Publications by authors named "Xiaoliang Wang"

324 Publications

Decreased CD8 Lymphocytic Infiltration in Multifocal and Multicentric Glioblastomas.

Front Oncol 2021 27;11:748277. Epub 2021 Sep 27.

Department of Geriatrics, Shengjing Hospital of China Medical University, Shenyang, China.

Purpose: Multifocal and multicentric glioblastomas (mGBMs) are associated with a poorer prognosis compared to unifocal glioblastoma (uGBM). The presence of CD8 tumor-infiltrating lymphocytes (TILs) is predictive of clinical outcomes in human malignancies. Here, we examined the CD8 lymphocytic infiltration in mGBMs.

Methods: The clinical data of 57 consecutive IDH wildtype primary mGBM patients with histopathological diagnoses were retrospectively reviewed. CD8 TILs were quantitatively evaluated by immunohistochemical staining. The survival function of CD8 TILs was assessed by Kaplan-Meier analysis and Cox proportional hazard models.

Results: No significant difference in the concentration of CD8 TILs was observed among foci from the same patient (P>0.150). The presence of CD8 TILs was similar between multifocal and multicentric GBMs (P=0.885). The concentration of CD8 TILs was significantly lower in mGBMs than in uGBMs (P=0.002). In mGBM patients, the CD8 TIL level was associated with preoperative KPS (P=0.018). The median overall survival (OS) of the 57 mGBMs was 9 months. A low CD8 TIL level (multivariate HR 4.404, 95% CI 1.954-9.926, P=0.0004) was an independent predictor of poor OS, while postoperative temozolomide chemotherapy (multivariate HR 6.076, 95% CI 2.330-15.842, P=0.0002) was independently associated with prolonged OS in mGBMs.

Conclusions: Decreased CD8 TIL levels potentially correlate with unfavorable clinical outcome in mGBMs, suggesting an influence of the local immuno-microenvironment on the progression of mGBMs.
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http://dx.doi.org/10.3389/fonc.2021.748277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8503598PMC
September 2021

Necessity of Intraoperative Level IIA Lymph Node Dissection in Patients with Carotid Body Tumors: A Retrospective Study of 126 Cases.

ORL J Otorhinolaryngol Relat Spec 2021 Oct 5:1-7. Epub 2021 Oct 5.

Department of Head and Neck Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China.

Background: Carotid body tumors (CBTs) are relatively uncommon neoplasms that rarely have malignant potential. However, malignant CBTs (MCBTs) are still associated with a poor prognosis and the treatment is still challenging clinically. Therefore, we evaluated the necessity of intraoperative level IIA lymph node dissection in patients with CBT.

Methods: The clinical characteristics, intraoperative details, and pathological diagnosis of 126 CBT patients who had undergone surgery were retrospectively reviewed. The patients were divided into 2 groups according to whether level IIA lymph node dissection was performed. The prognosis was analyzed using Kaplan-Meier curves and Cox model multivariate survival analysis.

Results: Among the 126 patients, 7 patients (10.3%) in the selective lymph node dissection (SLND) group (68 patients) were diagnosed with MCBTs with evidence of lymph node metastasis. Two patients (3.4%) in the lymph node nondissection (LNND) group (58 patients) were diagnosed with MCBTs later after the second operation because they could not be diagnosed as malignant initially because of the lack of lymph node pathology results although the pathology of the primary lesion showed features of malignancy. The SLND group had a significantly higher relapse-free survival rate than the LNND group (94.1% vs. 79.3%, p = 0.021). Patients with a confirmed diagnosis had a better prognosis than those with insufficient evidence of a malignancy due to the lack of lymph node information. Twenty-nine patients in the SLND group and 26 patients in the LNND group had postoperative nerve injuries, with no significant difference between the groups (p = 0.879).

Conclusion: Intraoperative dissection of level IIA lymph nodes around the tumor in CBT patients can help improve the diagnosis and prognosis of MCBTs without causing additional cranial nerve injury.
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http://dx.doi.org/10.1159/000519046DOI Listing
October 2021

A practical continuous curvilinear capsulorhexis self-training system.

Indian J Ophthalmol 2021 Oct;69(10):2678-2686

Shanxi Eye Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, P.R. China.

Purpose: To describe a practical, self-assembled continuous curvilinear capsulorhexis (CCC) self-training system to facilitate resident self-training and shorten the CCC learning curve.

Methods: This was a prospective experimental study that included a total of 600 capsulorhexis cases. A device for CCC practice was self-assembled and used for training and testing. Based on capsulorhexis manipulation experience, three main groups of residents (A, capsulorhexis experience with <50 cases; B, capsulorhexis experience with 400-500 cases; and C, capsulorhexis experience with >1000 cases) were created. Furthermore, based on different capsulorhexis conditions, each main group was divided into four subgroups (1, CCC without an anterior chamber cover and capsulorhexis marker; 2, CCC with an anterior chamber cover without a capsulorhexis marker; 3, CCC with an anterior chamber cover and a capsulorhexis marker; and 4, CCC with an anterior chamber cover and a capsulorhexis marker under 2.5 times magnification). Three CCC-related parameters, including acircularity index (AI), axis ratio (AR), and capsulorhexis time, were statistically evaluated.

Results: We compared the differences in study parameters among 50 consecutively completed capsulorhexis cases by one trainee with different capsulorhexis experience in each subgroup. The CCC-related parameter values in subgroups 1 and 4 were significantly different among the three groups (P < 0.001). The capsulorhexis time in subgroup 2 was significantly different among the three groups (P < 0.001). The capsulorhexis time and AI in subgroup 3 were significantly different among the three groups (P < 0.001). Moreover, with increasing manipulation experience (from group A-C), the capsulorhexis time, the AI, and AR tended to decrease. With the help of the CCC marker, in subgroups 3 and 4, the AI and AR were closer to 1.0.

Conclusion: This self-assembled CCC self-training system is practical. The CCC marker seems helpful for size specification and centration during self-training.
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http://dx.doi.org/10.4103/ijo.IJO_210_21DOI Listing
October 2021

Insights into angiosperm evolution, floral development and chemical biosynthesis from the Aristolochia fimbriata genome.

Nat Plants 2021 09 2;7(9):1239-1253. Epub 2021 Sep 2.

