Publications by authors named "T C Wang"

31,826 Publications

Autologous Fat Grafting in Facial Cosmetic Surgery: A National Survey.

Facial Plast Surg 2021 Feb 12;37(1):136-138. Epub 2021 Apr 12.

Department of Otolaryngology - Head and Neck Surgery, Oregon Health and Science University, Portland, Oregon.

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http://dx.doi.org/10.1055/s-0040-1721098DOI Listing
February 2021

Further lead optimization on Bax activators: Design, synthesis and pharmacological evaluation of 2-fluoro-fluorene derivatives for the treatment of breast cancer.

Eur J Med Chem 2021 Apr 3;219:113427. Epub 2021 Apr 3.

Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch (UTMB), Galveston, TX, 77555, United States; Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch (UTMB), Galveston, TX, 77555, United States. Electronic address:

To further pursue potent Bax activators with better safety profiles for the treatment of breast cancer, structural optimization was conducted based on lead compound CYD-4-61 through several strategies, including scaffold hopping on the 2-nitro-fluorene ring, replacement of the nitro group with bioisosteres to avoid potential toxicity, and further optimization on the upper pyridine by exploring diverse alkylamine linkers as a tail or replacing the pyridine with bioisosteric heterocycles. F-containing compound 22d (GL0388) exhibited a good balance between the activity and toxicity, displaying submicromolar activities against a variety of cancer cell lines with 5.8-10.7-fold selectivity of decreased activity to MCF-10A human mammary epithelial cell line. Compound 22d dose-dependently blocked colony formation of breast cancer cells and prevented the migration and invasion of MDA-MB-231 cells. Mechanism of action studies indicate that 22d activated Bax, rendering its insertion into mitochondrial membrane, thereby leading to cytochrome c release from the mitochondria into the cytoplasm, subsequently inducing release of apoptotic biomarkers. Further in vivo efficacy studies of 22d in human breast cancer xenografts arisen from MDA-MB-231 cells demonstrated that this drug candidate significantly suppressed tumor growth, indicating the therapeutic promise of this class of compounds for the treatment of breast cancer as well as the potential for developing F-radiolabeled imaging ligands as anticancer chemical probes.
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http://dx.doi.org/10.1016/j.ejmech.2021.113427DOI Listing
April 2021

Fraxinellone alleviates kidney fibrosis by inhibiting CUG-binding protein 1-mediated fibroblast activation.

Toxicol Appl Pharmacol 2021 Apr 9:115530. Epub 2021 Apr 9.

State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China. Electronic address:

Chronic Kidney Disease (CKD) is a serious threat to human health. In addition, kidney fibrosis is a key pathogenic intermediate for the progression of CDK. Moreover, excessive activation of fibroblasts is key to the development of kidney fibrosis and this process is difficult to control. Notably, fraxinellone is a natural compound isolated from Dictamnus dasycarpus and has a variety of pharmacological activities, including hepatoprotective, anti-inflammatory and anti-cancer effects. However, the effect of fraxinellone on kidney fibrosis is largely unknown. The present study showed that fraxinellone could alleviate folic acid-induced kidney fibrosis in mice in a dose dependent manner. Additionally, the results revealed that fraxinellone could effectively down-regulate the expression of CUGBP1, which was highly up-regulated in human and murine fibrotic renal tissues. Furthermore, expression of CUGBP1 was selectively induced by the Transforming Growth Factor-beta (TGF-β) through p38 and JNK signaling in kidney fibroblasts. On the other hand, downregulating the expression of CUGBP1 significantly inhibited the activation of kidney fibroblasts. In conclusion, these findings demonstrated that fraxinellone might be a new drug candidate and CUGBP1 could be a promising target for the treatment of kidney fibrosis.
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http://dx.doi.org/10.1016/j.taap.2021.115530DOI Listing
April 2021

Projecting the Global Potential Distribution of Cydia pomonella (Lepidoptera: Tortricidae) Under Historical and RCP4.5 Climate Scenarios.

J Insect Sci 2021 Mar;21(2)

Key Laboratory of Beijing for the Control of Forest Pests, Beijing Forestry University, Beijing, 100083, China.

The codling moth Cydia pomonella (L.) (Lepidoptera: Tortricidae) is a destructive pest of apple (Malus domestica (Rosales: Rosaceae)), pear (Pyrus spp. (Rosales: Rosaceae)), and other pome tree fruits; outbreaks cause significant ecological and economic losses. In this study, we used CLIMEX model to predict and evaluate the global risk of C. pomonella based on historical climate data (1989-2018) and simulated future climate data (2071-2100) under the RCP4.5 scenarios. Cydia pomonella exhibited a wide distribution under both historical and future climate conditions. Climate change is predicted to expand the northern boundary of the potential distribution from approximately 60°N to 75°N. Temperature was the most dominant factor in climatic suitability for the pest. Combinations of multiple meteorological factors (relative humidity and precipitation) associated with a failure to break diapause in certain regions also affect suitability, particularly in northern South America and central Africa. Irrigation only had a slight impact on species favorability in some areas. The projections established in our study present insight into the global potential suitability of C. pomonella under climate change scenarios by the end of the 21st century. Farmers should be aware of the risk associated with the pest based on the results, which would provide guidance for quarantine agencies and trade negotiators worldwide.
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http://dx.doi.org/10.1093/jisesa/ieab024DOI Listing
March 2021

Spatial Confinement for Cleaving and Reforming C=N Bonds of Fluorescent Molecules.

Authors:
Keyan Liu Tie Wang

Angew Chem Int Ed Engl 2021 Apr 12. Epub 2021 Apr 12.

Institute of Chemistry, Chinese Academy of Sciences, Analytical Chemistry, #2 North 1st Street, Zhongguancun, 100190, Beijing, CHINA.

