Publications by authors named "Ying Xiao"

634 Publications

Recovery of early postoperative muscle strength after deep neuromuscular block by means of ultrasonography with comparison of neostigmine versus sugammadex as reversal drugs: study protocol for a randomised controlled trial.

BMJ Open 2021 Feb 26;11(2):e043935. Epub 2021 Feb 26.

First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

Introduction: Despite the use of quantitative neuromuscular monitoring together with the administration of reversal drugs (neostigmine or sugammadex), the incidence of residual neuromuscular blockade defined as a train-of-four ratio (TOFr) <0.9 remains high. Even TOFr >0.9 cannot ensure adequate recovery of neuromuscular function when T1 height is not recovered completely. Thus, a mathematical correction of TOFr needs to be applied because the return of a normal TOFr can precede the return of a normal T1 twitch height. On the other hand, different muscles have different sensitivities to neuromuscular blockade agents; thus, complete recovery of one specific muscle group does not represent complete recovery of all other muscles. Therefore, our study aims to assess the muscle strength recovery of respiratory-related muscle groups by ultrasound and evaluate global strength using handgrip dynamometry in the early postoperative period when TOFr=0.9 and corrected TOFr (cTOFr)=0.9 with comparison of neostigmine versus sugammadex as reversal drugs.

Methods And Analysis: This study will be a prospective, single-blinded, randomised controlled trial involving 60 patients with American Society of Anesthesiologists physical status I-II and aged between 18 and 65 years, who will undergo microlaryngeal surgery. We will assess geniohyoid muscle, parasternal intercostal muscle, diaphragm, abdominal wall muscle and handgrip strength at four time points: before anaesthesia, TOFr=0.9, cTOFr=0.9 and 30 min after admission to the post anaesthesia care unit. Our primary objective will be to compare the effects of neostigmine and sugammadex on the recovery of muscle strength of different muscle groups in the early postoperative period when TOFr=0.9 and cTOFr=0.9. The secondary objective will be to observe the difference of muscle strength between the time points of TOFr=0.9 and cTOFr=0.9 to find out the clinical significance of cTOFr >0.9.

Ethics And Dissemination: The protocol was reviewed and approved by the Ethics Committee of The First Affiliated Hospital, Sun Yat-sen University. The findings will be disseminated to the public through peer-reviewed scientific journals.

Trial Registration Number: ChiCTR2000033832.
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http://dx.doi.org/10.1136/bmjopen-2020-043935DOI Listing
February 2021

R-JaunLab: Automatic Multi-Class Recognition of Jaundice on Photos of Subjects with Region Annotation Networks.

J Digit Imaging 2021 Feb 25. Epub 2021 Feb 25.

Department of Gastroenterology and Hepatology, Shenzhen University General Hospital, Shenzhen, 518055, China.

Jaundice occurs as a symptom of various diseases, such as hepatitis, the liver cancer, gallbladder or pancreas. Therefore, clinical measurement with special equipment is a common method that is used to identify the total serum bilirubin level in patients. Fully automated multi-class recognition of jaundice combines two key issues: (1) the critical difficulties in multi-class recognition of jaundice approaches contrasting with the binary class and (2) the subtle difficulties in multi-class recognition of jaundice represent extensive individuals variability of high-resolution photos of subjects, huge coherency between healthy controls and occult jaundice, as well as broadly inhomogeneous color distribution. We introduce a novel approach for multi-class recognition of jaundice to detect occult jaundice, obvious jaundice and healthy controls. First, region annotation network is developed and trained to propose eye candidates. Subsequently, an efficient jaundice recognizer is proposed to learn similarities, context, localization features and globalization characteristics on photos of subjects. Finally, both networks are unified by using shared convolutional layer. Evaluation of the structured model in a comparative study resulted in a significant performance boost (categorical accuracy for mean 91.38%) over the independent human observer. Our work was exceeded against the state-of-the-art convolutional neural network (96.85% and 90.06% for training and validation subset, respectively) and showed a remarkable categorical result for mean 95.33% on testing subset. The proposed network makes a performance better than physicians. This work demonstrates the strength of our proposal to help bringing an efficient tool for multi-class recognition of jaundice into clinical practice.
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http://dx.doi.org/10.1007/s10278-021-00432-7DOI Listing
February 2021

The role of CDX2 in renal tubular lesions during diabetic kidney disease.

Aging (Albany NY) 2021 Feb 17;13. Epub 2021 Feb 17.

Department of Pathophysiology, Guizhou Medical University, Guiyang 550025, Guizhou, China.

Renal tubules are vulnerable targets of various factors causing kidney injury in diabetic kidney disease (DKD), and the degree of tubular lesions is closely related to renal function. Abnormal renal tubular epithelial cells (RTECs) differentiation and depletion of cell junction proteins are important in DKD pathogenesis. Caudal-type homeobox transcription factor 2 (CDX2), represents a key nuclear transcription factor that maintains normal proliferation and differentiation of the intestinal epithelium. The present study aimed to evaluate the effects of CDX2 on RTECs differentiation and cell junction proteins in DKD. The results demonstrated that CDX2 was mainly localized in renal tubules, and downregulated in various DKD models. CDX2 upregulated E-cadherin and suppressed partial epithelial-mesenchymal transition (EMT), which can alleviate hyperglycemia-associated RTECs injury. Cystic fibrosis transmembrane conductance regulator (CFTR) was regulated by CDX2 in NRK-52E cells, and CFTR interfered with β-catenin activation by binding to Dvl2, which is an essential component of Wnt/β-catenin signaling. CFTR knockdown abolished the suppressive effects of CDX2 on Wnt/β-catenin signaling, thereby upregulating cell junction proteins and inhibiting partial EMT in RTECs. In summary, CDX2 can improve renal tubular lesions during DKD by increasing CFTR amounts to suppress the Wnt/β-catenin signaling pathway.
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http://dx.doi.org/10.18632/aging.202537DOI Listing
February 2021

Toward Individualized Voxel-Level Dosimetry for Radiopharmaceutical Therapy.

Int J Radiat Oncol Biol Phys 2021 Mar;109(4):902-904

Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland.

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http://dx.doi.org/10.1016/j.ijrobp.2020.08.026DOI Listing
March 2021

A Probability-Based Investigation on the Setup Robustness of Pencil-beam Proton Radiation Therapy for Skull-Base Meningioma.

Int J Part Ther 2021 28;7(3):34-45. Epub 2021 Jan 28.

Department of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.

Introduction: The intracranial skull-base meningioma is in proximity to multiple critical organs and heterogeneous tissues. Steep dose gradients often result from avoiding critical organs in proton treatment plans. Dose uncertainties arising from setup errors under image-guided radiation therapy are worthy of evaluation.

Patients And Methods: Fourteen patients with skull-base meningioma were retrospectively identified and planned with proton pencil beam scanning (PBS) single-field uniform dose (SFUD) and multifield optimization (MFO) techniques. The setup uncertainties were assigned a probability model on the basis of prior published data. The impact on the dose distribution from nominal 1-mm and large, less probable setup errors, as well as the cumulative effect, was analyzed. The robustness of SFUD and MFO planning techniques in these scenarios was discussed.