State Key Laboratory of Systematic and Evolutionary Botany, Institute of Botany, the Chinese Academy of Sciences, Beijing, China.

Aristolochia, a genus in the magnoliid order Piperales, has been famous for centuries for its highly specialized flowers and wide medicinal applications. Here, we present a new, high-quality genome sequence of Aristolochia fimbriata, a species that, similar to Amborella trichopoda, lacks further whole-genome duplications since the origin of extant angiosperms. As such, the A. fimbriata genome is an excellent reference for inferences of angiosperm genome evolution, enabling detection of two novel whole-genome duplications in Piperales and dating of previously reported whole-genome duplications in other magnoliids. Genomic comparisons between A. fimbriata and other angiosperms facilitated the identification of ancient genomic rearrangements suggesting the placement of magnoliids as sister to monocots, whereas phylogenetic inferences based on sequence data we compiled yielded ambiguous relationships. By identifying associated homologues and investigating their evolutionary histories and expression patterns, we revealed highly conserved floral developmental genes and their distinct downstream regulatory network that may contribute to the complex flower morphology in A. fimbriata. Finally, we elucidated the genetic basis underlying the biosynthesis of terpenoids and aristolochic acids in A. fimbriata.
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http://dx.doi.org/10.1038/s41477-021-00990-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445822PMC
September 2021

Correlation analysis of RDM1 gene with immune infiltration and clinical prognosis of hepatocellular carcinoma.

Biosci Rep 2021 Sep;41(9)

Center of Gallbladder Disease, Shanghai East Hospital, Institute of Gallstone Disease, School of Medicine, Tongji University, Shanghai 200092, China.

Purpose: Liver hepatocellular carcinoma (LIHC) is one of the most common primary malignant liver tumors worldwide. The RAD52 motif-containing protein 1 (RDM1) has been shown to play a role in mediating DNA damage repair and homologous recombination. The present study was designed to determine the expression of RDM1 and its prognostic value as well as its relationship with immune infiltration in LIHC patients.

Methods: Oncomine and Tumor Immunoassay Resource were used to assess the expression of RDM1. PrognoScan and Kaplan-Meier bioinformatics database were used to analyze the impact of clinical influencing factors on prognosis. Finally, the Tumor Immune Assessment Resource (TIMER) and Gene Expression Analysis Interactive Analysis (GEPIA) databases were used to detect the correlation between the expression of RDM1 and expression of marker genes related to immune infiltration. Immunohistochemistry (IHC) method was used to detect the expression level of RDM1 in 90 cases of hepatocellular carcinoma and adjacent normal liver tissues.

Results: RDM1 expression was up-regulated in most cancers. The expression of RDM1 was remarkably higher than that of the corresponding normal control genes in LIHC tissues. The increase in RDM1 messenger RNA (mRNA) expression was closely related to the decreases in overall survival (OS) and progression-free survival (PFS). Additionally, the increase in RDM1 mRNA expression was closely related to the infiltration levels of macrophages, CD8+ T cells and B cells and was positively correlated with a variety of immune markers in LIHC.

Conclusion: The findings of the present study demonstrate that RDM1 is a potentially valuable prognostic biomarker that can help determine the progression of cancer and is associated with immune cell infiltration in LIHC.
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http://dx.doi.org/10.1042/BSR20203978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450314PMC
September 2021

Protective effects of pretreatment with Fe, Cu, and Rb on phoxim poisoning in silkworm, Bombyx mori.

J Trace Elem Med Biol 2021 Aug 14;68:126844. Epub 2021 Aug 14.

College of Biotechnology and Sericultural Research Institute, Jiangsu University of Science and Technology, Zhenjiang, 212018, PR China. Electronic address:

Background: Phoxim is a widely used organophosphorus pesticide in agriculture. People are paying more and more attention to its toxicity. At present, there is no appropriate way to solve the phoxim poisoning of silkworm, which severely affected the development of sericulture. Fe, Cu, Rb exerted their biological effects through various forms in vivo.

Methods: To evaluate the effect of Fe/Cu/Rb on phoxim poisoning in silkworm, Bombyx mori were treated with fresh mulberry leaves soaked in 2.5 mg/L phoxim for 2 min with 50 mg/L FeCl, 150 mg/L CuCl, or 0.5 mg/L RbCl from 5 days of the fifth-instar silkworm.

Results: Fe, Cu, and Rb pretreatments significantly inhibited the phoxim-induced reduction of survival rate and alleviated the phoxim-induced poisoning symptoms. The protective effects of Fe, Cu, and Rb on phoxim poisoning might be due to their enhancement of superoxide dismutase (SOD), catalase (CAT), and carboxylesterase (CarE) in the hemolymph and fat body of silkworm. This enhancement might reduce reactive oxygen species (ROS) accumulation and oxidative stress (OS) caused by phoxim poisoning. Thereby it reduced the damage to silkworm tissues and cells.

Conclusions: These results showed that Fe, Cu, and Rb treatments protected the silkworm from phoxim poisoning by directly enhancing the activity of SOD, CAT, and CarE enzymes and reducing oxidative stress, but not dependent on the high expression of CYP genes. The use of Fe, Cu, and Rb to enhance the activity of SOD, CAT, and CarE enzymes may be an underlying effective way to solve phoxim poisoning in the silkworm industry.
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http://dx.doi.org/10.1016/j.jtemb.2021.126844DOI Listing
August 2021

The role of circulating blood microRNA-374 and microRNA-10 levels in the pathogenesis and therapeutic mechanisms of major depressive disorder.

Neurosci Lett 2021 10 18;763:136184. Epub 2021 Aug 18.

Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China. Electronic address:

Compelling recent evidence suggests that microRNAs (miRNAs) regulate specific mRNA transcripts at the transcriptomic level and coordinately influence complex regulatory networks, which may play a crucial role in the pathogenesis of major depressive disorder (MDD) and the treatment effects of antidepressants. To evaluate the possible involvement of miRNAs in the pathophysiology and therapeutic response of MDD, we conducted a miRNA expression array analysis of the peripheral blood mononuclear cells (PBMCs) of 5 depressed patients and 5 healthy controls (HCs). Subsequently, we chose 2 miRNAs for validation with real-time PCR (RT-PCR) analysis pre- and post-treatment in another group of 25 MDD patients and 25 HCs. In the array, 5 miRNAs were differentially expressed in medication-naïve MDD patients compared to HCs, of which 2 miRNAs were upregulated and 3 were downregulated. Furthermore, in comparison with HCs, MDD patients showed significantly lower expression levels of miR-374b and miR-10a before treatment. After 8 weeks of antidepressant treatment, both miR-374b and the miR-10a expression levels in MDD patients were significantly elevated only in responders. In conclusion, these results indicate the involvement of miR-374b and miR-10a in the biological mechanisms and therapeutic response of MDD, and provide new insights for exploring miRNAs as potential biomarkers for MDD.
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http://dx.doi.org/10.1016/j.neulet.2021.136184DOI Listing
October 2021

Spatial and temporal variability of brown carbon in United States: implications for direct radiative effects.

