Shanghai Medical University Research Articles

Development and multi-institutional validation of a deep learning model for grading of vesicoureteral reflux on voiding cystourethrogram: a retrospective multicenter study

Voiding cystourethrography (VCUG) is the gold standard for the diagnosis and grading of vesicoureteral reflux (VUR). However, VUR grading from voiding cystourethrograms is highly subjective with low reliability. This study aimed to develop a deep learning model to improve reliability for VUR grading on VCUG and compare its performance to that of clinicians. In this retrospective study in China, VCUG images were collected between January 2019 and September 2022 from our institution as an internal dataset for training and 4 external data sets as external testing set for validation. Samples were divided into training (N=1000) and validation sets (N=500), internal testing set (N=168), and external testing set (N=280). An ensemble learning-based model, Deep-VCUG, using Res-Net 101 and the voting methods was developed to predict VUR grade. The grading performance was assessed using heatmaps, area under the receiver operating characteristic curve (AUC), sensitivity, specificity, accuracy, and F1 score in the internal and external testing set. The performances of four clinicians (2 pediatric urologists and 2 radiologists) with and without the Deep-VCUG assisted to predict VUR grade were explored in external testing sets. A total of 1948 VCUG images were collected (Internal dataset=1668; multi-center external dataset=280). For assessing unilateral VUR grading, the Deep-VCUG achieved AUCs of 0.962 (95% confidence interval [CI]: 0.943-0.978) and 0.944 (95% [CI]: 0.921-0.964) in the internal and external testing sets, respectively, for bilateral VUR grading, the Deep-VCUG also achieved high AUCs of 0.960 (95% [CI]: 0.922-0.983) and 0.924 (95% [CI]: 0.887-0.957). The Deep-VCUG model using voting method outperformed single model and clinician in terms of classification based on VCUG image. Moreover, Under the Dee-VCUG assisted, the classification ability of junior and senior clinicians was significantly improved. The Deep-VCUG model is a generalizable, objective, and accurate tool for vesicoureteral reflux grading based on VCUG imaging and had good assistance with clinicians to VUR grading applicability. This study was supported by Natural Science Foundation of China, "Fuqing Scholar" Student Scientific Research Program of Shanghai Medical College, Fudan University, and the Program of Greater Bay Area Institute of Precision Medicine (Guangzhou).

Meet the First Authors.

HomeCirculation ResearchVol. 132, No. 6Meet the First Authors Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBMeet the First Authors Originally published16 Mar 2023https://doi.org/10.1161/RES.0000000000000603Circulation Research. 2023;132:672–673is related toGJA1-20k Rescues Cx43 Localization and Arrhythmias in Arrhythmogenic CardiomyopathySmooth Muscle MR in Post-Preeclampsia Hypertension (p 674)Download figureDownload PowerPointDr Lauren Biwer is a postdoctoral researcher in Dr Iris Jaffe’s lab at Tufts Medical Center. She became passionate about research in Dr Taben Hale’s lab at the University of Arizona and completed her PhD in Molecular Physiology at the University of Virginia with Dr Brant Isakson. When her sister developed preeclampsia, she became interested in mitigating future cardiovascular disease in women with complicated pregnancies. Lauren received a K99 grant to pursue this work and is thrilled to start her independent laboratory in the Yale Vascular Biology and Therapeutics program in November 2023. She enjoys traveling, outdoor activities, college sports and reading non-fiction. She can be found on Twitter @DrLaurenBiwer.Endosomal PI3Kγ Regulates Hypoxia Sensing (p 690)Download figureDownload PowerPointDr Yu Sun (Cynthia) earned her MD in Pathology from Shanghai Medical College at Fudan University in 2014. Following her clinical training, Cynthia joined the lab of Dr Naga Prasad in 2017 as a postdoctoral fellow to understand the mechanisms regulating βAR function in hypoxia. Unexpectedly, she found that hypoxia regulates endosomal βAR function by inhibition of resensitization through PI3K. Her current work focuses on dissecting the agonist-independent endosomal regulation of βARs, as acute hypoxia is the initial stress following ischemia. During her free time Cynthia enjoys reading and watching movies.Download figureDownload PowerPointKate Stenson is currently Senior Laboratory Technologist in the Department of Cardiovascular and Metabolic Sciences at Lerner Research Institute, Cleveland Clinic. She earned her undergraduate degrees in Marine Biology and Psychobiology from the University of New England in Maine. She joined Cleveland Clinic to further extend her hands-on approach from her undergraduate education to the mouse models of pathology, specifically heart failure. She is passionate about unraveling scientific discoveries through the use of animal models and during her spare time, when she is not imaging mice, she likes to play with her kids and take them to musicals.Dectin-1 Mediates Ang II Action in Heart (p 707)Download figureDownload PowerPointDr Shiju Ye earned his MS in Cardiovascular Disease at the Wenzhou Medical University, China, in 2019, and is now pursing his Cardiovascular Disease PhD at Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, China. Dr Ye’s recent research interests include Ang II related cardiac inflammation, heart failure, and the crosstalk between the cardiomyocytes and macrophages. Outside of the laboratory, he not only maintains an active social life and studies, but also focuses on learning clinical knowledge of cardiovascular disease.GJA1-20k Reduces Arrhythmias in ACM (p 744)Download figureDownload PowerPointDr Joseph Palatinus is an Assistant Professor of Medicine at the Nora Eccles Harrison Cardiovascular Research and Training Institute at the University of Utah and Critical Care Cardiologist at Intermountain Medical Center. He completed his residency at Beth Israel Deaconess Medical Center and cardiology and critical care medicine fellowships at Cedars Sinai Medical Center. His postdoctoral work focused on gap junction trafficking in the laboratory of Dr Robin Shaw. The Palatinus Lab is focused on mechanisms contributing to disease progression in arrhythmogenic cardiomyopathy. Dr Palatinus’s clinical interests are focused on the care of patients with cardiogenic shock in the CCU. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesGJA1-20k Rescues Cx43 Localization and Arrhythmias in Arrhythmogenic CardiomyopathyJoseph A. Palatinus, et al. Circulation Research. 2023;132:744-746 March 17, 2023Vol 132, Issue 6 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000603PMID: 36927179 Originally publishedMarch 16, 2023 PDF download Advertisement