Results: The target coverage was reduced and the plan dose hot spot increased by all setup uncertainty scenarios regardless of the planning techniques. For 1 mm nominal shifts, the deviations in clinical target volume (CTV) coverage D99% was -11 ± 52 cGy and -45 ± 147 cGy for SFUD and MFO plans. The setup uncertainties affected the organ at risk (OAR) dose both positively and negatively. The statistical average of the setup uncertainties had <100 cGy impact on the plan qualities for all patients. The cumulative deviations in CTV D95% were 1 ± 34 cGy and -7 ± 18 cGy for SFUD and MFO plans.

Conclusion: It is important to understand the impact of setup uncertainties on skull-base meningioma, as the tumor target has complex shape and is in proximity to multiple critical organs. Our work evaluated the setup uncertainty based on its probability distribution and evaluated the dosimetric consequences. In general, the SFUD plans demonstrated more robustness than the MFO plans in target coverages and brainstem dose. The probability-weighted overall effect on the dose distribution is small compared to the dosimetric shift during single fraction.
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http://dx.doi.org/10.14338/IJPT-20-00009.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886272PMC
January 2021

Intraductal papillary neoplasm of intrahepatic bile ducts complicated by chronic disseminated intravascular coagulation and thrombosis: A case report.

Medicine (Baltimore) 2021 Feb;100(5):e24454

Center of Hepatopancreatobiliary Diseases.

Rationale: Intraductal papillary neoplasm of the bile ducts (IPNB) is a relatively rare tumor that is clinically characterized by digestive symptoms. The concurrent occurrence of chronic disseminated intravascular coagulation (DIC) with thrombosis is an extremely rare combination, reported in patients with IPNB. The clinical features of chronic DIC include microangiopathic hemolytic anemia, thrombocytopenia, and hypofibrinogenemia. Here, we report the case of a mucin-producing IPNB patient with hematological abnormalities.

Patient Concerns: A 58-year-old male patient suffered from abdominal distension for more than 2 months with obstructive jaundice appearance. Abdominal contrast-enhanced computed tomography and magnetic resonance cholangiopancreatography showed a neoplasm in the right hepatic lobe. Multiple intravascular fillings were found in the inferior vena cava, pulmonary artery, and right atrium. Anemia and hypofibrinogenemia were discovered through routine laboratory tests. The count of platelets began to decline 25 days after admission, while 1 month after hospitalization, the patient developed abdominal pain, fever, and shock.

Diagnosis: Pathological examination demonstrated IPNB with a part of high-grade intraepithelial neoplasia. Cardiac and inferior vena cava emboli were diagnosed as thrombi without neoplastic cells. Immunohistochemically, tumor cells were positive for Vimentin (mesenchyme), CK7, CK19, MUC-1, MUC-5AC, MUC-6, S-100p (focal), Ki-67 (12%), and negative for Inhibin-α, ER, CK20, CEA, and MUC-2. Additionally, immunohistochemistry indicated that IPNB was a mucus-secretion gastric type. The laboratory tests confirmed the presence of chronic DIC.

Interventions: The patient was given anticoagulant therapy before hepatectomy and right atrium thrombectomy was performed under cardiopulmonary bypass.

Outcomes: After anticoagulant therapy, the levels of hemoglobin, platelet, and fibrinogen of the patient returned to normal. Hepatectomy and thrombus removal was successfully performed. Then, the patient was discharged 12 days after the operation. After 12 months of follow-up, the patient recovered well without any hematologic abnormalities and no signs of tumor recurrence were observed.

Lessons: IPNB may cause hematological complications, which can be easily misdiagnosed. It is essential to pay particular attention to the hematological abnormalities of patients with IPNB. Early detection and differential diagnosis of chronic DIC and thrombosis are necessary. We note that anticoagulant therapy coupled with surgery is an effective strategy to treat these complications.
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http://dx.doi.org/10.1097/MD.0000000000024454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870212PMC
February 2021

Outer membrane protein A inhibits the degradation of caspase-1 to regulate NLRP3 inflammasome activation and exacerbate the Acinetobacter baumannii pulmonary inflammation.

Microb Pathog 2021 Feb 8;153:104788. Epub 2021 Feb 8.

Department of Anatomy, School of Basic Medical Sciences, Guizhou Medical University/ Department of Respiratory and Critical Medicine, Guizhou Provincial People's Hospital, Guiyang, Guizhou, 550025, China. Electronic address:

Acinetobacter baumannii (A. baumannii), one of the major pathogens that causes severe nosocomial infections, is characterised by a high prevalence of drug resistance. It has been reported that A. baumannii triggers the NOD-like receptor 3 (NLRP3) inflammasome, but the role of its virulence-related outer membrane protein A (ompA) remains unclear. Therefore, this study aimed to explore the effects of ompA on the NLRP3 inflammasome and its underlying molecular mechanisms. Results showed that ompA enhanced inflammatory damage, which was reduced as a result of knockout of the ompA gene. Additionally, ompA-stimulated expression of NLRP3 inflammasome was significantly blocked by silencing caspase-1, but activation of NLRP3 inflammasome was not altered after silencing ASC; this indicated that ompA was dependent on the caspase-1 pathway to activate the inflammatory response. Simultaneously, the wild-type (WT) strains triggered NLRP3 inflammasome after inhibition of caspase-1 degradation by proteasome inhibitor MG-132, aggravating tissue damage. These findings indicated that ompA may be dependent on the caspase-1 pathway to enhance inflammation and exacerbate tissue damage. Taken together, these results confirmed a novel capsase-1-modulated mechanism underpinning ompA activity, which further reveals the NLRP3 inflammasome pathway as a potential immunomodulatory target against A. baumannii infections.
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http://dx.doi.org/10.1016/j.micpath.2021.104788DOI Listing
February 2021

Prognostic Value of Circulating sST2 for the Prediction of Mortality in Patients With Cardiac Light-Chain Amyloidosis.

Front Cardiovasc Med 2020 20;7:597472. Epub 2021 Jan 20.

Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Systemic light-chain (AL) amyloidosis is a multisystemic disorder leading to multiple organ dysfunction and mortality that is often caused by cardiac involvement. Soluble suppression of tumorigenicity 2 (sST2) is a novel biomarker identified for risk stratification of heart disease. The aim of this study was to investigate the value of circulating sST2 levels in prognosis and mortality risk assessments for the AL amyloidosis population. A total of 56 patients diagnosed with AL amyloidosis were enrolled in Peking Union Medical College Hospital (PUMCH) from January 2015 to May 2018. The relationships between the clinical parameters and overall survival (OS) and risk factors for disease progression were assessed. Additionally, receiver operating characteristic (ROC) curves, Kaplan-Meier analysis, and Cox hazard models were performed to explore the predictive value of sST2 in mortality rates. We found that the median OS of all patients was 7.3 [interquartile range (IQR) 4.4, 15.9] months. The median baseline sST2 level was 12.2 (IQR 5.1, 31.1) ng/ml, and the sST2 high group had more severe patients with a higher Mayo stage. In the ROC analysis, the area under the curve (AUC) was 0.728 [95% confidence interval (CI) 0.603-0.853] for sST2 to predict the outcomes of AL amyloidosis patients, and the optimal cutoff value was 12.34 ng/ml (sensitivity 80.2%, specificity 61.1%). Moreover, in multivariate Cox proportional hazards regression analysis, sST2 acted as an independent predictor of poor functional outcome in patients with AL amyloidosis. In AL amyloidosis patients, sST2 was a strong and independent prognostic biomarker for all-cause mortality, providing complementary prognostic information of a novel scoring system for risk stratification.
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http://dx.doi.org/10.3389/fcvm.2020.597472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855859PMC
January 2021

[Molecular genetics of medicinal plants, past achievement, and new era].