Geophys Res Lett 2020 Dec;47(23)

Department of Chemistry and Biochemistry and Geophysical Institute, University of Alaska Fairbanks, Fairbanks, AK, USA.

A newly developed dataset from the Interagency Monitoring of PROtected Visual Environments (IMPROVE) observation network, combined with a 3-D chemical transport model, is used to evaluate the spatial and temporal variability of brown carbon (BrC) in the United States. The model with BrC emitted from biomass burning and biofuel emissions agrees with the seasonal and spatial variability of BrC planetary boundary layer (PBL) absorption aerosol optical depth (AAOD) observations within a factor of 2. The model without whitening, the tendency for absorption to decrease with aerosol aging, overestimates the observed BrC PBL AAOD, and does not reflect the measured BrC PBL AAOD spatial variability. The model shows higher absorption direct radiative effects (DRE) from BrC at northern high latitudes than at mid-latitudes in spring and summer, due to boreal fire emissions, long whitening lifetimes and high surface albedos. These findings highlight the need to study BrC over the Arctic region.
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http://dx.doi.org/10.1029/2020gl090332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353956PMC
December 2020

Association Between Smoking and Molecular Subtypes of Colorectal Cancer.

JNCI Cancer Spectr 2021 Aug 14;5(4):pkab056. Epub 2021 Jun 14.

Departments of Cancer Biology and Genetics and Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.

Background: Smoking is associated with colorectal cancer (CRC) risk. Previous studies suggested this association may be restricted to certain molecular subtypes of CRC, but large-scale comprehensive analysis is lacking.

Methods: A total of 9789 CRC cases and 11 231 controls of European ancestry from 11 observational studies were included. We harmonized smoking variables across studies and derived sex study-specific quartiles of pack-years of smoking for analysis. Four somatic colorectal tumor markers were assessed individually and in combination, including mutation, mutation, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI) status. A multinomial logistic regression analysis was used to assess the association between smoking and risk of CRC subtypes by molecular characteristics, adjusting for age, sex, and study. All statistical tests were 2-sided and adjusted for Bonferroni correction.

Results: Heavier smoking was associated with higher risk of CRC overall and stratified by individual markers ( < .001). The associations differed statistically significantly between all molecular subtypes, which was the most statistically significant for CIMP and . Compared with never-smokers, smokers in the fourth quartile of pack-years had a 90% higher risk of CIMP-positive CRC (odds ratio = 1.90, 95% confidence interval = 1.60 to 2.26) but only 35% higher risk for CIMP-negative CRC (odds ratio = 1.35, 95% confidence interval = 1.22 to 1.49; = 2.1 x 10). The association was also stronger in tumors that were positive, MSI high, or wild type when combined ( < .001).

Conclusion: Smoking was associated with differential risk of CRC subtypes defined by molecular characteristics. Heavier smokers had particularly higher risk of CRC subtypes that were CIMP positive and MSI high in combination, suggesting that smoking may be involved in the development of colorectal tumors via the serrated pathway.
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http://dx.doi.org/10.1093/jncics/pkab056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346704PMC
August 2021

Cardioprotective Effect of Nec-1 in Rats Subjected to MI/R: Downregulation of Autophagy-Like Cell Death.

Cardiovasc Ther 2021 12;2021:9956814. Epub 2021 Jul 12.

Department of Physiology, Shanxi Medical University, Taiyuan 030001, China.

Objective: Necrostatin-1 (Nec-1), an inhibitor of necroptosis, has been reported to protect against myocardial ischemia-reperfusion (MI/R) injury. However, the contribution of the potential antinecroptotic effect of Nec-1 on its infarct limitation and cardiac function improvement effects after MI/R has not been investigated.

Methods: The present study investigated the effect of Nec-1 on myocardial infarct size, necroptosis, and cardiac functional recovery in rats subjected to myocardial ischemia-reperfusion (MI/R 30 min/12, 24, 48, and 72 h).

Results: The study showed that Nec-1 might reduce myocardial cell death and maintain myoarchitectonic integrity, consequently inhibiting the reactive fibrosis process in rats in myocardial ischemia/late reperfusion. Moreover, the administration of Nec-1 (0.6 mg/kg) at the onset of reperfusion significantly reduced the release of creatine kinase and downregulation of autophagy within 24 h after reperfusion, and there was a significantly positive correlation between them.

Conclusion: These results suggest that antinecroptosis treatment may improve the clinical outcomes of patients with ischemic heart disease.
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http://dx.doi.org/10.1155/2021/9956814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292081PMC
October 2021

New amide alkaloids and carbazole alkaloid from the stems of Clausena lansium.

Fitoterapia 2021 Oct 22;154:104999. Epub 2021 Jul 22.

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China. Electronic address:

Five unreported alkaloids including four amide alkaloids (1a, 2a, 3a, and 3b) and one carbazole alkaloid (4) with two known compounds (1b, 2b) were obtained from the stems of Clausena lansium. Their structures were demonstrated by spectroscopic experiments. And the absolute configurations of compounds 1a, 1b, 2b, and 3b were determined by single X-ray diffraction analysis. The neuroprotection assay showed that compound 4 had moderate inhibition effect on PC12 cells induced by serum withdrawal at the concentration of 10 μM. And compounds 1a and 4 had weak protective effects on primary neurons against oxygen glucose deprivation injury at the concentration of 10 μM.
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http://dx.doi.org/10.1016/j.fitote.2021.104999DOI Listing
October 2021

Evaluation of Precise Microwave Ranging Technology for Low Earth Orbit Formation Missions with Beidou Time-Synchronize Receiver.

Sensors (Basel) 2021 Jul 17;21(14). Epub 2021 Jul 17.

