Publications by authors named "Lin Cai"

514 Publications

6-Methyl-7-Aryl-7-Deazapurine Nucleosides as Anti-Trypanosoma cruzi Agents: Structure-Activity Relationship and in Vivo Efficacy.

ChemMedChem 2021 Apr 15. Epub 2021 Apr 15.

Faculty of Pharmaceutical Sciences Ghent University, Laboratory for Medicinal Chemistry, Ottergemsesteenweg 460, 9000, Gent, BELGIUM.

Chagas disease is a tropical infectious disease resulting in progressive organ-damage and currently lacks efficient treatment and vaccine options. The causative pathogen, Trypanosoma cruzi , requires uptake and processing of preformed purines from the host because it cannot synthesize these de novo , instigating the evaluation of modified purine nucleosides as potential trypanocides. By modifying the pyrimidine part of a previously identified 7-aryl-7-deazapurine nucleoside, we found that substitution of a 6-methyl for a 6-amino group allows retaining T. cruzi amastigote growth inhibitory activity but confers improved selectivity towards mammalian cells. By keeping the 6-methyl group unaltered, and introducing different 7-aryl groups, we identified several analogues with submicromolar antitrypanosomal activity. Compound 14 , which was stable in microsomes, was evaluated in an acute mouse model. Oral administration of 25 mg/kg b.i.d. suppressed peak parasitemia and protected mice from infection-related mortality, gave similar reductions as the reference drug of blood parasite loads determined by qPCR, but as benznidazole failed to induce sterile cure in the short time period of drug exposure (5 days).
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http://dx.doi.org/10.1002/cmdc.202100144DOI Listing
April 2021

Identification and validation of the clinical roles of the VHL-related LncRNAs in clear cell renal cell carcinoma.

J Cancer 2021 5;12(9):2702-2714. Epub 2021 Mar 5.

Department of Urology, Peking University First Hospital, Beijing 100034, P.R. China.

Accumulating evidence suggests that lncRNAs (long non-coding RNAs) function as oncogenes or tumor suppressor genes in ccRCC (clear cell renal cell carcinoma). Although VHL (Von Hippel-Lindau) gene inactivation is by far the most common carcinogenic driving event in ccRCC, the roles of VHL-related lncRNAs in ccRCC remain unknown. In this study, using RNA-seq and clinical data in TCGA-KIRC (the Cancer Genome Atlas-Kidney Renal Clear Cell Carcinoma), we identified VHL-related lncRNAs through WGCNA (Weighted Gene Co-expression Network Analysis), correlation analysis and catRAPID algorithm, and explored their clinical characteristics in ccRCC. Results showed that 10 lncRNAs (AC112220.2, AL391121.1, USP46-AS1, AL450326.1, MID1IP1-AS1, SUCLG2-AS1, RAP2C-AS1, FGD5-AS1, AC018647.2 and AC015922.2) were identified as VHL-related lncRNAs, and they were down-regulated in ccRCC tissues. Survival analysis results indicated that high expression groups of AC112220.2, AL391121.1, USP46-AS1, AL450326.1, SUCLG2-AS1, RAP2C-AS1, FGD5-AS1, AC018647.2 and AC015922.2 had significantly longer OS (Overall Survival) than their respective low expression groups. Meanwhile high AC112220.2, USP46-AS1, AL450326.1, SUCLG2-AS1, FGD5-AS1, AC018647.2 and AC015922.2 expression groups had remarkably longer DFS (Disease Free Survival) than their respective low expression groups. Besides, FGD5-AS1 and AL391121.1 expression were decreased in VHL mutant tissues compared with VHL non-mutant tissues. Moreover, high expression group of FGD5-AS1 had significantly longer OS and DFS than their respective low expression groups in VHL mutant ccRCC. In addition, we found that DNA hypermethylation may also play an important role in decreased FGD5-AS1 expression. Furthermore, we validated the expression of FGD5-AS1 in VHL mutant and non-mutant ccRCC tissues and cell lines. In conclusion, our results demonstrated that lncRNA FGD5-AS1 was significantly associated with VHL and can serve as a novel biomarker of ccRCC.
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http://dx.doi.org/10.7150/jca.55113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040721PMC
March 2021

Curcumin promotes the survival of ischemic random skin flaps via autophagy.

Am J Transl Res 2021 15;13(3):1337-1351. Epub 2021 Mar 15.

Department of Burn and Wound Center, The First Affiliated Hospital of Wenzhou Medical University Wenzhou 325000, China.

Random skin flaps have been widely applied in reconstructive and plastic surgery; however, necrosis usually happens due to insufficient blood supply in the ischemic area of flaps. Curcumin (CUR) is a primary bioactive compound of turmeric (, L.), which has been proven to be effective on anticancer, decreasing oxidative stress and apoptosis through activating autophagy, and promoting angiogenesis in ischemic tissue. Therefore, the potential therapeutic effect of CUR on promoting survival of ischemic random skin flaps and its underlying mechanism associated with autophagy were investigated. After establishment of dorsal random skin flaps, sixty mice were randomly divided into three groups: Control, CUR or CUR+3-methyladenine (3-MA, an autophagy inhibitor). The results showed that CUR increased the viability area and blood flow as well as relieved the edema of skin flaps through promoting angiogenesis, decreasing oxidative stress, and inhibiting apoptosis of the ischemic area. Further study confirmed that CUR activated autophagy in the random skin flaps, and 3-MA effectively reversed the effect on viability, neovascularization, oxidative stress and apoptosis, suggesting autophagy played a vital role in these CUR's protective effect on random skin flaps. Moreover, this CUR-induced autophagy should be mediated through downregulating the PI3K/AKT/mTOR signaling pathway. Together with secondary response of increased angiogenesis, reduced oxidative stress and apoptosis, CUR effectively improved survival of random skin flaps in vivo. To sum up, our research showed the great potential of CUR using as a promising flap protective therapy for random skin flap survival and regeneration.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014401PMC
March 2021

[Age-related differences in the management and outcome of acute coronary syndrome under the chest pain center model: a multicenter retrospective study].

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2021 Mar;33(3):318-323

Department of Cardiology, Third People's Hospital of Chengdu Affiliated to Southwest Jiaotong University, Chengdu 610031, Sichuan, China. Corresponding author: Cai Lin, Email:

Objective: To assess the age-related differences in the management strategies and outcomes of patients with acute coronary syndrome (ACS) under the chest pain center model.

Methods: Clinical data of 2 833 patients with ACS were enrolled in the retrospective observational registry between January 2017 and June 2019 at 11 hospitals with chest pain centers in Chengdu. The patients were divided into four groups according to their ages: < 55 years old group (n = 569), 55-64 years old group (n = 556), 65-74 years old group (n = 804), ≥ 75 years old group (n = 904). The collected data included the patients' demographic characteristics, cardiovascular risk factors, medical history, symptoms and signs of onset, experimental examination, types of ACS and the time from the symptom to the hospital (S-to-D), etc., and the clinical characteristics, management strategies, all-cause mortality in the hospital, and the incidence of major adverse cardiovascular and cerebrovascular events (MACCE) within 1 year after discharge were compared. The primary end point was the clinical outcome of ACS patients in different age groups, including all-cause deaths in the hospital and the incidence of MACCE within 1 year after discharge. The secondary end point was the proportion of ACS patients underwent percutaneous coronary intervention (PCI) in different age groups. Multivariate Logistic regression was used to analyze the risk factors of all-cause deaths in ACS patients. Kaplan-Meier curve was used to express the incidence of MACCE within 1 year after discharge in different age groups. Multivariate Cox regression was used to analyze the factors affecting the incidence of MACCE within 1 year after discharge of ACS patients.