Zhongguo Zhong Yao Za Zhi 2020 Dec;45(23):5577-5588

Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine,Institute of Chinese Materia Medica,China Academy of Chinese Medical Sciences Beijing 100700,China.

Unraveling the genetic basis of medicinal plant metabolism and developmental traits is a long-standing goal for pharmacologists and plant biologists. This paper discusses the definition of molecular genetics of medicinal plants, which is an integrative discipline with medicinal plants as the research object. This discipline focuses on the heredity and variation of medicinal plants, and elucidates the relationship between the key traits of medicinal plants(active compounds, yield, resistance, etc.) and genotype, studies the structure and function, heredity and variation of medicinal plant genes mainly at molecular level, so as to reveal the molecular mechanisms of transmission, expression and regulation of genetic information of medicinal plants. Specifically, we emphasize on three major aspects of this discipline.(1)Individual and population genetics of medicinal plants, this part mainly highlights the genetic mechanism of the domestication, the individual genomics at the species level, and the formation of genetic diversity of medicinal plants.(2)Elucidation of biosynthetic pathways of active compounds and their evolutionary significance. This part summarizes the biosynthesis, diversity and molecular evolution of active compounds in medicinal plants.(3) Molecular mechanisms that shaping the key agronomic traits by internal and external factors. This part focuses on the accumulation and distribution of active compounds within plants and the regulation of metabolic network by environmental factors. Finally, we prospect the future direction of molecular genetics of medicinal plants based on the rapid development of multi-omics technology, as well as the application of molecular genetics in the future strategies to achieve conservation and breeding of medicinal plants and efficient biosynthesis of active compounds.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20201016.601DOI Listing
December 2020

Adaptive Radiation Therapy (ART) Strategies and Technical Considerations: A State of the ART Review From NRG Oncology.

Int J Radiat Oncol Biol Phys 2021 Mar 24;109(4):1054-1075. Epub 2020 Oct 24.

Department of Radiation Oncology, Moffitt Cancer Center, Tampa, Florida.

The integration of adaptive radiation therapy (ART), or modifying the treatment plan during the treatment course, is becoming more widely available in clinical practice. ART offers strong potential for minimizing treatment-related toxicity while escalating or de-escalating target doses based on the dose to organs at risk. Yet, ART workflows add complexity into the radiation therapy planning and delivery process that may introduce additional uncertainties. This work sought to review presently available ART workflows and technological considerations such as image quality, deformable image registration, and dose accumulation. Quality assurance considerations for ART components and minimum recommendations are described. Personnel and workflow efficiency recommendations are provided, as is a summary of currently available clinical evidence supporting the implementation of ART. Finally, to guide future clinical trial protocols, an example ART physician directive and a physics template following standard NRG Oncology protocol is provided.
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http://dx.doi.org/10.1016/j.ijrobp.2020.10.021DOI Listing
March 2021

Cadherin-11 deficiency mitigates high-fat diet-induced inflammatory atrial remodeling and vulnerability to atrial fibrillation.

J Cell Physiol 2021 Jan 16. Epub 2021 Jan 16.

Department of Cardiology, Xinhua Hospital Affiliated To Shanghai Jiaotong University School of Medicine, Shanghai, China.

Atrial fibrillation (AF) is the most common cardiac arrhythmia nowadays. The occurrence of AF is closely associated with obesity. Cadherin-11 (Cad-11), as a member of the cadherin family, can make a contribution to diet-induced obesity and it will be informative to know whether Cad-11 exerts its effects on atrial remodeling and AF vulnerability in a diet-induced obesity model. In this study, we demonstrated that the expression of Cad-11 was significantly upregulated in the left atrium of AF patients with obesity and mice following 16 weeks of high-fat diet (HFD) feeding. Further confirmed that Cad-11 could regulate the activity of atrial fibroblasts by participating in inducing proinflammatory cytokines production. At animal levels, we found that although there was a lack of statistical difference in body weight, Cad-11 mice could markedly improve impaired glucose tolerance and hyperlipidemia. Adverse atrial structural remodeling, including atrial enlargement, inflammation, and fibrosis provoked by HFD feeding were mitigated in Cad-11 mice. Mechanistically, Cad-11 activated mitogen-activated protein kinases and nuclear factor-κB for interleukin-6 production in atrial fibroblasts that may contribute to the atrial fibrosis process in obesity-related AF, suggesting Cad-11 might be a new therapeutic target for obesity-related AF.
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http://dx.doi.org/10.1002/jcp.30257DOI Listing
January 2021

Effects of family history of diabetes on pancreatic β-cell function and diabetic ketoacidosis in newly diagnosed patients with type 2 diabetes: a cross-sectional study in China.

BMJ Open 2021 Jan 11;11(1):e041072. Epub 2021 Jan 11.

Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China

Objective: To investigate the association between a parental and/or sibling history of diabetes and clinical characteristics.

Design: A cross-sectional study.

Setting: The data were collected from the endocrinology department of The Second Xiangya Hospital of Central South University from June 2017 to October 2019.

Participants: A total of 894 newly diagnosed patients with type 2 diabetes were recruited. Data on clinical characteristics were collected from patient medical records. Pancreatic β-cell function and insulin resistance were calculated with the homeostatic model assessment. SPSS V.25.0 was used to perform the analysis.

Results: The percentages of patients with parental and sibling histories of diabetes were 14.8% and 9.8%, respectively. The prevalence of diabetic ketoacidosis (DKA) was 3.9%. Compared with those with no parental history of diabetes, patients with a parental history of diabetes were characterised by early-onset disease (41.70±10.88 vs 51.17±14.09 years), poor glycaemic control of fasting blood glucose (10.84±5.21 vs 8.91±4.38 mmol/L) and a high prevalence of DKA (7.6% vs 3.3%). The patients with a sibling history of diabetes had later disease onset (56.05±9.86 vs 49.09±14.29 years) and lower BMI (24.49±3.48 vs 25.69±3.86 kg/m) than those with no sibling history of diabetes. Univariate regression suggested that both parental history (p=0.037) and sibling history (p=0.011) of diabetes were associated with β-cell function; however, multiple regression analysis showed that only a sibling history of diabetes was associated with β-cell function (p=0.038). Univariate regression revealed a positive correlation between parental history of diabetes (p=0.023, OR=2.416, 95% CI 1.132 to 5.156) and DKA. Unfortunately, this correlation was not statistically significant for either patients with a parental history (p=0.234, OR=1.646, 95% CI 0.724 to 3.743) or those with a sibling history (p=0.104, OR=2.319, 95% CI 0.841 to 6.389) after adjustments for confounders.

