Publications by authors named "William Yang"

237 Publications

Transcriptome and IgH Repertoire Analyses Show That CD11c B Cells Are a Distinct Population With Similarity to B Cells Arising in Autoimmunity and Infection.

Front Immunol 2021 19;12:649458. Epub 2021 Mar 19.

Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States.

A distinct B cell population marked by elevated CD11c expression is found in patients with systemic lupus erythematosus (SLE). Cells with a similar phenotype have been described during chronic infection, but variable gating strategies and nomenclature have led to uncertainty of their relationship to each other. We isolated CD11c cells from peripheral blood and characterized them using transcriptome and IgH repertoire analyses. Gene expression data revealed the CD11c IgD and IgD subsets were highly similar to each other, but distinct from naive, memory, and plasma cell subsets. Although CD11c B cells were enriched in some germinal center (GC) transcripts and expressed numerous negative regulators of B cell receptor (BCR) activation, they were distinct from GC B cells. Gene expression patterns from SLE CD11c B cells were shared with other human diseases, but not with mouse age-associated B cells. IgH V-gene sequencing analysis showed IgD and IgD CD11c B cells had somatic hypermutation and were clonally related to each other and to conventional memory and plasma cells. However, the IgH repertoires expressed by the different subsets suggested that defects in negative selection during GC transit could contribute to autoimmunity. The results portray a pervasive B cell population that accumulates during autoimmunity and chronic infection and is refractory to BCR signaling.
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http://dx.doi.org/10.3389/fimmu.2021.649458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017342PMC
March 2021

Inhibiting the MNK1/2-eIF4E axis impairs melanoma phenotype switching and potentiates anti-tumor immune responses.

J Clin Invest 2021 Mar 9. Epub 2021 Mar 9.

Lady Davis Institute, Jewish General Hospital, Montréal, Canada.

Melanomas commonly undergo a phenotype switch, from a proliferative to an invasive state. Such tumor cell plasticity contributes to immunotherapy resistance, however, the mechanisms are not completely understood and thus therapeutically unexploited. Using melanoma mouse models, we demonstrated that blocking the MNK1/2-eIF4E axis inhibited melanoma phenotype switching and sensitized melanoma to anti-PD-1 immunotherapy. We showed that phospho-eIF4E-deficient murine melanomas expressed high levels of melanocytic antigens, with similar results verified in patient melanomas. Mechanistically, we identified phospho-eIF4E-mediated translational control of NGFR, a critical effector of phenotype switching. Genetic ablation of phospho-eIF4E reprogrammed the immunosuppressive microenvironment, exemplified by lowered production of inflammatory factors, decreased PD-L1 expression on dendritic cells and MDSCs, and increased CD8+ T-cell infiltrates. Finally, dual blockade of the MNK1/2-eIF4E axis and the PD-1/PD-L1 immune checkpoint demonstrated efficacy in multiple melanoma models regardless of their genomic classification. An increase in the presence of intratumoral stem-like TCF1+PD-1+CD8+ T cells, a characteristic essential for durable anti-tumor immunity, was detected in mice administered a MNK1/2 inhibitor and anti-PD-1 therapy. Using MNK1/2 inhibitors to repress phospho-eIF4E thus offers a new strategy to inhibit melanoma plasticity and improve response to anti-PD-1 immunotherapy.
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http://dx.doi.org/10.1172/JCI140752DOI Listing
March 2021

The discovery of a novel anti-metastatic Bcl3 inhibitor.

Mol Cancer Ther 2021 Mar 1. Epub 2021 Mar 1.

School of Pharmacy and Pharmaceutical Sciences, Cardiff University

The development of anti-metastatic drugs is an urgent healthcare priority for cancer patients, since metastasis is thought to account for around 90% of cancer deaths. Current anti- metastatic treatment options are limited and often associated with poor long-term survival and systemic toxicities. Bcl3, a facilitator protein of the NF-kB family, is associated with poor prognosis in a range of tumor types. Bcl3 has been directly implicated in the metastasis of tumor cells, yet is well tolerated when constitutively deleted in murine models, making it a promising therapeutic target. Here we describe the identification and characterization of the first small molecule Bcl3 inhibitor, by employing a virtual drug design and screening approach against a computational model of the Bcl3-NFkB1(p50) protein-protein interaction. From selected virtual screening hits, one compound (JS6) showed potent intracellular Bcl3-inhibitory activity. JS6 treatment led to reductions in Bcl3-NFkB1 binding, tumor colony formation and cancer cell migration in vitro; and tumor-stasis and anti-metastatic activity in vivo, whilst being devoid of overt systemic toxicity. These results represent a successful application of in silico screening in the identification of protein-protein inhibitors for novel intra-cellular targets, and confirm Bcl3 as a potential anti-metastatic target.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0283DOI Listing
March 2021

Digital Health Interventions for Cardiac Rehabilitation: Systematic Literature Review.

J Med Internet Res 2021 Feb 8;23(2):e18773. Epub 2021 Feb 8.

Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

Background: Cardiovascular disease (CVD) is the leading cause of death worldwide. Despite strong evidence supporting the benefits of cardiac rehabilitation (CR), over 80% of eligible patients do not participate in CR. Digital health technologies (ie, the delivery of care using the internet, wearable devices, and mobile apps) have the potential to address the challenges associated with traditional facility-based CR programs, but little is known about the comprehensiveness of these interventions to serve as digital approaches to CR. Overall, there is a lack of a systematic evaluation of the current literature on digital interventions for CR.

Objective: The objective of this systematic literature review is to provide an in-depth analysis of the potential of digital health technologies to address the challenges associated with traditional CR. Through this review, we aim to summarize the current literature on digital interventions for CR, identify the key components of CR that have been successfully addressed through digital interventions, and describe the gaps in research that need to be addressed for sustainable and scalable digital CR interventions.

Methods: Our strategy for identifying the primary literature pertaining to CR with digital solutions (defined as technology employed to deliver remote care beyond the use of the telephone) included a consultation with an expert in the field of digital CR and searches of the PubMed (MEDLINE), Embase, CINAHL, and Cochrane databases for original studies published from January 1990 to October 2018.

Results: Our search returned 31 eligible studies, of which 22 were randomized controlled trials. The reviewed CR interventions primarily targeted physical activity counseling (31/31, 100%), baseline assessment (30/31, 97%), and exercise training (27/31, 87%). The most commonly used modalities were smartphones or mobile devices (20/31, 65%), web-based portals (18/31, 58%), and email-SMS (11/31, 35%). Approximately one-third of the studies addressed the CR core components of nutrition counseling, psychological management, and weight management. In contrast, less than a third of the studies addressed other CR core components, including the management of lipids, diabetes, smoking cessation, and blood pressure.