Results: As age increased, the proportion of male patients gradually decreased, and the percentages of male patients aged < 55 years old, 55-64 years old, 65-74 years old, and ≥ 75 years old were 87.2% (496/569), 77.0% (428/556), 66.4% (534/804), and 60.1% (543/904), respectively; and ACS patients combined with hypertension, diabetes, coronary heart disease, and stroke history were more common [the percentages of patients with hypertension aged < 55 years old, 55-64 years old, 65-74 years old, ≥ 75 years old were 41.3% (235/569), 52.2% (290/556), 59.7% (480/804), and 66.9% (605/904); the percentages of diabetes were 18.6% (106/569), 25.5% (142/556), 27.0% (217/804), and 28.2% (255/904); the percentages of coronary heart disease were 10.1% (57/564), 13.9% (77/555), 17.6% (141/803), and 23.7% (213/899); the percentages of stroke were 0.7% (4/564), 4.0% (22/552), 4.5% (36/801), and 8.6% (77/894)]. But the percentages of patients with a history of active smoking, typical chest pain/chest tightness and dyslipidemia were significantly reduced [the percentages of smoking history were 60.2% (340/565), 48.0% (266/554), 33.7% (270/801), and 21.7% (195/899), typical chest pain/chest tightness were 96.9% (536/553), 96.4% (516/535), 91.8% (716/780), 90.2% (776/860); the percentages of dyslipidemia were 11.2% (63/565), 9.2% (51/553), 5.7% (46/802), and 4.9% (44/896)], the time of S-to-D was significantly prolonged [minutes: 176.0 (73.5, 557.0), 194.5 (89.3, 682.3), 221.0 (98.8, 940.5), and 270.0 (115.0, 867.0)], hemoglobin (Hb) level was significantly reduced (g/L: 145.44±17.43, 135.95±19.25, 129.75±19.03, 122.19±20.55), and the incidence of non-ST-segment elevation myocardial infarction (NSTEMI) increased significantly [18.6% (106/569), 20.5% (114/556), 26.6% (214/804), 26.5% (240/904)], and the differences were statistically significant (all P < 0.05). The proportion of Killip grade III-IV were the highest in patients aged ≥ 75 years old, 9.0% and 12.6%, respectively. Compared with the groups aged < 55 years old, 55-64 years old, and 65-74 years old, the proportion of patients aged ≥ 75 years old who underwent PCI was the lowest, and the all-cause mortality in the hospital and the incidence of 1-year MACCE of patients underwent PCI were significantly lower than those of patients underwent conservative treatment [6.0% (28/463) vs. 10.4% (45/434), 14.6% (43/294) vs. 24.3 % (55/226), both P < 0.05]. As age increased, the hospital all-cause mortality and the 1-year MACCE incidence increased (all-cause mortality rates in < 55 years old, 55-64 years old, 65-74 years old, ≥ 75 years old groups were 0.9%, 2.2%, 5.5%, 8.3%, and the 1-year MACCE incidences were 5.0%, 6.7%, 13.9%, 18.7%, both P < 0.01). The multivariate Logistic regression analysis showed that age, cardiogenic shock, ST-segment elevation myocardial infarction (STEMI), the number of vascular disease and underwent PCI were the independent risk factors of all-cause mortality [the odds ratio (OR) and 95% confidence interval (95%CI) were 1.644 (1.356-1.993), 11.794 (7.469-18.621), 2.449 (1.419-4.227), 1.334 (1.096-1.624), 0.391 (0.247-0.619), all P < 0.001]. Cox regression analysis showed that age, STEMI, the number of vascular disease and underwent PCI were independent risk factors of the occurrence of MACCE within 1 year after discharge [hazard ratio (HR) and 95%CI were 1.354 (1.205-1.521), 1.387 (1.003-1.916), 1.314 (1.155-1.495), 0.547 (0.402-0.745), all P < 0.05].

Conclusions: In the chest pain center model, compared with other age of ACS patients, the proportion of NSTEMI in elderly patients group aged ≥ 75 years old was higher, the proportion of PCI was lower, and the clinical outcome was worse. However, the prognosis of elderly patients receiving PCI treatment was better than the patients receiving conservative treatment.
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http://dx.doi.org/10.3760/cma.j.cn121430-20200806-00565DOI Listing
March 2021

Frequency of ST-segment elevation myocardial infarction, non-ST-segment myocardial infarction, and unstable angina: results from a Southwest Chinese Registry.

Rev Cardiovasc Med 2021 Mar;22(1):239-245

Department of Cardiology, Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, 82 Qinglong St. Chengdu, 610015 Sichuan, P. R. China.

The burden of cardiovascular disease is predicted to escalate in developing countries. The aim of this study is to assess the characteristics, management strategies and outcomes of the patients with acute coronary syndrome (ACS) who were admitted to hospitals under the chest pain center mode in southwest P. R. China. Adults hospitalized with a diagnosis of ACS were enrolled in the retrospective, observational registry between January 2017 and June 2019 at 11 hospitals in Chengdu, P. R. China. The collected data included the patients' baseline characteristics, clinical management and in-hospital outcomes. After Statistical analysis, (1) A total of 2857 patients with ACS, among which 1482 have ST-segment elevation myocardial infarction (STEMI), 681 have non-STEMI (NSTEMI) and 694 have unstable angina (UA) were enrolled in the study. (2) 61.3% of the ACS patients received reperfusion therapy. More patients with STEMI underwent percutaneous coronary intervention (PCI) compared with NSTEMI/UA patients (80.6% vs. 38.8%, < 0.001), while thrombolytics were administered in only 1.8% of STEMI patients. (3) The median time from symptoms to hospital was 190 min (IQR 94-468) in STEMI, 283 min (IQR 112-1084) in NSTEMI and 337 min (IQR 97-2220) in UA ( < 0.001), and the door-to-balloon time for primary PCI (pPCI) was 85 min (IQR 55-121) in STEMI. (4) The in-hospital outcomes for STEMI patients included death (8.1%) and acute heart failure (22.6%), while the outcomes for those with NSTEMI and UA were better: death (4.0% and 0.9%, < 0.001) and acute heart failure (15.3% and 9.9%, < 0.001). (5) Antiplatelet drugs, lipid-lowering drugs, β-blockers and angiotensin-converting enzyme inhibitors (ACEI) /angiotensin receptor blockers (ARB) were used in about 98.3%, 95.0%, 67.7% and 54.3% of the ACS patients, respectively. Therefore, the management capacity in Chengdu has relatively increased compared with previous studies, but important gaps still exist compared with developed countries, especially regarding the management of the NSTEMI/UA patients.
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http://dx.doi.org/10.31083/j.rcm.2021.01.103DOI Listing
March 2021

Elevation of miR-302b prevents multiple myeloma cell growth and bone destruction by blocking DKK1 secretion.

Cancer Cell Int 2021 Mar 31;21(1):187. Epub 2021 Mar 31.

Department of Orthopedics, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, China.

Background: Myeloma bone disease (MBD) is a severe complication of multiple myeloma (MM) mainly due to an imbalance between enhanced osteoclast activity and reduced osteoblast function. Previous studies have demonstrated that miRNAs play a vital role in the osteogenic differentiation of mesenchymal stromal cells (MSCs) in MM. However, the value of miR‑302b in MBD remains to be further elucidated. The aim of this study is to explore the role of miR‑302b in the regulation of MBD osteogenic differentiation and evaluate the potential of a new therapeutic strategy for the clinical treatment of MBD.