Conclusion: A sibling history of diabetes was associated with poor β-cell function, and a parental history of diabetes was associated with poor glycaemic control and a high prevalence of DKA.
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http://dx.doi.org/10.1136/bmjopen-2020-041072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802721PMC
January 2021

The role of Stim1 in the progression of lupus nephritis in mice.

Int J Clin Exp Pathol 2020 1;13(12):3021-3032. Epub 2020 Dec 1.

Department of Pathophysiology, Guizhou Medical University Guiyang 550025, China.

Objective: To investigate the expression of Stim1 in the kidneys of mice with lupus, and the effect of Stim1 on the progression of renal interstitial fibrosis.

Methods: Mice (MRL/lpr) with spontaneous lupus nephritis (LN) and normal control mice (C57/BL) were selected. Immunohistochemistry and Masson staining were used to determine the degree of renal interstitial fibrosis in kidney tissues. The expression of Stim1 and fibronectin in tissues was measured by qRT-PCR, western blotting, and immunohistochemistry. Urine protein, blood urea nitrogen, and serum creatinine levels in the mice were analyzed, and Spearman analysis was conducted to determine the correlation with Stim1 expression levels. Mouse renal tubular epithelial cells (mRTECs) were chosen as the experimental objects. After various treatments, the cells were divided into the blank control group, lipopolysaccharide (LPS) treatment group, LPS+siRNA-NC group and LPS+siRNA-Stim1 group. Western blotting and immunofluorescence were used to measure epithelial-mesenchymal transition (EMT)-related protein levels.

Results: There was significant interstitial fibrosis in the kidneys of LN mice. Compared with that in normal mice, the expression of Stim1 in the kidney tissues of LN mice was significantly increased, and Stim1 expression was positively correlated with fibronectin, urine protein, blood urea nitrogen and serum creatinine levels. LPS induced the expression of Stim1, fibronectin, and α-SMA in mRTECs and decreased the protein level of E-CA, while silencing Stim1 effectively alleviated the effects of LPS.

Conclusion: Stim1 is significantly increased in the kidneys of lupus mice, and it is possible to promote EMT in renal tubular epithelial cells and renal interstitial fibrosis by elevating fibronectin, which ultimately contributes to renal damage.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791395PMC
December 2020

[Therapeutic Effect of SPK1 Gene Transfected Adipose Derived Mesenchymal Stem Cells on Experimental Autoimmune Encephalomyelitis Mice and Its Effect on T Helper Cell 17/Regulatory T Cells Balance].

Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2020 Dec;42(6):755-765

Department of Rheumatology and Immunology,Wuhan Puren Hospital,Wuhan University of Science and Technology,Wuhan 430081,China.

Objective To investigate the therapeutic effect of SPK1 gene transfected adipose derived mesenchymal stem cells(ADMSC)on experimental autoimmune encephalomyelitis mice and the effect on T helper cell 17(Th17)/regulatory T(Treg) cells balance. Methods EAE was induced by myelin oligodendrocyte glycoprotein 35-55 in mice.Totally 44 mice were randomly divided into four groups:normal control group(NC group),model group(EAE group),ADMSC group,and ADMSC-SPK1 group.Forty days after injection,the pathological changes of brain and spinal cord,Th17/Treg-related inflammatory markers in brain tissue,expressions of interleukin-17A(IL-17A)and forkhead box protein p3(Foxp3)in brain and spinal cord tissue,and flow cytometric results of spleen immune cells were detected. Results Forty days after the injection,serious inflammatory cell infiltration and demyelination occurred in the brain and spinal cord of EAE group,whereas demyelination and axonal injury were improved in ADMSC group and ADMSC-SPK1 group.Compared with EAE group,the ADMSC group and ADMSC-SPK1 group had significantly improved levels of IL-17A(=1.021,=0.017;=1.193, =0.009)and tumor necrosis factor-α(TNF-α)(=2.540,=0.004; =3.005, =0.006).The expression level of IL-17A in mouse brain and spinal cord tissues was significantly reduced in the ADMSC group(=10.323,=0.013;=7.422,=0.008),and it was significantly lower in the ADMSC-SPK1 group than in the ADMSC group (=14.244, =0.017; =16.865,=0.006).The expression level of Foxp3 in the ADMSC group was significantly increased(=14.544, =0.008;=9.420,=0.002),and it was significantly higher in the ADMSC-SPK1 group than ADMSC group(=9.654,=0.005; =11.535, =0.009).The proportion of IL-17+IFN-γ+T cells in spleen decreased in ADMSC-SPK1 group,while that of CD25+Foxp3+Treg cells increased. Conclusions ADMSC transfected with SPK1 has an ideal therapeutic effect on EAE mice,and the effect is superior to ADMSC without SPK1 transfection.The mechanism may be that ADMSC-SPK1 can markedly reduce the Th17/Treg cell ratio and decrease the release of related inflammatory cytokines in EAE mice.
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http://dx.doi.org/10.3881/j.issn.1000-503X.11888DOI Listing
December 2020

The EGFR-HSF1 axis accelerates the tumorigenesis of pancreatic cancer.

J Exp Clin Cancer Res 2021 Jan 9;40(1):25. Epub 2021 Jan 9.

Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, China.

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant diseases because of its non-symptomatic tumorigenesis. We previous found heat shock factor 1 (HSF1) was critical for PDAC progression and the aim of this study was to clarified the mechanisms on early activation of HSF1 and its role in the pancreatic cancer tumorigenesis.

Methods: The expression and location of HSF1 on human or mice pancreatic tissues were examined by immunohistochemically staining. We mainly used pancreatic acinar cell 3-dimensional (3D) culture and a spontaneous pancreatic precancerous lesion mouse model called LSL-Kras; Pdx1-Cre (KC) (and pancreatitis models derived from KC mice) to explore the pro-tumorigenesis mechanisms of the HSF1 in vitro and in vivo. Bioinformatics and molecular experiments were used to explore the underlying mechanisms between HSF1 and epidermal growth factor receptor (EGFR).

Results: In this study, we found that pharmacological inhibition of HSF1 slowed pancreatic cancer initiation and suppressed the pancreatitis-induced formation of pancreatic precancerous lesion. Next, bioinformatics analysis revealed the closely linked between HSF1 and EGFR pathway and we also confirmed their parallel activation in pancreatic precancerous lesions. Besides, the pharmacological inhibition of EGFR suppressed the initiation of pancreatic cancer and the activation of HSF1 in vivo. Indeed, we demonstrated that the EGFR activation that mediated pancreatic cancer tumorigenesis was partly HSF1-dependent in vitro.

Conclusion: Hence, we concluded that the EGFR-HSF1 axis promoted the initiation of pancreatic cancer.
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http://dx.doi.org/10.1186/s13046-020-01823-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797143PMC
January 2021

Identification of two novel subgroups in patients with diabetes mellitus and their association with clinical outcomes: A two-step cluster analysis.