Conclusions: Digital technologies have the potential to increase access and participation in CR by mitigating the challenges associated with traditional, facility-based CR. However, previously evaluated interventions primarily focused on physical activity counseling and exercise training. Thus, further research is required with more comprehensive CR interventions and long-term follow-up to understand the clinical impact of digital interventions.
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http://dx.doi.org/10.2196/18773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899799PMC
February 2021

PIAS1 modulates striatal transcription, DNA damage repair, and SUMOylation with relevance to Huntington's disease.

Proc Natl Acad Sci U S A 2021 Jan;118(4)

Department of Neurobiology and Behavior, University of California, Irvine, CA 92697;

DNA damage repair genes are modifiers of disease onset in Huntington's disease (HD), but how this process intersects with associated disease pathways remains unclear. Here we evaluated the mechanistic contributions of protein inhibitor of activated STAT-1 (PIAS1) in HD mice and HD patient-derived induced pluripotent stem cells (iPSCs) and find a link between PIAS1 and DNA damage repair pathways. We show that PIAS1 is a component of the transcription-coupled repair complex, that includes the DNA damage end processing enzyme polynucleotide kinase-phosphatase (PNKP), and that PIAS1 is a SUMO E3 ligase for PNKP. Pias1 knockdown (KD) in HD mice had a normalizing effect on HD transcriptional dysregulation associated with synaptic function and disease-associated transcriptional coexpression modules enriched for DNA damage repair mechanisms as did reduction of PIAS1 in HD iPSC-derived neurons. KD also restored mutant HTT-perturbed enzymatic activity of PNKP and modulated genomic integrity of several transcriptionally normalized genes. The findings here now link SUMO modifying machinery to DNA damage repair responses and transcriptional modulation in neurodegenerative disease.
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http://dx.doi.org/10.1073/pnas.2021836118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848703PMC
January 2021

Highly accurate colorectal cancer prediction model based on Raman spectroscopy using patient serum.

World J Gastrointest Oncol 2020 Nov;12(11):1311-1324

Showa University Koto Toyosu Hospital, Tokyo 135-8577, Japan.

Background: Colorectal cancer (CRC) is an important disease worldwide, accounting for the second highest number of cancer-related deaths and the third highest number of new cancer cases. The blood test is a simple and minimally invasive diagnostic test. However, there is currently no blood test that can accurately diagnose CRC.

Aim: To develop a comprehensive, spontaneous, minimally invasive, label-free, blood-based CRC screening technique based on Raman spectroscopy.

Methods: We used Raman spectra recorded using 184 serum samples obtained from patients undergoing colonoscopies. Patients with malignant tumor histories as well as those with cancers in organs other than the large intestine were excluded. Consequently, the specific diseases of 184 patients were CRC (12), rectal neuroendocrine tumor (2), colorectal adenoma (68), colorectal hyperplastic polyp (18), and others (84). We used the 1064-nm wavelength laser for excitation. The power of the laser was set to 200 mW.

Results: Use of the recorded Raman spectra as training data allowed the construction of a boosted tree CRC prediction model based on machine learning. Therefore, the generalized values for CRC, adenomas, hyperplastic polyps, and neuroendocrine tumors were 0.9982, 0.9630, 0.9962, and 0.9986, respectively.

Conclusion: For machine learning using Raman spectral data, a highly accurate CRC prediction model with a high value was constructed. We are currently planning studies to demonstrate the accuracy of this model with a large amount of additional data.
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http://dx.doi.org/10.4251/wjgo.v12.i11.1311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667458PMC
November 2020

Disease-related Huntingtin seeding activities in cerebrospinal fluids of Huntington's disease patients.

Sci Rep 2020 11 20;10(1):20295. Epub 2020 Nov 20.

Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, USA.

In Huntington's disease (HD), the mutant Huntingtin (mHTT) is postulated to mediate template-based aggregation that can propagate across cells. It has been difficult to quantitatively detect such pathological seeding activities in patient biosamples, e.g. cerebrospinal fluids (CSF), and study their correlation with the disease manifestation. Here we developed a cell line expressing a domain-engineered mHTT-exon 1 reporter, which showed remarkably high sensitivity and specificity in detecting mHTT seeding species in HD patient biosamples. We showed that the seeding-competent mHTT species in HD CSF are significantly elevated upon disease onset and with the progression of neuropathological grades. Mechanistically, we showed that mHTT seeding activities in patient CSF could be ameliorated by the overexpression of chaperone DNAJB6 and by antibodies against the polyproline domain of mHTT. Together, our study developed a selective and scalable cell-based tool to investigate mHTT seeding activities in HD CSF, and demonstrated that the CSF mHTT seeding species are significantly associated with certain disease states. This seeding activity can be ameliorated by targeting specific domain or proteostatic pathway of mHTT, providing novel insights into such pathological activities.
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http://dx.doi.org/10.1038/s41598-020-77164-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679413PMC
November 2020

Approaching Inflammation Paradoxes-Proinflammatory Cytokine Blockages Induce Inflammatory Regulators.

Front Immunol 2020 19;11:554301. Epub 2020 Oct 19.

Centers for Cardiovascular Research, Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States.

The mechanisms that underlie various inflammation paradoxes, metabolically healthy obesity, and increased inflammations after inflammatory cytokine blockades and deficiencies remain poorly determined. We performed an extensive -omics database mining, determined the expressions of 1367 innate immune regulators in 18 microarrays after deficiencies of 15 proinflammatory cytokines/regulators and eight microarray datasets of patients receiving Mab therapies, and made a set of significant findings: 1) proinflammatory cytokines/regulators suppress the expressions of innate immune regulators; 2) upregulations of innate immune regulators in the deficiencies of IFNγ/IFNγR1, IL-17A, STAT3 and miR155 are more than that after deficiencies of TNFα, IL-1β, IL-6, IL-18, STAT1, NF-kB, and miR221; 3) IFNγ, IFNγR and IL-17RA inhibit 10, 59 and 39 proinflammatory cytokine/regulator pathways, respectively; in contrast, TNFα, IL-6 and IL-18 each inhibits only four to five pathways; 4) The IFNγ-promoted and -suppressed innate immune regulators have four shared pathways; the IFNγR1-promoted and -suppressed innate immune regulators have 11 shared pathways; and the miR155-promoted and -suppressed innate immune regulators have 13 shared pathways, suggesting negative-feedback mechanisms in their conserved regulatory pathways for innate immune regulators; 5) Deficiencies of proinflammatory cytokine/regulator-suppressed, promoted programs share signaling pathways and increase the likelihood of developing 11 diseases including cardiovascular disease; 6) There are the shared innate immune regulators and pathways between deficiency of TNFα in mice and anti-TNF therapy in clinical patients; 7) Mechanistically, up-regulated reactive oxygen species regulators such as myeloperoxidase caused by suppression of proinflammatory cytokines/regulators can drive the upregulation of suppressed innate immune regulators. Our findings have provided novel insights on various inflammation paradoxes and proinflammatory cytokines regulation of innate immune regulators; and may re-shape new therapeutic strategies for cardiovascular disease and other inflammatory diseases.
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http://dx.doi.org/10.3389/fimmu.2020.554301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604447PMC
October 2020

Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: A randomized, double-blind, placebo-controlled phase 3 trial.