Method: Our previous research demonstrated that MiR-302b belongs to the miR-302 cluster and is able to inhibit tumor growth and osteolysis in an orthotopic osteosarcoma xenograft tumor mouse model. In this study, we first transfected miR-302b mimics, miR-302b inhibitor, and miR-302b NC into MM1.S and RPMI8226 MM cells to detect the correlation between miR-302b expression in the pathological specimens and the clinicopathological features by qPCR, the target correlation between miR-302b and DKK1 by immunohistochemistry, qPCR and Western blot, and the correlation between miR-302b and the Wnt/β-catenin signaling pathway by Western blot. The effect of miR-302b on osteoblastogenesis was also studied in a subperiosteal tumorigenesis model of NOD/SCID nude mice.

Results: We found that increased miR-302b suppressed cell proliferation and induced cell apoptosis in RPMI 8226 and MM1.S cells. TargetScan online bioinformatic analysis predicted that miR-302b is able to bind to 3'UTR of DKK1 mRNA. Target binding of miR-302b to DKK1 was demonstrated by dual-luciferase reporter assay, qPCR, Western blot and immunohistochemistry, indicating that miR-302b is able to degrade DKK1 in RPMI 8226 and MM1.S cells. The model of co-culturing MM cells with preosteoblast MC3T3-E1 cells showed that miR-302b inhibits MM-induced suppression of osteoblast differentiation. Western blotting showed that miR-302b promotes the Wnt/β-catenin signaling pathway in MM cells. Micro-CT and immunohistochemistry results showed that miR-302b suppresses myeloma bone destruction in vivo.

Conclusion: miR-302b is able to target DKK1 and promote the Wnt/β-catenin signaling pathway in MM.
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http://dx.doi.org/10.1186/s12935-021-01887-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011228PMC
March 2021

Multifunctional Protein-Decorated Bioactive Glass Nanoparticles for Tumor-Specific Therapy and Bioimaging and .

ACS Appl Mater Interfaces 2021 Apr 29;13(13):14985-14994. Epub 2021 Mar 29.

Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an 710000, China.

Multifunctional nanocarriers with a simple structure and biocompatibility for bioimaging, potential tumor targeting, and precise antitumor ability are promising in cancer therapy. Bioactive glass is an important biomaterial and has been used in clinical bone tissue repair due to the high biocompatibility and bioactivity. Herein, we report fetal bovine serum (FBS)-decorated europium-doped bioactive glass nanoparticles (EuBGN@FBS) with excellent biosafety and enhanced tumor targeting for cancer imaging and therapy. EuBGN@FBS showed the controlled photoluminescent properties and pH-responsive anticancer drug release behavior. The FBS decoration significantly enhanced the dispersibility in physiological medium and improved hemocompatibility and cellular uptake of EuBGN. Relative to EuBGN, EuBGN@FBS could also efficiently image the cancer cell and show significantly enhanced targeted tumor imaging and chemotherapy while retaining negligible side effects. The simple and biocompatible structure with efficient tumor targeting, imaging, and therapy makes EuBGN@FBS highly promising in future cancer therapy.
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http://dx.doi.org/10.1021/acsami.1c01337DOI Listing
April 2021

Understanding and exploiting the fatty acid desaturation system in Rhodotorula toruloides.

Biotechnol Biofuels 2021 Mar 19;14(1):73. Epub 2021 Mar 19.

Temasek Life Sciences Laboratory, 1 Research Link, National University of Singapore, Singapore, 117604, Singapore.

Background: Rhodotorula toruloides is a robust producer of triacylglycerol owing to its fast growth rate and strong metabolic flux under conditions of high cell density fermentation. However, the molecular basis of fatty acid biosynthesis, desaturation and regulation remains elusive.

Results: We present the molecular characterization of four fatty acid desaturase (FAD) genes in R. toruloides. Biosynthesis of oleic acid (OA) and palmitoleic acid (POA) was conferred by a single-copy ∆9 Fad (Ole1) as targeted deletion of which abolished the biosynthesis of all unsaturated fatty acids. Conversion of OA to linoleic acid (LA) and α-linolenic acid (ALA) was predominantly catalyzed by the bifunctional ∆12/∆15 Fad2. FAD4 was found to encode a trifunctional ∆9/∆12/∆15 FAD, playing important roles in lipid and biomass production as well as stress resistance. Furthermore, an abundantly transcribed OLE1-related gene, OLE2 encoding a 149-aa protein, was shown to regulate Ole1 regioselectivity. Like other fungi, the transcription of FAD genes was controlled by nitrogen levels and fatty acids in the medium. A conserved DNA motif, (T/C)(G/A)TTGCAGA(T/C)CCCAG, was demonstrated to mediate the transcription of OLE1 by POA/OA. The applications of these FAD genes were illustrated by engineering high-level production of OA and γ-linolenic acid (GLA).

Conclusion: Our work has gained novel insights on the transcriptional regulation of FAD genes, evolution of FAD enzymes and their roles in UFA biosynthesis, membrane stress resistance and, cell mass and total fatty acid production. Our findings should illuminate fatty acid metabolic engineering in R. toruloides and beyond.
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http://dx.doi.org/10.1186/s13068-021-01924-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977280PMC
March 2021

3D Face From X: Learning Face Shape From Diverse Sources.

IEEE Trans Image Process 2021 25;30:3815-3827. Epub 2021 Mar 25.

We present a novel method to jointly learn a 3D face parametric model and 3D face reconstruction from diverse sources. Previous methods usually learn 3D face modeling from one kind of source, such as scanned data or in-the-wild images. Although 3D scanned data contain accurate geometric information of face shapes, the capture system is expensive and such datasets usually contain a small number of subjects. On the other hand, in-the-wild face images are easily obtained and there are a large number of facial images. However, facial images do not contain explicit geometric information. In this paper, we propose a method to learn a unified face model from diverse sources. Besides scanned face data and face images, we also utilize a large number of RGB-D images captured with an iPhone X to bridge the gap between the two sources. Experimental results demonstrate that with training data from more sources, we can learn a more powerful face model.
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http://dx.doi.org/10.1109/TIP.2021.3065798DOI Listing
March 2021

Clinical outcomes and risk factors for mortality from ventilator-associated events: A registry-based cohort study among 30,830 intensive care unit patients.

Infect Control Hosp Epidemiol 2021 Mar 11:1-8. Epub 2021 Mar 11.

Department of Infection Control, West China Hospital of Sichuan University, Chengdu, China.

Objective: To investigate the clinical impact of ventilator-associated events (VAEs) on adverse prognoses and risk factors for mortality among intensive care unit (ICU) patients receiving invasive mechanical ventilation (IMV) based on an ICU healthcare-associated infection (ICU-HAI) registry.

Design: A cohort study was conducted based on an ICU-HAI registry including 30,830 patients between 2015 and 2018.

Setting: The study was conducted using data from 5 adult ICUs of a referral hospital.

Patients: Adult patients in the ICU-HAI registry who received ≥4 consecutive IMV days.

Methods: Clinical outcomes and mortality risk factors for VAEs were analyzed using propensity score matching (PSM), multivariate regression models, and sensitivity analyses.

Results: Of 6,426 included patients, 1,803 developed 1,899 VAEs. After PSM, patients with VAEs did have prolonged length of stay in the ICU and in the hospital, increased hospitalization costs, longer days on mechanical ventilation, higher proportion of ≥9 days on mechanical ventilation, higher rate of failure in extubating mechanical ventilation, and excess all-cause mortality in the ICU. Older age (adjusted OR [aOR], 1.02), higher APACHE II score on ICU admission (aOR, 1.06), pneumonia (aOR, 1.49), blood transfusion (aOR 1.43), immunosuppressive drugs (aOR, 1.69), central-line catheter (aOR, 2.06), and ≥2 VAEs in the ICU (aOR, 1.99) were associated with higher risks for all-cause mortality in an ICU.

