tbuckley/cabot-search huggingface dataset:
TNF-mediated alveolar macrophage necroptosis drives disease pathogenesis during respiratory syncytial virus infection
Authors: Leonardo Duarte Santos, Krist Helen Antunes, Stéfanie Primon Muraro, Gabriela Fabiano de Souza, Amanda Gonzalez da Silva, Jaqueline de Souza Felipe, Larissa Cardoso Zanetti, Rafael Sanguinetti Czepielewski, Karen Magnus, Marcelo Scotta, Rita Mattiello, Fabio Maito, Ana Paula Duarte de Souza, Ricardo Weinlich, Marco Aurélio Ramirez Vinolo, Bárbara Nery Porto
Journal: European Respiratory Journal (2020)

Respiratory syncytial virus (RSV) is the major cause of acute bronchiolitis in infants under 2 years old. Necroptosis has been implicated in the outcomes of respiratory virus infections. We report that RSV infection triggers necroptosis in primary mouse macrophages and human monocytes in a RIPK1-, RIPK3- and MLKL-dependent manner. Moreover, necroptosis pathways are harmful to RSV clearance from alveolar macrophages. Additionally, Ripk3 −/− mice were protected from RSV-induced weight loss and presented with reduced viral loads in the lungs. Alveolar macrophage depletion also protected mice from weight loss and decreased lung RSV virus load. Importantly, alveolar macrophage depletion abolished the upregulation of Ripk3 and Mlkl gene expression induced by RSV infection in the lung tissue. Autocrine tumor necrosis factor (TNF)-mediated RSV-triggered macrophage necroptosis and necroptosis pathways were also involved in TNF secretion even when macrophages were committed to cell death, which can worsen lung injury during RSV infection. In line, Tnfr1 −/− mice had a marked decrease in Ripk3 and Mlkl gene expression and a sharp reduction in the numbers of necrotic alveolar macrophages in the lungs. Finally, we provide evidence that elevated nasal levels of TNF are associated with disease severity in infants with RSV bronchiolitis. We propose that targeting TNF and/or the necroptotic machinery may be valuable therapeutic approaches to reduce the respiratory morbidity caused by RSV infection in young children.
NCMP-12. RAPIDLY PROGRESSIVE NEUROPATHIES AS THE SOLE PRESENTATION OF NEUROLYMPHOMATOSIS
Authors: Pilar Guillermo Prieto Eibl, Appaji Rayi, Iyad Alnahhas, Pierre Giglio, Narendranath Epperla
Journal: Neuro-Oncology (2020)

Abstract Neurolymphomatosis (NL) is a rare and challenging entity characterized by hematological neoplastic infiltration of the peripheral nervous system. Only 40% of the cases have malignant cells on CSF sampling. We present a 52-year-old Caucasian male with primary refractory diffuse large B-cell lymphoma (DLBCL) who relapsed within 3 months of achieving complete remission to R-CHOP. First, he experienced right tongue numbness and lumbar pain. Initial MRI of the face, brain and entire spine, and CSF analysis were unremarkable. Three weeks later, he noticed left facial numbness, dysphonia, and left leg weakness. Neuraxis MRI revealed enhancement of left CN V3 and several cervical, thoracic, and lumbar nerve roots. PET/CT showed increased uptake at L4 nerve root. EMG/NGS showed left L5 denervation. After one week, he further developed new right CN VI palsy, left-sided ptosis, anisocoria, and right arm weakness. Repeat MRI showed worsening enhancement and thickening of multiple cranial nerves, cervical and lumbosacral plexus. Extensive testing for infectious, inflammatory, and paraneoplastic processes was negative. Patient underwent plasmapheresis with no response. Biopsy of nerve root was deferred due to potential permanent deficits that would impair his quality of life. Repeat CSF testing was negative for malignancy and PET/CT showed SUV of 23.8 at L4-5 with multiple new hypermetabolic foci in muscle and ribs. He received R-HD-methotrexate with clinical and radiographic (PET/CT) improvement following 2 cycles. He completed 4 cycles of R-HD methotrexate-based chemotherapy followed by autologous hematopoietic stem cell transplantation. Most of his symptoms resolved and he remained stable for about a year when PET/CT showed disease progression. He subsequently received CAR-T cell therapy with adequate tolerance and remains clinically stable. Even with negative initial imaging and CSF studies, a careful exam and attention to uncommon presentations along with serial advanced imaging (MRI, PET/CT) surveillance are key to early detection and timely treatment.
CSIG-07. c-Src PHOSPHORYLATES AND INACTIVATES THE CIC TUMOR SUPPRESSOR PROTEIN IN GLIOBLASTOMA
Authors: Severa Bunda, Pardeep Heir, Annie Li, Mamatjan Yasin, Gelareh Zadeh, Kenneth Aldape
Journal: Neuro-Oncology (2020)

