Publications by authors named "Jason Li"

151 Publications

A scalable, secure, and interoperable platform for deep data-driven health management.

Nat Commun 2021 10 1;12(1):5757. Epub 2021 Oct 1.

Department of Genetics, Stanford University, Stanford, CA, USA.

The large amount of biomedical data derived from wearable sensors, electronic health records, and molecular profiling (e.g., genomics data) is rapidly transforming our healthcare systems. The increasing scale and scope of biomedical data not only is generating enormous opportunities for improving health outcomes but also raises new challenges ranging from data acquisition and storage to data analysis and utilization. To meet these challenges, we developed the Personal Health Dashboard (PHD), which utilizes state-of-the-art security and scalability technologies to provide an end-to-end solution for big biomedical data analytics. The PHD platform is an open-source software framework that can be easily configured and deployed to any big data health project to store, organize, and process complex biomedical data sets, support real-time data analysis at both the individual level and the cohort level, and ensure participant privacy at every step. In addition to presenting the system, we illustrate the use of the PHD framework for large-scale applications in emerging multi-omics disease studies, such as collecting and visualization of diverse data types (wearable, clinical, omics) at a personal level, investigation of insulin resistance, and an infrastructure for the detection of presymptomatic COVID-19.
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http://dx.doi.org/10.1038/s41467-021-26040-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486823PMC
October 2021

CT slice alignment to whole-body reference geometry by convolutional neural network.

Phys Eng Sci Med 2021 Sep 10. Epub 2021 Sep 10.

Department of Physical Sciences, Peter MacCallum Cancer Centre, Melbourne, 3000, Australia.

Volumetric medical imaging lacks a standardised coordinate geometry which links image frame-of-reference to specific anatomical regions. This results in an inability to locate anatomy in medical images without visual assessment and precludes a variety of image analysis tasks which could benefit from a standardised, machine-readable coordinate system. In this work, a proposed geometric system that scales based on patient size is described and applied to a variety of cases in computed tomography imaging. Subsequently, a convolutional neural network is trained to associate axial slice CT image appearance with the standardised coordinate value along the patient superior-inferior axis. The trained neural network showed an accuracy of ± 12 mm in the ability to predict per-slice reference location and was relatively stable across all annotated regions ranging from brain to thighs. A version of the trained model along with scripts to perform network training in other applications are made available. Finally, a selection of potential use applications are illustrated including organ localisation, image registration initialisation, and scan length determination for auditing diagnostic reference levels.
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http://dx.doi.org/10.1007/s13246-021-01056-5DOI Listing
September 2021

CheXaid: deep learning assistance for physician diagnosis of tuberculosis using chest x-rays in patients with HIV.

NPJ Digit Med 2020 Sep 9;3(1):115. Epub 2020 Sep 9.

Stanford University AIMI Center, Stanford, CA, USA.

Tuberculosis (TB) is the leading cause of preventable death in HIV-positive patients, and yet often remains undiagnosed and untreated. Chest x-ray is often used to assist in diagnosis, yet this presents additional challenges due to atypical radiographic presentation and radiologist shortages in regions where co-infection is most common. We developed a deep learning algorithm to diagnose TB using clinical information and chest x-ray images from 677 HIV-positive patients with suspected TB from two hospitals in South Africa. We then sought to determine whether the algorithm could assist clinicians in the diagnosis of TB in HIV-positive patients as a web-based diagnostic assistant. Use of the algorithm resulted in a modest but statistically significant improvement in clinician accuracy (p = 0.002), increasing the mean clinician accuracy from 0.60 (95% CI 0.57, 0.63) without assistance to 0.65 (95% CI 0.60, 0.70) with assistance. However, the accuracy of assisted clinicians was significantly lower (p < 0.001) than that of the stand-alone algorithm, which had an accuracy of 0.79 (95% CI 0.77, 0.82) on the same unseen test cases. These results suggest that deep learning assistance may improve clinician accuracy in TB diagnosis using chest x-rays, which would be valuable in settings with a high burden of HIV/TB co-infection. Moreover, the high accuracy of the stand-alone algorithm suggests a potential value particularly in settings with a scarcity of radiological expertise.
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http://dx.doi.org/10.1038/s41746-020-00322-2DOI Listing
September 2020

The concurrence of DNA methylation and demethylation is associated with transcription regulation.

Nat Commun 2021 09 6;12(1):5285. Epub 2021 Sep 6.

Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA.

The mammalian DNA methylome is formed by two antagonizing processes, methylation by DNA methyltransferases (DNMT) and demethylation by ten-eleven translocation (TET) dioxygenases. Although the dynamics of either methylation or demethylation have been intensively studied in the past decade, the direct effects of their interaction on gene expression remain elusive. Here, we quantify the concurrence of DNA methylation and demethylation by the percentage of unmethylated CpGs within a partially methylated read from bisulfite sequencing. After verifying 'methylation concurrence' by its strong association with the co-localization of DNMT and TET enzymes, we observe that methylation concurrence is strongly correlated with gene expression. Notably, elevated methylation concurrence in tumors is associated with the repression of 40~60% of tumor suppressor genes, which cannot be explained by promoter hypermethylation alone. Furthermore, methylation concurrence can be used to stratify large undermethylated regions with negligible differences in average methylation into two subgroups with distinct chromatin accessibility and gene regulation patterns. Together, methylation concurrence represents a unique methylation metric important for transcription regulation and is distinct from conventional metrics, such as average methylation and methylation variation.
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http://dx.doi.org/10.1038/s41467-021-25521-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421433PMC
September 2021

identification and experimental validation of cellular uptake and intracellular labeling by a new cell penetrating peptide derived from CDN1.