Elevated Serum Interleukin-17 Levels in Thoracic Trauma Patients with Poor Prognosis: A Prospective Observational Study

To measure interleukin (IL)-17 serum levels in thoracic trauma patients and to correlate these levels with other cytokines and with patient prognosis. Methods: This prospective observational study recruited 130 thoracic trauma patients who were admitted to the Zhoupu Hospital Affiliated to Shanghai Medical College of Health June 2020 to April 2022 and 100 healthy volunteers. Patients were divided into two groups based on Injury Severity Score (ISS): ISS<16 (mild/moderate trauma) and ISS ≥16 (severe trauma). Serum IL-17, tumor necrosis factor α (TNF-α), IL-6, IL-1β and C-reactive protein (CRP) levels were measured by enzyme-linked immunosorbent assay. Patients with poor prognosis were defined as those who developed serious complications or died during hospitalization or follow-up. Results: Serum levels of IL-17, TNF-α, IL-6 and IL-1β were significantly elevated in patients with ISS ≥16 (p<0.05). Serum cytokines levels increased within 48 h in both groups and then gradually decreased during subsequent treatment and rehabilitation. Pearson's analysis indicated a positive correlation among IL-17, TNF-α and IL-1β. Serum IL-17 levels in patients with poor prognoses were higher than the patients with good prognoses at all time points (p<0.05). Furthermore, for patients with poor prognoses, the serum IL-17 levels had highest diagnostic value among all the cytokines measured. Logistic regression analysis showed that IL-17 was the risk factor for thoracic trauma patients with poor prognoses. Conclusion: Serum IL-17 levels were significantly elevated in thoracic trauma patients and decreased gradually with rehabilitation. IL-17 was a risk factor for thoracic trauma patients with poor prognoses. This study suggests a new diagnostic and therapeutic target for thoracic trauma patients.

Commentary: Endoscope-Assisted Microsurgical Resection of a Large Petroclival Meningioma Using a Retrosigmoid Approach: 2-Dimensional Operative Video.

*Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China; ‡National Center for Neurological Disorders; §Shanghai Key laboratory of Brain Function and Restoration and Neural Regeneration; ‖Neurosugical Institute of Fudan University, Shanghai, China; ¶Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China Correspondence: Feng Xu, MD, Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, No. 12 Wulumuqi Middle Rd, Shanghai, China. Email: [email protected]