Conclusions: Patients with VAEs indeed had poorer clinical outcomes. Older age, higher APACHE II score on ICU admission, pneumonia, blood transfusion, immunosuppressive drugs, central-line catheter, and ≥2 VAEs in the ICU were risk factors for all-cause mortality of VAE patients in the ICU.
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http://dx.doi.org/10.1017/ice.2021.64DOI Listing
March 2021

Downregulation of lncRNA ZNF582-AS1 due to DNA hypermethylation promotes clear cell renal cell carcinoma growth and metastasis by regulating the N(6)-methyladenosine modification of MT-RNR1.

J Exp Clin Cancer Res 2021 Mar 10;40(1):92. Epub 2021 Mar 10.

Department of Urology, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, China.

Background: Emerging evidence confirms that lncRNAs (long non-coding RNAs) are potential biomarkers that play vital roles in tumors. ZNF582-AS1 is a novel lncRNA that serves as a potential prognostic marker of cancers. However, the specific clinical significance and molecular mechanism of ZNF582-AS1 in ccRCC (clear cell renal cell carcinoma) are unclear.

Methods: Expression level and clinical significance of ZNF582-AS1 were determined by TCGA-KIRC data and qRT-PCR results of 62 ccRCCs. DNA methylation status of ZNF582-AS1 promoter was examined by MSP, MassARRAY methylation and demethylation analysis. Gain-of-function experiments were conducted to investigate the biological roles of ZNF582-AS1 in the phenotype of ccRCC. The subcellular localization of ZNF582-AS1 was detected by RNA FISH. iTRAQ, RNA pull-down and RIP-qRT-PCR were used to identify the downstream targets of ZNF582-AS1. rRNA MeRIP-seq and MeRIP-qRT-PCR were utilized to examine the N(6)-methyladenosine modification status. Western blot and immunohistochemistry assays were used to determine the protein expression level.

Results: ZNF582-AS1 was downregulated in ccRCC, and decreased ZNF582-AS1 expression was significantly correlated with advanced tumor stage, higher pathological stage, distant metastasis and poor prognosis. Decreased ZNF582-AS1 expression was caused by DNA methylation at the CpG islands within its promoter. ZNF582-AS1 overexpression inhibited cell proliferative, migratory and invasive ability, and increased cell apoptotic rate in vitro and in vivo. Mechanistically, we found that ZNF582-AS1 overexpression suppressed the N(6)-methyladenosine modification of MT-RNR1 by reducing rRNA adenine N(6)-methyltransferase A8K0B9 protein level, resulting in the decrease of MT-RNR1 expression, followed by the inhibition of MT-CO2 protein expression. Furthermore, MT-RNR1 overexpression reversed the decreased MT-CO2 expression and phenotype inhibition of ccRCC induced by increased ZNF582-AS1 expression.

Conclusions: This study demonstrates for the first time that ZNF582-AS1 functions as a tumor suppressor gene in ccRCC and ZNF582-AS1 may serve as a potential biomarker and therapeutic target of ccRCC.
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http://dx.doi.org/10.1186/s13046-021-01889-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945252PMC
March 2021

Ciclopirox and bortezomib synergistically inhibits glioblastoma multiforme growth via simultaneously enhancing JNK/p38 MAPK and NF-κB signaling.

Cell Death Dis 2021 Mar 5;12(3):251. Epub 2021 Mar 5.

Protein Quality Control and Diseases Laboratory, Key Laboratory of Medical Genetics of Zhejiang Province, Key Laboratory of Laboratory Medicine, Ministry of Education of China School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.

Ciclopirox (CPX) is an antifungal drug that has recently been reported to act as a potential anticancer drug. However, the effects and underlying molecular mechanisms of CPX on glioblastoma multiforme (GBM) remain unknown. Bortezomib (BTZ) is the first proteasome inhibitor-based anticancer drug approved to treat multiple myeloma and mantle cell lymphoma, as BTZ exhibits toxic effects on diverse tumor cells. Herein, we show that CPX displays strong anti-tumorigenic activity on GBM. Mechanistically, CPX inhibits GBM cellular migration and invasion by reducing N-Cadherin, MMP9 and Snail expression. Further analysis revealed that CPX suppresses the expression of several key subunits of mitochondrial enzyme complex, thus leading to the disruption of mitochondrial oxidative phosphorylation (OXPHOS) in GBM cells. In combination with BTZ, CPX promotes apoptosis in GBM cells through the induction of reactive oxygen species (ROS)-mediated c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) signaling. Moreover, CPX and BTZ synergistically activates nuclear factor kappa B (NF-κB) signaling and induces cellular senescence. Our findings suggest that a combination of CPX and BTZ may serve as a novel therapeutic strategy to enhance the anticancer activity of CPX against GBM.
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http://dx.doi.org/10.1038/s41419-021-03535-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935936PMC
March 2021

Targeting brain regions of interest in functional near-infrared spectroscopy-Scalp-cortex correlation using subject-specific light propagation models.

Hum Brain Mapp 2021 May 23;42(7):1969-1986. Epub 2021 Feb 23.

Department of Electronics and Electrical Engineering, Keio University, Yokohama, Japan.

Targeting specific brain regions of interest by the accurate positioning of optodes (emission and detection probes) on the scalp remains a challenge for functional near-infrared spectroscopy (fNIRS). Since fNIRS data does not provide any anatomical information on the brain cortex, establishing the scalp-cortex correlation (SCC) between emission-detection probe pairs on the scalp and the underlying brain regions in fNIRS measurements is extremely important. A conventional SCC is obtained by a geometrical point-to-point manner and ignores the effect of light scattering in the head tissue that occurs in actual fNIRS measurements. Here, we developed a sensitivity-based matching (SBM) method that incorporated the broad spatial sensitivity of the probe pair due to light scattering into the SCC for fNIRS. The SCC was analyzed between head surface fiducial points determined by the international 10-10 system and automated anatomical labeling brain regions for 45 subject-specific head models. The performance of the SBM method was compared with that of three conventional geometrical matching (GM) methods. We reveal that the light scattering and individual anatomical differences in the head affect the SCC, which indicates that the SBM method is compulsory to obtain the precise SCC. The SBM method enables us to evaluate the activity of cortical regions that are overlooked in the SCC obtained by conventional GM methods. Together, the SBM method could be a promising approach to guide fNIRS users in designing their probe arrangements and in explaining their measurement data.
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http://dx.doi.org/10.1002/hbm.25367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046049PMC
May 2021

Transgenerational Effects on the Coral Pocillopora damicornis Microbiome Under Ocean Acidification.

Microb Ecol 2021 Feb 12. Epub 2021 Feb 12.

CAS Key Laboratory of Tropical Marine Bio-resources and Ecology and Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, China.