Drug Deliv 2021 Dec;28(1):1722-1736

Department of Pathology and Immunology, Medical School, China Three Gorges University, Yichang, China.

Bioactive therapeutic molecules are generally impermeable to the cell membrane, hindering their utility and efficacy. A group of peptides called cell-penetrating peptides (CPPs) were found to have the capability of transporting different types of cargo molecules across the cell membrane. Here, we identified a short peptide named P2, which has a higher proportion of basic residues than the CDN1 (cyclin-dependent kinase inhibitor 1) protein it is derived from, and we used bioinformatic analysis and experimental validation to confirm the penetration property of peptide P2. We found that peptide P2 can efficiently enter different cell lines in a concentration-dependent manner. The endocytosis pathway, especially receptor-related endocytosis, may be involved in the process of P2 penetration. Our data also showed that peptide P2 is safe in cultured cell lines and red blood cells. Lastly, peptide P2 can efficiently deliver self-labeling protein HaloTag into cells for imaging. Our study illustrates that peptide P2 is a promising imaging agent delivery vehicle for future applications.
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http://dx.doi.org/10.1080/10717544.2021.1963352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409945PMC
December 2021

3'aQTL-atlas: an atlas of 3'UTR alternative polyadenylation quantitative trait loci across human normal tissues.

Nucleic Acids Res 2021 Aug 25. Epub 2021 Aug 25.

Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA.

Genome-wide association studies (GWAS) have identified thousands of non-coding single-nucleotide polymorphisms (SNPs) associated with human traits and diseases. However, functional interpretation of these SNPs remains a significant challenge. Our recent study established the concept of 3' untranslated region (3'UTR) alternative polyadenylation (APA) quantitative trait loci (3'aQTLs), which can be used to interpret ∼16.1% of GWAS SNPs and are distinct from gene expression QTLs and splicing QTLs. Despite the growing interest in 3'aQTLs, there is no comprehensive database for users to search and visualize them across human normal tissues. In the 3'aQTL-atlas (https://wlcb.oit.uci.edu/3aQTLatlas), we provide a comprehensive list of 3'aQTLs containing ∼1.49 million SNPs associated with APA of target genes, based on 15,201 RNA-seq samples across 49 human Genotype-Tissue Expression (GTEx v8) tissues isolated from 838 individuals. The 3'aQTL-atlas provides a ∼2-fold increase in sample size compared with our published study. It also includes 3'aQTL searches by Gene/SNP across tissues, a 3'aQTL genome browser, 3'aQTL boxplots, and GWAS-3'aQTL colocalization event visualization. The 3'aQTL-atlas aims to establish APA as an emerging molecular phenotype to explain a large fraction of GWAS risk SNPs, leading to significant novel insights into the genetic basis of APA and APA-linked susceptibility genes in human traits and diseases.
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http://dx.doi.org/10.1093/nar/gkab740DOI Listing
August 2021

In silico identification and experimental validation of cellular uptake by a new cell penetrating peptide P1 derived from MARCKS.

Drug Deliv 2021 Dec;28(1):1637-1648

Department of Pathology and Immunology, Medical School, China Three Gorges University, Yichang, China.

Viral vectors for vaccine delivery are challenged by recently reported safety issues like immunogenicity and risk for cancer development, and thus there is a growing need for the development of non-viral vectors. Cell penetrating peptides (CPPs) are non-viral vectors that can enter plasma membranes efficiently and deliver a broad range of cargoes. Our bioinformatic prediction and wet-lab validation data suggested that peptide P1 derived from MARCKS protein phosphorylation site domain is a new potential CPP candidate. We found that peptide P1 can efficiently internalize into various cell lines in a concentration-dependent manner. Receptor-mediated endocytosis pathway is the major mechanism of P1 penetration, although P1 also directly penetrates the plasma membrane. We also found that peptide P1 has low cytotoxicity in cultured cell lines as well as mouse red blood cells. Furthermore, peptide P1 not only can enter into cultured cells itself, but it also can interact with plasmid DNA and mediate the functional delivery of plasmid DNA into cultured cells, even in hard-to-transfect cells. Combined, these findings indicate that P1 may be a promising vector for efficient intracellular delivery of bioactive cargos.
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http://dx.doi.org/10.1080/10717544.2021.1960922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8330795PMC
December 2021

Timing of Social Transition for Transgender and Gender Diverse Youth, K-12 Harassment, and Adult Mental Health Outcomes.

J Adolesc Health 2021 Jul 13. Epub 2021 Jul 13.

The Fenway Institute, Boston, Massachusetts; Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts.

Purpose: Many transgender and gender diverse (TGD) youth undergo a social transition in which they change their gender expression to align with their gender identity. Our objective was to examine associations between timing of social transition (during the prepubertal childhood period, adolescence, or adulthood) and adult mental health outcomes.

Methods: We conducted a secondary analysis of the 2015 U.S. Transgender Survey, a cross-sectional nonprobability survey of 27,715 TGD adults in the United States. Based on self-reports, participants were categorized as having undergone social transition during childhood (ages 3-9 years), adolescence (ages 10-17 years), or adulthood (ages ≥18 years). Using multivariable logistic regression, we examined associations between timing of social transition and adult mental health outcomes.