COVID-2019 Vaccine A Scientometric Assessment of Global Publications during 2020

<p style="text-align: justify;"><strong>Objectives:</strong> The study presents a bibliometric assessment of COVID-19 vaccine research publications to understand the current and up-to-date scenario of COVID-19 vaccine research and to track important research players and identify the current areas. <strong>Materials and Methods: </strong>The global literature on COVID-19 vaccine research published during 2020 were searched in the Scopus database, using the keywords &ldquo;COVID-19 vaccine&rdquo; or &ldquo;Coronavirus 19 vaccine&rdquo; on 12 September 2020. The 343 global records on COVID-19 vaccine research were obtained which received 2636 citations and were published in 66 countries involving 280 organizations, 259 authors and 191 journals. The publication records obtained were statistically analyzed by using various bibliometric indices: document type, country, collaboration patterns, affiliation, journal name, and citation patterns. <strong>Results:</strong> Among top 12 countries, USA, U.K and China were the most productive and China, South Korea and USA were the most impactful. Nearly 51% publications of these top 12 countries were international collaborative. The top most productive organizations were Harvard Medical School, USA (12 papers), University of Washington, Seattle, USA (10 papers) and Fudan University, China (with 12, 10 and 8 papers. Th. top most impactful organizations in terms of citation per paper and relative citation index were Tongji Medical College, China (56.0 and 7.28), Shanghai Medical College, China (33.2 and 4.32) and Chinese Center for Disease Control and Prevention, China (23.5 and 3.06). The most productive journals were Nature, Science and Vaccine (24, 18 and 18 papers each) and the most impactful journals in terms of citations per paper were: Journal of Medical Virology (66.5), Cell (27.2) and New England Journal of Medicine (23.4). <strong>Conclusion:</strong> This results and findings emerging from the study shed new light on the major progress in the present time on hot topics on COVID-19 vaccine research. <p style="text-align: justify;"><strong>Key words: </strong>COVID-19, Vaccine, Global publications, Bibliometrics, Scientometrics.

Editorial introductions.

Editorial introductions.

NEOGAMES: A Serious Computer Game That Improves Long-Term Knowledge Retention of Neonatal Resuscitation in Undergraduate Medical Students.

Background: Serious games are potential alternatives for supplementing traditional simulation-based education for neonatal resuscitation training. However, evidence regarding the benefits of using serious games to improve long-term knowledge retention of neonatal resuscitation in undergraduate medical students is lacking.Objective: We designed a serious computer game “NEOGAMES” to train undergraduate medical students in neonatal resuscitation in a cost-friendly and accessible way and to examine whether serious game-based training improves long-term knowledge retention in medical students.Methods: “NEOGAMES” consists of a screen with images of an incubator, a baby, visual objects, anatomy, action cards, monitors, real-time feedback, and emotional components. Undergraduate medical students from Shanghai Medical College of Fudan University were invited to participate and were allocated to a game group or a control group. Participants in the game group played the game before the training. All the participants completed three written tests, pre- and post-training knowledge tests and a follow-up test after 6 months.Results: Eighty-one medical students participated in the study. The student demographic characteristics of the groups were comparable, including sex, age, and grade point average (GPA). Significant short-term knowledge improvement was noticed only for male students in the game group based on their 5.2-point higher test scores than those of the controls (p = 0.006). However, long-term knowledge improvement at 6 months was identified for both male and female students in the game group, with test scores 21.8 and 20 points higher, respectively, than those of the controls (P < 0.001). The long-term knowledge retention in the game group was almost 3 times higher than that in the control group.Conclusions: Long-term knowledge retention was nearly 3 times higher for the game group than for the control group. The improvement in knowledge supports the use of serious games for undergraduate medical education.

CpG2 hypermethylation in the CD95L promoter is associated with survival in patients with glioblastoma: An observational study

Background and Aim: Blockade of CD95/CD95 ligand (CD95 L) signaling is a promising therapeutic approach for the treatment of glioblastoma (GBM), while methylation of a single cytosine-phosphate-guanine site (CpG2) upstream of the CD95 L promoter has been identified as a prognostic biomarker for GBM. Here, we conducted the first investigation of CD95 L expression and CpG2 methylation levels in the CD95 L promoter in GBM patients. Materials and Methods: In this observational study, tissue samples were collected from 69 patients with a primary diagnosis of World Health Organization Grade IV GBM treated at the Department of Glioma Surgery, Huashan Hospital, Shanghai Medical College, Fudan University and tested for CD95 L expression using immunohistochemistry (IHC). The CpG2 methylation status of the samples was also evaluated, and its impact on overall survival (OS) was assessed by univariate analysis. The study was approved by the Hospital Institutional Review Board (approval No. 220) on July 7, 2015. Results: The IHC results showed a CD95 L detection rate of at least 43.5% for tissue samples with IHC scores of 2+ or 3+ and 78.3% for those with IHC scores of 1+, 2+, or 3+. Patients with high CpG2 methylation levels (≥52% higher than the median value; n = 32) had significantly longer median survival compared with those with low CpG2 methylation levels (n = 29) (22.95 vs. 14.5 months; P = 0.0084). GBM patients who underwent gross total tumor resection (n = 57) showed similar results. Those in the high CpG2 methylation group had longer median OS compared with that of patients in the low CpG2 methylation group (23.5 vs. 18.0 months; P = 0.0141). Conclusions: Our results showed a significant prevalence of CD95 L expression in GBM patients, whereas CpG2 hypermethylation within the CD95 L promoter was positively associated with survival. These findings support that CD95/CD95 L signaling blockade has potential as a therapeutic strategy targeting treatment-resistant GBM.