Molecules in confined spaces exhibit unusual behaviors that are not typically observed in bulk systems. Such behavior can provide alternative strategies for exploring new reaction pathways. Cleavage of the C=N bond of Nile red (NR) in solution is an irreversible reaction. Here, we used spatial confinement within a cationic-micelle confined system to convert this reaction to a reversible process. The fluorescence of NR shifted between red and green for nine cycles. The new chemical pathway based on spatial confinement can be attributed to two factors: increasing the local concentration of reactants and reducing the reaction energy barrier. This effect is supported by both experimental evidence and theoretical calculations. The cross-linked silica shell comprising the confinement chamber stabilizes the enclosed molecules. This reduces fluorophore leakage and maintains fluorescence intensity in most environments, including in solution, on paper, and in hydrogel films, and expands practical applications in encrypted information and multi-informational displays.
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http://dx.doi.org/10.1002/anie.202103471DOI Listing
April 2021

A marginal liver graft with hyperbilirubinemia transplanted successfully by ischemia-free liver transplantation.

Ann Transl Med 2021 Mar;9(5):425

Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

The shortage of transplant organs remains a serious issue worldwide, and using liver grafts from extended criteria donors could expand the donor pool. Extended criteria donor liver allografts have a high chance of complications such as primary nonfunction, early allograft dysfunction, and ischemic-type biliary lesions. How to employ these extended criteria donors safely and effectively warrants further investigation. Herein, we report the successful use of a marginal donor liver with hyperbilirubinemia to save the life of an acute-on-chronic liver failure recipient using a new surgical technique: ischemia-free liver transplantation (IFLT). The graft was retrieved for transplantation due to the following reasons: (I) the recipient was in a life-threatening situation and no living donor donation candidate was available; (II) the graft was considered transplantable except for cholestasis; and (III) IFLT could reduce ischemia/reperfusion injury (IRI), resuscitate the allograft , and maintain organ viability before transplantation. The graft was transplanted successfully using the IFLT procedure. Although anatomic biliary stricture occurred after surgery, no IRI-related complications were found during the follow-up. The use of liver grafts from extended criteria donors is safe and effective under IFLT. Additional IFLT clinical studies need to be performed, particularly concerning donor management, graft selection, and resuscitation.
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http://dx.doi.org/10.21037/atm-20-6296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033382PMC
March 2021

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

Impact of Distracting Emotional Stimuli on the Characteristics of Movement Performance: A Kinematic Study.

Front Psychol 2021 25;12:642643. Epub 2021 Mar 25.

Brain and Cognitive Neuroscience Research Center, Liaoning Normal University, Dalian, China.

It is well-documented that emotional stimuli impact both the cognitive and motor aspects of "goal-directed" behavior. However, how emotional distractors impact motor performance remains unclear. This study aimed to characterize how movement quality was impacted during emotional distractors. We used a modified oddball paradigm and documented the performance of pure movement. Participants were designated to draw a triangle or a polygon, while an emotional stimulus was presented. Speed was assessed using reaction time and movement time. The quality and precision of movement were assessed by calculating the accuracy and root-mean-square error (RMSE). Compared to drawings of triangles, polygons had higher accuracy under negative stimuli, but lower RMSE under positive stimuli. The results indicate that distracting emotional stimuli impact different aspects of movement quality, with movement complexity influencing accuracy under negative distractors and precision under positive distractors. This study provides further evidence that movement precision is an important feature of emotional embodiment that should be incorporated in future studies.
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http://dx.doi.org/10.3389/fpsyg.2021.642643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026889PMC
March 2021

Geographic Inequalities in Cardiovascular Mortality in the United States: 1999 to 2018.

Mayo Clin Proc 2021 Apr 8. Epub 2021 Apr 8.

Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham; Section of Cardiology, Birmingham Veterans Affairs Medical Center, Birmingham, AL. Electronic address:

Objective: To evaluate the trends in cardiovascular, ischemic heart disease (IHD), stroke, and heart failure mortality in the stroke belt in comparison with the rest of the United States.

Patients And Methods: We evaluated the nationwide mortality data of all Americans from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database from 1999 to 2018. Cause-specific deaths were identified in the stroke belt and nonstroke belt populations using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes. The relative percentage gap was estimated as the absolute difference computed relative to nonstroke belt mortality. Piecewise linear regression and age-period-cohort modeling were used to assess, respectively, the trends and to forecast mortality across the 2 regions.

Results: The cardiovascular mortality rate (per 100,000 persons) was 288.3 (95% CI, 288.0 to 288.6; 3,684,273 deaths) in the stroke belt region and 251.2 (95% CI, 251.0 to 251.3; 13,296,164 deaths) in the nonstroke belt region. In the stroke belt region, age-adjusted mortality rates due to all cardiovascular causes (average annual percentage change [AAPC] in mortality rates, -2.4; 95% CI, -2.8 to -2.0), IHD (AAPC, -3.8; 95% CI, -4.2 to -3.5), and stroke (AAPC, -2.8; 95% CI, -3.4 to -2.1) declined from 1999 to 2018. A similar decline in cardiovascular (AAPC, -2.5; 95% CI, -3.0 to -2.0), IHD (AAPC, -4.0; 95% CI, -4.3 to -3.7), and stroke (AAPC, -2.9; 95% CI, -3.2 to -2.2) mortality was seen in the nonstroke belt region. There was no overall change in heart failure mortality in both regions (P>.05). The cardiovascular mortality gap was 11.8% in 1999 and 15.9% in 2018, with a modest reduction in absolute mortality rate difference (~7 deaths per 100,000 persons). These patterns were consistent across subgroups of age, sex, race, and urbanization status. An estimated 101,953 additional cardiovascular deaths need to be prevented from 2020 to 2025 in the stroke belt to ameliorate the gap between the 2 regions.

Conclusion: Despite the overall decline, substantial geographic disparities in cardiovascular mortality persist. Novel approaches are needed to attenuate the long-standing geographic inequalities in cardiovascular mortality in the United States, which are projected to increase.
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http://dx.doi.org/10.1016/j.mayocp.2020.08.036DOI Listing
April 2021

PB1 S524G mutation of wild bird-origin H3N8 influenza A virus enhances virulence and fitness for transmission in mammals.

Emerg Microbes Infect 2021 Apr 12:1-46. Epub 2021 Apr 12.

Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun, 130122, China.

Influenza H3N8 viruses have been recovered frequently from wild bird species, including (primarily from migratory ducks) and (primarily from shorebirds). However, little attention has been given to the transmission ability of H3N8 avian influenza viruses among mammals. Here, we study the potential human health threat and the molecular basis of mammalian transmissibility of H3N8 avian influenza viruses isolated from wild bird reservoirs. We classified eight H3N8 viruses into seven different genotypes based on genomic diversity. Six of eight H3N8 viruses isolated naturally from wild birds have acquired the ability to bind to the human-type receptor. However, the affinity for α-2,6-linked SAs was lower than that for α-2,3-linked SAs. Experiments on guinea pigs demonstrated that three viruses transmitted efficiently to direct-contact guinea pigs without prior adaptation. Notably, one virus transmitted efficiently via respiratory droplets in guinea pigs but not in ferrets. We further found that the PB1 S524G mutation conferred T222 virus airborne transmissibility between ferrets. We also determined that the 524G mutant increased viral pathogenicity slightly in mice compared with the WT (wild type). Based on these results, we elucidated the potential human health threat and molecular basis of mammalian transmissibility of H3N8 influenza viruses. We emphasized the need for continued surveillance of the H3N8 influenza viruses circulating in birds.
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http://dx.doi.org/10.1080/22221751.2021.1912644DOI Listing
April 2021

Occurrence, spatiotemporal distribution, and risk assessment of current-use pesticides in surface water: A case study near Taihu Lake, China.

Sci Total Environ 2021 Mar 29;782:146826. Epub 2021 Mar 29.

School of Environment, Beijing Key Laboratory for Emerging Organic Contaminants Control, State Key Joint Laboratory of Environment Simulation and Pollution Control (SKLESPC), Tsinghua University, Beijing 100084, China. Electronic address:

This study involved the monitoring and risk assessment of current-use pesticides in surface water from the northwestern section of the Taihu Lake Basin (China) in 2019. In particular, 114 current-use pesticides were measured in samples collected during four campaigns spread across the wet, dry, and normal seasons. Pesticide concentrations were measured by means of a novel analytical method involving online solid-phase extraction coupled to LC-MS/MS. In total, 1 plant growth regulator, 34 herbicides, 23 insecticides, and 25 fungicides were detected. Detection frequencies greater than 90% were recorded for 26 pesticides; furthermore, acetamiprid, azoxystrobin, bentazone, carbendazim, isoprothiolane, metolachlor, paclobutrazol, and triadimenol were present in every sample. The measured pesticide concentrations varied widely, from below the detection limit to 10,600 ng/L (tricyclazole). The highest median concentrations for the fungicide, herbicide, and insecticide families were observed for carbendazim (135 ng/L), metolachlor (40 ng/L), and imidacloprid (31 ng/L), respectively. Twenty-two pesticides were quantitatively reported in Chinese surface water for the first time. The number and concentration of detected pesticides were significantly higher in June and September (wet season) compared to March and December (dry season). Agricultural areas of the study area were more contaminated than the residential and industrial sections. Imidacloprid was the only pesticide that exhibited high risk to sensitive ecological species (RQ > 1) in all four seasons. Isoproturon, isoprothiolane, and pretilachlor were identified as high risk in March (RQ = 4.5), September (1.3), and June (1.1), respectively; moreover, another eight pesticides posed a high ecological risk at specific sites. Seven pesticides recorded moderate risks (i.e., RQ = 0.1-1.0). Of the 18 pesticides with cases of high risk, a novel risk index, which accounted for frequency of PNEC exceedance, ranged from 6.7 (imidacloprid) to 7.1 × 10 (propiconazole). The integrated consideration of ecological risk and frequency of risk inform priorities for regional pesticide management and control.
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http://dx.doi.org/10.1016/j.scitotenv.2021.146826DOI Listing
March 2021

In-Vivo response to a novel pillared surface morphology for osseointegration in an ovine model.

J Mech Behav Biomed Mater 2021 Mar 29;119:104462. Epub 2021 Mar 29.

The University of New South Wales, Australia.

Primary stability and secondary fixation of orthopedic implants to bony tissues are important for healing and long-term functionality. Load sharing and stress transfer are key requirements of an effective implant/tissue interface. This paper presents a novel, macro-scale osseointegration surface morphology which addresses the implant/tissue interface from both the biologic as well as biomechanical perspective. The surface morphology is a controlled, engineered, open topography manifested as discrete pillars projecting from the implant enabling continuous bone ingrowth. The pillared surface is distinct from other porous surfaces and can be differentiated by the localization of the implant material into discrete pillars enabling a continuous mass of bone to freely and easily interdigitate into the pillared structure. Traditional porous structures distribute the implant material throughout the surface forcing the bone to grow in a discontinuous manner. Creating an open and continuous space or "open porosity" in and around the pillar structure allows the bone to easily interdigitate with the implant surface without encumberment from a continuous porous structure. An in-vivo study, using an established ovine model, was undertaken examining the effects of pillar morphology on bone ingrowth and mechanical performance. Cortical and cancellous sites were evaluated utilizing histology, histomophometry, and mechanical pushout, at 4 and 12 weeks. Robust bone ingrowth occurred for all morphologies as was noted in review of the study results. An increase in volume and maturity of bone was noted between the intermediated and final time points. Histomophometry demonstrated over 40% and 80% new bone occupied the available "ingrowth" area at 12 weeks for cancellous and cortical sites (respectively). Histologic review showed little fibrous tissue ingrowth at the interface with no adverse cellular reactions. Testing of cortical samples demonstrated a significant increase in pushout load between the 4 and 12 week timepoints and a 4-8 fold increase in pushout load as compared to the grit blast control. These results demonstrated the effectiveness of the novel interface for orthopedic applications in an in-vivo ovine model.
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http://dx.doi.org/10.1016/j.jmbbm.2021.104462DOI Listing
March 2021

Evaluation of patient-reported outcome measures in intermittent self-catheterization users: A systematic review.