Institute for Aerospace Studies, University of Toronto, Toronto, ON M1C 1A4, Canada.

In this study, submillimeter level accuracy K-band microwave ranging (MWR) equipment is demonstrated, aiming to verify the detection of the Earth's gravity field (EGF) and digital elevation models (DEM), through spacecraft formation flying (SFF) in low Earth orbit (LEO). In particular, this paper introduces in detail an integrated BeiDou III B1C/B2a dual frequency receiver we designed and developed, including signal processing scheme, gain allocation, and frequency planning. The receiver matched the 0.1 ns precise synchronize time-frequency benchmark for the MWR system, verified by a static and dynamic test, compared with a time interval counter synchronization solution. Moreover, MWR equipment ranging accuracy is explored in-depth by using different ranging techniques. The test results show that MWR achieved 40 μm and 1.6 μm/s accuracy for ranging and range rate during tests, using synchronous dual one-way ranging (DOWR) microwave phase accumulation frame, and 6 μm/s range rate accuracy obtained through a one-way ranging experiment. The ranging error sources of the whole MWR system in-orbit are analyzed, while the relative orbit dynamic models, for formation scenes, and adaptive Kalman filter algorithms, for SFF relative navigation designs, are introduced. The performance of SFF relative navigation using MWR are tested in a hardware in loop (HIL) simulation system within a high precision six degree of freedom (6-DOF) moving platform. The final estimation error from adaptive relative navigation system using MWR are about 0.42 mm (range/RMS) and 0.87 μm/s (range rate/RMS), which demonstrated the promising accuracy for future applications of EGF and DEM formation missions in space.
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http://dx.doi.org/10.3390/s21144883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8309731PMC
July 2021

MG53 suppresses NF-κB activation to mitigate age-related heart failure.

JCI Insight 2021 Sep 8;6(17). Epub 2021 Sep 8.

Department of Surgery, Division of Cardiac Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.

Aging is associated with chronic oxidative stress and inflammation that affect tissue repair and regeneration capacity. MG53 is a TRIM family protein that facilitates repair of cell membrane injury in a redox-dependent manner. Here, we demonstrate that the expression of MG53 was reduced in failing human hearts and aged mouse hearts, concomitant with elevated NF-κB activation. We evaluated the safety and efficacy of longitudinal, systemic administration of recombinant human MG53 (rhMG53) protein in aged mice. Echocardiography and pressure-volume loop measurements revealed beneficial effects of rhMG53 treatment in improving heart function of aged mice. Biochemical and histological studies demonstrated that the cardioprotective effects of rhMG53 are linked to suppression of NF-κB-mediated inflammation, reducing apoptotic cell death and oxidative stress in the aged heart. Repetitive administration of rhMG53 in aged mice did not have adverse effects on major vital organ functions. These findings support the therapeutic value of rhMG53 in treating age-related decline in cardiac function.
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http://dx.doi.org/10.1172/jci.insight.148375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492351PMC
September 2021

lncRNA LINC01296 Promotes Oral Squamous Cell Carcinoma Development by Binding with SRSF1.

Biomed Res Int 2021 11;2021:6661520. Epub 2021 Jun 11.

Department of Oral Disease Gaoxin Branch, Jinan Stomatological Hospital, Jinan, China.

Objective: Oral squamous cell carcinoma (OSCC) is the most common malignant tumor of the head and neck, with strong local invasiveness and cervical lymph node metastasis. The purpose of this study was to investigate the role of LINC01296 in oral squamous cell carcinoma and its possible mechanism.

Materials And Methods: GEPAI database analysis and clinical samples were used to detect the expression of LINC01296 in head and neck cancer. In vivo experiment, MTT, clone formation assay, and transwell were used to detect the proliferation, migration, and invasion of oral squamous cell carcinoma. The effect of LINC01296 on EMT was detected by western blot and qRT-PCR to measure the expression of epithelial and mesenchymal phenotypic markers. BALB/c nude mice were used to carry out in vitro treatment experiment. In terms of mechanism, the binding relationship between LINC01296 and SRSF1 was predicted and verified by the RBPDB database and RNA pull-down assay.

Results: LINC01296 was highly expressed in clinical samples and cell lines of oral squamous cell carcinoma. Overexpression of LINC01296 promoted the proliferation, invasion, and migration of oral squamous cell carcinoma cells and accelerated the formation of xenografts, while silencing LINC01296 inhibited tumor progression. In mechanism, LINC01296 plays a tumor-promoting role by binding to SRSF1 protein.

Conclusion: LINC01296 promotes malignant lesions in oral squamous cell carcinoma by binding to SRSF1 protein, which provides important experimental data and theoretical basis for the prevention, diagnosis, and treatment of oral squamous cell carcinoma.
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http://dx.doi.org/10.1155/2021/6661520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8214489PMC
June 2021

Preclinical evaluation of recombinant HFMD vaccine based on enterovirus 71 (EV71) virus-like particles (VLP): Immunogenicity, efficacy and toxicology.

Vaccine 2021 07 21;39(31):4296-4305. Epub 2021 Jun 21.

Shanghai Zerun Biotech Co., Ltd., Shanghai, China. Electronic address:

Enterovirus 71 (EV71) is one of the major causative agents for hand, foot and mouth disease (HFMD) in children. Currently, three inactivated EV71 vaccines have been approved by Chinese government. We previously demonstrated that recombinant EV71 virus-like particles (VLP) produced in Pichia pastoris can be produced at a high yield with a simple manufacturing process, and the candidate vaccine elicited protective humoral immune responses in mice. In present study, the nonclinical immunogenicity, efficacy and toxicity of the EV71 vaccine was comprehensively evaluated in rodents and non-human primates. The immunogenicity assessment showed that EV71 VLPs vaccine elicited high and persistent neutralizing antibody responses, which could be comparable with a licensed inactivated vaccine in animals. The immune sera of vaccinated mice also exhibited cross-neutralization activities to the heterologous subtypes of EV71. Both passive and maternal antigen specific antibodies protected the neonatal mice against the lethal EV71 challenge. Furthermore, nonclinical safety assessment of EV71 VLP vaccine showed no signs of systemic toxicity in animals. Therefore, the excellent immunogenicity, efficacy and toxicology data supported further evaluation of the VLP-based EV71 vaccine in humans.
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http://dx.doi.org/10.1016/j.vaccine.2021.06.031DOI Listing
July 2021

MCM8 is regulated by EGFR signaling and promotes the growth of glioma stem cells through its interaction with DNA-replication-initiating factors.

