tbuckley/cabot-search huggingface dataset:
POS1135 MONOSODIUM URATE CRYSTALS REDUCE SCHWANN CELLS VIABILITY
Authors: Y. Liu, Y. Huang, S. Sun, W. Deng, T. W. LI
Journal: Annals of the Rheumatic Diseases (2021)

Background: The prevalence of peripheral neuropathy in patients with gout almostly reaches 25%[1]. Demyelination caused by Schwann cell (SCs) injury and apoptosis is the major pathological feature of peripheral[2]. None of study has focused on the effects of monosodium urate (MSU) crystals on SCs. Objectives: To assess the effect of MSU crystals on SCs. Methods: Mouse-derived Schwann cells (RSC96) are stimulated with different concentrations of MSU crystals (0mg/ml,0.25mg/ml,0.5mg/ml) and time (24h,48h,72h). The migration ability of Schwann cells is evaluated by acratch assay, the proliferation level is assessed by the cell counting kit-8 (CCK-8) assay, and the apoptosis rate is detected by flow cytometry. Results: The acratch assay showed that the migration ability of SCs was worsened, CCK-8 assay suggested that proliferation of SCs was reduced in a dose-dependent manner (P&lt;0.05). According to the result of flow cytometry, the survival rate of SCs at 0.5mg/ml(78.60%±2.26%) was lower than that 0.25mg/ml(87.50%±0.95%)and 0mg/ml (98.80%±0.26%)(p&lt;0.05) at 24h. When the stimulation time increased to 72h, the survival rate at 0.5mg/ml(47.90%±11.70%) dropped significantly, which was significantly different from the other two groups(p&lt;0.05). Conclusion: MSU crystals can cause damage to Schwann cells. It may help to explain the reason of peripheral neuropathy in gout patients. References: [1]López-López, C.O., et al., Peripheral neuropathies in rheumatic diseases: More diverse and frequent than expected. A cross-sectional study. International journal of rheumatic diseases, 2020. 23(2): p. 226-232. [2]Liu, Y., S. Shao and H. Guo, Schwann cells apoptosis is induced by high glucose in diabetic peripheral neuropathy. Life sciences, 2020. 248: p. 117459. Figure 1. Flow cytometry assays of RSC96 on MSU crystals at 72h Disclosure of Interests: None declared.
OP0314 DOCK8 MUTATIONS IN COVID-19 AND MIS-C CYTOKINE STORM SYNDROME
Authors: R. Cron, M. Zhang, D. Absher, J. Bridges, A. Schnell, P. Bhatraju, A. Vagrecha, S. Lozinsky, S. Acharya, C. Levy, W. Chatham
Journal: Annals of the Rheumatic Diseases (2021)

Background: We recently identified DOCK8 as a novel gene associated with cytokine storm syndrome (CSS) 1 . Heterozygous missense mutations in DOCK8 diminish NK cell lytic function and contribute to increased pro-inflammatory cytokine production (CSS). CSS is a potential complication of COVID-19 with severe consequences 2 . Children are at risk of a SARS-CoV-2 post-infectious CSS, multisystem inflammatory syndrome in children (MIS-C) 3 . Host genetic factors associated with COVID-19 CSS and MIS-C CSS are unknown. Objectives: The goals are to identify and functionally study rare mutations in DOCK8 in patients with SARS-CoV-2 COVID-19 and MIS-C. Methods: To date, 16 adult patients enrolled in a COVID-19 CSS clinical trial at UAB had whole genome sequencing. Four (25%) had rare heterozygous DOCK8 mutations (3 missense, 1 intronic). A COVID-19 CSS adult patient in Seattle also had a DOCK8 missense mutation. In addition, DOCK8 missense mutations were identified in five children (UAB &amp; Northwell) hospitalized with MIS-C. DOCK8 mutations, or wild-type (WT) sequence controls, were introduced into human NK-92 cells by FOAMY virus transduction. WT and mutant DOCK8-expressing NK-92 cells were incubated with K562 target cells and