Three-Dimensional Visualization of Acupoints and Electroacupuncture Spatiotemporal Effects

Acupuncture has a long history and definite effectiveness in traditional Chinese medicine. Manual acupuncture and electroacupuncture stimulate specific acupoints on meridians to obtain local and/or systemic biological effects, but the mechanism behind these effects remains unclear. In the present study, we used three-dimensional tissue-clearing technology to study four specific acupoints on the Ren meridian of mice, which is located within the anatomic landmark of the linea alba. The distribution, density, branching, and relationships between blood vessels and nerves were quantitated. The acupoints and meridian before and after electroacupuncture were visualized and analyzed together with the surrounding structures using topological Mapper methods. We found that capillary branching and sympathetic neurovascular interactions (SNIs) were denser in the CV 4 acupoint (Guanyuan) compared with surrounding non-acupoints. Furthermore, SNIs in CV 4 indicated capabilities in topological amplification, which was confirmed by high resolution in vivo dynamic vascular imaging. After electro or manual acupuncture, CV 4 showed different degrees of increased blood flow detected with NIR-II probe of LZ-1105, compared with little increased in non-acupoints. Our research suggests that accumulated SNIs in acupoints might have capability of amplification that might be related to the acupuncture stimulation, and this provides a basis for further research to reveal the exact anatomic basis underlying the acupuncture. Funding Statement: This work was supported by the National Natural Science Foundation of China (NSFC 81673766 & 81973945 to Y.F.), the Innovative Research Team of High-level Local Universities in Shanghai, and the Development Project of Shanghai Peak Disciplines Integrated Chinese and Western Medicine (20180101 to Y.F.), and the Project Supported by Shanghai Municipal Science and Technology Major Project (No.2018SHZDZX01) and ZJLab. Declaration of Interests: The authors indicate no potential conflicts of interest. Ethics Approval Statement: The current study was approved by the Animal Ethics Committee of Shanghai Medical College, Fudan University, Shanghai, China (ID:20160225-013 and 20200306-004).

Experience of teaching and training for medical students at gastrointestinal surgery department under COVID-19 epidemic situation

In hospitals and medical schools as densely populated sites with high risk of coronavirus disease 2019 (COVID-19), it is vital to adjust the teaching and training strategy for medical students to ensure curriculum completion with safety. This article aims to introduce the experience of teaching and training for medical students under the epidemic situation at Department of Surgery, Shanghai Medical College, Fudan University and Zhongshan Hospital. The content includes exploring diversified online teaching models for undergraduate surgery courses and clinical practice, carrying out online graduate education and dissertation plans, and strengthening comprehensive education of medical humanity combined with knowledge of COVID-19 prevention. Through implementation of the above teaching strategies, scheduled learning plans of medical students can be well completed in an orderly, safe and quality-ensured manner. Our experience provides practical solution of medical teaching and could be advisable for other medical colleges and teaching hospitals.

Positive impact of COVID-19 on career choice in pediatric medical students: a longitudinal study.

BackgroundOn March 11th, 2020, the WHO made the assessment that coronavirus disease 2019 (COVID-19) could be characterized as a pandemic. Medical students experienced a greater degree of anxiety and psychological stress than during previous pandemics. Negative emotions were related to decreased medical career interest, increased career choice regret and dropout rates in medical students, which affected academic and professional development. The goal of this study was to investigate the impact of the current COVID-19 outbreak on the career preferences of pediatric medical students and to explore the underlying factors contributing to it.MethodsA prospective, longitudinal study was conducted among all 120 pediatric medical students from Shanghai Medical College of Fudan University on November 23rd, 2019, and February 21st, 2020 using a 7-item online questionnaire about career choice.ResultsA total of 106 (41 male and 65 female) students with a mean age of 21 years consented to participate in this study. The response rate was 100% in November 2019 and 98.1% in February 2020. Since the outbreak, career choices to practice medicine or pediatrics did not drop significantly, decreasing by only 4.3% and 2.2%, respectively. There was a positive impact of the COVID-19 outbreak on strengthening 66.7% of students’ beliefs and choices to become good pediatricians (P<0.001). Only 14 students (13.5%) thought that COVID-19 had a negative impact on their career choices, but the majority of them were in the 3rd (28.6%) and 4th (64.3%) years of medical education and had insufficient knowledge about the hospital environment and clinics.ConclusionsThe outbreak of COVID-19 might have an overall positive impact on career choice by strengthening students’ belief and choice to become good doctors and may decrease the choice regret and drop rates of the next generation of doctors. Special attention should be paid to students with insufficient clinical experience. Good protection for students, sharing outstanding stories regarding fighting the pandemic, and innovations of needs-based curriculum could be helpful during this pandemic. Future studies are warranted to confirm these findings.