Oncogene 2021 Jul 15;40(27):4615-4624. Epub 2021 Jun 15.

Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, China.

Mini-chromosome maintenance (MCM) proteins are critical components of DNA-replication-licensing factors. MCM8 is an MCM protein that exhibits oncogenic functions in several human malignancies. However, the role of MCM8 in glioblastomas (GBMs) has remained unclear. In the present study, we investigated the biological functions and mechanisms of MCM8 in glioma stem cells (GSCs). The clinical relevance of MCM8 mRNA expression was explored via TCGA and REMBRANDT datasets. The effects of MCM8 on the self-renewal and tumorigenicity of GSCs were examined both in vitro and in vivo. The regulation of MCM8 expression and its interacting proteins were also evaluated. We found that the expression of MCM8 was elevated in high-grade gliomas and classical molecular subtypes and was inversely correlated with patient prognosis. GSCs had a significantly higher expression of MCM8 compared with that in normal glioma cells. Silencing of MCM8 induced G0/G1 arrest and apoptosis, as well as inhibited the proliferation and self-renewal of GSCs. Forced expression of MCM8 enhanced clonogenicity of GSCs both in vitro and in vivo. MCM8 expression was regulated by EGFR signaling, which was mediated by NF-κB (p65). MCM8 interacted with DNA-replication-initiating factors-including EZH2, CDC6, and CDCA2-and influenced these factors to associate with chromatin. In addition, MCM8 knockdown increased the sensitivity of GSCs to radiation and TMZ treatments. Our findings suggest that MCM8, regulated by the EGFR pathway, maintains the clonogenic and tumorigenic potential of GSCs through interaction with DNA-replication-initiating factors; hence, MCM8 may represent a novel therapeutic target in GBMs.
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http://dx.doi.org/10.1038/s41388-021-01888-1DOI Listing
July 2021

Brownness of Organic Aerosol over the United States: Evidence for Seasonal Biomass Burning and Photobleaching Effects.

Environ Sci Technol 2021 07 15;55(13):8561-8572. Epub 2021 Jun 15.

Division of Atmospheric Sciences, Desert Research Institute, Reno, Nevada 89512, United States.

Light-absorptivity of organic aerosol may play an important role in visibility and climate forcing, but it has not been assessed as extensively as black carbon (BC) aerosol. Based on multiwavelength thermal/optical analysis and spectral mass balance, this study quantifies BC for the U.S. Interagency Monitoring of Protected Visual Environments (IMPROVE) network while developing a brownness index (γ) for non-BC organic carbon (OC*) to illustrate the spatiotemporal trends of light-absorbing brown carbon (BrC) content. OC* light absorption efficiencies range from 0 to 3.1 m gC at 405 nm, corresponding to the lowest and highest BrC content of 0 and 100%, respectively. BC, OC*, and γ explain >97% of the variability of measured spectral light absorption (405-980 nm) across 158 IMPROVE sites. Network-average OC* light absorptions at 405 nm are 50 and 28% those for BC over rural and urban areas, respectively. Larger organic fractions of light absorption occur in winter, partially due to higher organic brownness. Winter γ exhibits a dramatic regional/urban-rural contrast consistent with anthropogenic BrC emissions from residential wood combustion. The spatial differences diminish to uniformly low γ in summer, suggesting effective BrC photobleaching over the midlatitudes. An empirical relationship between BC, ambient temperature, and γ is established, which can facilitate the incorporation of organic aerosol absorptivity into climate and visibility models that currently assume either zero or static organic light absorption efficiencies.
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http://dx.doi.org/10.1021/acs.est.0c08706DOI Listing
July 2021

A general principle for spontaneous genetic symmetry breaking and pattern formation within cell populations.

J Theor Biol 2021 10 10;526:110809. Epub 2021 Jun 10.

Department of Mathematical Sciences, University of Essex, Colchester CO4 3SQ, UK. Electronic address:

Elements within biological systems interact and frequently self-organize from initially disordered states into highly structured patterns. The local self-activation and lateral inhibition mechanism, derived from the coupling between two reacting and diffusing chemicals, has been believed to be one of the main causes for biological pattern formation. Graded positional information can be produced by the limited diffusion of one single signaling molecule through cell populations with no pre-patterns being required. We demonstrate, using multiscale computations, that spontaneous symmetry breaking can be driven within expanding and non-expanding cell populations, without local self-enhancement of activators and long-range inhibition. Instead, cells can self-organize into structured gene patterns via a combination of timing gene expression in cells and the graded positional information which has been coupled to the gene expression. We show that the genetic symmetry breaking in expanding E. coli populations occurs at a critical colony size, which is independent of the cell doubling time but scales with the diffusion speed of the signaling molecule. We also show the quasi-3D structure of gene patterns, and observe that the wave length of periodic genetic stripes is in proportion to the genetic oscillation cycle time and in inverse proportion to cell doubling time. Our results provide insights into relevant biological development processes.
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http://dx.doi.org/10.1016/j.jtbi.2021.110809DOI Listing
October 2021

Membranization of Coacervates into Artificial Phagocytes with Predation toward Bacteria.

ACS Nano 2021 06 28;15(6):10048-10057. Epub 2021 May 28.

MIIT Key Laboratory of Critical Materials Technology for New Energy Conversion and Storage, School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin 150001, P. R. China.

Coacervate-based membraneless organelles with diverse functionality as well as the capability of mimicking intracellular physiological environments are attracting researchers' great interest. However, the further studies focusing on functionalized membranization of coacervate as a step toward an advanced membrane-bound protocell are still rare. In this study, we develop a way to compartmentalize coacervate based on reconstitution with a natural cellular wall, which could then serve as a promising chassis for the development of protocells with selective sequestration of various biomacromolecules. Significantly, the compartmentalized protocell could behave like a phagocyte and selectively capture, engulf, and then kill efficiently. Taken together, our studies present a strategy for advancing coacervate-based protocell design as well as the development of smart materials with on-demand functionalization.
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http://dx.doi.org/10.1021/acsnano.1c01694DOI Listing
June 2021

Discovery of Hyperstable Noncanonical Plant-Derived Epidermal Growth Factor Receptor Agonist and Analogs.