J Diabetes Investig 2021 Jan 7. Epub 2021 Jan 7.

Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.

Aims/introduction: The aim of this study was to determine whether distinct subphenotypes of patients with type 2 diabetes in the European classification exist in Chinese populations, and to further establish novel subphenotypes more suitable for Chinese populations.

Material And Methods: The research retrospectively analyzed 5414 patients with type 2 diabetes from the National Clinical Research Center for Metabolic Diseases Diabetes Center in China, and a two-step cluster analysis was carried out. First, we confirmed the European classification in Chinese populations by six parameters, including age at disease onset, body mass index, glycosylated hemoglobin, homeostatic model assessment 2 to estimate β-cell function and insulin resistance, and glutamate decarboxylase antibodies. Furthermore, triglycerides and uric acid were added to refine the cluster analysis, and Cox regression was used to evaluate the risk of diabetic complications.

Results: Just three clusters were replicated in our cohort according to Emma Ahlqvist's European classification. When other variables were added to the cluster analysis, seven subgroups were identified, including five clusters of the European classification and two novel subgroups, namely, uric acid-related diabetes and inheritance-related diabetes. Compared with patients with inheritance-related diabetes, patients with severe insulin-resistant diabetes showed a higher risk of diabetic peripheral neuropathy, hypertension and chronic kidney disease, and the uric acid-related diabetes subgroup showed a higher risk of coronary heart disease, cerebral vascular disease and end-stage renal disease. Patients with severe insulin-deficient diabetes showed a higher risk of diabetic retinopathy and diabetic foot than those with inheritance-related diabetes. Furthermore, there were sex-specific associations between subgroups and clinical outcomes. No significant difference was observed in the prevalence of cancer in each subgroup.

Conclusions: Seven subgroups of type 2 diabetes were identified in Chinese populations, with distinct characteristics and disparate clinical outcomes. This etiology-based stratification might contribute to the diagnosis and management of type 2 diabetes.
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http://dx.doi.org/10.1111/jdi.13494DOI Listing
January 2021

Silencing of long non‑coding RNA NEAT1 inhibits hepatocellular carcinoma progression by downregulating SMO by sponging microRNA‑503.

Mol Med Rep 2021 Mar 5;23(3). Epub 2021 Jan 5.

Department of Clinical Laboratory, Jinan Chain Medical Laboratory Co., Ltd., Jinan, Shandong 250000, P.R. China.

Hepatocellular carcinoma (HCC) poses an increasing threat to humans, due to its poor prognosis. Nuclear‑enriched abundant transcript 1 (NEAT1), a type of long non‑coding (lnc)RNA, has been found to function in a variety of cancer types. However, the role of NEAT1 in HCC is poorly understood. Reverse transcription‑quantitative PCR was used to detect the expression levels of NEAT1, microRNA (miR)‑503 and Smoothened (SMO) mRNA in HCC tissues and cells. MTT and flow cytometry assays were used to investigate cell viability and apoptosis, respectively, while Transwell assays were performed to investigate cell invasion and migration. StarBase and TargetScan were utilized to predict the target sequence between miR‑503 and NEAT1 or SMO, the results of which were verified using a dual‑luciferase reporter assay. The protein expression level of SMO was measured using western blot. The RNA expression level of NEAT1 and SMO was significantly elevated in HCC tissues and cells compared with that in the corresponding healthy tissues and cells, which was contrary to miR‑503 expression level. NEAT1 silencing was found to restrict the viability, migration and invasion of the cells, while simultaneously induced apoptosis in the HCC cell line. Further studies found that miR‑503 expression was negatively correlated with NEAT1 or SMO. It was also confirmed that NEAT1 directly interacted with miR‑503 and miR‑503 could bind to the 3'‑untranslated region of SMO. Furthermore, overexpression of NEAT1 or SMO could reverse the effects of miR‑503‑mediated inhibition on cell viability, invasion, migration and promotion of apoptosis in the HCC cell lines. These results demonstrated that downregulation of NEAT1 impeded the viability, migration, invasion and induced apoptosis through the NEAT1/miR‑503/SMO axis in the HCC cell line.
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http://dx.doi.org/10.3892/mmr.2020.11807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821340PMC
March 2021

The Association of Low Molecular Weight Heparin Use and In-hospital Mortality Among Patients Hospitalized with COVID-19.

Cardiovasc Drugs Ther 2021 Jan 4. Epub 2021 Jan 4.

Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan, 430030, China.

Purpose: To determine the association between low molecular weight heparin (LMWH) use and mortality in hospitalized COVID-19 patients.

Methods: We conducted a retrospective study of patients consecutively enrolled from two major academic hospitals exclusively for COVID-19 in Wuhan, China, from January 26, 2020, to March 26, 2020. The primary outcome was adjusted in-hospital mortality in the LMWH group compared with the non-LMWH group using the propensity score.

Results: Overall, 525 patients with COVID-19 enrolled with a median age of 64 years (IQR 19), and 49.33% men. Among these, 120 (22.86%) were treated with LMWH. Compared with the non-LMWH group, the LMWH group was more likely to be older and male; had a history of hypertension, diabetes, coronary heart disease (CHD), or stroke; and had more severe COVID-19 parameters such as higher inflammatory cytokines or D-dimer. Compared with non-LMWH group, LMWH group had a higher unadjusted in-hospital mortality rate (21.70% vs. 11.10%; p = 0.004), but a lower adjusted mortality risk (adjusted odds ratio [OR], 0.20; 95% CI, 0.09-0.46). A propensity score-weighting analysis demonstrated similar findings (adjusted OR, 0.18; 95% CI, 0.10-0.30). Subgroup analysis showed a significant survival benefit among those who were severely (adjusted OR, 0.07; 95% CI, 0.02-0.23) and critically ill (adjusted OR, 0.32; 95% CI, 0.15-0.65), as well as among the elderly patients' age > 65, IL-6 > 10 times upper limit level, and D-dimer > 5 times upper limit level.

Conclusions: Among hospitalized COVID-19 patients, LMWH use was associated with lower all-cause in-hospital mortality than non-LMWH users. The survival benefit was particularly significant among more severely ill patients.
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http://dx.doi.org/10.1007/s10557-020-07133-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779648PMC
January 2021

The Relationship Between Simple Renal Cysts and Renal Function in Patients With Type 2 Diabetes.

Front Physiol 2020 15;11:616167. Epub 2020 Dec 15.

Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.