Clinical characteristics of myelin oligodendrocyte glycoprotein antibody associated myelitis

Objective: To evaluate the clinical characteristics of myelin oligodendrocyte glycoprotein antibody (MOG-IgG) associated myelitis in a cohort of Chinese Han adults. Methods: From January 2016 to December 2017, 70 patients with MOG-IgG associated disorders (MOGAD) and 120 patients with aquaporin 4 antibody (AQP4-IgG) positive neuromyelitis optica spectrum disorders (NMOSD) visited the NMO/MS clinic or the neurology ward of Huashan Hospital, and the neurophthalmology clinic of Eye and ENT hospital, Shanghai Medical College, Fudan University were enrolled. The clinical and paraclinical data of the patients were retrospectively reviewed. The characteristics of MOG-IgG associated myelitis were further clarified. Results: Sixteen of the 70 patients with MOGAD had ever experienced myelitis. The frequency of myelitis was 18.6% at the first attack and 22.9% throughout the disease duration. The onset age of MOG-IgG associated myelitis was 9-57(30±11) years, and the female to male ratio was 0.6∶1. Compared with AQP4-IgG positive myelitis attacks, MOG-IgG associated myelitis attacks were more common to be accompanied by feverish prodromal symptom (30.8%) while less common to exhibit painful tonic (12.5%). Longitudinally extensive myelitis (>3 vertebral segments) was less frequent (56.3%), and short-segment myelitis and multiple short-segment myelitis could also be seen. MRI showed that MOGAD patients had more lower spinal cord lesions (20%), fewer cervical cord lesions (40%) and less transverse lesions (52%). Axial H sign was a distinct feature (36%). MOG-IgG associated myelitis attack also demonstrated a lower EDSS score after treatment. Conclusion: MOG-IgG associated myelitis should be recognized as an important clinical component of MOGAD.

KLF4 Initiates Sustained Activation of YAP After AKI to Promote Renal Fibrosis

Acute renal injury (AKI) has been recognized as long-term risks for progressing into chronic kidney disease (CKD) and interstitial fibrosis. Hippo pathway was previously noticed facilitating the renal tubular repair after AKI. In the ischemia-reperfusion (IR)-induced AKI to CKD animal model, the expression and nucleus distribution of YAP were persistently increased to the end of experiment (21 days after IR surgery). The sustained activation of YAP in post-acute phase of AKI was involved in renal functional decline and interstitial fibrosis. Activation of YAP increased the expression of transforming growth factor-β (TGF-β) and connective tissue growth factor (CTGF). Reprogramming factor KLF4 was lined on the upstream of YAP. KLF4 upregulated the expression of YAP and ITCH. ITCH facilitates YAP activation and nuclear translocation via degrading LATS1. Knockdown on KLF4 attenuated the increase in YAP and nuclear translocation as well as renal functional deterioration and interstitial fibrosis. The expression and nuclear distribution of YAP were also increased in biopsy sample from CKD patients. In conclusion, the activation of YAP in the post-acute phase of AKI is implicated in renal functional deterioration and fibrosis although it exhibits beneficial effect in acute phase. Reprogramming factor KLF4 is responsible for the persistent activation of YAP. Shutting down the activation of KLF4-YAP pathway appropriately might be a way to prevent the transition of AKI into CKD. Funding Statement: This research was financially supported by the Natural Science Foundation of China No. 81873603, 81670664 to Lu L and No. 81770718 to Wang X. Declaration of Interests: All the authors declared no conflict of interests exists. Ethics Approval Statement: All experiments using mice were performed according to the criteria of the Medical Laboratory Animal Administrative Committee of Shanghai and the Guide for Care and Use of Laboratory Animals of Fudan University, and protocols were approved by the Ethics Committee for Experimental Research, Shanghai Medical College, Fudan University

Prognosis of the 8th TNM Staging System for Penile Cancer and Refinement of Prognostication by Incorporating High Risk Human Papillomavirus Status.