Abstract Capicua (CIC) is a transcriptional repressor that counteracts activation of genes in response to receptor tyrosine kinase (RTK)/Ras/MEK/ERK signaling. Following activation of RTK, ERK enters the nucleus and serine-phosphorylates CIC, releasing it from its targets to permit gene expression. We recently showed that ERK triggers ubiquitin-mediated degradation of CIC in glioblastoma (GBM). In this study, we examined whether another important downstream effector of RTK/EGFR, the non-receptor tyrosine kinase c-Src, affects CIC repressor function in GBM. We found that c-Src binds and tyrosine phosphorylates CIC on residue 1455 to promote nuclear export of CIC. On the other hand, CIC mutant allele (CIC-Y1455F), that escapes c-Src-mediated tyrosine phosphorylation, remains localized to the nucleus and retains strong repressor function against CIC targets, the oncogenic ETV transcription factors. Furthermore, we show that the orally available Src family kinase inhibitor, dasatinib, which prevents EGF-mediated tyrosine phosphorylation of CIC and attenuates elevated ETV levels, reduces viability of GBM cells and glioma stem cells (GSC), but not of their control cells with undetectable c-Src activity. In fact, GBM cells and GSC expressing the tyrosine-defective CIC mutant (Y1455F) lose sensitivity to dasatinib, further endorsing the effect of dasatinib on Src-mediated tyrosine phosphorylation of CIC. Importantly we show that combined inhibition of Src and MEK/ERK results in greatest stabilization of CIC and attenuation of proliferation compared to either inhibitor alone. These findings elucidate important mechanisms of CIC regulation and provide the rationale to target c-Src alongside ERK pathway inhibitors as a way to fully restore CIC tumor suppressor function in neoplasms such as GBM.
Lockdowns don’t kill women, abusive men do
Authors: Ian Sinha
Journal: BMJ (2020)

Bavli and colleagues report that public health interventions against covid-19 are associated with increased rates of domestic violence.1 To tackle issues around the murder of women at the hands of men we need a wider change of narrative across society and the media.

We need to change how women are portrayed when they are murdered by men. Headlines must stop trying to provide context (“he murdered her after she . . .”). This apportions blame to the …
DDRE-15. THE COMBINATION THERAPY OF PARP INHIBITOR AND TMZ IN DIFFUSE MIDLINE GLIOMA HARBORING H3 K27M-MUTANT
Authors: Shigeo Ohba, Rintaro Hashizume, Yuichi Hirose
Journal: Neuro-Oncology (2020)