J Med Chem 2021 06 20;64(11):7746-7759. Epub 2021 May 20.

School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.

Here, we report the discovery of the first plant-derived and noncanonical epidermal growth factor receptor (EGFR) agonist, the 36-residue bleogen pB1 from of the Cactaceae family. We show that bleogen pB1 is a low-affinity EGFR agonist using a suite of chemical, biochemical, cellular, and animal experiments which include incisor eruption and wound-healing mouse models. A focused positional scanning pB1 library of Ala- and d-amino acid scans yielded a high-affinity pB1 analog, [K29k]pB1, with a 60-fold-improved EGFR affinity and mitogenicity. We show that the potency of [K29k]pB1 and the epidermal growth factor (EGF) is comparable in a diabetic mouse wound-healing model. We also show that both bleogen pB1 and [K29k]pB1 are hyperstable, being >100-fold more stable than EGF against proteolytic degradation. Overall, our discovery of a noncanonical proteolytic-resistant EGFR agonist scaffold could open new avenues for developing wound healing and skin regeneration therapeutics and biomaterials.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00551DOI Listing
June 2021

A Preliminary Investigation on Plasma Cell Adhesion Molecules Levels by Protein Microarray Technology in Major Depressive Disorder.

Front Psychiatry 2021 12;12:627469. Epub 2021 Apr 12.

Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Major depressive disorder (MDD) is a serious mental disorder, and there is a great difficulty to diagnose and treat. Hitherto, relatively few studies have explored the correlation between the levels of plasma cell adhesion molecules and MDD. Thirty outpatients with acute episodes of MDD in Shanghai Mental Health Center and 34 healthy volunteers from the community were recruited as subjects. Protein microarray technology was applied to compared the differences in plasma levels of 17 kinds of adhesion molecular proteins between the two groups. Meanwhile, the diagnostic value of different proteins in depression was discussed by using the receiver operating characteristic curve. The levels of Carcinoembryonic Antigen Related Cell Adhesion Molecule-1(CEACAM-1) and Neural Cell Adhesion Molecule (NrCAM) in MDD patients were significantly higher than those in healthy controls ( < 0.05). The area under ROC curve of CEACAM-1 combined with NrCAM was 0.723, with the sensitivity 0.800 and the specificity 0.676. The plasma levels of CEACAM-1 and NrCAM were significantly up-regulated in MDD, and their combined application was of potential diagnostic value, deserving to expand the sample size for further verification.
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http://dx.doi.org/10.3389/fpsyt.2021.627469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071998PMC
April 2021

Construction of Hybrid Bi-microcompartments with Exocytosis-Inspired Behavior toward Fast Temperature-Modulated Transportation of Living Organisms.

Angew Chem Int Ed Engl 2021 09 19;60(38):20795-20802. Epub 2021 Jul 19.

MIIT Key Laboratory of Critical Materials Technology for New Energy Conversion and Storage, School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin, 150001, China.

Inspired by the unique characteristics of living cells, the creation of life-inspired functional ensembles is a rapidly expanding research topic, enabling transformative applications in various disciplines. Herein, we report a facile method for the fabrication of phospholipid and block copolymer hybrid bi-microcompartments via spontaneous asymmetric assembly at the water/tributyrin interface, whereby the temperature-mediated dewetting of the inner microcompartments allowed for exocytosis to occur in the constructed system. The exocytosis location and commencement time could be controlled by the buoyancy of the inner microcompartment and temperature, respectively. Furthermore, the constructed bi-microcompartments showed excellent biocompatibility and a universal loading capacity toward cargoes of widely ranging sizes; thus, the proliferation and temperature-programmed transportation of living organisms was achieved. Our results highlight opportunities for the development of complex mesoscale dynamic ensembles with life-inspired behaviors and provide a novel platform for on-demand transport of various living organisms.
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http://dx.doi.org/10.1002/anie.202102846DOI Listing
September 2021

Chain dynamics and crystalline network structure of poly[-3-hydroxybutyrate--4-hydroxybutyrate] as revealed by solid-state NMR.

Soft Matter 2021 Apr;17(15):4195-4203

National Synchrotron Radiation Lab and Anhui Provincial Engineering Laboratory of Advanced Functional Polymer Film, CAS Key Laboratory of Soft Matter Chemistry, University of Science and Technology of China, Hefei 230026, China.

The chain dynamics and crystalline network structure of poly[R-3-hydroxybutyrate-co-4-hydroxybutyrate] (P(3HB-co-4HB)) were systematically investigated by the combination of various solid-state NMR techniques. High-resolution 13C cross-polarization (CP) and direct-polarization (DP) MAS with selective recycle delay times were first used to check the presence or absence of the 4HB unit in the crystalline domain. The results show that the 4HB unit is excluded from the crystalline domain. Afterward, 1H MAS Nuclear Overhauser Effect Spectroscopy (NOESY) with different mixing times was used, which shows that no micro-phase separation exists in the amorphous domain. 1H magic-sandwich-echo (MSE)-FID at elevated temperature shows the absence of motions on a timescale of 100 μs and below in the crystalline domain, as evidenced by the invariant second moment M2 of the proton line shape. Finally, the crystalline based network density was characterized directly by magic and polarization echo (MAPE)-double quantum (DQ) NMR, which shows a significant decreasing tendency after 80 °C. Such a decreasing crystalline network density, together with the reduced relaxation time, results in the significant decrement of the maximum stretch ratio and modulus in the high-temperature region.
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http://dx.doi.org/10.1039/d0sm02216kDOI Listing
April 2021

PM pollution in China's Guanzhong Basin and the USA's San Joaquin Valley mega-regions.

Faraday Discuss 2021 03 24;226:255-289. Epub 2020 Dec 24.

Division of Atmospheric Sciences, Desert Research Institute, Reno, Nevada, USA.