Results: After adjusting for demographic and potential confounding variables, childhood social transition was associated with lower odds of lifetime marijuana use (adjusted odds ratio .7, 95% confidence interval = .5-.8, p < .0001) when compared with adult social transition. Before adjusting for K-12 harassment based on gender identity, adolescent social transition was associated with adverse mental health outcomes, including greater odds of lifetime suicide attempts when compared with adult social transition (adjusted odds ratio 1.3, 95% confidence interval = 1.1-1.7, p = .004). These associations were no longer significant after further adjusting for K-12 harassment.

Conclusions: Although past research has shown TGD youth who undergo social transition have favorable mental health outcomes in the short term, they may have worse mental health in adulthood if not protected from K-12 harassment based on gender identity. It is the responsibility of clinicians to emphasize the importance of adolescents having safe and affirming social environments.
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http://dx.doi.org/10.1016/j.jadohealth.2021.06.001DOI Listing
July 2021

A Deep Learning Model to Automate Skeletal Muscle Area Measurement on Computed Tomography Images.

Front Oncol 2021 7;11:580806. Epub 2021 May 7.

Physical Sciences, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Background: Muscle wasting (Sarcopenia) is associated with poor outcomes in cancer patients. Early identification of sarcopenia can facilitate nutritional and exercise intervention. Cross-sectional skeletal muscle (SM) area at the third lumbar vertebra (L3) slice of a computed tomography (CT) image is increasingly used to assess body composition and calculate SM index (SMI), a validated surrogate marker for sarcopenia in cancer. Manual segmentation of SM requires multiple steps, which limits use in routine clinical practice. This project aims to develop an automatic method to segment L3 muscle in CT scans.

Methods: Attenuation correction CTs from full body PET-CT scans from patients enrolled in two prospective trials were used. The training set consisted of 66 non-small cell lung cancer (NSCLC) patients who underwent curative intent radiotherapy. An additional 42 NSCLC patients prescribed curative intent chemo-radiotherapy from a second trial were used for testing. Each patient had multiple CT scans taken at different time points prior to and post- treatment (147 CTs in the training and validation set and 116 CTs in the independent testing set). Skeletal muscle at L3 vertebra was manually segmented by two observers, according to the Alberta protocol to serve as ground truth labels. This included 40 images segmented by both observers to measure inter-observer variation. An ensemble of 2.5D fully convolutional neural networks (U-Nets) was used to perform the segmentation. The final layer of U-Net produced the binary classification of the pixels into muscle and non-muscle area. The model performance was calculated using Dice score and absolute percentage error (APE) in skeletal muscle area between manual and automated contours.

Results: We trained five 2.5D U-Nets using 5-fold cross validation and used them to predict the contours in the testing set. The model achieved a mean Dice score of 0.92 and an APE of 3.1% on the independent testing set. This was similar to inter-observer variation of 0.96 and 2.9% for mean Dice and APE respectively. We further quantified the performance of sarcopenia classification using computer generated skeletal muscle area. To meet a clinical diagnosis of sarcopenia based on Alberta protocol the model achieved a sensitivity of 84% and a specificity of 95%.

Conclusions: This work demonstrates an automated method for accurate and reproducible segmentation of skeletal muscle area at L3. This is an efficient tool for large scale or routine computation of skeletal muscle area in cancer patients which may have applications on low quality CTs acquired as part of PET/CT studies for staging and surveillance of patients with cancer.
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http://dx.doi.org/10.3389/fonc.2021.580806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138051PMC
May 2021

Preexisting Depression and Daytime Sleepiness in Women and Men.

Behav Sleep Med 2021 May 18:1-13. Epub 2021 May 18.

Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

: Sleep problems can persist following the treatment of depression and remission of symptoms. The extent to which having a previous history of depression may be associated with current daytime sleepiness is largely unknown.: Data were obtained from the spring 2017 American College Health Association-National College Health Assessment (ACHA-NCHA) survey (92 institutions) which assessed self-reported health in U.S. college students ( = 41,670). Among the sample, 93.5% were 18-24 year of age, and 69.6% women. Logistic regression estimated the association between reported prior lifetime diagnosis of depression and daytime sleepiness from the past 7 days, while adjusting for depressive symptoms and antidepressant use from the past year. Unadjusted and adjusted logistic regression models stratified by gender were performed.: Among those who reported problems with sleepiness, 31.6% women and 19.4% men had a preexisting depression diagnosis. Individuals with preexisting depression were more likely than those without this diagnosis to report sleepiness problems (women:  = 1.4,  = 1.3-1.6, < .001; men:  = 1.2,  = 1.0-1.4, < .01). However, this association differed significantly by gender, with women with a preexisting depression diagnosis having a 13.0% greater likelihood of sleepiness compared to men.: Those with a preexisting depression diagnosis, and specifically women, may be at risk for daytime sleepiness even in the absence of current depressive mood-related symptoms. Given that many individuals are at risk for daytime sleepiness, mental health initiatives, including those on college campuses, should incorporate sleep hygiene within their programming.
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http://dx.doi.org/10.1080/15402002.2021.1924720DOI Listing
May 2021

Structural basis of tetanus toxin neutralization by native human monoclonal antibodies.