J Allergy Clin Immunol 2020 Oct 21. Epub 2020 Oct 21.

University of California San Diego, San Diego, Calif.

Background: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein in development for the prophylaxis of hereditary angioedema (HAE) attacks.

Objective: Our aim was to determine the efficacy, safety, and tolerability of berotralstat in patients with HAE over a 24-week treatment period (the phase 3 APeX-2 trial).

Methods: APeX-2 was a double-blind, parallel-group study that randomized patients at 40 sites in 11 countries 1:1:1 to receive once-daily berotralstat in a dose of 110 mg or 150 mg or placebo (Clinicaltrials.gov identifier NCT03485911). Patients aged 12 years or older with HAE due to C1 inhibitor deficiency and at least 2 investigator-confirmed HAE attacks in the first 56 days of a prospective run-in period were eligible. The primary efficacy end point was the rate of investigator-confirmed HAE attacks during the 24-week treatment period.

Results: A total of 121 patients were randomized; 120 of them received at least 1 dose of the study drug (n = 41, 40, and 39 in the 110-mg dose of berotralstat, 150-mg of dose berotralstat, and placebo groups, respectively). Berotralstat demonstrated a significant reduction in attack rate at both 110 mg (1.65 attacks per month; P = .024) and 150 mg (1.31 attacks per month; P < .001) relative to placebo (2.35 attacks per month). The most frequent treatment-emergent adverse events that occurred more with berotralstat than with placebo were abdominal pain, vomiting, diarrhea, and back pain. No drug-related serious treatment-emergent adverse events occurred.

Conclusion: Both the 110-mg and 150-mg doses of berotralstat reduced HAE attack rates compared with placebo and were safe and generally well tolerated. The most favorable benefit-to-risk profile was observed at a dose of 150 mg per day.
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http://dx.doi.org/10.1016/j.jaci.2020.10.015DOI Listing
October 2020

Pulmonary Deposition of Radionucleotide-Labeled Palivizumab: Proof-of-Concept Study.

Front Pharmacol 2020 19;11:1291. Epub 2020 Aug 19.

New Vaccines, Murdoch Children's Research Institute, Parkville, VIC, Australia.

Objective: Current prevention and/or treatment options for respiratory syncytial virus (RSV) infections are limited as no vaccine is available. Prophylaxis with palivizumab is very expensive and requires multiple intramuscular injections over the RSV season. Here we present proof-of-concept data using nebulized palivizumab delivery as a promising new approach for the prevention or treatment of severe RSV infections, documenting both aerosol characteristics and pulmonary deposition patterns in the lungs of lambs.

Design: Prospective animal study.

Setting: Biosecurity Control Level 2-designated large animal research facility at the Murdoch Children's Research Institute, Melbourne, Australia.

Subjects: Four weaned Border-Leicester/Suffolk lambs at 5 months of age.

Interventions: Four lambs were administered aerosolized palivizumab conjugated to Tc-99m, under gaseous anesthesia, using either the commercially available AeroNeb Go or the investigational HYDRA device, placed in-line with the inspiratory limb of a breathing circuit. Lambs were scanned in a single-photon emission computed tomography (SPECT/CT) scanner in the supine position during the administration procedure.

Measurements And Main Results: Both the HYDRA and AeroNeb Go produced palivizumab aerosols in the 1-5 µm range with similar median (geometric standard deviation and range) aerosol droplet diameters for the HYDRA device (1.84 ± 1.40 μm, range = 0.54-5.41μm) and the AeroNeb Go (3.07 ± 1.56 μm, range = 0.86-10 μm). Aerosolized palivizumab was delivered to the lungs at 88.79-94.13% of the total aerosolized amount for all lambs, with a small proportion localized to either the trachea or stomach. No difference between devices were found. Pulmonary deposition ranged from 6.57 to 9.25% of the total dose of palivizumab loaded in the devices, mostly in the central right lung.

Conclusions: Aerosolized palivizumab deposition patterns were similar in all lambs, suggesting a promising approach in the control of severe RSV lung infections.
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http://dx.doi.org/10.3389/fphar.2020.01291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466567PMC
August 2020

ROS systems are a new integrated network for sensing homeostasis and alarming stresses in organelle metabolic processes.

Redox Biol 2020 10 27;37:101696. Epub 2020 Aug 27.

Centers for Cardiovascular Research and Inflammation, Translational and Clinical Lung Research, USA; Metabolic Disease Research and Cardiovascular Research and Thrombosis Research, Departments of Pharmacology, Microbiology and Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA. Electronic address:

Reactive oxygen species (ROS) are critical for the progression of cardiovascular diseases, inflammations and tumors. However, the mechanisms of how ROS sense metabolic stress, regulate metabolic pathways and initiate proliferation, inflammation and cell death responses remain poorly characterized. In this analytic review, we concluded that: 1) Based on different features and functions, eleven types of ROS can be classified into seven functional groups: metabolic stress-sensing, chemical connecting, organelle communication, stress branch-out, inflammasome-activating, dual functions and triple functions ROS. 2) Among the ROS generation systems, mitochondria consume the most amount of oxygen; and nine types of ROS are generated; thus, mitochondrial ROS systems serve as the central hub for connecting ROS with inflammasome activation, trained immunity and immunometabolic pathways. 3) Increased nuclear ROS production significantly promotes cell death in comparison to that in other organelles. Nuclear ROS systems serve as a convergent hub and decision-makers to connect unbearable and alarming metabolic stresses to inflammation and cell death. 4) Balanced ROS levels indicate physiological homeostasis of various metabolic processes in subcellular organelles and cytosol, while imbalanced ROS levels present alarms for pathological organelle stresses in metabolic processes. Based on these analyses, we propose a working model that ROS systems are a new integrated network for sensing homeostasis and alarming stress in metabolic processes in various subcellular organelles. Our model provides novel insights on the roles of the ROS systems in bridging metabolic stress to inflammation, cell death and tumorigenesis; and provide novel therapeutic targets for treating those diseases. (Word count: 246).
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http://dx.doi.org/10.1016/j.redox.2020.101696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767745PMC
October 2020

DNA methylation study of Huntington's disease and motor progression in patients and in animal models.