Arch Phys Med Rehabil 2021 Apr 8. Epub 2021 Apr 8.

School of Nursing, Tianjin Medical University, Observatory Road, Heping District, Tianjin 300070, People's Republic of China. Electronic address:

Objective: To identify patient-reported outcome measurements (PROMs) for intermittent self-catheterization (ISC) users, critically assess and summarize the quality of the measurement properties, and describe the application scenarios on each instrument.

Data Sources: PubMed, EMBASE, Medline, PsycINFO and relevant reference lists were systematically searched until December 2019 (updated May 2020).

Study Selection: Two reviewers independently identified original English language publications that evaluated the psychometric properties of specific PROMs used in ISC patients.

Data Extraction: The following data were obtained: author and publication year, content of domains/subscales, number of items, response options, constructs measured, language and information on measurement properties.

Data Synthesis: Eleven publications were deemed eligible, including 6 PROMs for measuring patients' ISC-related quality of life, self-confidence, satisfaction, difficulties, acceptance and adherence to treatment. The Intermittent Self-Catheterization Questionnaire provided the most detail, and the Intermittent Catheterization Acceptance Test could be evaluated on the most COSMIN properties.

Conclusion: Several tools are available for ISC users, but at present there is no comprehensive, concise and robust instrument with good psychometric properties. Further research on psychometric properties is needed to verify the remaining properties of existing scales and to develop novel tools for clinicians, researchers and patients.
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http://dx.doi.org/10.1016/j.apmr.2021.03.020DOI Listing
April 2021

A systematic review and meta-analysis of the effect of routine early angiography in patients with return of spontaneous circulation after Out-of-Hospital Cardiac Arrest.

Resuscitation 2021 Apr 7. Epub 2021 Apr 7.

Rescu, Emergency Department, St Michael's Hospital, Division of Emergency Medicine, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

Background: Early coronary angiography (CAG) has been reported in individual studies and systematic reviews to significantly improve outcomes of patients with return of spontaneous circulation (ROSC) after cardiac arrest (CA).

Methods: We undertook a systematic review and meta-analysis to evaluate the impact of early CAG on key clinical outcomes in comatose patients after ROSC following out-of-hospital CA of presumed cardiac origin. We searched the PubMED, EMBASE, CINAHL, ERIC and Cochrane Central Register of Controlled Trials databases from 1990 until April 2020. Eligible studies compared patients undergoing early CAG to patients with late or no CAG. When randomized controlled trials (RCTs) existed for a specific outcome, we used their results to estimate the effect of the intervention. In the absence of randomized data, we used observational data. We excluded studies at high risk of bias according to the Robins-I tool from the meta-analysis. The GRADE system was used to assess certainty of evidence at an outcome level.

Results: Of 3738 citations screened, 3 randomized trials and 41 observational studies were eligible for inclusion. Evidence certainty across all outcomes for the RCTs was assessed as low. Randomised data showed no benefit from early as opposed to late CAG across all critical outcomes of survival and survival with favourable neurologic outcome for undifferentiated patients and for patient subgroups without ST-segment-elevation on post ROSC ECG and shockable initial rhythm.

Conclusion: These results do not support routine early CAG in undifferentiated comatose patients and patients without STE on post ROSC ECG after OHCA.

Review Registration: PROSPERO - CRD42020160152.
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http://dx.doi.org/10.1016/j.resuscitation.2021.03.019DOI Listing
April 2021

Externalizing Behaviors are Associated with Increased Parenting Stress in Caregivers of Young Children with Autism.

J Autism Dev Disord 2021 Apr 10. Epub 2021 Apr 10.

Brain Development Imaging Laboratories, Department of Psychology, San Diego State University, 6363 Alvarado Ct., Suite 200, San Diego, CA, 92120, USA.

Parents of children diagnosed with autism spectrum disorder (ASD) report higher levels of stress than parents of typically developing children. Few studies have examined factors associated with parental stress in early childhood. Even fewer have investigated the simultaneous influence of sociodemographic, clinical, and developmental variables on parental stress. We examined factors associated with stress in parents of young children with ASD. Multiple regression models were used to test for associations between socioeconomic indices, developmental measures, and parental stress. Externalizing behaviors, communication, and socialization skills accounted for variance in parental stress, controlling for ASD diagnosis. Results highlight the importance of interventions aimed at reducing externalizing behaviors in young children as well as addressing stress in caregivers of children with ASD.
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http://dx.doi.org/10.1007/s10803-021-04995-wDOI Listing
April 2021

A robotic system for spine surgery positioning and pedicle screw placement.

Int J Med Robot 2021 Apr 9. Epub 2021 Apr 9.

School of Mechanical Engineering and Automation, Beihang University, Beijing, China.

Background: In recent years, surgeons have explored minimally invasive methods of percutaneous pedicle screw implantation, which can effectively reduce human injury. This paper presents an accurate and efficient positioning method and robot system for percutaneous needle placement under c-arm fluoroscopy.

Methods: A simple five degree of freedom (DOF) robot with an unique end-effector is designed to perform perspective calibration and image space registration. The principle of pedicle standard axis positioning is adopted to make the axis of the pedicle overlap with the x-ray axis of c-arm.

Results: Then, clinical operation is carried out to verify the clinical feasibility of the designed robot and positioning method. The experimental results show that a total of 26 pedicle screws were accurately implanted. The accuracy of Grade A is 96.15%. The positioning time of a single guide pin is about 154.77 second, and three x-ray films need to be taken on average.

Conclusions: The positioning accuracy is increased by using present method. In addition, this method is simple in operation, short in operation time, low in X-ray exposure. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/rcs.2262DOI Listing
April 2021

Are medical record front page data suitable for risk adjustment in hospital performance measurement? Development and validation of a risk model of in-hospital mortality after acute myocardial infarction.

BMJ Open 2021 Apr 9;11(4):e045053. Epub 2021 Apr 9.

National Clinical Research Center of Cardiovascular Diseases, NHC Key Laboratory of Clinical Research for Cardiovascular Medications, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular Diseases, Beijing, China

Objectives: To develop a model of in-hospital mortality using medical record front page (MRFP) data and assess its validity in case-mix standardisation by comparison with a model developed using the complete medical record data.