Cell Rep 2021 May;35(5):109070

Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China; Trinomab Biotech Co., Ltd, Zhuhai 519040, China; Institute of Biomedicine, Jinan University, Guangzhou 510632, China. Electronic address:

Four potent native human monoclonal antibodies (mAbs) targeting distinct epitopes on tetanus toxin (TeNT) are isolated with neutralization potency ranging from approximately 17 mg to 6 mg each that are equivalent to 250 IU of human anti-TeNT immunoglobulin. TT0170 binds fragment B, and TT0069 and TT0155 bind fragment AB. mAb TT0067 binds fragment C and blocks the binding of TeNT to gangliosides. The co-crystal structure of TT0067 with fragment C of TeNT at a 2.0-Å resolution demonstrates that mAb TT0067 directly occupies the W pocket of one of the receptor binding sites on TeNT, resulting in blocking the binding of TeNT to ganglioside on the surface of host cells. This study reveals at the atomic level the mechanism of action by the TeNT neutralizing antibody. The key neutralization epitope on the fragment C of TeNT identified in our work provides the critical information for the development of fragment C of TeNT as a better and safer tetanus vaccine.
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http://dx.doi.org/10.1016/j.celrep.2021.109070DOI Listing
May 2021

Psychiatric impacts of the COVID-19 global pandemic on U.S. sexual and gender minority young adults.

Psychiatry Res 2021 05 3;299:113855. Epub 2021 Mar 3.

Departments of Pediatric Newborn and Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

The COVID-19 pandemic has caused unprecedented isolation and mental health effects; few studies have characterized this in sexual and gender (SGM) minority young people, a particularly vulnerable population. This cross-sectional study sought to analyze the mental health outcomes of SGM young people (18-30 years) during the early stages of the pandemic in the United States (April 13-June 18, 2020) and to explore how factors related to SGM identity impact mental health, such as lifetime discrimination, family support, and pre-existing mental health conditions. An online survey collected socio-demographic information and assessed for both mental health (depression (PHQ-8), anxiety (GAD-7), PTSD (PCL-C)) and COVID-19-related outcomes (COVID-19-related worries and COVID-19-related grief). Out of 981 participants, 320 (32.6%) identified as SGM. SGM had significantly higher levels of depression and PTSD symptoms as well as COVID-19-related worries and grief than non-SGM, even after controlling for family support, lifetime discrimination, and pre-existing mental health diagnoses. These findings suggest that not only has the COVID-19 pandemic disproportionately impacted SGM mental health, but that minority stress factors cannot fully explain this impact. Thus, clinicians and societal stakeholders (schools, employers, policymakers) must think beyond traditional minority stress factors (family support, discrimination) and pre-pandemic disparities to support this vulnerable population as the pandemic progresses.
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http://dx.doi.org/10.1016/j.psychres.2021.113855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278978PMC
May 2021

Presenting age and features of females diagnosed with autism spectrum disorder.

J Paediatr Child Health 2021 08 1;57(8):1182-1189. Epub 2021 Mar 1.

Child Development Unit, Women's and Children's Hospital, Adelaide, South Australia, Australia.

Aim: Autism spectrum disorder (ASD) is reportedly more prevalent in males than in females. Hypotheses for this gender imbalance include differing presentations in females. The aim of this study was to identify gender-based ASD differences in age at presentation, clinical features, comorbidities and severity levels.

Methods: A cross-sectional study was conducted at a Child Development Unit. Children diagnosed with ASD during a 6-month period were analysed.

Results: A total of 195 children were analysed with a male-to-female ratio of 2.8:1. No difference was found between gender and age at diagnosis. Males were more likely to display deficits in imaginative play and use repeated or learned phrases. Females were more likely to present with proprioception and vestibular issues, fears reflecting sensory avoidance and ASD of lesser severity.

Conclusion: Our study supports the hypothesis that gender-based differences exist within ASD presenting features. These differences should be considered when assessing for ASD in females to avoid under recognition.
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http://dx.doi.org/10.1111/jpc.15417DOI Listing
August 2021

Almond consumption increased UVB resistance in healthy Asian women.

J Cosmet Dermatol 2021 Sep 24;20(9):2975-2980. Epub 2021 Jan 24.

Department of Medicine, David Geffen School of Medicine, Center for Human Nutrition, Los Angeles, CA, USA.

Background: Almonds are a rich source of phenolic and polyphenolic compounds, which have antioxidant activity. In vitro and in vivo studies have demonstrated that topical application of almond oil and almond skin extract reduces UVB-induced photoaging. Ultraviolet-B (UVB) protection by oral almond consumption has not been previously studied in humans.

Objectives: To investigate whether oral almond consumption can increase resistance to UVB radiation and reduce skin aging in healthy Asian women.

Methods: Thirty-nine female participants (18-45 years) with Fitzpatrick skin type II-IV were randomly assigned to consume either 1.5 oz of almonds or 1.8 oz of pretzels daily for 12 weeks. Minimal erythema dose (MED) was determined using a standardized protocol, which determined the minimal radiation needed to induce erythema on the inner arm following UVB exposure. Facial skin texture was evaluated by two dermatologists using the Clinician's Erythema Assessment scale and Allergan Roughness scale. Facial melanin index, hydration, sebum, and erythema were determined using a cutometer.

Results: The MED was increased in the subjects consuming almonds compared to the control group consuming pretzels. There were no differences noted between the groups consuming almonds versus pretzels in Allergan roughness, melanin, hydration, or sebum on facial skin.

Conclusions: Our findings suggest that daily oral almond consumption may lead to enhanced protection from UV photodamage by increasing the MED.
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http://dx.doi.org/10.1111/jocd.13946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8451851PMC
September 2021

Maternal health behaviors during pregnancy in rural Northwestern China.

BMC Pregnancy Childbirth 2020 Nov 30;20(1):745. Epub 2020 Nov 30.