The Guanzhong Basin (GZB) of northwest China is examined as a mega-region containing the mega-city of Xi'an. The concept of a "mega-region" is more accurate than that of a "mega-city" for air quality management as there is an interaction between urban and non-urban emissions. Parallels are drawn between the GZB and the San Joaquin Valley (SJV) mega-region of central California for excessive wintertime PM concentrations. Long-term chemical composition measurements show the usual high levels of organic and elemental carbon, minerals, sulfate, nitrate, and ammonium. Wintertime provides prolonged high pressure systems in both areas punctuated by unstable precipitation events. Sluggish nighttime winds allow pollutants such as ammonia from distant agricultural operations, to mix with urban pollutants, sometimes serving as a reactor to create secondary sulfates and nitrates, and possibly some secondary organic compounds. A shallow surface layer forms at night in the SJV and GZB that couples to an upper level inversion after sunrise, allowing pollutants accumulated aloft to mix to the surface. Although current air quality management strategies have focused on urban emissions, and PM levels are on a downward trend, future management efforts must consider reducing emissions from a variety of sources in the larger region of these basins. Agricultural emissions are important in the SJV, but are just being addressed in the GZB. Tactics developed for the SJV would probably be effective in other areas of the world with similar emissions, topography, and meteorology. Experiments related to agricultural NO emissions, emission inventory enhancements, source apportionment, and estimates of precursor limitations for ammonium nitrate formation, have been conducted in the SJV that can be tested in the GZB.
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http://dx.doi.org/10.1039/d0fd00094aDOI Listing
March 2021

Cardiac Oxidative Signaling and Physiological Hypertrophy in the Na/K-ATPase α1α2 Mouse Model of High Affinity for Cardiotonic Steroids.

Int J Mol Sci 2021 Mar 27;22(7). Epub 2021 Mar 27.

Marshall Institute for Interdisciplinary Research, Huntington, WV 25703, USA.

The Na/K-ATPase is the specific receptor for cardiotonic steroids (CTS) such as ouabain and digoxin. At pharmacological concentrations used in the treatment of cardiac conditions, CTS inhibit the ion-pumping function of Na/K-ATPase. At much lower concentrations, in the range of those reported for endogenous CTS in the blood, they stimulate hypertrophic growth of cultured cardiac myocytes through initiation of a Na/K-ATPase-mediated and reactive oxygen species (ROS)-dependent signaling. To examine a possible effect of endogenous concentrations of CTS on cardiac structure and function in vivo, we compared mice expressing the naturally resistant Na/K-ATPase α1 and age-matched mice genetically engineered to express a mutated Na/K-ATPase α1 with high affinity for CTS. In this model, total cardiac Na/K-ATPase activity, α1, α2, and β1 protein content remained unchanged, and the cardiac Na/K-ATPase dose-response curve to ouabain shifted to the left as expected. In males aged 3-6 months, increased α1 sensitivity to CTS resulted in a significant increase in cardiac carbonylated protein content, suggesting that ROS production was elevated. A moderate but significant increase of about 15% of the heart-weight-to-tibia-length ratio accompanied by an increase in the myocyte cross-sectional area was detected. Echocardiographic analyses did not reveal any change in cardiac function, and there was no fibrosis or re-expression of the fetal gene program. RNA sequencing analysis indicated that pathways related to energy metabolism were upregulated, while those related to extracellular matrix organization were downregulated. Consistent with a functional role of the latter, an angiotensin-II challenge that triggered fibrosis in the α1α2 mouse failed to do so in the α1α2. Taken together, these results are indicative of a link between circulating CTS, Na/K-ATPase α1, ROS, and physiological cardiac hypertrophy in mice under baseline laboratory conditions.
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http://dx.doi.org/10.3390/ijms22073462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036649PMC
March 2021

The efficacy of escitalopram in major depressive disorder: a multicenter randomized, placebo-controlled double-blind study.

Int Clin Psychopharmacol 2021 05;36(3):133-139

Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine.

The aim of the study was to conduct a multicenter randomized double-blinded placebo-controlled clinical study to evaluate the efficacy of a generic form of escitalopram in treating major depressive disorder (MDD). A total of 390 MDD patients admitted to hospitals in six cities in China were randomized to receive the generic version of escitalopram, the proprietary form of escitalopram (Lexapro) or placebo. During the 8-week treatment, the Hamilton rating scale for depression-17 (HAM-D17), Hamilton Anxiety Rating Scale (HAMA), Montgomery-Åsberg Depression Rating Scale (MADRS), Clinical Global Impressions scale (CGI), current visual analogue scale pain levels (VAS-P1) and Sheehan Disability Scale (SDS) assessments were performed at week 0, 1, 2, 4, 6 and 8 to evaluate treatment responses. HAM-D17, MADRS, HAMA and CGI-S levels of patients who received escitalopram or Lexapro decreased steadily during 8 weeks' treatment, whereas the placebo group showed a relatively smaller reduction of these levels (P < 0.001). SDS and VAS-P1 both decreased after treatment with generic escitalopram or proprietary escitalopram Lexapro. Our results indicated that both the generic escitalopram and proprietary escitalopram Lexapro had potent efficacy in treating MDD.
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http://dx.doi.org/10.1097/YIC.0000000000000350DOI Listing
May 2021

The Na/K-ATPase α1/Src interaction regulates metabolic reserve and Western diet intolerance.

Acta Physiol (Oxf) 2021 07 4;232(3):e13652. Epub 2021 Apr 4.

Marshall Institute for Interdisciplinary Research, Marshall University, Huntington, WV, USA.

Aim: Highly prevalent diseases such as insulin resistance and heart failure are characterized by reduced metabolic flexibility and reserve. We tested whether Na/K-ATPase (NKA)-mediated regulation of Src kinase, which requires two NKA sequences specific to the α1 isoform, is a regulator of metabolic capacity that can be targeted pharmacologically.

Methods: Metabolic capacity was challenged functionally by Seahorse metabolic flux analyses and glucose deprivation in LLC-PK1-derived cells expressing Src binding rat NKA α1, non-Src-binding rat NKA α2 (the most abundant NKA isoform in the skeletal muscle), and Src binding gain-of-function mutant rat NKA α2. Mice with skeletal muscle-specific ablation of NKA α1 (skα1-/-) were generated using a MyoD:Cre-Lox approach and were subjected to treadmill testing and Western diet. C57/Bl6 mice were subjected to Western diet with or without pharmacological inhibition of NKA α1/Src modulation by treatment with pNaKtide, a cell-permeable peptide designed by mapping one of the sites of NKA α1/Src interaction.