Reef-building corals are inhabited by functionally diverse microorganisms which play important roles in coral health and persistence in the Anthropocene. However, our understanding of the complex associations within coral holobionts is largely limited, particularly transgenerational exposure to environmental stress, like ocean acidification. Here we investigated the microbiome development of an ecologically important coral Pocillopora damicornis following transgenerational exposure to moderate and high pCO (partial pressure of CO) levels, using amplicon sequencing and analysis. Our results showed that the Symbiodiniaceae community structures in adult and juvenile had similar patterns, all of which were dominated by Durusdinium spp., previously known as clade D. Conversely, prokaryotic communities varied between adults and juveniles, possibly driven by the effect of host development. Surprisingly, there were no significant changes in both Symbiodiniaceae and prokaryotic communities with different pCO treatments, which was independent of the life history stage. This study shows that ocean acidification has no significant effect on P. damicornis microbiome, and warrants further research to test whether transgenerational acclimation exists in coral holobiont to projected future climate change.
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http://dx.doi.org/10.1007/s00248-021-01690-2DOI Listing
February 2021

The earth's gravity field recovery using the third invariant of the gravity gradient tensor from GOCE.

Sci Rep 2021 Feb 11;11(1):3581. Epub 2021 Feb 11.

MOE Key Laboratory of Fundamental Physical Quantities Measurement, Hubei Key Laboratory of Gravitation and Quantum Physics, School of Physics, Huazhong University of Science and Technology, Wuhan, 430074, China.

Due to the independence of the gradiometer instrument's orientation in space, the second invariant [Formula: see text] of gravity gradients in combination with individual gravity gradients are demonstrated to be valid for gravity field determination. In this contribution, we develop a novel gravity field model named I3GG, which is built mainly based on three novel elements: (1) proposing to utilize the third invariant [Formula: see text] of the gravity field and steady-state ocean circulation explorer (GOCE) gravity gradient tensor, instead of using the [Formula: see text], similar to the previous studies; (2) applying an alternative two-dimensional fast fourier transform (2D FFT) method; (3) showing the advantages of [Formula: see text] over [Formula: see text] in the effect of measurement noise from the theoretical and practical computations. For the purpose of implementing the linearization of the third invariant, this study employs the theory of boundary value problems with sphere approximation at an accuracy level of [Formula: see text]. In order to efficiently solve the boundary value problems, we proposed an alternative method of 2D FFT, which uses the coherent sampling theory to obtain the relationship between the 2D FFT and the third invariant measurements and uses the pseudo-inverse via QR factorization to transform the 2D Fourier coefficients to spherical harmonic ones. Based on the GOCE gravity gradient data of the nominal mission phase, a novel global gravity field model (I3GG) is derived up to maximum degree/order 240, corresponding to a spatial resolution of 83 km at the equator. Moreover, in order to investigate the differences of gravity field determination between [Formula: see text] with [Formula: see text], we applied the same processing strategy on the second invariant measurements of the GOCE mission and we obtained another gravity field model (I2GG) with a maximum degree of 220, which is 20 degrees lower than that of I3GG. The root-mean-square (RMS) values of geoid differences indicates that the effects of measurement noise of I3GG is about 20% lower than that on I2GG when compared to the gravity field model EGM2008 (Earth Gravitational Model 2008) or EIGEN-5C (EIGEN: European Improved Gravity model of the Earth by New techniques). Then the accuracy of I3GG is evaluated independently by comparison the RMS differences between Global Navigation Satellite System (GNSS)/leveling data and the model-derived geoid heights. Meanwhile, the re-calibrated GOCE data released in 2018 is also dealt with and the corresponding result also shows the similar characteristics.
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http://dx.doi.org/10.1038/s41598-021-81840-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878776PMC
February 2021

Minimally invasive ileal ureter replacement: Comparative analysis of robot-assisted laparoscopic versus conventional laparoscopic surgery.

Int J Med Robot 2021 Feb 2:e2230. Epub 2021 Feb 2.

Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Centre, Beijing, China.

Background: This study is an initial comparative analysis of perioperative and intermediate-term functional outcomes between patients who underwent robot-assisted laparoscopic (RALS) or conventional laparoscopic surgery (LS).

Materials And Methods: A total of 25 patients who underwent ileal ureter replacement (10 RALS and 15 LS) were followed by functional cine magnetic resonance urography (MRU) combined with a modified Whitaker test. Also, the characteristics, perioperative data and functional outcomes of the patients were compared.

Results: The estimated blood loss, postoperative hospital stay and time to oral intake were significantly lower in the RALS group. At the median 14-month follow-up, all the patients showed improved renal function and were symptom-free, with no signs of leakage or stenosis observed by cine MRU combined with a modified Whitaker test.

Conclusions: RALS with an extracorporeal bowel resection is feasible and appears to be safe, with quick postoperative recovery and encouraging outcomes.
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http://dx.doi.org/10.1002/rcs.2230DOI Listing
February 2021

Copper-Loaded Biodegradable Bone Wax with Antibacterial and Angiogenic Properties in Early Bone Repair.

ACS Biomater Sci Eng 2021 02 27;7(2):663-671. Epub 2021 Jan 27.

Department of Orthopedics, Zhongnan Hospital of Wuhan University, No. 169, Donghu Road, Wuhan 430071, China.

Traditional bone wax has lots of shortcomings such as the risk of infection and inflammation and the ability to hinder osteogenesis that limit its clinical applications. In this study, we designed a novel biodegradable bone wax with desirable angiogenic and antibacterial ability and low foreign body reaction by mixing calcium sulfate, poloxamer, and cupric ions. To evaluate its biocompatibility and angiogenetic effect , we cultured human umbilical vein endothelial cells (HUVECs) with the indicated bone wax to observe cell viability and vessel-like tubular formation. The bone wax was then implanted in a critical-sized bone defect rat model for 4 and 8 weeks to successfully stimulate angiogenesis . Finally, the bone wax extract was incubated with Gram-positive to confirm its antibacterial ability. The copper-loaded biodegradable bone wax overcomes the drawbacks of traditional bone wax and provides a new approach for the treatment of bone injuries.
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http://dx.doi.org/10.1021/acsbiomaterials.0c01471DOI Listing
February 2021

Evaluation of Demineralized Bone Matrix Particles Delivered by Alginate Hydrogel for a Bone Graft Substitute: An Animal Experimental Study.

Med Sci Monit 2021 Jan 22;27:e928617. Epub 2021 Jan 22.

Department of Spine Surgery and Musculoskeletal Tumor, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China (mainland).

BACKGROUND Our objective was to explore a synthetic alginate hydrogel delivery system for the delivery of demineralized bone matrix (DBM) particles for bone graft substitutes. MATERIAL AND METHODS The physiochemical properties of surface morphology, porosity measurements, in vitro degradation, equilibrium swelling, and mechanical testing of combined DBM powder and alginate in amounts of 0 mg/1 mL, 25 mg/1 mL, 50 mg/1 mL, and 100 mg/1 mL were detected. In vitro cell culture and in vivo studies using Sprague-Dawley rats were performed to evaluate the biocompatibility and osteoinductivity of DBM-alginate (ADBM) composites. RESULTS DBM particles were uniformly scattered in all composites, and macro-scale pores were omnipresent. All composites showed a similar low degradation rate, with approximately 85% of weight remaining after 15 days. As the concentration of DBM particles in composites increased, degradation in collagenase and elastic modulus increased and the pore area and swelling ratio significantly decreased. No cytotoxicity of ADBM or alginate on mesenchymal stem cells (MSCs) was observed. Cell cultivation with ADBM showed greater osteogenic potential, evidenced by the upregulation of alkaline phosphatase and alizarin red staining activity and the mRNA expression level of marker genes RUNX2, OCN, OPN, and collagen I compared with the cells grown in alginate. Evaluation of ectopic bone formation revealed the osteoinductivity of the ADBM composites was significantly greater than that of DBM particles. Osteoinduction of the composites was demonstrated by a cranial defect model study. CONCLUSIONS The delivery of DBM particles using a synthetic alginate hydrogel carrier may be a promising approach in bone tissue engineering for bone defects.
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http://dx.doi.org/10.12659/MSM.928617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836326PMC
January 2021

A radial 3D polycaprolactone nanofiber scaffold modified by biomineralization and silk fibroin coating promote bone regeneration in vivo.