: Simple renal cysts (SRCs) are the most common acquired cystic kidney disease, but the relationship between SRCs and renal function has not been clarified in patients with type 2 diabetes mellitus (T2DM). : A retrospective study was conducted to analyze the clinical features of renal cysts and ultrasound data of the kidney in 4,304 patients with T2DM. : The prevalence of SRCs in patients with T2DM was 21.1%. Compared to patients with no SRCs, patients with SRCs had worse renal function (estimated glomerular filtration rate: 108.65 ± 40.93 vs. 92.38 ± 42.1 ml/min/1.73 m, < 0.05). After adjusting the confounders, SRC was related to estimated glomerular filtration rate in patients with T2DM [odds ratio = 1.49, 95% confidence interval (1.24, 1.79), < 0.01]. Age, gout, proteinuria, cerebrovascular disease (CVD), and increased serum phosphorus levels were associated with SRCs in patients with T2DM. : SRCs are associated with worse renal function in patients with T2DM. More attention should be paid to gout, proteinuria, CVD, serum phosphorus levels, and renal function in T2DM patients with SRCs.
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http://dx.doi.org/10.3389/fphys.2020.616167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770177PMC
December 2020

EI24 alleviates renal interstitial fibrosis through inhibition of epithelial-mesenchymal transition and fibroblast activation.

FASEB J 2021 Jan;35(1):e21239

Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, China.

Etoposide-induced 2.4 (EI24) exerts tumor suppressor activity through participating in cell apoptosis, autophagy, and inflammation. However, its role in renal diseases has not been elucidated. This study showed that the EI24 level decreased gradually in the kidneys of mice with unilateral ureteral obstruction (UUO) and in another fibrosis model induced by diabetic kidney disease. The overexpression of EI24 was used to investigate the possible role both in vivo and in vitro. The overexpression 1 day after UUO through tail vein injection alleviated the progression of renal interstitial fibrosis (RIF). EI24 inhibited epithelial-mesenchymal transition, excessive deposition of the extracellular matrix, and activation of fibroblasts. Furthermore, administration of EI24-overexpressing plasmids restrained the phosphorylation of nuclear factor-κB (NF-κB) and c-Jun kinase (JNK) through regulating the proteasome-dependent degradation of TRAF2, and then, inhibited the expression of downstream inflammation-associated cytokines (interleukin-6, tumor necrosis factor-α, and monocyte chemotactic protein-1) and infiltration of macrophages and neutrophils in mouse kidney after UUO. In conclusion, the data indicated that EI24, a novel anti-fibrosis regulator, was important in the progression of RIF.
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http://dx.doi.org/10.1096/fj.202002089RDOI Listing
January 2021

Extrahepatic bile duct reconstruction in pigs with heterogenous animal-derived artificial bile ducts: A preliminary experience.

World J Gastroenterol 2020 Dec;26(46):7312-7324

Department of Hepatopancreatobiliary Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102200, China.

Background: Extrahepatic biliary duct injury (BDI) remains a complicated issue for surgeons. Although several approaches have been explored to address this problem, the high incidence of complications affects postoperative recovery. As a nonimmunogenic scaffold, an animal-derived artificial bile duct (ada-BD) could replace the defect, providing good physiological conditions for the regeneration of autologous bile duct structures without changing the original anatomical and physiologic conditions.

Aim: To evaluate the long-term feasibility of a novel heterogenous ada-BD for treating extrahepatic BDI in pigs.

Methods: Eight pigs were randomly divided into two groups in the study. The animal injury model was developed with an approximately 2 cm segmental defect of various parts of the common bile duct (CBD) for all pigs. A 2 cm long novel heterogenous animal-derived bile duct was used to repair this segmental defect (group A, ada-BD-to-duodenum anastomosis to repair the distal CBD defect; group B, ada-BD-to-CBD anastomosis to repair the intermedial CBD defect). The endpoint for observation was 6 mo (group A) and 12 mo (group B) after the operation. Liver function was regularly tested. Animals were euthanized at the above endpoints. Histological analysis was carried out to assess the efficacy of the repair.

Results: The median operative time was 2.45 h (2-3 h), with a median anastomosis time of 60.5 min (55-73 min). All experimental animals survived until the endpoints for observation. The liver function was almost regular. Histologic analysis indicated a marked biliary epithelial layer covering the neo-bile duct and regeneration of the submucosal connective tissue and smooth muscle without significant signs of immune rejection. In comparison, the submucosal connective tissue was more regular and thicker in group B than in group A, and there was superior integrity of the regeneration of the biliary epithelial layer. Despite the advantages of the regeneration of the bile duct smooth muscle observed in group A, the effect on the patency of the ada-BD grafts in group B was not confirmed by macroscopic assessment and cholangiography.

Conclusion: This approach appears to be feasible for repairing a CBD defect with an ada-BD. A large sample study is needed to confirm the durability and safety of these preliminary results.
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http://dx.doi.org/10.3748/wjg.v26.i46.7312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739164PMC
December 2020

WRKY34 positively regulates yield, lignan biosynthesis and stress tolerance in .

Acta Pharm Sin B 2020 Dec 8;10(12):2417-2432. Epub 2020 Jan 8.

Research and Development Center of Chinese Medicine Resources and Biotechnology, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.

Yield potential, pharmaceutical compounds production and stress tolerance capacity are 3 classes of traits that determine the quality of medicinal plants. The autotetraploid has greater yield, higher bioactive lignan accumulation and enhanced stress tolerance compared with its diploid progenitor. Here we show that the transcription factor WRKY34, with higher expression levels in tetraploid than in diploid , has large pleiotropic effects on an array of traits, including biomass growth rates, lignan biosynthesis, as well as salt and drought stress tolerance. Integrated analysis of transcriptome and metabolome profiling demonstrated that expression had far-reaching consequences on both primary and secondary metabolism, reprograming carbon flux towards phenylpropanoids, such as lignans and flavonoids. Transcript-metabolite correlation analysis was applied to construct the regulatory network of WRKY34 for lignan biosynthesis. One candidate target 4CL3, a key rate-limiting enzyme of lignan biosynthesis as indicated in our previous study, has been demonstrated to indeed be activated by WRKY34. Collectively, the results indicate that the differentially expressed WRKY34 has contributed significantly to the polyploidy vigor of , and manipulation of this gene will facilitate comprehensive improvements of herb.
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http://dx.doi.org/10.1016/j.apsb.2019.12.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745056PMC
December 2020

Lipid Profile Features and Their Associations With Disease Severity and Mortality in Patients With COVID-19.

Front Cardiovasc Med 2020 4;7:584987. Epub 2020 Dec 4.