Design: A nationally representative retrospective study.

Setting: Representative hospitals in China, covering 161 hospitals in modelling cohort and 156 hospitals in validation cohort.

Participants: Representative patients admitted for acute myocardial infarction. 8370 patients in modelling cohort and 9704 patients in validation cohort.

Primary Outcome Measures: In-hospital mortality, which was defined explicitly as death that occurred during hospitalisation, and the hospital-level risk standardised mortality rate (RSMR).

Results: A total of 14 variables were included in the model predicting in-hospital mortality based on MRFP data, with the area under receiver operating characteristic curve of 0.78 among modelling cohort and 0.79 among validation cohort. The median of absolute difference between the hospital RSMR predicted by hierarchical generalised linear models established based on MRFP data and complete medical record data, which was built as 'reference model', was 0.08% (10th and 90th percentiles: -1.8% and 1.6%). In the regression model comparing the RSMR between two models, the slope and intercept of the regression equation is 0.90 and 0.007 in modelling cohort, while 0.85 and 0.010 in validation cohort, which indicated that the evaluation capability from two models were very similar.

Conclusions: The models based on MRFP data showed good discrimination and calibration capability, as well as similar risk prediction effect in comparison with the model based on complete medical record data, which proved that MRFP data could be suitable for risk adjustment in hospital performance measurement.
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http://dx.doi.org/10.1136/bmjopen-2020-045053DOI Listing
April 2021

Epigenetic Aging and Hematopoietic Cell Transplantation in Patients With Severe Aplastic Anemia.

Transplant Cell Ther 2021 Apr 16;27(4):313.e1-313.e8. Epub 2021 Jan 16.

Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Electronic address:

Cellular aging in hematopoietic cell transplantation (HCT) is important in the context of immune reconstitution and age-related complications. Recently, several DNA-methylation (DNAm)-based biomarkers of aging known as "epigenetic clocks" have been introduced as novel tools to predict cellular age. Here, we used Cox proportional hazards models to assess the possible associations of donor pre-HCT DNAm age, and its post-HCT changes, using the recently published lifespan-associated epigenetic clock known as "DNAm-GrimAge," with outcomes among patients with severe aplastic anemia (SAA). The study included 732 SAA patients from the Transplant Outcomes in Aplastic Anemia project, who underwent unrelated donor HCT and for whom a donor pre-HCT blood DNA sample was available; 41 also had a post-HCT sample collected at day 100. In multivariable analyses, we found similar associations for donor chronological age and pre-HCT DNAm-GrimAge with post-HCT survival (hazard ratio [HR] per decade = 1.13; 95% confidence interval [CI], 0.99-1.28; P = .07 and HR = 1.14; 95% CI, 0.99-1.28; P = .06, respectively). In donors with 10+ years of GrimAge acceleration (ie, deviation from expected DNAm age for chronological age), elevated risks of chronic graft versus host disease (HR = 2.4; 95% CI, 1.21-4.65; P = .01) and possibly post-HCT mortality (HR = 1.79; 95% CI, 0.96-3.33; P = .07) were observed. In the subset with post-HCT samples, we observed a significant increase in DNAm-GrimAge in the first 100 days after HCT (median change 12.5 years, range 1.4 to 26.4). Higher DNAm-GrimAge after HCT was associated with inferior survival (HR per year = 1.11; 95% CI, 1.02-1.21; P = .01), predominantly within the first year after HCT. This study highlights the possible role cellular aging may play in HCT outcomes.
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http://dx.doi.org/10.1016/j.jtct.2021.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036238PMC
April 2021

Association of ST6GAL1 and CYP19A1 polymorphisms in the 3'-UTR with astrocytoma risk and prognosis in a Chinese Han population.

BMC Cancer 2021 Apr 9;21(1):391. Epub 2021 Apr 9.

Department of Otorhinolaryngology Head and Neck Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, 277 YanTa West Road, Xi'an, 710061, Shaanxi, China.

Background: Astrocytoma is a common type of central nervous system tumor. In this study, we investigated the correlation between ST6GAL1 and CYP19A1 polymorphisms and the risk and prognosis of astrocytoma.

Methods: A total of 365 astrocytoma patients and 379 healthy controls were genotyped using the Agena MassARRAY system. The correlation between ST6GAL1 and CYP19A1 variants and astrocytoma risk was calculated using logistic regression. The survival rate of patients with astrocytoma was analyzed to evaluate prognosis.

Results: We found that the ST6GAL1-rs2239611 significantly decreased the risk of astrocytoma in the codominant model (p = 0.044) and dominant model (p = 0.049). In stratified analyses, CYP19A1-rs2255192 might be associated with a higher risk of astrocytoma among the low-grade subgroup under recessive (p = 0.034) and additive (p = 0.030) models. However, CYP19A1-rs4646 had a risk-decreasing effect on the high-grade subgroup in the codominant model (p = 0.044). The results of Cox regression analysis showed that the CYP19A1-rs2239611 and -rs1042757 polymorphisms were significantly correlated with the prognosis of astrocytoma.

Conclusion: Our results suggest that ST6GAL1 and CYP19A1 genes may be a potential biomarker of genetic susceptibility and prognosis to astrocytoma in the Chinese Han population.
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http://dx.doi.org/10.1186/s12885-021-08110-1DOI Listing
April 2021

Efficient development of silk fibroin membranes on liquid surface for potential use in biomedical materials.

Int J Biol Macromol 2021 Apr 6. Epub 2021 Apr 6.

