, the structural information of the interaction between tubulin and IC261 is still unclear. Here, we provided a high-resolution (2.85 Å) crystal structure of tubulin and IC261 complex, revealed the intermolecular interaction between tubulin and IC261, and analyzed the structure-activity relationship (SAR). Subsequently, the structure of tubulin-IC261 complex was compared with tubulin-colchicine complex to further elucidate the novelty of IC261. Furthermore, eight optimal candidate compounds of new IC261-based microtubule inhibitors were obtained through molecular docking studies. In conclusion, the co-crystal structure of tubulin-IC261 complex paves a way for the design and development of microtubule inhibitor drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules26040946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916759PMC
February 2021

Case Report: Multi-Modality Imaging of a Right Atrial Pseudoaneurysm in a Patient With Breast Cancer.

Front Cardiovasc Med 2020 15;7:623580. Epub 2021 Jan 15.

Department of Radiology, The First Affiliated Hospital of China Medical University, Shenyang, China.

Cardiac pseudoaneurysms occur when a blood vessel wall is injured and the leaking blood is collected in the surrounding tissue. They are very rare events and have a high risk of rupture and poor prognosis. We report a case of right atrial pseudoaneurysm in a 54-year-old female patient diagnosed with breast cancer and lung metastasis. The patient underwent five intrapericardial infusions of cisplatin and nine cycles of systemic chemotherapy. Non-contrast-enhanced computed tomography (CT) was performed at follow-up evaluation during the chemotherapeutic process as this patient was contraindicated to iodine. CT without contrast and ultrasonography showed a crescent-shaped lesion near the right atrium but its nature could not be determined. Cardiac magnetic resonance (CMR) imaging with gadolinium contrast provided important information as an alternative enhanced imaging modality. By combining CT, ultrasonography and CMR images with the medical history of the patient, we inferred that the lesion was a pseudoaneurysm in the right atrium. This condition was related to the erosion of metastasized tumor cells or the accumulated cardiac toxicity of multiple cycles of chemotherapy or pericardiocentesis. This single case report suggests that cardiac rupture should be considered as a potential complication in patients with suspected pericardial metastasis. CMR imaging is an excellent tool for the detection of right atrial rupture.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcvm.2020.623580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864283PMC
January 2021

Design, synthesis, and biological evaluation of quinazolin-4(3)-one derivatives co-targeting poly(ADP-ribose) polymerase-1 and bromodomain containing protein 4 for breast cancer therapy.

Acta Pharm Sin B 2021 Jan 24;11(1):156-180. Epub 2020 Jun 24.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China.

This study was aimed to design the first dual-target small-molecule inhibitor co-targeting poly (ADP-ribose) polymerase-1 (PARP1) and bromodomain containing protein 4 (BRD4), which had important cross relation in the global network of breast cancer, reflecting the synthetic lethal effect. A series of new BRD4 and PARP1 dual-target inhibitors were discovered and synthesized by fragment-based combinatorial screening and activity assays that together led to the chemical optimization. Among these compounds, was selected and exhibited micromole enzymatic potencies against BRD4 and PARP1, respectively. Compound was further shown to efficiently modulate the expression of BRD4 and PARP1. Subsequently, compound was found to induce breast cancer cell apoptosis and stimulate cell cycle arrest at G1 phase. Following pharmacokinetic studies, compound showed its antitumor activity in breast cancer susceptibility gene 1/2 () wild-type MDA-MB-468 and MCF-7 xenograft models without apparent toxicity and loss of body weight. These results together demonstrated that a highly potent dual-targeted inhibitor was successfully synthesized and indicated that co-targeting of BRD4 and PARP1 based on the concept of synthetic lethality would be a promising therapeutic strategy for breast cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.apsb.2020.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838034PMC
January 2021

Neural adaptive control of air-breathing hypersonic vehicles robust to actuator dynamics.

ISA Trans 2021 Jan 11. Epub 2021 Jan 11.

Space Control and Inertial Technology Research Center, Harbin Institute of Technology, Harbin, 150001, PR China. Electronic address:

This paper investigates the neural adaptive control problem for air-breathing hypersonic vehicles. For the velocity subsystem, a radial basis function neural network (RBFNN)-based adaptive controller is first designed, which employs the auxiliary variable to compensate for the saturation nonlinearity of the scramjet control command. For the altitude subsystem, an RBFNN-based controller addresses actuator constraints and dynamics using the model predictive control, as well as counteracts uncertainties and disturbances using the neural adaptive mechanism. The effectiveness of the proposed control is verified by simulations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.isatra.2021.01.017DOI Listing
January 2021

Effects of long-term afforestation and natural grassland recovery on soil properties and quality in Loess Plateau (China).