Int J Biol Macromol 2021 Mar 11;172:19-29. Epub 2021 Jan 11.

Department of Spine Surgery and Musculoskeletal Tumor, Zhongnan Hospital of Wuhan University, 168 Donghu Street, Wuchang District, Wuhan 430071, Hubei, China.. Electronic address:

The treatment and repair of large bone defects remains a major therapeutic challenge in the clinical setting. Nanofiber scaffolds fabricated via the electrospinning technique have been developed as a universal method for bone regeneration due to their suitable properties. However, traditional two-dimensional (2D) nanofiber mats are usually too dense, which may prevent cell infiltration and growth, thereby restricting their application. Herein, a three-dimensional (3D) polycaprolactone nanofiber scaffold was developed, modified by biomineralization and silk fibroin coating. The scaffold possessed a parallel array of nanofiber surfaces, mimicking the parallel structure of fibrils in natural bone tissue. Furthermore, the fabricated radially or laterally interconnected macrochannels were investigated to elucidate the effect of the scaffold structure on bone regeneration. In vitro studies revealed that the scaffolds could guide cell arrangement and that the radially aligned scaffold demonstrated a stronger ability to promote cell proliferation. In vivo results showed that the radially aligned scaffold could guide tissue arrangement and remodeling and support a significantly faster regeneration rate of bone tissue. Therefore, 3D-mineralized polycaprolactone nanofiber scaffolds with radially interconnected macrochannels and aligned nanofibers are expected to be used in tissue engineering, including in the repair of bone defects, cartilage or other composite tissues.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.01.036DOI Listing
March 2021

The photocatalytic antibacterial molecular mechanisms towards Pseudomonas syringae pv. tabaci by g-C N nanosheets: insights from the cytomembrane, biofilm and motility disruption.

Pest Manag Sci 2021 May 28;77(5):2302-2314. Epub 2021 Jan 28.

College of Plant Protection, Southwest University, Chongqing, China.

Background: Antibacterial photocatalytic therapy has been employed as a promising strategy to combat antibiotic-resistant bacteria in the water disinfection field, especially some non-metal inorganic nanomaterials. However, their antibacterial activities on plant phytopathogens are poorly understood. Here, the photocatalytic antibacterial mechanism of the urea-synthesized graphitic carbon nitride nanosheets (g-C N nanosheets) against Pseudomonas syringae pv. tabaci was systematically investigated in vitro and in vivo.

Results: The g-C N nanosheets exhibited remarkable concentration-dependent and irradiation-time-dependent antibacterial properties, and the 0.5 mg mL concentration ameliorated tobacco wildfire disease in host plants. Specifically, under visible irradiation, g-C N nanosheets produced numerous reactive oxygen species (ROS), supplementing the plentiful extracellular and intracellular ROS in bacteria. After exposing light-induced g-C N nanosheets for 1 h, 500 genes were differentially expressed, according to transcriptome analyses. Notably, the expression of genes related 'antioxidant activity' and 'membrane transport' was sharply upregulated, and those related to 'bacterial chemotaxis', 'biofilm formation', 'energy metabolism' and 'cell motility' were downregulated. After exposure for over 2 h, the longer-time pressure on the target bacteria cause the decreased biofilm formation and flagellum motility, further injuring the cell membranes leading to cytoplasm leakage and damaged DNA, eventually resulting in the bacterial death. Concomitantly, the attachment of g-C N nanosheets was a synergistic physical antibacterial pathway. The infection capacity assessment also supported the earlier supposition.

Conclusion: These results provide novel insights into the photocatalytic antibacterial mechanisms of g-C N nanosheets at the transcriptome level, which are expected to be useful for dissecting the response pathways in antibacterial activities and for improving g-C N -based photocatalysts practices in plant disease control. © 2021 Society of Chemical Industry.
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http://dx.doi.org/10.1002/ps.6257DOI Listing
May 2021

Developing and applying a classification system for ranking the biological effects of endocrine disrupting chemicals on male rockfish Sebastiscus marmoratus in the Maowei Sea, China.

Mar Pollut Bull 2021 Feb 5;163:111931. Epub 2021 Jan 5.

Laboratory of Marine Biology and Ecology, Third Institute of Oceanography, Ministry of Natural Resources, Xiamen 361005, China. Electronic address:

Endocrine disrupting compounds (EDCs) in marine environments has become a major environmental concern. Nonetheless, the biological effects of EDCs on organisms in coastal environments remain poorly characterized. In this study, biomonitoring of EDCs in male fish Sebastiscus marmoratus was carried out in the Maowei Sea, China. The results showed that the concentration of 4-nonylphenol (4-NP) was below the detection limit, the concentrations of 4-tert-octylphenol (4-t-OP) and bisphenol A (BPA) in seawater were moderate compared with those in other global regions, and the possible sources are the municipal wastewater discharge. Nested ANOVA analyses suggest significant differences of the brain aromatase activities and plasma vitellogenin (VTG) expression between the port area and the oyster farming area. A new fish expert system (FES) was developed for evaluating the biological effects of EDCs on fish. Our findings show that the FES is a potential tool to evaluate the biological effects of marine pollutants.
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http://dx.doi.org/10.1016/j.marpolbul.2020.111931DOI Listing
February 2021

Cell-cycle arrest and senescence in TP53-wild type renal carcinoma by enhancer RNA-P53-bound enhancer regions 2 (p53BER2) in a p53-dependent pathway.

Cell Death Dis 2021 Jan 5;12(1). Epub 2021 Jan 5.

Department of Urology, Peking University First Hospital, Beijing, People's Republic of China.

TP53 is a classic tumor suppressor, but its role in kidney cancer remains unclear. In our study, we tried to explain the role of p53 in kidney cancer through the p53-related enhancer RNA pathway. Functional experiments were used to explore whether P53-bound enhancer regions 2 (p53BER2) has a role in the cell cycle and senescence response of TP53-wild type (WT) renal cancer cells in vitro or vivo. RNA-sequencing was used to identify the potential target of p53BER2. The results showed that the expression level of P53BER2 was downregulated in renal cancer tissues and cell lines, further dual-luciferase experiments and APR-256-reactivated experiments showed p53BER2 expresses in a p53-dependent way. Moreover, knockdown p53BER2 could reverse nutlin-3-induced cytotoxic effect in TP53-WT cell lines. Further exploration showed the downregulation of p53BER2 could reverse nutlin-3-induced G1-arrest and senescence in TP53-WT cell lines. What is more, the knockdown of p53BER2 showed resistance to nutlin-3 treatment in vivo. Additionally, we found BRCA2 could be regulated by p53BER2 in vitro and vivo; further experiment showed p53BER2 could induce cell-cycle arrest and DNA repair by mediating BRCA2. In summary, the p53-associated enhancer RNA-p53BER2 mediates the cell cycle and senescence of p53 in TP53-WT renal cancer cells.
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http://dx.doi.org/10.1038/s41419-020-03229-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791070PMC
January 2021

Preclinical efficacy of stem cell therapy for skin flap: a systematic review and meta-analysis.

Stem Cell Res Ther 2021 Jan 7;12(1):28. Epub 2021 Jan 7.

Department of Burn, The First Affiliated Hospital of Wenzhou Medical University, Nan Bai Xiang, Wenzhou, Zhejiang, 325000, People's Republic of China.