compared for cytolysis and degranulation (CD107a). Results: One COVID-19 patient DOCK8 mutation (Gly523Arg) reduced NK cell degranulation by 30% and cytolysis by 23% (n=3) (Figure 1). Similar studies of 3 MIS-C patients with DOCK8 missense mutations (Arg899Trp, Ala2Thr, Pro687Leu) revealed up to 31% reduced NK cell degranulation and 48% reduction in cytolysis by 3 distinct mutations (n=3). Two-way ANOVA analysis revealed statistically significant (p&lt;0.05) differences in NK cell degranulation and lysis for four unique DOCK8 mutations. Conclusion: Heterozygous DOCK8 missense mutations may contribute to severe COVID-19 and MIS-C CSS by partial dominant-negative effects yielding decreased NK cell cytolysis. References: [1]Schulert GS, Cron RQ. The genetics of macrophage activation syndrome. Genes Immun 2020: 21 :169-181. [2] Cron RQ, Chatham WW. The rheumatologist’s role in COVID-19. J Rheumatol 2020: 47 :639-642. [3]Reiff D, Mannion ML, Samuy N, Scalici P, Cron RQ. Distinguishing active pediatric COVID-19 from MIS-C. Pediatr Rheumatol Online J, in press . Disclosure of Interests: Randy Cron Consultant of: SOBI, Novartis, Pfizer, Sironax, Grant/research support from: SOBI, Mingce Zhang: None declared, Remy Cron: None declared, Devin Absher: None declared, John Bridges: None declared, Amanda Schnell: None declared, Pavan Bhatraju: None declared, Anshul Vagrecha: None declared, Shannon Lozinsky: None declared, Suchitra Acharya: None declared, Carolyn Levy: None declared, Winn Chatham Grant/research support from: SOBI.
Targeting a Radiosensitizing Antibody–Drug Conjugate to a Radiation-Inducible Antigen
Authors: Calvin D. Lewis, Abhay K. Singh, Fong-Fu Hsu, Dinesh Thotala, Dennis E. Hallahan, Vaishali Kapoor
Journal: Clinical Cancer Research (2021)

Abstract Purpose: We recently discovered that anti-TIP1 antibody activates endocytosis in cancer cells, which facilitates retention of antibody and dissociation of a conjugated drug. To improve the pharmacokinetics and cancer specificity of radiosensitizing drugs, we utilized antibody–drug conjugates (ADCs) that bind specifically to radiation-inducible antigen, TIP1, on non–small cell lung cancer (NSCLC). This approach exploits the long circulation time of antibodies to deliver a radiosensitizing drug to cancer each day during radiotherapy. Experimental Design: Antibodies to TIP1 were prioritized based on affinity, cancer-specific binding, and internalization. The lead antibody, 7H5, was conjugated with a cytotoxic drug MMAE because of its ability to radiosensitize cancer. Cytotoxicity, colony formation, and tumor growth studies were performed with 7H5-VcMMAE in combination with radiation. Results: 7H5 showed a high affinity to recombinant TIP1 protein and radiation-inducible TIP1 on the cancer cell surface. 7H5 undergoes endocytosis in NSCLC cells in vitro. We obtained an average drug-to-antibody ratio (DAR) of 4.25 for 7H5-VcMMAE. A 70% reduction in viable cells was observed following 7H5-VcMMAE treatment compared with 7H5 alone in both A549 and H1299 cells. 7H5-VcMMAE sensitized NSCLC cells to radiation, thereby significantly decreasing the surviving fraction. The ADC combined with radiation showed a prolonged delay in tumor growth and improved survival in A549 and H1299 tumor models. Conclusions: Targeting radiation-inducible TIP1 with a radiosensitizing ADC is a promising strategy to enhance the therapeutic efficacy of NSCLC. This novel approach of targeting with ADCs to radiation-inducible antigens will lead to clinical trials in lung cancer patients treated with radiotherapy.