Results: Metabolic studies in mutant cell lines revealed that the Src binding regions of NKA α1 are required to maintain metabolic reserve and flexibility. Skα1-/- mice had decreased exercise endurance and mitochondrial Complex I dysfunction. However, skα1-/- mice were resistant to Western diet-induced insulin resistance and glucose intolerance, a protection phenocopied by pharmacological inhibition of NKA α1-mediated Src regulation with pNaKtide.

Conclusions: These results suggest that NKA α1/Src regulatory function may be targeted in metabolic diseases. Because Src regulatory capability by NKA α1 is exclusive to endotherms, it may link the aerobic scope hypothesis of endothermy evolution to metabolic dysfunction.
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http://dx.doi.org/10.1111/apha.13652DOI Listing
July 2021

Adherence to and determinants of guideline-recommended biomarker testing and targeted therapy in patients with gastroesophageal adenocarcinoma: Insights from routine practice.

Cancer 2021 Jul 17;127(14):2562-2570. Epub 2021 Mar 17.

Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Background: Anti human epidermal growth factor receptor 2 (anti-HER2) therapy with trastuzumab improves overall survival in patients with advanced, HER2-positive gastroesophageal adenocarcinoma (GEA) and is now incorporated into national guidelines. However, little is known about adherence to and determinants of timely HER2 testing and trastuzumab initiation in routine practice.

Methods: The authors performed a cross-sectional study of patients who had advanced GEA diagnosed between January 2011 and June 2019 in a nationwide electronic health record-derived database. The annual prevalences of both timely HER2 testing (defined within 21 days after advanced diagnosis) and timely trastuzumab initiation (defined within 14 days after a positive HER2 result) were calculated. Log-binomial regressions estimated adjusted prevalence ratios comparing timely HER2 testing and trastuzumab initiation by patient and tumor characteristics.

Results: In total, the cohort included 6032 patients with advanced GEA of whom 1007 were HER2-positive. Between 2011 and 2019, timely HER2 testing increased from 22.4% to 44.5%, whereas timely trastuzumab initiation remained stable at 16.3%. No appreciable differences in timely testing or trastuzumab initiation were noted by age, sex, race, or insurance status. Compared with patients who had metastatic disease at diagnosis, patients who had early stage GEA who did not undergo surgery were less likely to receive timely HER2 testing and trastuzumab initiation (testing prevalence ratio, 0.69; 95% CI, 0.64-0.75; treatment prevalence ratio, 0.32; 95% CI, 0.18-0.56), as were patients with early stage disease who subsequently developed a distant recurrence (testing prevalence ratio, 0.56; 95% CI, 0.47-0.65; treatment prevalence ratio, 0.61; 95% CI, 0.24-1.55).

Conclusions: In patients with advanced GEA, guideline-recommended HER2 testing and anti-HER2 therapy remain underused. Uptake may improve with universal HER2 testing regardless of stage.
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http://dx.doi.org/10.1002/cncr.33514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249344PMC
July 2021

The role of SAMM50 in non-alcoholic fatty liver disease: from genetics to mechanisms.

FEBS Open Bio 2021 Jul 27;11(7):1893-1906. Epub 2021 May 27.

Department of General Surgery, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, China.

Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation. SAMM50 encodes Sam50, a mitochondrial outer membrane protein involved in the removal of reactive oxygen species, mitochondrial morphology and regulation of mitophagy. Certain single nucleotide polymorphisms of SAMM50 have been reported to be correlated with NAFLD. However, the contribution of SAMM50 polymorphisms to the occurrence and severity of fatty liver in the Chinese Han cohort has rarely been reported. Here, we investigated the association between SAMM50 polymorphisms (rs738491 and rs2073082) and NAFLD in a Chinese Han cohort, as well as the mechanistic basis of this association. Clinical information and blood samples were collected from 380 NAFLD cases and 380 normal subjects for the detection of genotypes and biochemical parameters. Carriers of the rs738491 T allele or rs2073082 G allele of SAMM50 exhibit increased susceptibility to NAFLD [odds ratio (OR) = 1.39; 95% confidence interval (CI) = 1.14-1.71, P = 0.001; OR = 1.31; 95% CI = 1.05-1.62, P = 0.016, respectively] and are correlated with elevated serum triglyceride, alanine aminotransferase and aspartate aminotransferase levels. The presence of the T allele (TT + CT) of rs738491 (P < 0.01) or G allele (AG + GG) of rs2073082 (P = 0.03) is correlated with the severity of fatty liver in the NAFLD cohort. In vitro studies indicated that SAMM50 gene polymorphisms decrease its expression and SAMM50 deficiency results in increased lipid accumulation as a result of a decrease in fatty acid oxidation. Overexpression of SAMM50 enhances fatty acid oxidation and mitigates intracellular lipid accumulation. Our results confirm the association between the SAMM50 rs738491 and rs2073082 polymorphisms and the risk of fatty liver in a Chinese cohort. The underlying mechanism may be related to decreased fatty acid oxidation caused by SAMM50 deficiency.
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http://dx.doi.org/10.1002/2211-5463.13146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255833PMC
July 2021

Claulansine F-Donepezil Hybrids as Anti-Alzheimer's Disease Agents with Cholinergic, Free-Radical Scavenging, and Neuroprotective Activities.

Molecules 2021 Feb 28;26(5). Epub 2021 Feb 28.

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

The multifactorial nature of Alzheimer's disease (AD) calls for the development of multitarget agents addressing key pathogenic processes. A total of 26 Claulansine F-donepezil hybrids were designed and synthesized as multitarget drugs. Among these compounds, six compounds exhibited excellent acetylcholinesterase (AChE) inhibitory activity (half maximal inhibitory concentration (IC) 1.63-4.62 μM). Moreover, ()-3-(8-(-Butyl)-3,3-dimethyl-3,11-dihydropyrano[3,2-a]carbazol-5-yl)--((1-(2-chlorobenzyl)piperidin-4-yl)methyl)acrylamide () exhibited better neuroprotective effects against OGD/R (oxygen-glucose deprivation/reoxygenation) than lead compound Claulansine F. Furthermore, could cross the blood-brain barrier in vitro. More importantly, compared to edaravone, had stronger free-radical scavenging activity. Molecular docking studies revealed that could interact with the catalytic active site of AChE. All of these outstanding in vitro results indicate as a leading structure worthy of further investigation.
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http://dx.doi.org/10.3390/molecules26051303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957565PMC
February 2021
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