We evaluated the prognostic value of the 8th TNM staging system and assessed a modified N stage incorporating high risk human papillomavirus status in a multicenter cohort. Included in analysis were 292 patients with M0 penile squamous cell carcinoma from a total of 6 referral centers. High risk human papillomavirus status was examined. The Chinese multicenter cohort of 230 patients was used to validate the 8th TNM staging system and propose a modified N classification. The modified classification was further validated in an independent cohort of 62 patients at Moffitt Cancer Center. Median followup was 48.9 months. Of the patients 42% had node positive disease. In the primary cohort the 8th TNM staging system achieved better discriminative ability compared with the 7th edition (C-index 0.769 vs 0.751, p=0.029). The 8th N category better stratified survival between pN1 and pN2 (p <0.001) and reclassified 15% of node positive cases into pN1 with 64% 5-year overall survival. High risk human papillomavirus status further stratified pN2-3 disease (p=0.040) and pN2-3 high risk human papillomavirus negative status was associated with 32% 5-year survival. The newly proposed 3-tier classification (1-pN1, 2-pN2-3 high risk human papillomavirus positive and 3-pN2-3 high risk human papillomavirus negative) significantly increased the C-index from 0.620 to 0.666 compared with the 8th N classification of pN1 and pN2-3 (p=0.04). In the external validation cohort significantly improved results were observed using the modified N classification (C-index 0.567-0.641, p=0.027). The 8th edition of the AJCC (American Joint Committee on Cancer) Staging System for penile cancer showed better discriminative ability for prognostic stratification. Adding high risk human papillomavirus status further improved the prognostic stratification in patients with node positive disease.

Bach1-Induced Suppression of Angiogenesis Is Dependent on the BTB Domain

The transcription factor BTB and CNC homology 1 (Bach1) impairs angiogenesis after ischemic injury by suppressing Wnt/β-catenin signaling; however, the specific domains responsible for the antiangiogenic effects of Bach1 remain unclear. This study determined the role of the BTB domain of Bach1 in ischemic angiogenesis. Bach1 is highly expressed in circulating endothelial cells from acute myocardial infarction patients, and is the early induction gene after ischemic inuced injury. Mice were treated with adenoviruses coding for GFP (AdGFP), Bach1 (AdBach1), or a Bach1 mutant lacking the BTB domain (AdBach1-ΔBTB) after surgically induced hind-limb ischemia. Measures of blood-flow recovery, capillary density, and the expression of vascular endothelial growth factor (VEGF) were significantly lower in the AdBach1 group, but not in AdBach1-ΔBTB animals. Furthermore, transfection with AdBach1, but not AdBach1-ΔBTB, in human umbilical-vein endothelial cells (HUVECs) was associated with significant declines in 1) capillary density and hemoglobin content in the Matrigel-plug assay, 2) proliferation, migration, tube formation, and VEGF transcriptional activity and mRNA expression in HUVECs. Bach1 binds directly with TCF4, and this interaction is mediated by residues 81-89 of the Bach1 BTB domain and the N-terminal CTNNB1 domain of TCF4. Bach1, but not Bach1-ΔBTB, also copreciptated with histone deacetylase 1 (HDAC1), while the full-length HDAC1 proteins, but not HDAC1 mutants lacking the protein-interaction domain, co-precipitated with Bach1. Collectively, these results demonstrate that the anti-angiogenic activity of Bach1 is crucially dependent on molecular interactions that are mediated by the protein's BTB domain, and this domain could be a drug target for angiogenic therapy. Funding Statement: This work was supported by the Great Program (91639103 to D. Meng), and General Programs (81670450 and 81873469 to D. Meng, 81570081 and 81770083 to S. Li, 81800234 to L. Jiang, 81572713 to X. Zhi, 81873536 to X. Wang) of the National Natural Science Foundation of China, the National Key Research and Development Program of China (2018YFC1313600 to S. Li). Declaration of Interests: The authors state: None. Ethics Approval Statement: HUVECs were isolated (12) from the fresh umbilical cord of normal parturients with informed consent. The procedure was approved by the Ethics Committee of Experimental Research at Fudan University Shanghai Medical College. All experimental protocols were approved by the Ethics Committee of Experimental Research at Fudan University Shanghai Medical College and performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH publication No 85-23).