Direct and indirect immune effects of CMP-001, a virus-like particle containing a TLR9 agonist
Authors: Shakoora A Sabree, Andrew P Voigt, Sue E Blackwell, Ajaykumar Vishwakarma, Michael S Chimenti, Aliasger K Salem, George J Weiner
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background CMP-001, also known as vidutolimod, is a virus-like particle containing a TLR9 agonist that is showing promise in early clinical trials. Our group previously demonstrated that the immunostimulatory effects of CMP-001 are dependent on an anti-Qβ antibody response which results in opsonization of CMP-001 and uptake by plasmacytoid dendritic cells (pDCs) that then produce interferon (IFN)-α. IFN-α then leads to an antitumor T-cell response that is responsible for the in vivo efficacy of CMP-001. Here, we explore mechanisms by which the initial effects of CMP-001 on pDCs activate other cells that can contribute to development of an antitumor T-cell response. Methods Uptake of CMP-001 by various peripheral blood mononuclear cell (PBMC) populations and response to anti-Qβ-coated CMP-001 were evaluated by flow cytometry and single-cell RNA sequencing. Purified monocytes were treated with anti-Qβ-coated CMP-001 or recombinant IFN-α to evaluate direct and secondary effects of anti-Qβ-coated CMP-001 on monocytes. Results Monocytes had the highest per cell uptake of anti-Qβ-coated CMP-001 with lower levels of uptake by pDCs and other cell types. Treatment of PBMCs with anti-Qβ-coated CMP-001 induced upregulation of IFN-responsive genes including CXCL10, PDL1, and indoleamine-2,3-dioxygenase (IDO) expression by monocytes. Most of the impact of anti-Qβ-coated CMP-001 on monocytes was indirect and mediated by IFN-α, but uptake of anti-Qβ-coated CMP-001 altered the monocytic response to IFN-α and resulted in enhanced expression of PDL1, IDO, and CD80 and suppressed expression of CXCL10. These changes included an enhanced ability to induce autologous CD4 T-cell proliferation. Conclusions Anti-Qβ-coated CMP-001 induces IFN-α production by pDCs which has secondary effects on a variety of cells including monocytes. Uptake of anti-Qβ-coated CMP-001 by monocytes alters their response to IFN-α, resulting in enhanced expression of PDL1, IDO and CD80 and suppressed expression of CXCL10. Despite aspects of an immunosuppressive phenotype, these monocytes demonstrated increased ability to augment autologous CD4 T-cell proliferation. These findings shed light on the complexity of the mechanism of action of anti-Qβ-coated CMP-001 and provide insight into pathways that may be targeted to further enhance the efficacy of this novel approach to immunotherapy.