Nat Commun 2020 09 10;11(1):4529. Epub 2020 Sep 10.

Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.

Although Huntington's disease (HD) is a well studied Mendelian genetic disorder, less is known about its associated epigenetic changes. Here, we characterize DNA methylation levels in six different tissues from 3 species: a mouse huntingtin (Htt) gene knock-in model, a transgenic HTT sheep model, and humans. Our epigenome-wide association study (EWAS) of human blood reveals that HD mutation status is significantly (p < 10) associated with 33 CpG sites, including the HTT gene (p = 6.5 × 10). These Htt/HTT associations were replicated in the Q175 Htt knock-in mouse model (p = 6.0 × 10) and in the transgenic sheep model (p = 2.4 × 10). We define a measure of HD motor score progression among manifest HD cases based on multiple clinical assessments. EWAS of motor progression in manifest HD cases exhibits significant (p < 10) associations with methylation levels at three loci: near PEX14 (p = 9.3 × 10), GRIK4 (p = 3.0 × 10), and COX4I2 (p = 6.5 × 10). We conclude that HD is accompanied by profound changes of DNA methylation levels in three mammalian species.
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http://dx.doi.org/10.1038/s41467-020-18255-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484780PMC
September 2020

Author Correction: Striatal neurons directly converted from Huntington's disease patient fibroblasts recapitulate age-associated disease phenotypes.

Nat Neurosci 2020 Oct;23(10):1307

Department of Developmental Biology, Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41593-020-00714-3DOI Listing
October 2020

Brainwide Genetic Sparse Cell Labeling to Illuminate the Morphology of Neurons and Glia with Cre-Dependent MORF Mice.

Neuron 2020 10 13;108(1):111-127.e6. Epub 2020 Aug 13.

Center for Neurobehavioral Genetics, Jane and Terry Semel Institute for Neuroscience and Human Behavior, and Department of Psychiatry and Biobehavioral Sciences, Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address:

Cajal recognized that the elaborate shape of neurons is fundamental to their function in the brain. However, there are no simple and generalizable genetic methods to study neuronal or glial cell morphology in the mammalian brain. Here, we describe four mouse lines conferring Cre-dependent sparse cell labeling based on mononucleotide repeat frameshift (MORF) as a stochastic translational switch. Notably, the optimized MORF3 mice, with a membrane-bound multivalent immunoreporter, confer Cre-dependent sparse and bright labeling of thousands of neurons, astrocytes, or microglia in each brain, revealing their intricate morphologies. MORF3 mice are compatible with imaging in tissue-cleared thick brain sections and with immuno-EM. An analysis of 151 MORF3-labeled developing retinal horizontal cells reveals novel morphological cell clusters and axonal maturation patterns. Our study demonstrates a conceptually novel, simple, generalizable, and scalable mouse genetic solution to sparsely label and illuminate the morphology of genetically defined neurons and glia in the mammalian brain.
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http://dx.doi.org/10.1016/j.neuron.2020.07.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572760PMC
October 2020

Long-term, open-label extension study of the efficacy and safety of epicutaneous immunotherapy for peanut allergy in children: PEOPLE 3-year results.

J Allergy Clin Immunol 2020 10 10;146(4):863-874. Epub 2020 Jul 10.

DBV Technologies, Montrouge, France; Division of Pediatric Allergy and Immunology, Icahn School of Medicine at Mount Sinai, New York, NY.

Background: The PEPITES (Peanut EPIT Efficacy and Safety) trial, a 12-month randomized controlled study of children with peanut allergy and 4 to 11 years old, previously reported the safety and efficacy of epicutaneous immunotherapy (EPIT) for peanut allergy (250 μg, daily epicutaneous peanut protein; DBV712 250 μg).

Objective: We sought to assess interim safety and efficacy of an additional 2 years of EPIT from the ongoing (5-year treatment) PEOPLE (PEPITES Open-Label Extension) study.

Methods: Subjects who completed PEPITES were offered enrollment in PEOPLE. Following an additional 2 years of daily DBV712 250 μg, subjects who had received DBV712 250 μg in PEPITES underwent month-36 double-blind, placebo-controlled food challenge with an optional month-38 sustained unresponsiveness assessment.

Results: Of 213 eligible subjects who had received DBV712 250 μg in PEPITES, 198 (93%) entered PEOPLE, of whom 141 (71%) had assessable double-blind, placebo-controlled food challenge at month 36. At month 36, 51.8% of subjects (73 of 141) reached an eliciting dose of ≥1000 mg, compared with 40.4% (57 of 141) at month 12; 75.9% (107 of 141) demonstrated increased eliciting dose compared with baseline; and 13.5% (19 of 141) tolerated the full double-blind, placebo-controlled food challenge of 5444 mg. Median cumulative reactive dose increased from 144 to 944 mg. Eighteen subjects underwent an optional sustained unresponsiveness assessment; 14 of those (77.8%) maintained an eliciting dose of ≥1000 mg at month 38. Local patch-site skin reactions were common but decreased over time. There was no treatment-related epinephrine use in years 2 or 3. Compliance was high (96.9%), and withdrawals due to treatment-related adverse events were low (1%).

Conclusions: These results demonstrate that daily EPIT treatment for peanut allergy beyond 1 year leads to continued response from a well-tolerated, simple-to-use regimen.
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http://dx.doi.org/10.1016/j.jaci.2020.06.028DOI Listing
October 2020

Vascular Endothelial Cells and Innate Immunity.

Arterioscler Thromb Vasc Biol 2020 06 27;40(6):e138-e152. Epub 2020 May 27.

From the Centers of Inflammation, Translational, and Clinical Lung Research (Y. Shao, Y. Sun, Y.L., F.S., C.D., C.J., K.X., X.J., X.Y.), Temple University, Lewis Katz School of Medicine, Philadelphia, PA.