Abstract Diffuse midline glioma harboring H3 K27M-mutant (DMG) is a newly defined entity, and the prognosis of DMG is very poor. Combined of radiotherapy and chemotherapy is a standard therapeutic approach, because surgical debulking for providing relief to patients is not an option. Temozolomide (TMZ) is often used for the treatment of gliomas. TMZ is an alkylating agent that adds a methyl group to DNA (O6-guanine, N7-guanine, and N3-adenine). TMZ-induced cytotoxicity is mainly derived from O6-methylguanine, which is repaired by O6-methylguanine DNA methyltransferase (MGMT). Unfortunately, most DMG lacks MGMT promoter hypermethylation, which contributes to less effectiveness of TMZ in DMG. Because N7-methylguanine and N3-methyladenine are repaired via base excision repair, poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor combined with TMZ was considered to be effective to suppress the proliferation of DMG. The purpose of the study is to evaluate whether PARP inhibitor sensitizes DMG to TMZ. A patient-derived DMG cell line, SF8628, showed the expression of MGMT, resulted in resistant to TMZ. We evaluated the effects of multiple PARP inhibitors: talazoparib, olaparib, niraparib, A-966492 in SF8628 DMG cells. These PARP inhibitors suppressed the proliferation of SF8628 cells in a dose dependent manner. Moreover, PARP inhibitors enhanced TMZ-induced cytotoxicity in SF8628. The combined treatment of PARP inhibitor and TMZ induced apoptosis. These results would support a possibility that the combination treatment of PARP inhibitor and TMZ is an effective approach in DMG.
TMOD-23. A NOVEL BRAF V600E LOW-GRADE GLIOMA MOUSE MODEL HIGHLIGHTS EXOMIC AND TUMOR IMMUNE ALTERATIONS AND DIFFERING THERAPEUTIC RESPONSES IN LOW- AND HIGH-GRADE GLIOMAS
Authors: Anne Marie Barrette, Lasse Meyer, Yoko Hirata, Stefan Grossauer, Edbert Lu, Whitney Tamaki, Claudia Petritsch, Wei Wang
Journal: Neuro-Oncology (2020)

Abstract Pediatric low-grade glioma (pLGG), the most common brain cancer in children, is difficult to treat especially at recurrence. The BRAF V600E mutation is the second most common mutation in pLGG, and in a high-risk group for progression is associated with deletion of the tumor suppressor CDKN2A. A better understanding of the factors contributing to progression, in particular the role of the immune infiltrate is needed, but studies have been hindered by the lack of low-grade glioma mouse models. We utilized transgenic mice with a cre-activatable (CA) allele of BRAF V600E to generate endogenous models for low-grade gliomas. We found that BRAF V600E expression cooperates with hemizygous CDKN2A deletion to induce low-grade gliomas, with tumors forming at a greater latency than by homozygous deletion. Cell line derivatives from low-grade lesions continue to grow slower upon orthotopic injection than those we previously derived from high-grade tumors. Murine LGG can progress to higher grade tumors within the mouse lifespan and we observe exomic changes and alterations in the tumor immune infiltrate associated with progression, the details of which will be discussed at the meeting. High-grade cells’ phenotypic changes within in vivo passage are accompanied by exomic changes. The high-grade glioma immune infiltrate is altered by dual MAPK pathway inhibition with dabrafenib and trametinib. Adding dual immune checkpoint inhibition by anti-PD-L1 and anti-CTLA-4 antibodies significantly extends survival of dabrafenib-trametinib dual treatment. Human BRAF V600E mutant tumors reportedly have a higher tumor immune infiltrate than that of BRAF wildtype gliomas, consistent with our murine RESULTS: Here we present a novel model for BRAF V600E mutant gliomas in mice that has a frequent rate of progression, similar to human BRAF V600E mutant gliomas, and an active immune infiltrate in high grade tumors which makes them susceptible to the immunostimulatory effects of dual checkpoint inhibition.
CRISPR Screening of CAR T Cells and Cancer Stem Cells Reveals Critical Dependencies for Cell-Based Therapies
Authors: Dongrui Wang, Briana C. Prager, Ryan C. Gimple, Brenda Aguilar, Darya Alizadeh, Hongzhen Tang, Deguan Lv, Renate Starr, Alfonso Brito, Qiulian Wu, Leo J.Y. Kim, Zhixin Qiu, Peng Lin, Michael H. Lorenzini, Behnam Badie, Stephen J. Forman, Qi Xie, Christine E. Brown, Jeremy N. Rich
Journal: Cancer Discovery (2020)