BRCA2 heterozygosity delays cytokinesis in unmodified primary human fibroblasts
Authors: Asta Jonsdottir, Peter Devilee, Hans Tanke, Karoly Szuhai, Jorunn Eyfjord
Journal: Cancer Research (2008)

5069  Backround: Inherited mutations in the tumour suppressor gene BRCA2 greatly increase the risk of developing breast, ovarian and other types of cancers. So far, most studies have focused on the role of BRCA-pathways in the maintenance of genomic stability.  In this study we investigated the possible role of the BRCA2 protein in cytokinesis in unmodified primary human fibroblast carrying a heterozygous mutation in the BRCA2 gene. A delay in the process has been shown in Brca2 heterozygous and homozygous murine embryonic fibroblast cell lines.  Methods:Cell divisions of unmodified primary human fibroblasts, derived from individuals that carry the heterozygous Icelandic 999del5 BRCA2 founder mutation, the heterozygous Dutch 1537del4BRCA2 mutation, and individuals that do not carry a BRCA2 mutation, were monitored with time lapse live-cell imaging. To investigate the localization of the BRCA2 protein immunofluorescence staining using antibody directed against BRCA2 was carried out. Cells with delayed cytokinesis were specifically examined by performing an immunofluorecence staining directly after live-cell imaging allowing a relocation of cells of interest.  Results:We demonstrate that unmodified primary human fibroblasts derived from heterozygous BRCA2 mutation carriers show significantly prolonged cytokinesis. Subset of the BRCA2+/- cells shows greatly enhanced division time (40 minutes or longer) making the mean cell division time 6 minutes longer in mutated cells (33 minutes ) compared to BRCA2+/+ cells (27 minutes).  The BRCA2 protein localizes and accumulates to the midbody during cytokinesis, but no difference was observed in distribution and localization between BRCA2 mutant and wild type samples and cells with delayed cytokinesis and normal division time.  Conclusions:The delayed cytokinesis phenotype of the BRCA2 heterozygous cells and localization of the BRCA2 protein to the midbody confirms that BRCA2 plays a role in cytokinesis and our observations indicate that this is caused by haploinsufficiency resulting in BRCA2 protein level that is below a functional threshold needed for cytokinesis.
Granulomatous Dermatitis Associated With Rubella Virus Infection in an Adult With Immunodeficiency
Authors: Bridget E. Shields, Ludmila Perelygina, Sara Samimi, Paul Haun, Thomas Leung, Emily Abernathy, Min-hsin Chen, LiJuan Hao, Joseph Icenogle, Beth Drolet, Barbara Wilson, Joshua S. Bryer, Ross England, Emily Blumberg, Karolyn A. Wanat, Kathleen Sullivan, Misha Rosenbach
Journal: JAMA Dermatology (2021)

Immunodeficiency-related, vaccine-derived rubella virus (RuV) as an antigenic trigger of cutaneous and visceral granulomas is a rare, recently described phenomenon in children and young adults treated with immunosuppressant agents.To perform a comprehensive clinical, histologic, immunologic, molecular, and genomic evaluation to elucidate the potential cause of an adult patient's atypical cutaneous granulomas.A prospective evaluation of skin biopsies, nasopharyngeal swabs, and serum samples submitted to the Centers for Disease Control and Prevention was conducted to assess for RuV using real-time reverse-transcriptase polymerase chain reaction (RT-PCR) and viral genomic sequencing. The samples were obtained from a man in his 70s with extensive cutaneous granulomas mimicking both cutaneous sarcoidosis (clinically) and CD8+ granulomatous cutaneous T-cell lymphoma (histopathologically). The study was conducted from September 2019 to February 2021.Identification and genotyping of a novel immunodeficiency-related RuV-associated granulomatous dermatitis.Immunohistochemistry for RuV capsid protein and RT-PCR testing for RuV RNA revealed RuV in 4 discrete skin biopsies from different body sites. In addition, RuV RNA was detected in the patient's nasopharyngeal swabs by RT-PCR. The full viral genome was sequenced from the patient's skin biopsy (RVs/Philadelphia.PA.USA/46.19/GR, GenBank Accession #MT249313). The patient was ultimately diagnosed with a novel RuV-associated granulomatous dermatitis.The findings of this study suggest that clinicians and pathologists may consider RuV-associated granulomatous dermatitis during evaluation of a patient because it might have implications for the diagnosis of cutaneous sarcoidosis, with RuV serving as a potential antigenic trigger, and for the diagnosis of granulomatous cutaneous T-cell lymphoma, with histopathologic features that may prompt an evaluation for immunodeficiency and/or RuV.