In addition to the roles of endothelial cells (ECs) in physiological processes, ECs actively participate in both innate and adaptive immune responses. We previously reported that, in comparison to macrophages, a prototypic innate immune cell type, ECs have many innate immune functions that macrophages carry out, including cytokine secretion, phagocytic function, antigen presentation, pathogen-associated molecular patterns-, and danger-associated molecular patterns-sensing, proinflammatory, immune-enhancing, anti-inflammatory, immunosuppression, migration, heterogeneity, and plasticity. In this highlight, we introduce recent advances published in both and many other journals: (1) several significant characters classify ECs as novel immune cells not only in infections and allograft transplantation but also in metabolic diseases; (2) several new receptor systems including conditional danger-associated molecular pattern receptors, nonpattern receptors, and homeostasis associated molecular patterns receptors contribute to innate immune functions of ECs; (3) immunometabolism and innate immune memory determine the innate immune functions of ECs; (4) a great induction of the immune checkpoint receptors in ECs during inflammations suggests the immune tolerogenic functions of ECs; and (5) association of immune checkpoint inhibitors with cardiovascular adverse events and cardio-oncology indicates the potential contributions of ECs as innate immune cells.
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http://dx.doi.org/10.1161/ATVBAHA.120.314330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263359PMC
June 2020

Long-term safety and efficacy of subcutaneous C1-inhibitor in older patients with hereditary angioedema.

Ann Allergy Asthma Immunol 2020 09 20;125(3):334-340.e1. Epub 2020 May 20.

University of California, San Diego School of Medicine, La Jolla, California.

Background: Patients aged 65 years and older with hereditary angioedema (HAE) owing to C1-inhibitor (C1-INH) deficiency may have an altered response to treatment and are at higher risk for treatment-related adverse events (AEs) because of comorbidities and polypharmacy.

Objective: To investigate the safety and efficacy of subcutaneous C1 esterase inhibitor (C1-INH) in patients aged 65 years and older treated in an open-label extension of a phase 3 trial.

Methods: Eligible patients (≥4 attacks for more than 2 consecutive months) were randomized to receive twice-weekly subcutaneous C1-INH with a dosage of 40 IU/kg or 60 IU/kg for 52 to 140 weeks. Safety end points and efficacy outcomes were evaluated for patients aged 65 years and above and younger than 65 years.

Results: Of the 126 patients treated, 10 were 65 years and older (mean age [range], 68 [65-72 years]). A total of 8 of 10 patients had multiple comorbidities, and 6 of these 10 patients were taking more than 5 non-HAE-related drugs concomitantly. AEs occurring in more than 1 patient included injection site bruising (n = 2, related), injection site pain (n = 2, related), urinary tract infection (n = 2, unrelated), and diarrhea (n = 2, unrelated). No thromboembolic events or cases of anaphylaxis were reported. Two patients aged 65 years and older experienced unrelated serious AEs (dehydration and hypokalemia in 1 and pneumonia and an HAE attack leading to hospitalization in another). A total of 6 of 9 evaluable patients were responders, with a greater than or equal to 50% reduction in HAE attacks vs prestudy; 6 of 10 patients had less than 1 attack over 4 weeks and 3 were attack-free (median attack rate, 0.52 attacks per month).

Conclusion: Subcutaneous C1-INH was well-tolerated and effective in the management of HAE in patients aged 65 years and older with multiple comorbid conditions and polypharmacy.
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http://dx.doi.org/10.1016/j.anai.2020.05.015DOI Listing
September 2020

Contribution of Germline Predisposition Gene Mutations to Breast Cancer Risk in African American Women.

J Natl Cancer Inst 2020 12;112(12):1213-1221

Departments of Health Sciences Research, Laboratory Medicine and Pathology, and Oncology, Mayo Clinic, Rochester, MN 55902, USA.

Background: The risks of breast cancer in African American (AA) women associated with inherited mutations in breast cancer predisposition genes are not well defined. Thus, whether multigene germline hereditary cancer testing panels are applicable to this population is unknown. We assessed associations between mutations in panel-based genes and breast cancer risk in 5054 AA women with breast cancer and 4993 unaffected AA women drawn from 10 epidemiologic studies.

Methods: Germline DNA samples were sequenced for mutations in 23 cancer predisposition genes using a QIAseq multiplex amplicon panel. Prevalence of mutations and odds ratios (ORs) for associations with breast cancer risk were estimated with adjustment for study design, age, and family history of breast cancer.

Results: Pathogenic mutations were identified in 10.3% of women with estrogen receptor (ER)-negative breast cancer, 5.2% of women with ER-positive breast cancer, and 2.3% of unaffected women. Mutations in BRCA1, BRCA2, and PALB2 were associated with high risks of breast cancer (OR = 47.55, 95% confidence interval [CI] = 10.43 to >100; OR = 7.25, 95% CI = 4.07 to 14.12; OR = 8.54, 95% CI = 3.67 to 24.95, respectively). RAD51D mutations were associated with high risk of ER-negative disease (OR = 7.82, 95% CI = 1.61 to 57.42). Moderate risks were observed for CHEK2, ATM, ERCC3, and FANCC mutations with ER-positive cancer, and RECQL mutations with all breast cancer.

Conclusions: The study identifies genes that predispose to breast cancer in the AA population, demonstrates the validity of current breast cancer testing panels for use in AA women, and provides a basis for increased referral of AA patients for cancer genetic testing.
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http://dx.doi.org/10.1093/jnci/djaa040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735769PMC
December 2020

Omalizumab Re-Treatment and Step-Up in Patients with Chronic Spontaneous Urticaria: OPTIMA Trial.

J Allergy Clin Immunol Pract 2020 Jul - Aug;8(7):2372-2378.e5. Epub 2020 Apr 6.

Novartis Pharmaceuticals Canada Inc, Dorval, QC, Canada.

Background: Omalizumab shows greater clinical benefit with 300 mg dose than with the 150 mg dose.

Objective: To determine outcomes postwithdrawal, relapse, and re-treatment in omalizumab responders, and from stepping up to 300 mg after insufficient symptom control with 150 mg.

Methods: This was a prospective, randomized (3:4), open-label, noncomparator study (clinicaltrials.gov: NCT02161562). A total of 314 adult patients with chronic spontaneous urticaria and symptomatic on H-antihistamines were enrolled between August 1, 2014, and November 6, 2015. Patients received 150 mg/300 mg omalizumab, every 4 weeks for 24 weeks. Omalizumab 150 mg dose could be stepped up to 300 mg between week 8 and week 24, if the 7-day sum of the daily Urticaria Activity Score (UAS7) was more than 6. If patients relapsed after treatment withdrawal at week 24, they could be re-treated with the same dose on which omalizumab was started. Patients on 300 mg could extend treatment by 12 weeks if they did not achieve symptom control on 300 mg in the initial dosing phase. The primary end point was the proportion of well-controlled patients who relapsed postwithdrawal, and achieved symptom control at the end of re-treatment. Symptom control was assessed using UAS7 (UAS7 ≤ 6 = well controlled).