Division of Cardiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Emerging studies have described and analyzed epidemiological, clinical, laboratory, and radiological features of COVID-19 patients. Yet, scarce information is available regarding the association of lipid profile features and disease severity and mortality. We conducted a prospective observational cohort study to investigate lipid profile features in patients with COVID-19. From 9 February to 4 April 2020, a total of 99 patients (31 critically ill and 20 severely ill) with confirmed COVID-19 were included in the study. Dynamic alterations in lipid profiles were recorded and tracked. Outcomes were followed up until 4 April 2020. We found that high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-1 (apoA-1) levels were significantly lower in the severe disease group, with mortality cases showing the lowest levels ( < 0.0001). Furthermore, HDL-C and apoA-1 levels were independently associated with disease severity (apoA-1: odds ratio (OR): 0.651, 95% confidence interval (CI): 0.456-0.929, = 0.018; HDL-C: OR: 0.643, 95% CI: 0.456-0.906, = 0.012). For predicting disease severity, the areas under the receiver operating characteristic curves (AUCs) of HDL-C and apoA-1 levels at admission were 0.78 (95% CI, 0.70-0.85) and 0.85 (95% CI, 0.76-0.91), respectively. For in-hospital deaths, HDL-C and apoA-1 levels demonstrated similar discrimination ability, with AUCs of 0.75 (95% CI, 0.61-0.88) and 0.74 (95% CI, 0.61-0.88), respectively. Moreover, patients with lower serum concentrations of apoA-1 (<0.95 g/L) or HDL-C (<0.84 mmol/l) had higher mortality rates during hospitalization (log-rank < 0.001). Notably, levels of apoA-1 and HDL-C were inversely proportional to disease severity. The survivors of severe cases showed significant recovery of apoA-1 levels at the end of hospitalization (vs. midterm apoA-1 levels, = 0.02), whereas the mortality cases demonstrated continuously lower apoA-1 levels throughout hospitalization. Correlation analysis revealed that apoA-1 and HDL-C levels were negatively correlated with both admission levels and highest concentrations of C-reactive protein and interleukin-6. Severely ill COVID-19 patients featured low HDL-C and apoA-1 levels, which were strongly correlated with inflammatory states. Thus, low apoA-1 and HDL-C levels may be promising predictors for severe disease and in-hospital mortality in patients suffering from COVID-19.
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http://dx.doi.org/10.3389/fcvm.2020.584987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746652PMC
December 2020

ANXA1 affects murine hair follicle growth through EGF signaling pathway.

Gene 2021 Mar 14;771:145343. Epub 2020 Dec 14.

State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, Inner Mongolia University, Hohhot, Inner Mongolia 010070, China. Electronic address:

Annexin A1 (ANXA1), a calcium-dependent phospholipid binding protein expressed in animals, plants and microorganisms, participates in various cellular physiological activities. Previous proteomics analysis indicates that the level of ANXA1 in mice dorsal skin changes during hair growth cycle, we speculate that ANXA1 may play an important role in hair follicle (HF) development. Thus, Anxa1 knock-out (KO) and over-expression (OE) mice were constructed to test its function. Our results showed that in addition to the diameter of HF and hair shaft, ANXA1 could participate in hair growth by affecting the density of HF, and the proliferation of hair follicle stem cells (HFSCs). Meanwhile, molecular analysis showed that EGF signaling pathway is involved in the function of ANXA1. The expression of Anxa1 is negatively correlated with the levels of Egf, Notch1, Mkk7, and phosphorylated AKT1 and ERK/2 proteins. The levels of Egf, Notch1, Mkk7 and phosphorylation of AKT1 and ERK/2 increased in Anxa1 KO mice but decreased in Anxa1 OE mice. Taken together, our results suggested that ANXA1 could affect the hair growth by regulating the HFSCs proliferation through EGF signaling pathway.
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http://dx.doi.org/10.1016/j.gene.2020.145343DOI Listing
March 2021

Integration of Risk Survival Measures Estimated From Pre- and Posttreatment Computed Tomography Scans Improves Stratification of Patients With Early-Stage Non-small Cell Lung Cancer Treated With Stereotactic Body Radiation Therapy.

Int J Radiat Oncol Biol Phys 2021 Jan 19. Epub 2021 Jan 19.

Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Purpose: To predict overall survival of patients receiving stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (ES-NSCLC), we developed a radiomic model that integrates risk of death estimates and changes based on pre- and posttreatment computed tomography (CT) scans. We hypothesize this innovation will improve our ability to stratify patients into various oncologic outcomes with greater accuracy.

Methods And Materials: Two cohorts of patients with ES-NSCLC uniformly treated with SBRT (a median dose of 50 Gy in 4-5 fractions) were studied. Prediction models were built on a discovery cohort of 100 patients with treatment planning CT scans, and then were applied to a separate validation cohort of 60 patients with pre- and posttreatment CT scans for evaluating their performance.

Results: Prediction models achieved a c-index up to 0.734 in predicting survival outcomes of the validation cohort. The integration of the pretreatment risk of survival measures (risk-high vs risk-low) and changes (risk-increase vs risk-decrease) in risk of survival measures between the pretreatment and posttreatment scans further stratified the patients into 4 subgroups (risk: high, increase; risk: high, decrease; risk: low, increase; risk: low, decrease) with significant difference (χ = 18.549, P = .0003, log-rank test). There was also a significant difference between the risk-increase and risk-decrease groups (χ = 6.80, P = .0091, log-rank test). In addition, a significant difference (χ = 7.493, P = .0062, log-rank test) was observed between the risk-high and risk-low groups obtained based on the pretreatment risk of survival measures.

Conclusion: The integration of risk of survival measures estimated from pre- and posttreatment CT scans can help differentiate patients with good expected survival from those who will do more poorly following SBRT. The analysis of these radiomics-based longitudinal risk measures may help identify patients with early-stage NSCLC who will benefit from adjuvant treatment after lung SBRT, such as immunotherapy.
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http://dx.doi.org/10.1016/j.ijrobp.2020.12.014DOI Listing
January 2021

NRG Oncology Survey on Practice and Technology Use in SRT and SBRT Delivery.

Front Oncol 2020 27;10:602607. Epub 2020 Nov 27.

Cancer Institute, Allegheny Health Network, Pittsburgh, PA, United States.

Purpose: To assess stereotactic radiotherapy (SRT)/stereotactic body radiotherapy (SBRT) practices by polling clinics participating in multi-institutional clinical trials.

Methods: The NRG Oncology Medical Physics Subcommittee distributed a survey consisting of 23 questions, which covered general technologies, policies, and procedures used in the Radiation Oncology field for the delivery of SRT/SBRT (9 questions), and site-specific questions for brain SRT, lung SBRT, and prostate SBRT (14 questions). Surveys were distributed to 1,996 radiotherapy institutions included on the membership rosters of the five National Clinical Trials Network (NCTN) groups. Patient setup, motion management, target localization, prescriptions, and treatment delivery technique data were reported back by 568 institutions (28%).

Results: 97.5% of respondents treat lung SBRT patients, 77.0% perform brain SRT, and 29.1% deliver prostate SBRT. 48.8% of clinics require a physicist present for every fraction of SBRT, 18.5% require a physicist present for the initial SBRT fraction only, and 14.9% require a physicist present for the entire first fraction, including set-up approval for all subsequent fractions. 55.3% require physician approval for all fractions, and 86.7% do not reposition without x-ray imaging. For brain SRT, most institutions (83.9%) use a planning target volume (PTV) margin of 2 mm or less. Lung SBRT PTV margins of 3 mm or more are used in 80.6% of clinics. Volumetric modulated arc therapy (VMAT) is the dominant delivery method in 62.8% of SRT treatments, 70.9% of lung SBRT, and 68.3% of prostate SBRT.

Conclusion: This report characterizes SRT/SBRT practices in radiotherapy clinics participating in clinical trials. Data made available here allows the radiotherapy community to compare their practice with that of other clinics, determine what is achievable, and assess areas for improvement.
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http://dx.doi.org/10.3389/fonc.2020.602607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729187PMC
November 2020

Offline Quality Assurance for Intensity Modulated Radiation Therapy Treatment Plans for NRG-HN001 Head and Neck Clinical Trial Using Knowledge-Based Planning.