Author Correction: Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma
Authors: Laura K. Donovan, Alberto Delaidelli, Sujith K. Joseph, Kevin Bielamowicz, Kristen Fousek, Borja L. Holgado, Alex Manno, Dilakshan Srikanthan, Ahmed Z. Gad, Randy Van Ommeren, David Przelicki, Cory Richman, Vijay Ramaswamy, Craig Daniels, Jonelle G. Pallota, Tajana Douglas, Alyssa C. M. Joynt, Joonas Haapasalo, Carolina Nor, Maria C. Vladoiu, Claudia M. Kuzan-Fischer, Livia Garzia, Stephen C. Mack, Srinidhi Varadharajan, Matthew L. Baker, Liam Hendrikse, Michelle Ly, Kaitlin Kharas, Polina Balin, Xiaochong Wu, Lei Qin, Ning Huang, Ana Guerreiro Stucklin, A. Sorana Morrissy, Florence M. G. Cavalli, Betty Luu, Raul Suarez, Pasqualino De Antonellis, Antony Michealraj, Avesta Rastan, Meenakshi Hegde, Martin Komosa, Olga Sirbu, Sachin A. Kumar, Zied Abdullaev, Claudia C. Faria, Stephen Yip, Juliette Hukin, Uri Tabori, Cynthia Hawkins, Ken Aldape, Mads Daugaard, John M. Maris, Poul H. Sorensen, Nabil Ahmed, Michael D. Taylor
Journal: Nature Medicine (2021)
Abstract 15919: Modified “34ms” Late Potential Criteria for Positive Saecg in ARVC to Improve Identification of VT Substrate
Authors: Cory M Tschabrunn, Erica S Zado, Pasquale Santangeli, David S Frankel, Gregory Supple, David J Callans, Francis E Marchlinski
Journal: Circulation (2019)

Introduction: Although a task force criterion for diagnosis, SAECGs are not often utilized for excluding ARVC because of its “limited sensitivity”. Hypothesis: We sought to modify criteria for (+)S...
Manganese silicate nanospheres-incorporated hydrogels：starvation therapy and tissue regeneration
Authors: Hongshi Ma, Qingqing Yu, Yu Qu, Yufang Zhu, Chengtie Wu
Journal: Bioactive Materials (2021)

To prevent postoperative skin tumor recurrence and repair skin wound, a glucose oxidase (GOx)-loaded manganese silicate hollow nanospheres (MS HNSs)-incorporated alginate hydrogel (G/MS-SA) was constructed for starvation-photothermal therapy and skin tissue regeneration. The MS HNSs showed a photothermal conversion efficiency of 38.5%, and endowed composite hydrogels with satisfactory photothermal effect. Taking advantage of the catalytic activity of Mn ions, the composite hydrogels could decompose hydrogen peroxide (H2O2) into oxygen (O2), which can alleviate the problem of tumor hypoxia microenvironment and endow GOx with an ability to consume glucose in the presence of O2 for tumor starvation. Meanwhile, hyperthermia triggered by near infrared (NIR) irradiation could not only accelerate the reaction rate of H2O2 decomposition by MS HNSs and glucose consumption by GOx, but also ablate tumor cells. The anti-tumor results showed that synergistic effect of starvation-photothermal therapy led to the highest death rate of tumor cells among all groups, and its anti-tumor effect was obviously improved as compared with that of single photothermal treatment or starvation treatment. Interestingly, the introduction of MS HNSs into hydrogels could distinctly promote the epithelialization of the wound beds by releasing Mn ions as compared with the hydrogels without MS HNSs. It is expected that such a multifunctional platform with starvation-photothermal therapy will be promising for treating tumor-caused skin defects in combination of its regeneration bioactivity in the future.