Results: Overall, 115 of 314 patients had adequate symptom control at week 24 (end of the initial dosing period) and 56 were re-treated after relapse postwithdrawal; 87.8% (95% CI, 78.6%-96.9%) regained symptomatic control (UAS7 ≤ 6). Most (141 of 178) patients initially treated with 150 mg required step-up to 300 mg, which resulted in a 9.5-point (95% CI, 7.6-11.3) improvement in UAS7 over the mean change observed initially on 150 mg.

Conclusions: Step-up to 300 mg helps a greater proportion of patients achieve symptom control, and re-treatment with omalizumab is as effective as initial therapy.
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http://dx.doi.org/10.1016/j.jaip.2020.03.022DOI Listing
April 2020

Huntington's Disease: Genome-wide Neuroprotection Screening Goes Viral.

Neuron 2020 04;106(1):4-6

Center for Neurobehavioral Genetics, Jane and Terry Semel Institute for Neuroscience & Human Behavior, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. Electronic address:

Forward genetic screen, typically performed in invertebrates or mammalian cell lines, has been instrumental in discovering genes essential for neural function. In this issue of Neuron, Wertz et al. (2020) demonstrate the first viral-mediated, genome-wide screen to identify neuroprotective genes in wild-type and Huntington's disease (HD) mouse brains.
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http://dx.doi.org/10.1016/j.neuron.2020.03.020DOI Listing
April 2020

End-stage renal disease is different from chronic kidney disease in upregulating ROS-modulated proinflammatory secretome in PBMCs - A novel multiple-hit model for disease progression.

Redox Biol 2020 07 20;34:101460. Epub 2020 Feb 20.

Center for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Centers for Metabolic Disease Research, Cardiovascular Research, & Thrombosis Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Departments of Pharmacology, Microbiology and Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA. Electronic address:

Background: The molecular mechanisms underlying chronic kidney disease (CKD) transition to end-stage renal disease (ESRD) and CKD acceleration of cardiovascular and other tissue inflammations remain poorly determined.

Methods: We conducted a comprehensive data analyses on 7 microarray datasets in peripheral blood mononuclear cells (PBMCs) from patients with CKD and ESRD from NCBI-GEO databases, where we examined the expressions of 2641 secretome genes (SG).

Results: 1) 86.7% middle class (molecular weight >500 Daltons) uremic toxins (UTs) were encoded by SGs; 2) Upregulation of SGs in PBMCs in patients with ESRD (121 SGs) were significantly higher than that of CKD (44 SGs); 3) Transcriptomic analyses of PBMC secretome had advantages to identify more comprehensive secretome than conventional secretomic analyses; 4) ESRD-induced SGs had strong proinflammatory pathways; 5) Proinflammatory cytokines-based UTs such as IL-1β and IL-18 promoted ESRD modulation of SGs; 6) ESRD-upregulated co-stimulation receptors CD48 and CD58 increased secretomic upregulation in the PBMCs, which were magnified enormously in tissues; 7) M1-, and M2-macrophage polarization signals contributed to ESRD- and CKD-upregulated SGs; 8) ESRD- and CKD-upregulated SGs contained senescence-promoting regulators by upregulating proinflammatory IGFBP7 and downregulating anti-inflammatory TGF-β1 and telomere stabilizer SERPINE1/PAI-1; 9) ROS pathways played bigger roles in mediating ESRD-upregulated SGs (11.6%) than that in CKD-upregulated SGs (6.8%), and half of ESRD-upregulated SGs were ROS-independent.

Conclusions: Our analysis suggests novel secretomic upregulation in PBMCs of patients with CKD and ESRD, act synergistically with uremic toxins, to promote inflammation and potential disease progression. Our findings have provided novel insights on PBMC secretome upregulation to promote disease progression and may lead to the identification of new therapeutic targets for novel regimens for CKD, ESRD and their accelerated cardiovascular disease, other inflammations and cancers. (Total words: 279).
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http://dx.doi.org/10.1016/j.redox.2020.101460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327976PMC
July 2020

MNK1 signaling induces an ANGPTL4-mediated gene signature to drive melanoma progression.

Oncogene 2020 04 4;39(18):3650-3665. Epub 2020 Mar 4.

Division of Experimental Medicine, Faculty of Medicine, McGill University, Montréal, QC, Canada.

The BRAF mutation occurs in more than 50% of cutaneous melanomas, and results in the constitutive activation of the mitogen-activated protein kinases (MAPK) pathway. MAP kinase-interacting serine/threonine-protein kinase 1 and 2 (MNK1/2) are downstream effectors of the activated MAPK pathway, and important molecular targets in invasive and metastatic cancer. Despite the well-known role of MNK1 in regulating mRNA translation, little is known concerning the impact of its aberrant activation on gene transcription. Here, we show that changes in the activity, or abundance, of MNK1 result in changes in the expression of pro-oncogenic and pro-invasive genes. Among the MNK1-upregulated genes, we identify Angiopoietin-like 4 (ANGPTL4), which in turn promotes an invasive phenotype via its ability to induce the expression of matrix metalloproteinases (MMPs). Using a pharmacologic inhibitor of MNK1/2, SEL201, we demonstrate that BRAF-mutated cutaneous melanoma cells are reliant on MNK1/2 for invasion and lung metastasis.
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http://dx.doi.org/10.1038/s41388-020-1240-5DOI Listing
April 2020

Steroidogenic Factor 1 (NR5A1) Activates ATF3 Transcriptional Activity.

Int J Mol Sci 2020 Feb 20;21(4). Epub 2020 Feb 20.

Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA.

Steroidogenic Factor 1 (SF-1/NR5A1), an orphan nuclear receptor, is important for sexual differentiation and the development of multiple endocrine organs, as well as cell proliferation in cancer cells. Activating transcription factor 3 (ATF3) is a transcriptional repressor, and its expression is rapidly induced by DNA damage and oncogenic stimuli. Since both NR5A1 and ATF3 can regulate and cooperate with several transcription factors, we hypothesized that NR5A1 may interact with ATF3 and plays a functional role in cancer development. First, we found that NR5A1 physically interacts with ATF3. We further demonstrated that ATF3 expression is up-regulated by NR5A1. Moreover, the promoter activity of the is activated by NR5A1 in a dose-dependent manner in several cell lines. By mapping the promoter as well as the site-directed mutagenesis analysis, we provide evidence that NR5A1 response elements (-695 bp and -665 bp) are required for expression by NR5A1. It is well known that the transcriptional activities of NR5A1 are modulated by post-translational modifications, such as small ubiquitin-related modifier (SUMO) modification and phosphorylation. Notably, we found that both SUMOylation and phosphorylation of NR5A1 play roles, at least in part, for NR5A1-mediated expression. Overall, our results provide the first evidence of a novel relationship between NR5A1 and ATF3.
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http://dx.doi.org/10.3390/ijms21041429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073147PMC
February 2020

Does Femoral Component Cementation Affect Costs or Clinical Outcomes After Hip Arthroplasty in Medicare Patients?