Sci Total Environ 2021 May 21;770:144833. Epub 2021 Jan 21.

Environment Management Laboratory, Mykolas Romeris University, LT-08303 Vilnius, Lithuania.

Long-term afforestation has important implications on soil properties and quality in semi-arid areas. A large-scale afforestation project has been carried out in the Loess Plateau in the last 20 years. This work aims to study the afforestation (Robinia pseudoacacia, Caragana korshinskii and natural grassland recover 10, 20, 30, and 40 years after) impacts on soil properties and quality. The results showed that coverage and root biomass (RB) was the highest 30 years after the restoration in Robinia pseudoacacia and Caragana korshinskii treatments, while the highest 40 years post-restoration in natural grasslands. Sand content and BD showed the highest values 10 years post afforestation in all study areas. Clay, Silt, mean weight diameter (MWD), and geometric mean diameter (GMD) in Robinia pseudoacacia, Caragana korshinskii had the highest values 30 years after the afforestation, while in natural grasslands, this was observed 40 years after. In Robinia pseudoacacia, Caragana korshinskii treatments, soil moisture content (SMC) reached the highest levels 30 years post afforestation at 20-40 and 40-60 cm. Regarding natural grasslands, SMC had the highest values 40 years post-afforestation. Sand content and BD increased with soil depth, while the opposite was identified in RB, clay, silt, MWD, GMD and SMC. In Robinia pseudoacacia and Caragana korshinskii treatments, soil organic matter, total nitrogen, available nitrogen, total phosphorous, and available phosphorus had the highest levels 40 years post-restoration at 0-20 cm, while at 20-40 and 40-60 cm, the highest concentrations were identified 30 years after. In all the treatments, the soil quality index (SQI) was the highest 40 years post-restoration. The values of SQI were always higher in natural grasslands than in Robinia pseudoacacia and Caragana korshinskii treatments. Overall, natural recovery (natural grasslands) is more efficient than afforestation (Robinia pseudoacacia and Caragana korshinskii treatments) in soil quality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.scitotenv.2020.144833DOI Listing
May 2021

Preparation and Physico-Chemical Performance Optimization of Sintering-Free Lightweight Aggregates with High Proportions of Red Mud.

Materials (Basel) 2021 Jan 5;14(1). Epub 2021 Jan 5.

National Engineering Laboratory for Reducing Emissions from Coal Combustion, Engineering Research Center of Environmental Thermal Technology of Ministry of Education, Shandong Key Laboratory of Energy Carbon Reduction and Resource Utilization, School of Energy and Power Engineering, Shandong University, Jinan 250061, China.

Sintering-free lightweight aggregates were prepared with high proportions of red mud and a binder material derived from whole solid wastes through rolling granulation at room temperature. The preparation process was optimized by changing the material matching and size parameters of the SFLAs. The physico-chemical performance, including the density, mechanical strength, water absorption, hydration products, heavy metal leaching, and microstructure were evaluated by jointly employing X-ray Fluorescence, X-ray Diffraction, and Inductively Coupled Plasma Optical Emission Spectrometry, Shadow Electron Microscope, etc. The results indicated that the red mud and waste-based binders were highly compatible in the granulation process, with up to 80% red mud being successfully added. The sintering-free lightweight aggregates products at the binder content of 30% and the size coverage of 10-16 mm exhibited a bulk density of 900-1000 kg·m, a 28 d cylinder compressive strength of 9.2-11.3 MPa, and water absorption of less than 10%. Owing to the formation of important hydration products, ettringite, the heavy metal leaching of the sintering-free lightweight aggregates was also proven to be environmentally acceptable. This work provides a promising pathway to prepare low-cost, high-strength, and green lightweight aggregates through the large-scale utilization of solid waste red mud.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ma14010218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794722PMC
January 2021

NMR-Based Methods for Protein Analysis.

Anal Chem 2021 02 13;93(4):1866-1879. Epub 2021 Jan 13.

Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences-Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan 430071, China.