Rural Education Action Program, Freeman Spogli Institute for International Studies, Stanford University, Encina Hall, 616 Jane Stanford Way, Palo Alto, CA, 94305, USA.

Background: Maternal health during pregnancy is a key input in fetal health and child development. This study aims to systematically describe the health behaviors of pregnant women in rural China and identify which subgroups of women are more likely to engage in unhealthy behaviors during pregnancy.

Methods: We surveyed 1088 pregnant women in rural northwestern China on exposure to unhealthy substances, nutritional behaviors, the timing and frequency of antenatal care, and demographic characteristics.

Results: Pregnant women were active in seeking antenatal care and had low rates of alcohol consumption (5.1%), exposure to toxins (4.8%), and exposure to radiation (2.9%). However, tobacco exposure was widespread (40.3%), as was low dietary diversity (61.8%), unhealthy weight gain (59.7%), unhealthy pre-pregnancy BMI (29.7%), and no folic acid intake (17.1%). Maternal education is closely linked to better health behaviors, whereas experience with a previous pregnancy is not.

Conclusions: Tobacco exposure and unhealthy nutritional behaviors are common among pregnant women in rural northwestern China. The findings indicate that in the absence of professional health information, relying on experience of previous pregnancies alone may not help rural women avoid unhealthy maternal behaviors. Maternal health education campaigns targeting nutrition and tobacco exposure during pregnancy may improve maternal, fetal, and child health in rural China.
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http://dx.doi.org/10.1186/s12884-020-03444-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708178PMC
November 2020

Machine-Learning and Chemicogenomics Approach Defines and Predicts Cross-Talk of Hippo and MAPK Pathways.

Cancer Discov 2021 03 18;11(3):778-793. Epub 2020 Nov 18.

Department of Discovery Oncology, Genentech, Inc., South San Francisco, California.

Hippo pathway dysregulation occurs in multiple cancers through genetic and nongenetic alterations, resulting in translocation of YAP to the nucleus and activation of the TEAD family of transcription factors. Unlike other oncogenic pathways such as RAS, defining tumors that are Hippo pathway-dependent is far more complex due to the lack of hotspot genetic alterations. Here, we developed a machine-learning framework to identify a robust, cancer type-agnostic gene expression signature to quantitate Hippo pathway activity and cross-talk as well as predict YAP/TEAD dependency across cancers. Further, through chemical genetic interaction screens and multiomics analyses, we discover a direct interaction between MAPK signaling and TEAD stability such that knockdown of YAP combined with MEK inhibition results in robust inhibition of tumor cell growth in Hippo dysregulated tumors. This multifaceted approach underscores how computational models combined with experimental studies can inform precision medicine approaches including predictive diagnostics and combination strategies. SIGNIFICANCE: An integrated chemicogenomics strategy was developed to identify a lineage-independent signature for the Hippo pathway in cancers. Evaluating transcriptional profiles using a machine-learning method led to identification of a relationship between YAP/TAZ dependency and MAPK pathway activity. The results help to nominate potential combination therapies with Hippo pathway inhibition..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0706DOI Listing
March 2021

Mechanistic Insights to the Binding of Antibody CR3022 Against RBD from SARS-CoV and HCoV-19/SARS-CoV-2: A Computational Study.

Comb Chem High Throughput Screen 2021 ;24(7):1069-1082

Institute of Biomedicine, Jinan University, Guangzhou, 510632, China.

Aims & Objective: Coronavirus Disease 2019 (COVID-19) caused by the human coronavirus 2019 (HCoV-19, also known as SARS-CoV-2) infection is currently in a global outbreak. COVID-19 has posed a huge threat to public health and economic stability worldwide. CR3022, a human monoclonal neutralizing antibody isolated from a Severe Acute Respiratory Syndrome (SARS) recovery patient, was confirmed to be able to bind the S protein of HCoV-19 with a certain degree of neutralizing activity. Crystal structural information indicated that CR3022 could bind to the epitope on the receptor binding domain (RBD) of HCoV-19, whose epitope consists of 28 amino acids, and 24 of them are conserved in SARS-CoV of SARS. However, the crystal structure is only a static conformation at a certain moment in time, and it cannot provide dynamic details of the interaction between antigen and antibody.

Methods: In this study, molecular dynamics (MD) simulation combined with MM/PBSA and CAS methods were performed to investigate the mechanism of binding of CR3022 against SARS-CoVRBD and HCoV-19-RBD in order to determine their holographic dynamic information.

Results: It was found that the CR3022-SARS-CoV-RBD complex was more stable during 100ns MD run than that of the CR3022-HCoV-19-RBD system. There were common conservative amino acids on the β2 sheet of RBD, including Tyr369, Phe377, Lys378, Tyr380, Gly381, Lys386, Leu390 and others. These conservative amino acids play significant roles in the binding process of CR3022 antibody against SARS-CoV-RBD and HCoV-19-RBD. It was also found that the binding mode of CR3022 to its native target SARS-CoV-RBD is more comprehensive and uniform. Moreover, the β2 sheet residue Thr385 and non-β2 sheet residues Arg408 and Asp428 of the CR3022-SARS-CoV-RBD system were found to be crucial for their binding affinities, thus forming a special conformational epitope. However, these key amino acids are not present in the CR3022-HCoV-19-RBD system. The binding mode of CR3022 and HCoV-19-RBD is similar to that of SARS-CoV-RBD, but the deficiency of crucial hydrogen-bonds and salt-bridges. Therefore, the binding of CR3022 and HCoV-19-RBD only draws on the partial mode of the binding of CR3022 and SARS-CoV-RBD, so there is a loss of affinity.