Background: A skin flap is one of the most critical surgical techniques for the restoration of cutaneous defects. However, the distal necrosis of the skin flap severely restricts the clinical application of flap surgery. As there is no consensus on the treatment methods to prevent distal necrosis of skin flaps, more effective and feasible interventions to prevent skin flaps from necrosis are urgently needed. Stem therapy as a potential method to improve the survival rate of skin flaps is receiving increasing attention.

Methods: This review followed the recommendations from the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statements. Twenty studies with 500 animals were included by searching Web of Science, EMBASE, PubMed, and Cochrane Library databases, up until October 8, 2020. Moreover, the references of the included articles were searched manually to obtain other studies. All analyses were conducted using Review Manager V.5.3 software.

Results: Meta-analysis of all 20 studies demonstrated stem cell treatment has significant effects on reducing necrosis of skin flap compared with the control group (SMD: 3.20, 95% CI 2.47 to 3.93). Besides, subgroup analysis showed differences in the efficacy of stem cells in improving the survival rate of skin flaps in areas of skin flap, cell type, transplant types, and method of administration of stem cells. The meta-analysis also showed that stem cell treatment had a significant effect on increasing blood vessel density (SMD: 2.96, 95% CI 2.21 to 3.72) and increasing the expression of vascular endothelial growth factor (VEGF, SMD: 4.34, 95% CI 2.48 to 6.1).

Conclusions: The preclinical evidence of our systematic review indicate that stem cell-based therapy is effective for promoting early angiogenesis by up regulating VEGF and ultimately improving the survival rate of skin flap. In summary, small area skin flap, the administration method of intra-arterial injection, ASCs and MSCs, and xenogenic stem cells from humans showed more effective for the survival of animal skin flaps. In general, stem cell-based therapy may be a promising method to prevent skin flap necrosis.
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http://dx.doi.org/10.1186/s13287-020-02103-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791712PMC
January 2021

Management of acute spinal cord compression in multiple myeloma.

Crit Rev Oncol Hematol 2021 Apr 30;160:103205. Epub 2020 Dec 30.

Department of Hematology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei 430071, China. Electronic address:

Spinal cord compression (SCC) is a devastating complication of multiple myeloma and has the potential to cause loss of neurological function. The common symptoms of SCC are back pain, motor weakness, and sensory change. Once diagnosed, the patient should be managed as soon as possible to prevent permanent loss of neurological function. Currently, there have been a number of studies describing the mechanism and management experience of SCC in patients with myeloma. The clinical features, diagnostic strategies, and the roles of different therapeutic options are herein reviewed.
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http://dx.doi.org/10.1016/j.critrevonc.2020.103205DOI Listing
April 2021

Foam shares antibiotic resistomes and bacterial pathogens with activated sludge in wastewater treatment plants.

J Hazard Mater 2021 Apr 15;408:124855. Epub 2020 Dec 15.

Institute of Pesticide and Environmental Toxicology, College of Agriculture & Biotechnology, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Biology of Crop Pathogens and Insects, Ministry of Agriculture, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Biology of Crop Pathogens and Insects of Zhejiang Province, Zhejiang University, Hangzhou 310058, China. Electronic address:

Foaming is a common operational problem that occurs in activated sludge (AS) from many wastewater treatment plants (WWTPs), but the characteristic of antibiotic resistance genes (ARGs) and human pathogenic bacteria (HPB) in foams is generally lacking. Here, we used a metagenomic approach to characterize the profile of ARGs and HPB in foams and AS from full-scale WWTPs receiving pesticide wastewater. No significant difference in the microbial communities was noted between the AS and foam samples. The diversity and abundance of ARGs in the foams were similar to those in the pertinent AS samples. Procrustes analysis suggested that the bacterial community is the major driver of ARGs. Metagenomic assembly also indicated that most ARGs (e.g., multidrug, rifamycin, peptides, macrolide-lincosamide-streptogramin, tetracycline, fluoroquinolone, and beta-lactam resistance genes) were carried by chromosomes rather than mobile genetic elements. Moreover, the relative abundances of HPB, Pseudomonas putida and Mycobacterium smegmatis, were enriched in the foam samples. Nine HPB were identified as carriers of 21 ARG subtypes, of which Pseudomonas aeruginosa could carry 12 ARG subtypes. Overall, this study indicates the prevalence of ARGs, HPB, and ARG-carrying HPB in foams, which highlights the potential risk of foams in spreading ARGs and HPB into the surrounding environments.
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http://dx.doi.org/10.1016/j.jhazmat.2020.124855DOI Listing
April 2021

Long-term observation of catheter ablation vs. pharmacotherapy in the management of persistent and long-standing persistent atrial fibrillation (CAPA study).

Europace 2020 Dec 26. Epub 2020 Dec 26.

Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan university, Hubei Key Laboratory of Cardiology, Wuhan, Hubei 430060, China.

Aims : The roles of radiofrequency catheter ablation (RFCA) and pharmacotherapy in treating persistent and long-standing persistent atrial fibrillation (AF) have not been sufficiently investigated. We conducted a multicentre, randomized, controlled trial to compare the effects of RFCA and pharmacotherapy on the prognosis of these patients.

Methods And Results : A total of 648 patients with persistent and long-standing persistent AF were enrolled from 30 centres and randomized to either the ablation group (n = 327) or the pharmacotherapy group (n = 321). After 54.2 ± 10.6 months of follow-up, the primary endpoints occurred significantly more rarely in the ablation group than in the pharmacotherapy group (10.4% vs. 17.4%; hazard ratio 0.59, 95% confidence interval 0.48-0.75; P < 0.001). The incidence of stroke/transient ischaemic attack (TIA) was significantly lower in the ablation group (4.2% vs. 7.2%, P < 0.001). Likewise, the incidence of new-onset congestive heart failure (CHF) was lower in the ablation group (2.8% vs. 7.2%, P < 0.001). More patients had sinus rhythm in the ablation group than in the pharmacotherapy group (60.6% vs. 20.9%, P < 0.001), but fewer patients were on antiarrhythmic drugs (24.4% vs. 41.6%, P < 0.001) and warfarin (60.8% vs. 83.9%, P = 0.001). Both the 6-min walk distance and the quality of life (QoL) were improved in the ablation group at the end of follow-up.

Conclusion : In patients with persistent and long-standing persistent AF, RFCA-based treatment was superior to pharmacotherapy in decreasing stroke/TIA and new-onset CHF and improving QoL.
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http://dx.doi.org/10.1093/europace/euaa356DOI Listing
December 2020

The Genotype-Phenotype Association of Von Hipple Lindau Disease Based on Mutation Locations: A Retrospective Study of 577 Cases in a Chinese Population.

Front Genet 2020 10;11:532588. Epub 2020 Dec 10.

Department of Urology, Peking University First Hospital, Beijing, China.

Purpose: Von Hippel-Lindau (VHL) disease is a hereditary kidney cancer syndrome, with which patients are more likely to get affected by renal cell carcinoma (RCC), pancreatic cyst or tumor (PCT), central nervous system hemangioblastoma (CHB), retinal angiomas (RA), and pheochromocytoma (PHEO). Mutations of VHL gene located in 3p25 may impair the function of the VHL protein and lead to the disease. It's unclear why obvious phenotype varieties exist among VHL patients. Here we aimed to ascertain whether the mutation types and locations affect the phenotype.

Methods: We enrolled 577 Chinese VHL patients from 211 families and divided them into three groups and six subgroups according to their mutation types and locations. Cox survival analysis and Kaplan-Meier analysis were used to compare intergroup age-related tumor risks.