J Arthroplasty 2020 06 23;35(6):1489-1496.e4. Epub 2020 Jan 23.

Department of Orthopaedic Surgery, Lenox Hill Hospital, New York, NY.

Background: Bundled payment initiatives were introduced to reduce costs and improve quality of care. Cemented vs cementless femoral fixation is a modifiable variable that may influence the cost and quality of care. New bundled payment data from the Centers for Medicare and Medicaid Services allowed us to study the influence of femoral fixation strategy on (1) 90-day costs; (2) readmission rates; (3) reoperation rates; (4) length of stay (LOS); and (5) discharge disposition for Medicare patients undergoing total hip arthroplasty.

Methods: We retrospectively studied 1671 primary total hip arthroplasty Medicare cases, comparing 359 patients who received cemented femoral fixation to 1312 patients who received cementless fixation. Centers for Medicare and Medicaid Services cost data as well as clinical data were reviewed. Demographic differences were present between the 2 cohorts. Statistical analyses were performed, including multiple regression models to adjust for baseline differences.

Results: Controlling for cohort differences, cemented patients were significantly more likely to be discharged home compared to cementless patients. Cemented patients also demonstrated trends toward lower costs, lower readmission rates, and shorter LOS compared to cementless patients. All reoperations within the early postoperative period occurred in patients managed with cementless femoral fixation.

Conclusion: Among Medicare patients, cemented femoral fixation outperformed cementless fixation with respect to discharge disposition and also trended toward superiority with regards to LOS, readmission, cost of care, and reoperation. Cemented femoral fixation remains relevant and useful despite the rising popularity of cementless fixation.
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http://dx.doi.org/10.1016/j.arth.2020.01.035DOI Listing
June 2020

Mobile health application platform 'Corrie' personalises and empowers the heart attack recovery patient experience in the hospital and at home for an underserved heart attack survivor.

BMJ Case Rep 2020 Feb 17;13(2). Epub 2020 Feb 17.

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide with an estimated 17.5 million deaths annually, according to the World Health Organization (WHO). CVD prevention efforts have the potential to prevent the majority of these deaths by supporting guideline-directed medical therapy (GDMT) and lifestyle modification. Mobile health (mHealth) has the potential to address this gap, but has limited evaluation in clinical studies to date. We present the case of a middle-aged patient of low socioeconomic status, with multiple comorbidities, and no prior smartphone experience, who suffered an acute myocardial infarction (MI) and was given the Corrie intervention while hospitalised. The patient demonstrated improvement in lifestyle modification, adherence to GDMT and post-MI recovery through 2.4 years follow-up. This case supports (1) the potential of mHealth interventions to enhance patient experience and outcomes, (2) intuitive design for adoption and improvement in end user experience and (3) the capability of mHealth to reach and empower underserved patients.
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http://dx.doi.org/10.1136/bcr-2019-231801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046423PMC
February 2020

Bcl-3 promotes multi-modal tumour cell migration via NF-κB1 mediated regulation of Cdc42.

Carcinogenesis 2020 Oct;41(10):1432-1443

European Cancer Stem Cell Research Institute, School of Bioscience, Cardiff University, Cardiff, UK.

A key challenge in the implementation of anti-metastatics as cancer therapies is the multi-modal nature of cell migration, which allows tumour cells to evade the targeted inhibition of specific cell motility pathways. The nuclear factor-kappaB (NF-κB) co-factor B-cell lymphoma 3 (Bcl-3) has been implicated in breast cancer cell migration and metastasis, yet it remains to be determined exactly which cell motility pathways are controlled by Bcl-3 and whether migrating tumour cells are able to evade Bcl-3 intervention. Addressing these questions and the mechanism underpinning Bcl-3's role in this process would help determine its potential as a therapeutic target. Here we identify Bcl-3 as an upstream regulator of the two principal forms of breast cancer cell motility, involving collective and single-cell migration. This was found to be mediated by the master regulator Cdc42 through binding of the NF-κB transcription factor p50 to the Cdc42 promoter. Notably, Bcl-3 depletion inhibited both stable and transitory motility phenotypes in breast cancer cells with no evidence of migratory adaptation. Overexpression of Bcl-3 enhanced migration and increased metastatic tumour burden of breast cancer cells in vivo, whereas overexpression of a mutant Bcl-3 protein, which is unable to bind p50, suppressed cell migration and metastatic tumour burden suggesting that disruption of Bcl-3/NF-κB complexes is sufficient to inhibit metastasis. These findings identify a novel role for Bcl-3 in intrinsic and adaptive multi-modal cell migration mediated by its direct regulation of the Rho GTPase Cdc42 and identify the upstream Bcl-3:p50 transcription complex as a potential therapeutic target for metastatic disease.
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http://dx.doi.org/10.1093/carcin/bgaa005DOI Listing
October 2020

A pilot validation of CFD model results against PIV observations of haemodynamics in intracranial aneurysms treated with flow-diverting stents.

J Biomech 2020 02 24;100:109590. Epub 2019 Dec 24.

Monash Imaging & Department of Surgery, School of Clinical Sciences at Monash Health, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.

Flow-diverting (FD) stents are one of three common modes of treating intracranial aneurysms, yet knowledge of their effect on haemodynamics is incomplete. We used particle image velocimetry (PIV) to measure spatially-varying velocity of blood-analogue fluid within a patient-specific aneurysm model, and compared the observed flow behaviour to predictions from a computational fluid dynamics (CFD) model. In PIV experiments we characterised the flow on multiple cross-sections for three different arterial flowrates (150, 250, 400 mL/min) after deployment of a commercially-available FD stent. Our flow-diverting (FD) stent model for CFD simulation was constructed using a permeability adapted from the literature. Aneurysmal haemodynamics without the FD stent treatment provided good similarities between CFD and PIV results, and the results with a Silk stent treatment also provided acceptable concordances, thereby validating the use of CFD as a convenient and flexible tool for investigating intra-aneurysmal flow dynamics after FD stent treatment. Furthermore, for the first time, the porous-medium FD model stent was validated to be both efficient and effective to predict the flow-diversion effects of a FD stent treatment with a patient-specific intracranial aneurysm. Through the qualitative and quantitative comparison of CFD predictions against the experimental outcomes, this study gives confidence for future studies on aneurysmal haemodynamics and FD stent treatment effects to use CFD simulation.
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http://dx.doi.org/10.1016/j.jbiomech.2019.109590DOI Listing
February 2020

Strategies for the Successful Implementation of a Novel iPhone Loaner System (iShare) in mHealth Interventions: Prospective Study.