Profile of Junying Yuan

Cell biologist Junying Yuan vividly remembers the moment when, during her second year of graduate school at Harvard University in 1983, a thin, restless Huntington’s disease patient was wheeled into her “Neurobiology of Disease” class. “I was appalled that modern medicine could do little for him,” she says. “He and others suffering from neurodegenerative diseases made a lasting impression on me. I became emotionally motivated to try to help these patients.” Photograph of Junying Yuan. Image courtesy of Aaron Washington for Harvard Medical School. Over the subsequent three decades, Yuan and her team have made major discoveries concerning the molecular mechanisms regulating cell death involved in normal development and a wide range of disorders. Her achievements include discovery of the regulated necrotic cell death pathway termed “necroptosis” and its key mediator, the kinase receptor-interacting serine/threonine-protein 1 (RIPK1). She and her colleagues also discovered the evolutionarily conserved role of caspase enzymes in regulating mammalian apoptosis. Elected to the National Academy of Sciences in 2017, Yuan reviews her team’s research on RIPK1, a kinase that is now a pharmaceutical target, in her Inaugural Article (IA). Yuan was born in Shanghai, China, to a family of scholars. Her father and mother were both professors at Fudan University Shanghai Medical College. Yuan’s paternal grandfather Kaiji was an organic chemistry professor at the college. During China’s cultural revolution, a sociopolitical movement from 1966 to 1976, universities closed and many textbooks were burned. The period adversely affected Yuan’s family, and Yuan thought factory work or farming was her only vocational option. Her high-school teacher Zhaiyang Lu, however, recognized her talent and urged Yuan to press on with her education. Since the only local science textbooks, dated to before the Cultural Revolution, were locked in the school library, Lu procured the books for her. Before returning them, …

Role and mechanism of circular RNA protein arginine methyltransferase 5 in proliferation, migration of colorectal cancer cells

Objective To evaluate the role of circular RNA protein arginine methyltransferase 5 (circPRMT5) in the genesis and progression of colorectal cancer. Methods From January 2013 to December 2017, 96 patients with colorectal cancer who underwent radical resection in Department of General Surgery, Jiading District Central Hospital Affiliated to Shanghai Medical College of Health were collected. The expression of circPRMT5 in colorectal cancer tissues was examined by real-time polymerase chain reaction (RT-PCR). The correlation between circPRMT5 expression level and age, gender, tumor size, tumor location, pathological differentiation, TNM stage, lymph node metastasis of patients with colorectal cancer was analyzed. The SW620 and LOVO cells were divided into control group, circPRMT5-lenti group and circPRMT5-shRNA-lenti group according to different interventions. The effects of circPRMT5 expression level on viability, apoptosis, mitochondrial membrane potential and migration of SW620 and LOVO cells were detected. The influence of circPRMT5 expression level on E-cadherin, Slug, N-cadherin and vimentin was determined by Western blotting method. The potential target miRNA of circPRMT5 was predicted by Starbase V2.0. Student′s t test, analysis of variance and chi-square test were performed for statistical analysis. Results The results of RT-PCR showed that the expression of circPRMT5 in colorectal cancer tissues was higher than that of adjacent cancer tissues (2.167±0.345 vs. 1.103±0.144), and the difference was statistically significant (t=26.847, P<0.01). The circPRMT5 expression level was positively correlated with tumor size, TNM stage, lymph node metastasis and distant metastasis (χ2=6.010, 10.971, 5.321 and 6.272, all P<0.05). The upregulation of circPRMT5 expression could promote proliferation and migration of SW620 and LOVO cells. The circPRMT5 downregulation could inhibit cell proliferation, induce apoptosis and decrease mitochondrial membrane potential. The results of Western blotting indicated that, compared with those of control group, the expression of Slug, N-cadherin and vimentin increased in circPRMT5-lenti group (1.023±0.038 vs. 2.105±0.042, 1.051±0.309 vs. 2.277±0.111, 1.055±0.040 vs. 2.002±0.537, respectively), however the expression of E-cadherin decreased (2.074±0.214 vs. 0.627±0.023), and the differences were statistically significant (t=31.817, 22.065, 14.536 and 9.148, all P<0.01). Compared with the control group, the expression of Slug, N-cadherin and vimentin decreased in circPRMT5-shRNA-lenti group (1.023±0.038 vs. 0.585±0.023, 1.051±0.309 vs. 0.616±0.043, 1.055±0.040 vs. 0.537±0.022), while the expression of E-cadherin increased (2.074±0.214 vs. 2.756±0.148), and the differences were statistically significant (t=-13.795, -14.252, -11.794 and -13.116, all P<0.05). A total of 21 miRNAs might have potential binding sites with circPRMT5 predicted by Starbase V2.0 software. The expression of miRNA4735-3p, miRNA202-3p, miRNA326, let-7i-5p and miRNA4500 was negatively correlated with circPRMT5 expression in both SW620 and LOVO cells confirmed by RT-PCR. Conclusion CircPRMT5 is an important oncogenic gene in the genesis and progress of colorectal cancer, and may have certain potential application prospect in the research and development for colorectal cancer. Key words: Colorectal neoplasms; circPRMT5; Epithelial-mesenchymal transition

BMPR2 Deficiency Inhibits Fatty Acid Oxidation and Renders White Adipocytes Vulnerable to TNFα-Induced Apoptosis