Results: Patients with nonsense or frameshift mutations that were located before residues 117 of VHL protein (NoF1 subgroup) hold lower age-related risks of VHL associated tumors ( = 0.638, 95%CI 0.461-0.883, = 0.007), CHB ( = 0.596, 95%CI 0.409-0.868, = 0.007) or PCT ( = 0.595, 95%CI 0.368-0.961, = 0.034) than patients whose mutations were located after residues 117 (NoF2 subgroup). Patients in NoF1 subgroup still had lower age-related risks of CHB ( = 0.652, 95%CI 0.476-0.893, = 0.008) and PCT ( = 0.605, 95%CI 0.398-0.918, = 0.018) compared with those in combined NoF2 subgroup and other truncating mutation patients. NoF1 subgroup correspondingly had a longer estimated median lifespan (64 vs. 55 year, = 0.037) than NoF2 subgroup. Among patients with missense mutations of VHL, only a small minority (23 of 286 missense mutations carriers) carried mutations involving neither HIF-α binding region nor elongin C binding region, who were grouped in MO subgroup. MO subgroup seemed to have a higher age-related risk of PHEO. In the whole cohort ( = 577), PHEO was an independent protective factor for CHB ( = 0.001) and survival ( = 0.005). RA and CHB failed to predict the age-related risk of each other.

Conclusion: The mutation types and locations of VHL gene are associated with phenotypes. Genetic counselors could predict phenotypes more accurately based on more detailed genotype-phenotype correlations. Further genotype-phenotype studies should focus on the prediction of tumor recurrence, progression, and metastasis. The deep molecular mechanism of genotype-phenotype correlation is worth further exploring.
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http://dx.doi.org/10.3389/fgene.2020.532588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762453PMC
December 2020

Association of Statin Use With the In-Hospital Outcomes of 2019-Coronavirus Disease Patients: A Retrospective Study.

Front Med (Lausanne) 2020 17;7:584870. Epub 2020 Nov 17.

Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan, China.

Statins have multiple protective effects on inflammation, immunity and coagulation, and may help alleviate pneumonia. However, there was no report focusing on the association of statin use with in-hospital outcomes of patients with coronavirus disease 2019 (COVID-19). We investigated the association between the use of statins and in-hospital outcomes of patients with COVID-19. In this retrospective case series, consecutive COVID-19 patients admitted at 2 hospitals in Wuhan, China, from March 12, 2020 to April 14, 2020 were analyzed. A 1:1 matched cohort was created by propensity score-matched analysis. Demographic data, laboratory findings, comorbidities, treatments and in-hospital outcomes were collected and compared between COVID-19 patients taking and not taking statins. A total of 2,147 patients with COVID-19 were enrolled in this study. Of which, 250 patients were on statin therapy. The mortality was 2.4% (6/250) for patients taking statins while 3.7% (70/1,897) for those not taking statins. In the multivariate Cox model, after adjusting for age, gender, admitted hospital, comorbidities, in-hospital medications and blood lipids, the risk was lower for mortality (adjusted HR, 0.428; 95% CI, 0.169-0.907; = 0.029), acute respiratory distress syndrome (ARDS) (adjusted HR, 0.371; 95% CI, 0.180-0.772; = 0.008) or intensive care unit (ICU) care (adjusted HR, 0.319; 95% CI, 0.270-0.945; = 0.032) in the statin group vs. the non-statin group. After propensity score-matched analysis based on 18 potential confounders, a 1:1 matched cohort (206:206) was created. In the matched cohort, the Kaplan-Meier survival curves showed that the use of statins was associated with better survival ( = 0.025). In a Cox regression model, the use of statins was associated with lower risk of mortality (unadjusted HR, 0.254; 95% CI, 0.070-0.926; = 0.038), development of ARDS (unadjusted HR, 0.240; 95% CI, 0.087-0.657; = 0.006), and admission of ICU (unadjusted HR, 0.349; 95% CI, 0.150-0.813; = 0.015). The results remained consistent when being adjusted for age, gender, total cholesterol, triglyceride, low density lipoprotein cholesterol, procalcitonin, and brain natriuretic peptide. The favorable outcomes in statin users remained statistically significant in the first sensitivity analysis with comorbid diabetes being excluded in matching and in the second sensitivity analysis with chronic obstructive pulmonary disease being added in matching. In this retrospective analysis, the use of statins in COVID-19 patients was associated with better clinical outcomes and is recommended to be continued in patients with COVID-19.
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http://dx.doi.org/10.3389/fmed.2020.584870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717990PMC
November 2020

Antihypertensive drugs are associated with reduced fatal outcomes and improved clinical characteristics in elderly COVID-19 patients.

Cell Discov 2020 Oct 29;6(1):77. Epub 2020 Oct 29.

The State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Biochemistry, Peking Union Medical College, Beijing, 100005, China.

The novel coronavirus (CoV) severe acute respiratory syndrome (SARS)-CoV-2 outbreak began at the end of 2019 in Wuhan, China, and has spread to over 200 countries. In this multicenter retrospective study, we identified 2190 adult patients admitted for laboratory-confirmed COVID-19 in three participating centers. Multivariate logistic regression was conducted in patients with comorbid hypertension to examine the potential association between clinical outcomes, disease severity, and clinical characteristics with the use of ACEI, ARB, calcium-channel blockers (CCB), beta-blockers (BB), and thiazide diuretics. The clinical outcome, dyspnea, and fatigue were significantly improved in patients, especially elderly patients who were older than 65 years, who took ARB drugs prior to hospitalization compared to patients who took no drugs. The reduction of disease severity of elderly COVID-19 patients was associated with CCB and ACEI users. Clinical indices, including CRP, lymphocyte count, procalcitonin D dimer, and hemoglobin, were significantly improved in elderly ARB users. In addition, the clinical outcomes were statistically significantly improved in patients who took antihypertension drugs ARB, BB, and CCB after statistical adjustment by all ages, gender, baseline of blood pressures, and coexisting medical conditions. Our data indicate that hypertension drugs ARB, ACEI, CCB, and BB might be beneficial for COVID-19 patients.
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http://dx.doi.org/10.1038/s41421-020-00221-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595708PMC
October 2020

Nitric oxide-generating compound and bio-clickable peptide mimic for synergistically tailoring surface anti-thrombogenic and anti-microbial dual-functions.

Bioact Mater 2021 Jun 23;6(6):1618-1627. Epub 2020 Nov 23.

Key Laboratory of Advanced Technology for Materials of the Education Ministry, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China.

Application of extracorporeal circuits and indwelling medical devices has saved many lives. However, it is accompanied with two major complications: thrombosis and infection. To address this issue, we apply therapeutic nitric oxide gas (NO) and antibacterial peptide for synergistically tailoring such devices for surface anti-thrombogenic and antifouling dual functions. Such functional surface is realized by stepwise conjugation of NO-generating compound of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelated copper ions (Cu-DOTA) and dibenzylcyclooctyne- (DBCO-) modified antimicrobial peptide based on carbodiimide and click chemistry respectively. The integration of peptide and Cu-DOTA grants the modified surface the ability to not only efficiently inhibit bacterial growth, but also catalytically generate NO from endogenous s-nitrosothiols (RSNO) to reduce adhesion and activation of platelets, preventing the formation of thrombus. We envision that the stepwise synergistic modification strategy by using anticoagulant NO and antibacterial peptide would facilitate the surface multifunctional engineering of extracorporeal circuits and indwelling medical devices, with reduced clinical complications associated with thrombosis and infection.
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http://dx.doi.org/10.1016/j.bioactmat.2020.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695912PMC
June 2021