JMIR Mhealth Uhealth 2019 12 16;7(12):e16391. Epub 2019 Dec 16.

School of Medicine, Johns Hopkins University, Baltimore, MD, United States.

Background: As smartphone ownership continues to rise, health care systems and technology companies are driven to develop mobile health (mHealth) interventions as both diagnostic and therapeutic tools. An important consideration during mHealth intervention development is how to achieve health equity despite demographic differences in smartphone ownership. One solution is through the recirculation of loaner smartphones; however, best practices for implementing such programs to optimize security, privacy, scalability, and convenience for participants are not well defined.

Objective: In this tutorial, we describe how we implemented our novel Corrie iShare program, a 30-day loaner iPhone and smartwatch recirculation program, as part of a multi-center mHealth intervention to improve recovery and access to guideline-directed therapy following acute myocardial infarction.

Methods: We conducted a prospective study utilizing a smartphone app and leveraged iOS enterprise features as well as cellular data service to automate recirculation.

Results: Our configuration protocol was shortened from 1 hour to 10 minutes. Of 200 participants, 92 (46.0%) did not own an iPhone and would have been excluded from the study without iShare. Among iShare participants, 72% (66/92) returned their loaned smartphones.

Conclusions: The Corrie iShare program demonstrates the potential for a sustainable and scalable mHealth loaner program, enabling broader population reach while optimizing user experience. Implementation may face institutional constraints and software limitations. Consideration should be given to optimizing loaner returns.
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http://dx.doi.org/10.2196/16391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937543PMC
December 2019

Twenty Novel Disease Group-Specific and 12 New Shared Macrophage Pathways in Eight Groups of 34 Diseases Including 24 Inflammatory Organ Diseases and 10 Types of Tumors.

Front Immunol 2019 14;10:2612. Epub 2019 Nov 14.

Centers for Inflammation, Translational and Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States.

The mechanisms underlying pathophysiological regulation of tissue macrophage (Mφ) subsets remain poorly understood. From the expression of 207 Mφ genes comprising 31 markers for 10 subsets, 45 transcription factors (TFs), 56 immunometabolism enzymes, 23 trained immunity (innate immune memory) enzymes, and 52 other genes in microarray data, we made the following findings. (1) When 34 inflammation diseases and tumor types were grouped into eight categories, there was differential expression of the 31 Mφ markers and 45 Mφ TFs, highlighted by 12 shared and 20 group-specific disease pathways. (2) Mφ in lung, liver, spleen, and intestine (LLSI-Mφ) express higher M1 Mφ markers than lean adipose tissue Mφ (ATMφ) physiologically. (3) Pro-adipogenic TFs C/EBPα and PPARγ and proinflammatory adipokine leptin upregulate the expression of M1 Mφ markers. (4) Among 10 immune checkpoint receptors (ICRs), LLSI-Mφ and bone marrow (BM) Mφ express higher levels of CD274 (PDL-1) than ATMφ, presumably to counteract the M1 dominant status via its reverse signaling behavior. (5) Among 24 intercellular communication exosome mediators, LLSI- and BM- Mφ prefer to use RAB27A and STX3 than RAB31 and YKT6, suggesting new inflammatory exosome mediators for propagating inflammation. (6) Mφ in peritoneal tissue and LLSI-Mφ upregulate higher levels of immunometabolism enzymes than does ATMφ. (7) Mφ from peritoneum and LLSI-Mφ upregulate more trained immunity enzyme genes than does ATMφ. Our results suggest that multiple new mechanisms including the cell surface, intracellular immunometabolism, trained immunity, and TFs may be responsible for disease group-specific and shared pathways. Our findings have provided novel insights on the pathophysiological regulation of tissue Mφ, the disease group-specific and shared pathways of Mφ, and novel therapeutic targets for cancers and inflammations.
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http://dx.doi.org/10.3389/fimmu.2019.02612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880770PMC
November 2020

Anti-inflammatory cytokines IL-35 and IL-10 block atherogenic lysophosphatidylcholine-induced, mitochondrial ROS-mediated innate immune activation, but spare innate immune memory signature in endothelial cells.

Redox Biol 2020 01 6;28:101373. Epub 2019 Nov 6.

Centers for Inflammation, Translational & Clinical Lung Research, Department of Pharmacology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, 19140, USA; Centers for Metabolic Disease Research, Cardiovascular Research, Thrombosis Research, Department of Pharmacology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, 19140, USA. Electronic address:

It has been shown that anti-inflammatory cytokines interleukin-35 (IL-35) and IL-10 could inhibit acute endothelial cell (EC) activation, however, it remains unknown if and by what pathways IL-35 and IL-10 could block atherogenic lipid lysophosphatidylcholine (LPC)-induced sustained EC activation; and if mitochondrial reactive oxygen species (mtROS) can differentiate mediation of EC activation from trained immunity (innate immune memory). Using RNA sequencing analyses, biochemical assays, as well as database mining approaches, we compared the effects of IL-35 and IL-10 in LPC-treated human aortic ECs (HAECs). Principal component analysis revealed that both IL-35 and IL-10 could similarly and partially reverse global transcriptome changes induced by LPC. Gene set enrichment analyses showed that while IL-35 and IL-10 could both block acute EC activation, characterized by upregulation of cytokines/chemokines and adhesion molecules, IL-35 is more potent than IL-10 in suppressing innate immune signatures upregulated by LPC. Surprisingly, LPC did not induce the expression of trained tolerance itaconate pathway enzymes but induced trained immunity enzyme expressions; and neither IL-35 nor IL-10 was found to affect LPC-induced trained immunity gene signatures. Mechanistically, IL-35 and IL-10 could suppress mtROS, which partially mediate LPC-induced EC activation and innate immune response. Therefore, anti-inflammatory cytokines could reverse mtROS-mediated acute and innate immune trans-differentiation responses in HAECs, but it could spare metabolic reprogramming and trained immunity signatures, which may not fully depend on mtROS. Our characterizations of anti-inflammatory cytokines in blocking mtROS-mediated acute and prolonged EC activation, and sparing trained immunity are significant for designing novel strategies for treating cardiovascular diseases, other inflammatory diseases, and cancers.
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http://dx.doi.org/10.1016/j.redox.2019.101373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920093PMC
January 2020