State Key Laboratory of Silkworm Genome Biology, Chongqing Engineering Research Center of Biomaterial Fiber and Modern Textile, College of Sericulture, Textile and Biomass Science, Southwest University, Chongqing 400715, China. Electronic address:

Silk fibroin (SF) protein is versatile for the application of biomaterials due to its excellent mechanical properties, biocompatibility and biodegradability. However, the efficient way to fabricate SF membranes with special structure is still challenging. Here, we develop an efficient and simple way to create SF membranes on the liquid (i.e. subphase) surface. It is essential to prepare highly concentrated SF solution with low surface tension by dissolving the degummed SF powders in 6% (w/v) LiBr/methanol solution by one step. 95 wt% polyethylene glycol (PEG) 200 and 30 wt% (NH)SO are the subphases, on which the SF solution spreads quickly, generating nonporous and microporous SF membranes (SFM-1 and SFM-2), respectively. PEG 200 causes more ordered molecular packing (β-sheets) in SFM-1. While Fast diffusion and denaturation of SF on (NH)SO solution lead to the formation of microporous, water-unstable membrane SFM-2. Both membranes have good transparency, hydrophilicty, and mechanical properties. To fabricate antibacterial biomaterials, we design a composite membrane by SFM-1 and SFM-2 sandwiching a layer of hydroxypropyl trimethylammonium chloride chitosan (HACC) to provide antibacterial functions. The sandwich membrane has good cell viability and antibacterial properties, showing potential use for biomedical materials.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.04.019DOI Listing
April 2021

Impact of Previously Unrecognized HLA Mismatches Using Ultrahigh Resolution Typing in Unrelated Donor Hematopoietic Cell Transplantation.

J Clin Oncol 2021 Apr 9:JCO2003643. Epub 2021 Apr 9.

Anthony Nolan Research Institute, Royal Free Hospital, London, UK.

Purpose: Ultrahigh resolution (UHR) HLA matching is reported to result in better outcomes following unrelated donor hematopoietic cell transplantation, improving survival and reducing post-transplant complications. However, most studies included relatively small numbers of patients. Here we report the findings from a large, multicenter validation study.

Methods: UHR HLA typing was available on 5,140 conventionally 10 out of 10 HLA-matched patients with malignant disease transplanted between 2008 and 2017.

Results: After UHR HLA typing, 82% of pairs remained 10 out of 10 UHR-matched; 12.3% of patients were 12 out of 12 UHR HLA-matched. Compared with 12 out of 12 UHR-matched patients, probabilities of grade 2-4 acute graft-versus-host disease (aGVHD) were significantly increased with UHR mismatches (overall = .0019) and in those patients who were HLA-DPB1 T-cell epitope permissively mismatched or nonpermissively mismatched (overall = .0011). In the T-cell-depleted subset, the degree of UHR HLA mismatch was only associated with increased transplant-related mortality (TRM) (overall = .0068). In the T-cell-replete subset, UHR HLA matching was associated with a lower probability of aGVHD (overall = .0020); 12 out of 12 UHR matching was associated with reduced TRM risk when compared with HLA-DPB1 T-cell epitope permissively mismatched patients, whereas nonpermissive mismatching resulted in a greater risk (overall = .0003).

Conclusion: This study did not confirm that UHR 12 out of 12 HLA matching increases the probability of overall survival but does demonstrate that aGVHD risk, and in certain settings TRM, is lowest in UHR HLA-matched pairs and thus warrants consideration when multiple 10 out of 10 HLA-matched donors of equivalent age are available.
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http://dx.doi.org/10.1200/JCO.20.03643DOI Listing
April 2021

Biocidal efficacy of tutin and its influence on immune cells and expression of growth-blocking and neuroglian peptides in Mythimna separata (Lepidoptera: Noctuidae).

Arch Insect Biochem Physiol 2021 Apr 9:e21767. Epub 2021 Apr 9.

College of Forestry, Northwest A&F University, Yangling, Shaanxi, China.

Mythimna separata Walker (Lepidoptera: Noctuidae) is one of the major pests that can cause severe damage to grain crops. The development of low-toxicity and high-performance botanical insecticides is becoming the focus of new pesticide research to control M. separata. Tutin, a sesquiterpene lactone compound obtained from Coriaria sinica Maxim, a native Chinese poisonous plant, has antifeedant, absorption, and stomach poisoning against a variety of pests. To understand the toxic effect of tutin on M. separata larvae, we set out to determine their antifeedant, mortality, paralysis, weight change, and to examine the spreading of M. separata hemocytes under different concentrations of tutin treatment. Tissue distribution of the immune-associated gene growth-blocking peptide (GBP) and neuroglian peptide (Nrg) was detected by reverse transcription polymerase chain reaction (PCR). Furthermore, real-time quantitative PCR was carried out to determine the expression profiles of GBP and Nrg after different concentrations of tutin stimulation. Our results revealed that tutin exhibited significant antifeedant and insecticidal activities, paralysis, weight loss to M. separata. Besides, tutin significantly influenced on the morphology of hemocytes and enhanced the expression of GBP and Nrg in M. separata.
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http://dx.doi.org/10.1002/arch.21767DOI Listing
April 2021

[Identification of TCF3-ZNF384 fusion by transcriptome sequencing in B cell acute lymphoblastic leukemia and its laboratory and clinical characteristics].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2021 Apr;38(4):351-354

Department of Pathology and Laboratory Medicine, Beijing Ludaopei Hospital, Beijing 100176, China.

Objective: To detect fusion gene with pathological significance in a patient with refractory and relapsed acute B cell lymphoblastic leukemia (B-ALL) and to explore its laboratory and clinical characteristics.

Methods: Transcriptome sequencing was used to detect potential fusion transcripts. Other laboratory results and clinical data of the patient were also analyzed.

Results: The patient was found to harbor TCF3 exon 17-ZNF384 exon 7 in-frame fusion transcript. The minimal residual disease (MRD) has remained positive after multiple chemotherapy protocols including CD19-, CD22- targeted chimeric antigen receptor T cells immunotherapy. The patient eventually achieved complete remission and sustained MRD negativity after allogeneic hemopoietic stem cell transplantation (allo-HSCT).