Distinct Clinical Physiologic Phenotypes of Patients With Laryngeal Symptoms Referred for Reflux Evaluation
Authors: Rena Yadlapati, Alexander M. Kaizer, Daniel R. Sikavi, Madeline Greytak, Jennifer X. Cai, Thomas L. Carroll, Samir Gupta, Sachin Wani, Paul Menard-Katcher, Tsung-Chin Wu, Philip Weissbrod, Andrew M. Vahabzadeh-Hagh, John E. Pandolfino, Walter W. Chan
Journal: Clinical Gastroenterology and Hepatology (2021)
Overall Survival of Men with Metachronous Metastatic Hormone-sensitive Prostate Cancer Treated with Enzalutamide and Androgen Deprivation Therapy
Authors: Christopher J. Sweeney, Andrew J. Martin, Martin R. Stockler, Stephen Begbie, Kim N. Chi, Simon Chowdhury, Xanthi Coskinas, Mark Frydenberg, Wendy E. Hague, Lisa G. Horvath, Anthony M. Joshua, Nicola J. Lawrence, Gavin M. Marx, John McCaffrey, Ray McDermott, Margaret McJannett, Scott A. North, Francis Parnis, Wendy Parulekar, David W. Pook, M. Neil Reaume, Shahneen K. Sandhu, Alvin Tan, Thean Hsiang Tan, Alastair Thomson, Emily Tu, Francisco Vera-Badillo, Scott G. Williams, Sonia Yip, Alison Y. Zhang, Robert R. Zielinski, Ian D. Davis
Journal: European Urology (2021)
Medications That Prolong the QT Interval
Authors: Carol Cappuccio
Journal: JAMA (2003)

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Enhanced Antitumor Efficacy through an “AND gate” Reactive Oxygen‐Species‐Dependent pH‐Responsive Nanomedicine Approach
Authors: Eliézer Jäger, Jana Humajová, Yusuf Dölen, Jan Kučka, Alessandro Jäger, Rafał Konefał, Jan Pankrác, Ewa Pavlova, Tomáš Heizer, Luděk Šefc, Martin Hrubý, Carl G. Figdor, Martijn Verdoes
Journal: Advanced Healthcare Materials (2021)

Anticancer drug delivery strategies are designed to take advantage of the differential chemical environment in solid tumors independently, or to high levels of reactive oxygen species (ROS) or to low pH, compared to healthy tissue. Here, the design and thorough characterization of two functionalizable "AND gate" multiresponsive (MR) block amphiphilic copolymers are reported, aimed to take full advantage of the coexistence of two chemical cues-ROS and low pH-present in the tumor microenvironment. The hydrophobic blocks contain masked pH-responsive side chains, which are exposed exclusively in response to ROS. Hence, the hydrophobic polymer side chains will undergo a charge shift in a very relevant pH window present in the extracellular milieu in most solid tumors (pH 5.6-7.2) after demasking by ROS. Doxorubicin (DOX)-loaded nanosized "AND gate" MR polymersomes (MRPs) are fabricated via microfluidic self-assembly. Chemical characterization reveals ROS-dependent pH sensitivity and accelerated DOX release under influence of both ROS and low pH. Treatment of tumor-bearing mice with DOX-loaded nonresponsive and "AND gate" MRPs dramatically decreases cardiac toxicity. The most optimal "AND gate" MRPs outperform free DOX in terms of tumor growth inhibition and survival, shedding light on chemical requirements for successful cancer nanomedicine.
Methotrexate hampers immunogenicity to BNT162b2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease
Authors: Rebecca H Haberman, Ramin Herati, David Simon, Marie Samanovic, Rebecca B Blank, Michael Tuen, Sergei B Koralov, Raja Atreya, Koray Tascilar, Joseph R Allen, Rochelle Castillo, Amber R Cornelius, Paula Rackoff, Gary Solomon, Samrachana Adhikari, Natalie Azar, Pamela Rosenthal, Peter Izmirly, Jonathan Samuels, Brian Golden, Soumya M Reddy, Markus F Neurath, Steven B Abramson, Georg Schett, Mark J Mulligan, Jose U Scher
Journal: Annals of the Rheumatic Diseases (2021)

To investigate the humoral and cellular immune response to messenger RNA (mRNA) COVID-19 vaccines in patients with immune-mediated inflammatory diseases (IMIDs) on immunomodulatory treatment.