Nuclear magnetic resonance (NMR) spectroscopy is a well-established method for analyzing protein structure, interaction, and dynamics at atomic resolution and in various sample states including solution state, solid state, and membranous environment. Thanks to rapid NMR methodology development, the past decade has witnessed a growing number of protein NMR studies in complex systems ranging from membrane mimetics to living cells, which pushes the research frontier further toward physiological environments and offers unique insights in elucidating protein functional mechanisms. In particular, in-cell NMR has become a method of choice for bridging the huge gap between structural biology and cell biology. Herein, we review the recent developments and applications of NMR methods for protein analysis in close-to-physiological environments, with special emphasis on in-cell protein structural determination and the analysis of protein dynamics, both difficult to be accessed by traditional methods.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.analchem.0c03830DOI Listing
February 2021

Oxygenated phosphatidylethanolamine navigates phagocytosis of ferroptotic cells by interacting with TLR2.

Cell Death Differ 2021 Jan 11. Epub 2021 Jan 11.

Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou, 510632, China.

During cancer therapy, phagocytic clearance of dead cells plays a vital role in immune homeostasis. The nonapoptotic form of cell death, ferroptosis, exhibits extraordinary potential in tumor treatment. However, the phagocytosis mechanism that regulates the engulfment of ferroptotic cells remains unclear. Here, we establish a novel pathway for phagocytic clearance of ferroptotic cells that is different from canonical mechanisms by using diverse ferroptosis models evoked by GPX4 dysfunction/deficiency. We identified the oxidized phospholipid, 1-steaoryl-2-15-HpETE-sn-glycero-3-phosphatidylethanolamine (SAPE-OOH), as a key eat-me signal on the ferroptotic cell surface. Enriching the plasma membrane with SAPE-OOH increased the efficiency of phagocytosis of ferroptotic cells by macrophage, a process that was suppressed by lipoprotein-associated phospholipase A. Ligand fishing, lipid blotting, and cellular thermal shift assay screened and identified TLR2 as a membrane receptor that directly recognized SAPE-OOH, which was further confirmed by TLR2 inhibitors and gene silencing studies. A mouse mammary tumor model of ferroptosis verified SAPE-OOH and TLR2 as critical players in the clearance of ferroptotic cells in vivo. Taken together, this work demonstrates that SAPE-OOH on ferroptotic cell surface acts as an eat-me signal and navigates phagocytosis by targeting TLR2 on macrophages.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41418-020-00719-2DOI Listing
January 2021

Inflammatory cytokines-stimulated human muscle stem cells ameliorate ulcerative colitis via the IDO-TSG6 axis.

Stem Cell Res Ther 2021 Jan 9;12(1):50. Epub 2021 Jan 9.

The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Key Laboratory of Stem Cells and Medical Biomaterials of Jiangsu Province, Medical College of Soochow University, 199 Renai Road, Suzhou, 215123, Jiangsu, People's Republic of China.

Background: Muscle stem cells (MuSCs) are absolutely required for the formation, repair, and regeneration of skeletal muscle tissue. Increasing evidence demonstrated that tissue stem cells, especially mesenchymal stem cells (MSCs), can exert therapeutic effects on various degenerative and inflammatory disorders based on their immunoregulatory properties. Human mesenchymal stem cells (hMSCs) treated with interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) were reported to possess anti-inflammatory functions by producing TNF-stimulated gene 6 (TSG-6). However, whether human muscle stem cells (hMuSCs) also possess TSG-6 mediated anti-inflammatory functions has not been explored.

Methods: The ulcerative colitis mouse model was established by subjecting mice to dextran sulfate sodium (DSS) in drinking water for 7 days. hMuSCs were pretreated with IFN-γ and TNF-α for 48 h and were then transplanted intravenously at day 2 of DSS administration. Body weights were monitored daily. Indoleamine 2,3-dioxygenase (IDO) and TSG-6 in hMuSCs were knocked down with short hairpin RNA (shRNA) and small interfering RNA (siRNA), respectively. Colon tissues were collected for length measurement and histopathological examination. The serum level of IL-6 in mice was measured by enzyme-linked immunosorbent assay (ELISA). Real-time PCR and Western blot analysis were performed to evaluate gene expression.

Results: hMuSCs treated with inflammatory factors significantly ameliorated inflammatory bowel disease (IBD) symptoms. IDO and TSG-6 were greatly upregulated and required for the beneficial effects of hMuSCs on IBD. Mechanistically, the tryptophan metabolites, kynurenine (KYN) or kynurenic acid (KYNA) produced by IDO, augmented the expression of TSG-6 through activating their common receptor aryl hydrocarbon receptor (AHR).