Conclusion: Thus, in order to better fight the epidemic of COVID-19 with the CR3022 antibody, this antibody needs to further improve the neutralization efficiency of HCoV-19 through mutation of it's CDR region.
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http://dx.doi.org/10.2174/1386207323666201026160500DOI Listing
July 2021

Correction to: Serum microRNA is a biomarker for post-operative monitoring in glioma.

J Neurooncol 2020 Sep;149(3):401

Department of Surgery, University of Melbourne, Parkville, VIC, Australia.

For the reference citation '[57]' in the second paragraph of the Results section of the original article there was no corresponding entry in the References section. It should have referred to the below mentioned article by Ebrahimkhani et al. (2018).
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http://dx.doi.org/10.1007/s11060-020-03630-5DOI Listing
September 2020

CheXaid: deep learning assistance for physician diagnosis of tuberculosis using chest x-rays in patients with HIV.

NPJ Digit Med 2020 9;3:115. Epub 2020 Sep 9.

Stanford University AIMI Center, Stanford, CA USA.

Tuberculosis (TB) is the leading cause of preventable death in HIV-positive patients, and yet often remains undiagnosed and untreated. Chest x-ray is often used to assist in diagnosis, yet this presents additional challenges due to atypical radiographic presentation and radiologist shortages in regions where co-infection is most common. We developed a deep learning algorithm to diagnose TB using clinical information and chest x-ray images from 677 HIV-positive patients with suspected TB from two hospitals in South Africa. We then sought to determine whether the algorithm could assist clinicians in the diagnosis of TB in HIV-positive patients as a web-based diagnostic assistant. Use of the algorithm resulted in a modest but statistically significant improvement in clinician accuracy ( = 0.002), increasing the mean clinician accuracy from 0.60 (95% CI 0.57, 0.63) without assistance to 0.65 (95% CI 0.60, 0.70) with assistance. However, the accuracy of assisted clinicians was significantly lower ( < 0.001) than that of the stand-alone algorithm, which had an accuracy of 0.79 (95% CI 0.77, 0.82) on the same unseen test cases. These results suggest that deep learning assistance may improve clinician accuracy in TB diagnosis using chest x-rays, which would be valuable in settings with a high burden of HIV/TB co-infection. Moreover, the high accuracy of the stand-alone algorithm suggests a potential value particularly in settings with a scarcity of radiological expertise.
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http://dx.doi.org/10.1038/s41746-020-00322-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481246PMC
September 2020

Serum microRNA is a biomarker for post-operative monitoring in glioma.

J Neurooncol 2020 Sep 11;149(3):391-400. Epub 2020 Sep 11.

Department of Surgery, University of Melbourne, Parkville, VIC, Australia.

Purpose: A circulating biomarker has potential to provide more accurate information for glioma progression post treatment, however no such biomarker is currently available. We aimed to discover a microRNA serum biomarker for longitudinal monitoring of glioma patients.

Methods: A prospectively collected cohort of 91 glioma patients and 17 healthy controls underwent pre and post-operative serum miRNA profiling using Nanostring®. Differentially expressed miRNAs were discovered using a machine learning random forest analysis. Candidate miRNAs were then assessed by droplet digital PCR in 11 patients with multiple follow up samples and compared to tumor volume based on magnetic resonance imaging.

Results: A 9-gene miRNA signature was identified that could distinguish between glioma and healthy controls with 99.8% accuracy. Two miRNAs miR-223 and miR-320e, best demonstrated dynamic changes that correlated closely with tumor volume in LGG and GBM respectively. Importantly, miRNA levels did not increase in two cases of pseudo-progression, indicating the potential utility of this test in guiding treatment decisions.

Conclusions: We identified a highly accurate 9-miRNA signature associated with glioma serum. Additionally, we observed dynamic changes in specific miRNAs correlating with tumor volume over long-term follow up. These results support a large prospective validation study of serum miRNA biomarkers in glioma.
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http://dx.doi.org/10.1007/s11060-020-03566-wDOI Listing
September 2020

A MXI1-NUTM1 fusion protein with MYC-like activity suggests a novel oncogenic mechanism in a subset of NUTM1-rearranged tumors.

Lab Invest 2021 01 1;101(1):26-37. Epub 2020 Sep 1.

Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia.

Most NUTM1-rearranged neoplasms (NRNs) have fusions between NUTM1 and BRD (bromodomain-containing) family members and are termed NUT carcinomas (NCs) because they show some squamous differentiation. However, some NRNs are associated with fusions between NUTM1 and members of the MAD (MAX dimerization) gene family of MYC antagonists. Here we describe a small round cell malignancy from the gastro-esophageal junction with a previously unreported fusion between NUTM1 and the MAD family member MXI1. In contrast to NCs, the MXI1-NUTM1 tumor did not show squamous differentiation and did not express MYC, TP63 or SOX2, genes known to be targets of BRD-NUTM1 proteins and critical for NC oncogenesis. Transcriptome analysis showed paradoxical enrichment of MYC target genes in the MXI1-NUTM1 tumor despite the lack of MYC expression. When expressed in vitro MXI1-NUTM1 partially phenocopied MYC, enhancing cell proliferation and cooperating with oncogenic HRAS to produce anchorage-independent cell growth. These data provide evidence that MAD family members, which are normally repressors of MYC activity, can be converted into MYC-like mimics by fusion to NUTM1. The pathological features and novel oncogenic mechanism of the MXI1-NUTM1 tumor show that identification of NUTM1 fusion partners can be important for accurate diagnostic classification of some NRN subtypes, and potentially may guide therapeutic options.
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http://dx.doi.org/10.1038/s41374-020-00484-3DOI Listing
January 2021

A natural impact-resistant bicontinuous composite nanoparticle coating.