Conclusion: Transcriptome sequencing can effectively detect potential fusion genes with clinical significance in leukemia. TCF3-ZNF384 positive B-ALL has unique laboratory and clinical characteristics, may not well respond to chemotherapy and immunotherapy, and is more likely to relapse. Timely allo-HSCT treatment may help such patients to achieve long-term disease-free survival. TCF3-ZNF384 positive B-ALL is not uncommon in pediatric patients but has not been effectively identified.
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http://dx.doi.org/10.3760/cma.j.cn511374-20200416-00273DOI Listing
April 2021

Low Expression Indicates a Biomarker of Poor Prognosis in Patients with Renal Cell Carcinoma.

Biomed Res Int 2021 24;2021:6682758. Epub 2021 Mar 24.

Key Laboratory of JiLin Province for Zoonosis Prevention and Control, Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun 130122, China.

It was initially found that neural-restrictive silencer factor/repressor 1-silencing transcription factor () is a transcriptional repressor of neuronal genes in nonneuronal cells. However, it is reported to be abundantly expressed in various types of aggressive cancer cells. In this study, we evaluated the expression patterns of in renal cell carcinoma and found that its expression is lower in tumor tissues compared to normal tissues. The chi-square test showed that the low expression was closely related to patients' clinicopathologic parameters, including the pathologic stage and survival status. ROC curve showed that had excellent clinical diagnostic prospect. In addition, patients with low expression had poor over survival (OS) and relapse-free survival (RFS). Univariate and multivariate Cox regression analysis confirmed that the low expression was an independent predictor of poor prognosis in renal cell carcinoma. Gene set enrichment analysis identified P53 pathway, reactive oxygen species pathway, glycolysis, DNA repair, cholesterol homeostasis, and MYC targets V2 enriched with low expression phenotype. These results suggested that may be a novel biomarker for the diagnosis and prognosis of renal cell carcinoma in clinical applications.
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http://dx.doi.org/10.1155/2021/6682758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012131PMC
March 2021

Customized self-expanding bare metal Y stents in the treatment of malignant carinal stenosis: a retrospective analysis.

Ann Palliat Med 2021 Mar 29. Epub 2021 Mar 29.

Department of Respiratory and Critical Care Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Background: Self-expanding Y metal stent insertion is a safe and effective palliative method for malignant lesions involving the lower trachea, tracheal carina, and the main-stem bronchi. However, the length and degree of airway stenosis in different patients tend to vary, which leads to a call for a customized Y stent that could achieve a better treatment effect.

Methods: This retrospective analysis included patients who received customized self-expanding bare metallic Y stents for malignant carinal stenosis at Beijing Tiantan Hospital, Capital Medical University between January 2007 and June 2020. CT scans and initial bronchoscopy were performed to provide reliable data for stent selection and size customization. Data on technical success, clinical success, and follow-up were analyzed.

Results: A total of 36 patients (26 males and 10 females; median age, 61 years; age range, 30-83 years) were enrolled. Technical success was 97.2% (35/36), while clinical success was 97.2% (35/36). There was no procedure-related mortality. Out of 35 patients, 4 (11.4%) had stent-associated complications that did not affect the procedure of stent insertion. Re-stenosis of the stent due to tumor progression was the main midand long-term stent-related complication (65% and 57.1%, respectively), followed by stent fractures (5% and 14.3%, respectively).

Conclusions: The current study described the design and insertion of customized self-expanding bare metal Y-stents and demonstrated the feasibility of their use for maintaining tracheal and main-stem bronchus patency in malignant carinal stenosis. This approach could be used as a bridging method before commencing adjuvant therapy and final palliative therapy for the relief of symptoms.
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http://dx.doi.org/10.21037/apm-20-2332DOI Listing
March 2021

The role of spontaneous portal-systemic shunts in liver transplantation: case report and literature review.

Ann Palliat Med 2021 Mar 24. Epub 2021 Mar 24.

Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China.

We described two liver transplants for patients with end-stage liver disease and spontaneous portal-systemic shunt (SPSS). We ligated the splenorenal shunt (SRS) in the first case but did not ligate it in the second case. Postoperative examination revealed significant differences in portal blood flow velocity, serum ammonia level, liver function and prognosis between two cases. The portal blood flow in the first case was sufficient with decreased serum ammonia and immediate liver graft function. The portal blood flow was insufficient and serum ammonia level was not significantly reduced after operation in the second case probably because SRS was still present after surgery. The first case recovered well after operation and was discharged uneventfully, however, the second patient suffered early allograft dysfunction (EAD) after operation and died of pulmonary infection on postoperative day (POD) 18. Proper management of SPSS in liver transplantation (LT) is important because it can affect the function of liver graft and patient prognosis, so we reviewed the relevant literature and list different types of SPSS and their clinical characteristics. We recommend that SPSS greater than 8 mm in diameter should be ligated in LT with non-small size graft to ensure adequate portal flow and preserved with small size liver graft to avoid portal hypertransfusion and portal hypertension except obviously insufficient portal blood flow.
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http://dx.doi.org/10.21037/apm-20-2431DOI Listing
March 2021

Impact of subsidies on innovations of environmental protection and circular economy in China.

J Environ Manage 2021 Apr 5;289:112385. Epub 2021 Apr 5.

The Circular Economy Research Institute, Tongji University, Shanghai, 200092, China. Electronic address:

Technological innovations in China's energy conservation and environmental protection industry (EEPI) are capital-intensive and useful to mitigate environmental externality, thus they need policy support and government subsidies (GSs) at the emerging stage. Nevertheless, research is limited on the influence of GSs onto innovation performance of China's EEPI, with particular to the effect of GSs from enterprise level. This study investigated 62 listed energy conservation and environmental protection enterprises (EEPEs) in China's market in 2013-2018. The innovation performance of these enterprises was quantitatively evaluated, and multivariate regression models were devised to examine GSs and other potential drivers that might influence the innovation. Key findings include (1) EEPEs' investment in R&D and protection of intellectual properties played a positive intermediary and regulatory role between GSs and enterprise innovation performance (correlation at the significance level of 0.05 (p = 0.045; p = 0.036)). (2) There is a significant positive correlation at the significance level of 0.05 (p = 0.011), which indicates that the strongest positive relation between GSs and innovation performance was identified in an environment of low external regulation and high internal regulation, and the effects were more significant for non-state-owned EEPEs(correlation at the significance level of 0.05 (p = 0.018)). (3) The promotion of GSs to innovation was found less effective in the three most developed regions in China, i.e., the Yangtze River Delta, the Pearl River Delta, and the Beijing-Tianjin-Hebei Area. Nonetheless it was more effective for enterprise engaged in the circular economy and resource recycling (correlation at a significant level of 0.05 (P = 0.048)). These findings may shed lights on decision making of green technology development for environmental conservation and circular economy.
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http://dx.doi.org/10.1016/j.jenvman.2021.112385DOI Listing
April 2021

Treatable traits in elderly asthmatics from the Australasian Severe Asthma Network: a prospective cohort study.