Conclusion: Inflammatory cytokines-treated hMuSCs can alleviate DSS-induced colitis through IDO-mediated TSG-6 production.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13287-020-02118-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796621PMC
January 2021

Doping practices in international weightlifting: analysis of sanctioned athletes/support personnel from 2008 to 2019 and retesting of samples from the 2008 and 2012 Olympic Games.

Sports Med Open 2021 Jan 7;7(1). Epub 2021 Jan 7.

School of Pharmacy and Biomolecular Sciences, University of Brighton, Huxley Building, Lewes Road, Brighton, UK.

Background: The pervasiveness of doping and findings of anti-doping corruption threaten weightlifting's position at the 2024 Olympic Games. Analysing the practices of doping in weightlifters could identify patterns in doping that assist in future detection.

Methods: We analysed publicly available data on sanctioned athletes/support personnel from the International Weightlifting Federation between 2008 and 2019 and announced retrospective Anti-Doping Rule Violations (ADRVs) from the 2008 and 2012 Olympic Games.

Results: There were 565 sanctions between 2008 and 2019 of which 82% related to the detection of exogenous Anabolic Androgenic Steroid (AAS) metabolites and markers indicating endogenous AAS usage. The detection of exogenous AAS metabolites, markers of endogenous AAS usage and other substance metabolites varied by IWF Continental Federation (p ≤ 0.05) with Europe (74%, 11%, 15%) and Asia (70%, 15%, 15%) showing a higher detection of exogenous AAS compared to Pan America (37%, 30%, 33%) and Africa (50%, 17%, 33%). When looking at the 10 most detected substances, the nations with the highest number of sanctions (range 17-35) all had at least one overrepresented substance that accounted for 38-60% of all detected substances. The targeted re-analysis of samples from the 2008 and 2012 Olympic Games due to the discovery of long-term metabolites for exogenous AAS resulted in 61 weightlifters producing retrospective ADRVs. This includes 34 original medallists (9 gold, 10 silver and 15 bronze), the highest of any sport identified by Olympic Games sample re-testing. The exogenous AAS dehydrochloromethyltestosterone and stanozolol accounted for 83% of detected substances and were present in 95% of these samples.

Conclusion: Based on these findings of regional differences in doping practices, weightlifting would benefit from the targeted testing of certain regions and continuing investment in long-term sample storage as the sensitivity and specificity of detection continues to improve.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40798-020-00293-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790029PMC
January 2021

Antitumor activity and mechanism of resistance of the novel HDAC and PI3K dual inhibitor CUDC-907 in pancreatic cancer.

Cancer Chemother Pharmacol 2021 Mar 3;87(3):415-423. Epub 2021 Jan 3.

Key Laboratory for Molecular Enzymology and Engineering, National Engineering Laboratory for AIDS Vaccine, The Ministry of Education, School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun, Jilin, China.

Purpose: Pancreatic cancer is a highly malignant disease with an extremely poor prognosis. The benefit of chemotherapy treatment for pancreatic cancer is very limited. Therefore, new therapeutic targets and approaches are urgently needed for this deadly disease. Multi-target therapy is a potential and feasible treatment strategy. Given the important roles that histone deacetylases (HDACs) and phosphoinositide-3-kinase (PI3K) play in pancreatic cancer, we investigated the antitumor activity and mechanism of novel HDAC and PI3K dual inhibitor CUDC-907 in pancreatic cancer.

Methods And Results: MTT assay and flow cytometric analysis were used to examine the in vitro antitumor activity of CUDC-907. A BxPC-3-derived xenograft mouse model was used to determine CUDC-907 in vivo efficacy. The TUNEL assay as used to determine apoptosis in tumors in vivo post CUDC-907 treatment. Western blots were used to determine the effect of CUDC-907 on protein levels. Our results show that CUDC-907 decreased viable cells and induced cell death in a concentration-dependent manner. Furthermore, CUDC-907 showed promising in vivo antitumor activity in the BxPC-3-derived xenograft mouse model while exhibiting tolerable toxicity. Furthermore, long-term treatment with CUDC-907 induced phosphorylation of AKT, S6 (ribosomal protein S6), and ERK (extracellular regulated protein kinase), and inhibition of PI3K (phosphatidylinositol 3-kinase), mTOR (mammalian target of rapamycin), or ERK significantly enhanced CUDC-907-induced cell death in pancreatic cell lines.

Conclusion: Taken together, these findings support the clinical development of CUDC-907 for the treatment of pancreatic cancer and identify compensatory activation of mTOR and MEK/ERK as a possible mechanism of resistance to CUDC-907.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00280-020-04210-0DOI Listing
March 2021