Nat Mater 2020 11 17;19(11):1236-1243. Epub 2020 Aug 17.

Department of Chemical and Environmental Engineering, University of California, Riverside, CA, USA.

Nature utilizes the available resources to construct lightweight, strong and tough materials under constrained environmental conditions. The impact surface of the fast-striking dactyl club from the mantis shrimp is an example of one such composite material; the shrimp has evolved the capability to localize damage and avoid catastrophic failure from high-speed collisions during its feeding activities. Here we report that the dactyl club of mantis shrimps contains an impact-resistant coating composed of densely packed (about 88 per cent by volume) ~65-nm bicontinuous nanoparticles of hydroxyapatite integrated within an organic matrix. These mesocrystalline hydroxyapatite nanoparticles are assembled from small, highly aligned nanocrystals. Under impacts of high strain rates (around 10 s), particles rotate and translate, whereas the nanocrystalline networks fracture at low-angle grain boundaries, form dislocations and undergo amorphization. The interpenetrating organic network provides additional toughening, as well as substantial damping, with a loss coefficient of around 0.02. An unusual combination of stiffness and damping is therefore achieved, outperforming many engineered materials.
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http://dx.doi.org/10.1038/s41563-020-0768-7DOI Listing
November 2020

Molecular comparison of pure ovarian fibroma with serous benign ovarian tumours.

BMC Res Notes 2020 Jul 22;13(1):349. Epub 2020 Jul 22.

Cancer Genomics Program, Peter MacCallum Cancer Centre, East Melbourne, Australia.

Objective: Ovarian fibromas and adenofibromas are rare ovarian tumours. They are benign tumours composed of spindle-like stromal cells (pure fibroma) or a mixture of fibroblast and epithelial components (adenofibroma). We have previously shown that 40% of benign serous ovarian tumours are likely primary fibromas due to the neoplastic alterations being restricted to the stromal compartment of these tumours. We further explore this finding by comparing benign serous tumours to pure fibromas.

Results: Performing copy number aberration (CNA) analysis on the stromal component of 45 benign serous tumours and 8 pure fibromas, we have again shown that trisomy of chromosome 12 is the most common aberration in ovarian fibromas. CNAs were more frequent in the pure fibromas than the benign serous tumours (88% vs 33%), however pure fibromas more frequently harboured more than one CNA event compared with benign serous tumours. As these extra CNA events observed in the pure fibromas were unique to this subset our data indicates a unique tumour evolution. Gene expression analysis on the two cohorts was unable to show gene expression changes that differed based on tumour subtype. Exome analysis did not reveal any recurrently mutated genes.
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http://dx.doi.org/10.1186/s13104-020-05194-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376903PMC
July 2020

Adrenal and renal abscesses following glue embolization of gastric varices: a case description.

Quant Imaging Med Surg 2020 Jul;10(7):1566-1569

Department of Radiology, Queen Mary Hospital, University of Hong Kong, Hong Kong, China.

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http://dx.doi.org/10.21037/qims-19-1026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358424PMC
July 2020

The Hippo pathway oncoprotein YAP promotes melanoma cell invasion and spontaneous metastasis.

Oncogene 2020 07 19;39(30):5267-5281. Epub 2020 Jun 19.

Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC, 3000, Australia.

Melanoma is a deadly form of skin cancer that accounts for a disproportionally large proportion of cancer-related deaths in younger people. Compared with most other skin cancers, a feature of melanoma is its high metastatic capacity, although the mechanisms that confer this are not well understood. The Hippo pathway is a key regulator of organ growth and cell fate that is deregulated in many cancers. To analyse the Hippo pathway in cutaneous melanoma, we generated a transcriptional signature of melanoma cells that overexpressed YAP, the key downstream Hippo pathway oncoprotein. YAP-mediated transcriptional activity varied in melanoma cell lines but did not cluster with known genetic drivers of melanomagenesis such as BRAF and NRAS mutations. Instead, it correlated strongly with published gene expression profiles linked to melanoma cell invasiveness and varied throughout the metastatic cascade in melanoma patient tumours. Consistent with this, YAP was both necessary and sufficient for melanoma cell invasion in vitro. In vivo, YAP promoted spontaneous melanoma metastasis, whilst the growth of YAP-expressing primary tumours was impeded. Finally, we identified the YAP target genes AXL, THBS1 and CYR61 as key mediators of YAP-induced melanoma cell invasion. These data suggest that YAP is a critical regulator of melanoma metastasis.
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http://dx.doi.org/10.1038/s41388-020-1362-9DOI Listing
July 2020

The Role of Bone Morphogenetic Protein Signaling in Non-Alcoholic Fatty Liver Disease.

Sci Rep 2020 06 19;10(1):9831. Epub 2020 Jun 19.

Cardiovascular Research Center and Cardiology Division of the Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.