Adv Radiat Oncol 2020 Nov-Dec;5(6):1342-1349. Epub 2020 May 22.

Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania.

Purpose: This study aimed to investigate whether a disease site-specific, multi-institutional knowledge based-planning (KBP) model can improve the quality of intensity modulated radiation therapy treatment planning for patients enrolled in the head and neck NRG-HN001clinical trial and to establish a threshold of improvements of treatment plans submitted to the clinical trial.

Methods And Materials: Fifty treatment plans for patients enrolled in the NRG-HN001 clinical trial were used to build a KBP model; the model was then used to reoptimize 50 other plans. We compared the dosimetric parameters of the submitted and KBP reoptimized plans. We compared differences between KBP and submitted plans for single- and multi-institutional treatment plans.

Results: Mean values for the dose received by 95% of the planning target volume (PTV_6996) and for the maximum dose (D0.03cc) of PTV_6996 were 0.5 Gy and 2.1 Gy higher in KBP plans than in the submitted plans, respectively. Mean values for D0.03cc to the brain stem, spinal cord, optic nerve_R, optic nerve_L, and chiasm were 2.5 Gy, 1.9 Gy, 6.4 Gy, 6.6 Gy, and 5.7 Gy lower in the KBP plans than in the submitted plans. Mean values for D to parotid_R and parotid_L glands were 2.2 Gy and 3.8 Gy lower in KBP plans, respectively. In 33 out of 50 KBP plans, we observed improvements in sparing of at least 7 organs at risk (OARs) (brain stem, spinal cord, optic nerves (R & L), chiasm, and parotid glands [R & L]). A threshold of improvement of OARs sparing of 5% of the prescription dose was established for providing the quality assurance results back to the treating institution.

Conclusions: A disease site-specific, multi-institutional, clinical trial-based KBP model improved sparing of OARs in a large number of reoptimized plans submitted to the NRG-HN001 clinical trial, and the model is being used as an offline quality assurance tool
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http://dx.doi.org/10.1016/j.adro.2020.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718499PMC
May 2020

Overview of the First NRG-NCI Workshop on Dosimetry of Systemic Radiopharmaceutical Therapy (RPT).

J Nucl Med 2020 Dec 4. Epub 2020 Dec 4.

McMaster University.

In 2018, the National Cancer Institute (NCI) and the NRG Oncology partnered for the first time to host a joint Workshop on Systemic Radiopharmaceutical Therapy (RPT) to specifically address issues and strategies of dosimetry for future clinical trials. The workshop focused on (1) current dosimetric approaches for clinical trials, (2) strategies under development that would provide optimal dose reporting, and (3) future desired/optimized approaches for the new and novel emerging radionuclides and carriers in development. In this proceedings, we review the main approaches that are applied clinically to calculate the absorbed dose: These include absorbed doses calculated over a variety of spatial scales including organ, suborgan, and voxel, all achievable within the Medical Internal Radiation Dose (MIRD) schema (S-value) can be calculated with analytic methods or Monte Carlo methods, the latter in most circumstances. This proceeding will also contrast currently available methods and tools with those used in the past, to propose a pathway whereby dosimetry helps the field by optimizing the biological effect of the treatment and trial design in the drug approval process to reduce financial and logistical costs. We will also discuss the dosimetric equivalent of biomarkers to help bring a precision medicine approach to RPT implementation-when merited by evidence collected during early-phase trial investigations. Advances in the methodology and related tools have made dosimetry the optimum biomarker for RPT.
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http://dx.doi.org/10.2967/jnumed.120.255547DOI Listing
December 2020

Pathological Mechanisms and Potential Therapeutic Targets of Pulmonary Arterial Hypertension: A Review.

Aging Dis 2020 Dec 1;11(6):1623-1639. Epub 2020 Dec 1.

1Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Pulmonary arterial hypertension (PAH) is a progressive cardiovascular disease characterized by pulmonary vasculature reconstruction and right ventricular dysfunction. The mortality rate of PAH remains high, although multiple therapeutic strategies have been implemented in clinical practice. These drugs mainly target the endothelin-1, prostacyclin and nitric oxide pathways. Management for PAH treatment includes improving symptoms, enhancing quality of life, and extending survival rate. Existing drugs developed to treat the disease have resulted in enormous economic and healthcare liabilities. The estimated cost for advanced PAH has exceeded $200,000 per year. The pathogenesis of PAH is associated with numerous molecular processes. It mainly includes germline mutation, inflammation, dysfunction of pulmonary arterial endothelial cells, epigenetic modifications, DNA damage, metabolic dysfunction, sex hormone imbalance, and oxidative stress, among others. Findings based on the pathobiology of PAH may have promising therapeutic outcomes. Hence, faced with the challenges of increasing healthcare demands, in this review, we attempted to explore the pathological mechanisms and alternative therapeutic targets, including other auxiliary devices or interventional therapies, in PAH. The article will discuss the potential therapies of PAH in detail, which may require further investigation before implementation.
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http://dx.doi.org/10.14336/AD.2020.0111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673851PMC
December 2020

Lidocaine inhibits glioma cell proliferation, migration and invasion by modulating the circEZH2/miR-181b-5p pathway.

Neuroreport 2021 01;32(1):52-60

Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University.

Background: Lidocaine is well known as a local anesthetic that has been reported to play an antitumor role in numerous cancers, including glioma. Circular RNAs (circRNAs) play multiple biological roles in cancers. The aim of this study was to determine the effects of lidocaine in glioma in vitro and in vivo and explore functional mechanisms.

Methods: The effects of lidocaine on glioma progression were investigated by cell proliferation, migration and invasion using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, colony formation assay and transwell assay. The expression of CD133 and glial fibrillary acidic protein (GFAP) was quantified by western blot to assess cell differentiation. The expression of circEZH2 and miR-181b-5p was detected by a quantitative real-time PCR (qRT-PCR). The target relationship between circEZH2 and miR-181b-5p was verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. The effect of lidocaine on tumor growth in vivo was investigated by establishing Xenograft models.

Results: Lidocaine inhibited proliferation, migration, invasion and induced differentiation of glioma cells in vitro. Lidocaine suppressed the expression of circEZH2, and circEZH2 was highly expressed in glioma tissues and cells. CircEZH2 overexpression partly inhibited the function of lidocaine. CircEZH2 was a sponge of miR-181b-5p, and miR-181b-5p was downregulated in glioma tissues and cells. Besides, miR-181b-5p restoration reversed the effects of circEZH2 overexpression to repress the malignant behaviors of glioma cells. In addition, lidocaine mediated the circEZH2/miR-181b-5p axis to inhibit tumor growth in vivo.

Conclusion: Lidocaine suppressed glioma progression by modulating the circEZH2/miR-181b-5p pathway.
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http://dx.doi.org/10.1097/WNR.0000000000001560DOI Listing
January 2021