J Allergy Clin Immunol Pract 2021 Apr 5. Epub 2021 Apr 5.

Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia.

Background: Data on treatable traits (TTs) in different populations are limited.

Objective: To assess TTs in elderly patients with asthma and compare them to younger patients, to evaluate the association of TTs with future exacerbations, and develop an exacerbation prediction model.

Methods: We consecutively recruited 521 participants at West China Hospital, Sichuan University based on the Australasian Severe Asthma Network, classified as elderly (n = 62) and non-elderly (n = 459). Participants underwent a multidimensional assessment to characterize the TTs and were then followed up for 12 months. TTs and their relationship with future exacerbations were described. Based on the TTs and asthma control levels, an exacerbation prediction model was developed, and the overall performance was externally validated in an independent cohort.

Results: A total of 38 TTs were assessed. Elderly asthmatics had more chronic metabolic diseases, fixed airflow limitation, emphysema and neutrophilic inflammation, while non-elderly asthmatics exhibited more allergic characteristics and psychiatric diseases. Nine traits were associated with increased future exacerbations, of which exacerbation prone, upper respiratory infection-induced asthma attack (URI), cardiovascular disease, diabetes and depression were the strongest. A model including exacerbation prone, psychiatric disease, cardiovascular disease, URI, non-eosinophilic inflammation, cachexia, food allergy and asthma control was developed to predict exacerbation risk and showed good performance.

Conclusions: TTs can be systematically assessed in elderly patients with asthma, some of which are associated with future exacerbations, proving their clinical utility of evaluating them. A model based on TTs can be used to predict exacerbation risk in people with asthma.
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http://dx.doi.org/10.1016/j.jaip.2021.03.042DOI Listing
April 2021

Hesperidin alleviates bupivacaine anesthesia-induced neurotoxicity in SH-SY5Y cells by regulating apoptosis and oxidative damage.

J Biochem Mol Toxicol 2021 Apr 8:e22787. Epub 2021 Apr 8.

Anesthesiology Department, Shanxi People's Hospital, Taiyuan, China.

Local anesthetic with bupivacaine (BV) administration may cause severe neurotoxicity and neurological complications in developing neurons. Any substances that can mitigate the toxic effects of BV are of great importance in surgical procedures and pain management. The present study attempted to investigate if hesperidin (HN) could inhibit or prevent BV-induced neurotoxicity in SH-SY5Y cells. Exposure of BV at 5 mM resulted in a significant decrease of cell viability and a remarkable increase of lactate dehydrogenase release via the induction of apoptosis and production of reactive oxygen species. Moreover, a loss of mitochondrial membrane potential, decreased Bcl-2 protein expression, as well as increased expression of cytoplasmic cytochrome c, Bax, and cleaved caspase-3 protein was also observed in BV-stimulated SH-SY5Y cells. In addition, BV stimulation impaired the balance of oxidation-reduction and inflammation system, as evidenced by the increased malondialdehyde content, decreased superoxide dismutase and catalase activity, and reduced level of reduced glutathione, interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α. However, these iatrogenic changes were all reversed by the HN (5, 10, and 20 μM) supplement for 48 h in a concentration-dependent manner. In conclusion, HN can protect SH-SY5Y cells against BV-stimulated neurotoxicity via the inhibition of apoptosis, oxidative stress, and inflammation response. The present findings suggested that HN may be an effective alternative agent to inhibit or prevent BV-induced neurotoxicity in human patients.
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http://dx.doi.org/10.1002/jbt.22787DOI Listing
April 2021

First-in-human evaluation of the novel mitochondrial complex I inhibitor ASP4132 for treatment of cancer.

Invest New Drugs 2021 Apr 8. Epub 2021 Apr 8.

Ball Pharma Consulting, LLC, Chicago, IL, USA.

Background We assessed the safety, tolerability, and pharmacokinetics of mitochondrial complex 1 inhibitor ASP4132. Methods This phase I dose-escalation/dose-expansion study enrolled patients with treatment refractory advanced solid tumors to assess safety, dose-limiting toxicities (DLTs), efficacy and pharmacokinetic or oral ASP4132. Results Overall, 39 patients received ASP4132. Acceptable tolerability of ASP4132 5 mg in the first patient led to enrollment in the 10-mg dose cohort. After two DLTs at the 10-mg dose, additional patients were enrolled in the 5-mg cohort; a 7.5-mg cohort and two intermittent-dosing cohorts (ASP4132 10 mg for 3 days, then 4 days off; ASP4132 15 mg for 1 day, then 6 days off). ASP4132 5 mg was well tolerated; however, multiple DLTs such as fatigue, mental status changes, dizziness, lactic acidosis, enteritis, and posterior reversible encephalopathy syndrome were observed in higher dose cohorts (7.5-mg and intermittent 10-mg and 15-mg dose cohorts). Stable disease (+ 4 % to + 15 %) was observed in 8/39 (20.5 %) patients. ASP4132 plasma pharmacokinetics were characterized by high variability, with rapid absorption and accumulation from slow elimination. Conclusions ASP4132 showed limited clinical activity, and DLTs prohibited dose escalation. Further research is required to determine if DLTs will limit clinical activity of other mitochondrial complex I inhibitors. Clinical Trial ID (clinicaltrials.gov): NCT02383368, March 9, 2015.
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http://dx.doi.org/10.1007/s10637-021-01112-7DOI Listing
April 2021