Non-alcoholic fatty liver disease (NAFLD) affects over 30% of adults in the United States. Bone morphogenetic protein (BMP) signaling is known to contribute to hepatic fibrosis, but the role of BMP signaling in the development of NAFLD is unclear. In this study, treatment with either of two BMP inhibitors reduced hepatic triglyceride content in diabetic (db/db) mice. BMP inhibitor-induced decrease in hepatic triglyceride levels was associated with decreased mRNA encoding Dgat2, an enzyme integral to triglyceride synthesis. Treatment of hepatoma cells with BMP2 induced DGAT2 expression and activity via intracellular SMAD signaling. In humans we identified a rare missense single nucleotide polymorphism in the BMP type 1 receptor ALK6 (rs34970181;R371Q) associated with a 2.1-fold increase in the prevalence of NAFLD. In vitro analyses revealed R371Q:ALK6 is a previously unknown constitutively active receptor. These data show that BMP signaling is an important determinant of NAFLD in a murine model and is associated with NAFLD in humans.
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http://dx.doi.org/10.1038/s41598-020-66770-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305229PMC
June 2020

Liquid Biopsy Serial Monitoring of Treatment Responses and Relapse in Advanced Esophageal Squamous Cell Carcinoma.

Cancers (Basel) 2020 May 26;12(6). Epub 2020 May 26.

Department of Clinical Oncology, University of Hong Kong, Hong Kong, China.

(1) Background: Early predictive markers to track treatment responses are needed for advanced esophageal squamous cell carcinoma (ESCC) patients. We examined the prognostication and risk stratification role of liquid biopsy serial monitoring for this deadly cancer. (2) Methods: Circulating tumor cells (CTCs) and plasma cell-free DNA (cfDNA) were isolated from 60 ESCC patients treated by chemotherapy (CT) at five serial timepoints: baseline (CTC1/cfDNA1), CT pre-cycle III (CTC2/cfDNA2), CT post-cycle IV, end of CT and relapse. (3) Results: In 45/57 ESCC patients with evaluable CTC counts at CT pre-cycle III, positive CTC2 (≥3 CTCs) is independently associated with response at interim reassessment and progression-free survival (PFS) in multivariate analysis. In 42/57 ESCC patients with changes of CTC1/CTC2 and cfDNA1/cfDNA2, patients categorized into four risk groups based on the number of favorable and unfavorable changes of CTC1/CTC2 and cfDNA1/cfDNA2, were independently associated with overall survival (OS) by multivariate analysis. (4) Conclusions: CTC counts at pre-cycle III are independently associated with response at interim reassessment and PFS. Combined changes of CTC counts and cfDNA levels from baseline to pre-cycle III are independently associated with OS. Longitudinal liquid biopsy serial monitoring provides complementary information for prediction and prognosis for CT responses in advanced ESCC.
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http://dx.doi.org/10.3390/cancers12061352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352685PMC
May 2020

Using incognito standardised patients to evaluate quality of eye care in China.

Br J Ophthalmol 2021 03 20;105(3):311-316. Epub 2020 May 20.

Centre for Public Health, Queen's University Belfast, Belfast, Belfast, UK.

Background/aims: Few studies have objectively examined the quality of eye care in China. We assessed refractive care using the incognito standardised patient (SP) approach, a gold standard for evaluating clinical practice.

Methods: A total of 52 SPs were trained to provide standardised responses during eye examinations, and underwent automated and non-cycloplegic, subjective refraction by a senior ophthalmologist from Zhongshan Ophthalmologic Center, a national-level clinical and research centre. SPs subsequently received subjective refraction and eye exams at a randomly selected sample of 40 public hospitals and 93 private optical shops in Shaanxi, Northwestern China. Difference between expert and local refraction in the better-seeing eye was calculated by the vector diopteric method, and completeness of exams assessed against national standards. SP and provider demographic information and provider clinical experience were recorded.

Results: SPs (n=52, mean (range) age, 25.7 (22-31) years, 28.8% male) underwent 133 eye exams (mean total duration 15.0±11.7 min) by 133 local refractionists (24-60 years, 30.3% male). Only 93 (69.9%), 121 (91.0%) and 104 (78.2%) of local refractionists assessed vision, automated and subjective refraction, respectively. The median inaccuracy was -0.25 diopters (D), while 25.6% of results differed by an absolute value of ≥1.0 D and 6.0% by ≥2.0 D. Predictors of inaccurate refraction included spectacle power <-6.0 D (OR=2.66; 95% CI, 1.27 to 5.56), service at a public (vs private) hospital (OR=2.01; 95% CI, 1.11 to 3.63) and provider male sex (OR=2.03; 95% CI, 1.11 to 3.69).

Conclusion: Inaccurate refractions are common in Northwestern China, particularly in public facilities. Important assessments, including subjective refraction, are frequently omitted.
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http://dx.doi.org/10.1136/bjophthalmol-2019-315103DOI Listing
March 2021

Pervasive functional translation of noncanonical human open reading frames.

Science 2020 03;367(6482):1140-1146

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.

Ribosome profiling has revealed pervasive but largely uncharacterized translation outside of canonical coding sequences (CDSs). In this work, we exploit a systematic CRISPR-based screening strategy to identify hundreds of noncanonical CDSs that are essential for cellular growth and whose disruption elicits specific, robust transcriptomic and phenotypic changes in human cells. Functional characterization of the encoded microproteins reveals distinct cellular localizations, specific protein binding partners, and hundreds of microproteins that are presented by the human leukocyte antigen system. We find multiple microproteins encoded in upstream open reading frames, which form stable complexes with the main, canonical protein encoded on the same messenger RNA, thereby revealing the use of functional bicistronic operons in mammals. Together, our results point to a family of functional human microproteins that play critical and diverse cellular roles.
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http://dx.doi.org/10.1126/science.aay0262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289059PMC
March 2020
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