Adipocyte apoptosis is a normal process for adipose tissue self-renewal, however overt apoptosis is pathologically involved in both obesity and lipodystrophy. Pro-inflammatory cytokines are generally regarded as inducers for adipocyte apoptosis, but whether some innate defects of adipocytes affect their apoptotic susceptibility has rarely been studied. Here, we found BMPR2 knockout adipocytes were prone to TNFα-induced apoptosis both in vivo and ex vivo. BMPR2 deficiency in adipocytes inhibited phosphorylation of lipid-droplet-coating protein, perilipin, and impaired lipolysis stimulated by TNFα. Impaired lipolysis failed to supply fatty acid for mitochondrial oxidation, oxidative phosphorylation and stimulated mitochondria-mediated apoptosis. These results suggest that the innate functional integrity of adipocytes determines their ability to survive when interacting with inflammatory factors, which may explain why adipocytes among individuals show discrepancy for apoptotic responses to the same inflammatory pressure. Funding: This study was supported by the National Natural Science Foundation of China (grant no. 31670787 to S.W.Q. and 31571471 to Q.Q.T.), the Ministry of Science and technology of China grant (2013CB530601 to Q.Q.T), and the State Key Program of National Natural Science Foundation of China (grant no. 81390353 to Q.Q.T.). The research was partially supported by 985 Project (985-YFX0302). Declaration of Interest: All authors have no competing interests to declare, financial or otherwise. Ethical Approval: This study was approved by the ethics committees of Shanghai Medical College, Fudan University and was in accordance with the principle of the Helsinki Declaration II. The written informed consent was obtained from each participant.

CD73 Alleviates GSDMD-Mediated Pyroptosis in Spinal Cord Injury Through PI3K/AKT/Foxo1 Signaling

Neuroinflammation-induced secondary injury is an important cause of sustained progression of spinal cord injury. Inflammatory programmed cell death pyroptosis executed by the pore-forming protein gasdermin D (GSDMD) is recently regarded as an essential step of neuroinflammation. However, it is unclear whether CD73, a widely accepted immunosuppressive molecule, can inhibit pyroptosis via mediating GSDMD. Here, we reported molecular evidence for CD73 suppresses the activation of NLRP3 inflammasome complexes to reduce the maturation of GSDMD, leading to decreased pyroptosis in macrophages/microglia. Further analysis revealed that adenosine-A2B adenosine receptor-NF-κB cascade is a possible mechanism of CD73 regulation. Importantly, we determined that CD73 inhibited the expression of GSDMD at the transcriptional level through NF-κB, thereby alleviating macrophages/microglia pyroptosis. What’s more, we confirmed the accumulation of HIF-1α promotes the overexpression of CD73 after SCI, and the increased CD73 in turn upregulates the expression of HIF-1α, eventually forming a positive feedback regulatory loop. In summary, our results demonstrate that CD73 alleviates GSDMD-mediated pyroptosis of macrophages/microglia in spinal cord injury by blocking NF-κB signal. Our data reveal a novel function of CD73 on microphages/microglia pyroptosis, suggesting a unique therapeutic opportunity for mitigating the disease process in SCI. Funding Statement: This work was supported by the National Natural Science Foundation of China [grant number 81772385, 81871522]. Declaration of Interests: The authors declare that they do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted. Ethics Approval Statement: All study surgical procedures and experiment protocols were performed in accordance with standard guidelines approved by the Ethics Committee of Experimental Research, Shanghai Medical College, Fudan University (Shanghai, China). The animal experiments were approved by the Institutional Animal Care and Use Committee of Fudan University.

Panel of seven long noncoding RNA as a candidate prognostic biomarker for ovarian cancer.

Ovarian cancer is one of the most common and lethal gynecological malignancies. The diagnosis of ovarian cancer is often at an advanced stage. Accumulated evidence suggests that long noncoding RNAs (lncRNAs) play important roles during ovarian tumorigenesis. In this study, using the lncRNA-mining approach, we analyzed lncRNA expression profiles of 493 ovarian cancer patients from Gene Expression Omnibus datasets, and identified a signature group of seven lncRNAs (BC037530, AK021924, AK094536, AK094536, BC062365, BC004123 and BC007937) associated with patient survival in the training dataset GSE9891. We also formulated a risk score model to divide patients into low-risk and high-risk groups based on the expression of these seven lncRNAs. We further validated the predictive power of our risk score model in two other datasets, GSE26193 and GSE63885. Our analysis showed that the seven-lncRNA signature can serve as an independent predictor apart from Federation of Gynecology and Obstetrics (FIGO) stage and patient age. Further investigation revealed the seven-lncRNA signature correlated with few critical signaling pathways involved in cancer. Combined, all these findings strongly support that the seven-lncRNA signature can serve as a strong prognosis biomarker.