Glioblastoma (GBM) contains self-renewing GBM stem cells (GSC) potentially amenable to immunologic targeting, but chimeric antigen receptor (CAR) T-cell therapy has demonstrated limited clinical responses in GBM. Here, we interrogated molecular determinants of CAR-mediated GBM killing through whole-genome CRISPR screens in both CAR T cells and patient-derived GSCs. Screening of CAR T cells identified dependencies for effector functions, including TLE4 and IKZF2. Targeted knockout of these genes enhanced CAR antitumor efficacy. Bulk and single-cell RNA sequencing of edited CAR T cells revealed transcriptional profiles of superior effector function and inhibited exhaustion responses. Reciprocal screening of GSCs identified genes essential for susceptibility to CAR-mediated killing, including RELA and NPLOC4, the knockout of which altered tumor-immune signaling and increased responsiveness of CAR therapy. Overall, CRISPR screening of CAR T cells and GSCs discovered avenues for enhancing CAR therapeutic efficacy against GBM, with the potential to be extended to other solid tumors. SIGNIFICANCE: Reciprocal CRISPR screening identified genes in both CAR T cells and tumor cells regulating the potency of CAR T-cell cytotoxicity, informing molecular targeting strategies to potentiate CAR T-cell antitumor efficacy and elucidate genetic modifications of tumor cells in combination with CAR T cells to advance immuno-oncotherapy.This article is highlighted in the In This Issue feature, p. 995.
Wireless sensors for continuous, multimodal measurements at the skin interface with lower limb prostheses
Authors: Jean Won Kwak, Mengdi Han, Zhaoqian Xie, Ha Uk Chung, Jong Yoon Lee, Raudel Avila, Jessica Yohay, Xuexian Chen, Cunman Liang, Manish Patel, Inhwa Jung, Jongwon Kim, Myeong Namkoong, Kyeongha Kwon, Xu Guo, Christopher Ogle, Dominic Grande, Dennis Ryu, Dong Hyun Kim, Surabhi Madhvapathy, Claire Liu, Da Som Yang, Yoonseok Park, Ryan Caldwell, Anthony Banks, Shuai Xu, Yonggang Huang, Stefania Fatone, John A. Rogers
Journal: Science Translational Medicine (2020)

Precise form-fitting of prosthetic sockets is important for the comfort and well-being of persons with limb amputations. Capabilities for continuous monitoring of pressure and temperature at the skin-prosthesis interface can be valuable in the fitting process and in monitoring for the development of dangerous regions of increased pressure and temperature as limb volume changes during daily activities. Conventional pressure transducers and temperature sensors cannot provide comfortable, irritation-free measurements because of their relatively rigid construction and requirements for wired interfaces to external data acquisition hardware. Here, we introduce a millimeter-scale pressure sensor that adopts a soft, three-dimensional design that integrates into a thin, flexible battery-free, wireless platform with a built-in temperature sensor to allow operation in a noninvasive, imperceptible fashion directly at the skin-prosthesis interface. The sensor system mounts on the surface of the skin of the residual limb, in single or multiple locations of interest. A wireless reader module attached to the outside of the prosthetic socket wirelessly provides power to the sensor and wirelessly receives data from it, for continuous long-range transmission to a standard consumer electronic device such as a smartphone or tablet computer. Characterization of both the sensor and the system, together with theoretical analysis of the key responses, illustrates linear, accurate responses and the ability to address the entire range of relevant pressures and to capture skin temperature accurately, both in a continuous mode. Clinical application in two prosthesis users demonstrates the functionality and feasibility of this soft, wireless system.
Nanocellulose‐Reinforced Hydroxyapatite Nanobelt Membrane as a Stem Cell Multi‐Lineage Differentiation Platform for Biomimetic Construction of Bioactive 3D Osteoid Tissue In Vitro
Authors: Feng Liu, Benjie Wei, Xiaoying Xu, Baojin Ma, Shan Zhang, Jiazhi Duan, Ying Kong, Hongru Yang, Yuanhua Sang, Shuhua Wang, Wei Tang, Chao Liu, Hong Liu
Journal: Advanced Healthcare Materials (2020)

Abstract Severe bone defects, especially accompanied by vascular and peripheral nerve injuries, remain a massive challenge. Most studies related to bone tissue engineering have focused on osteogenic differentiation of mesenchymal stem cells (MSCs), and ignored the formation of blood vessels and nerves in the newly generated bone owing to the lack of proper materials and methodology for tuning stem cells differentiated into osteogenic, neuronal, and endothelial cells (ECs) in the same scaffold system. Herein, a nanocellulose‐reinforced hybrid membrane with good mechanical properties and control over biodegradation by assembling ultralong hydroxyapatite nanobelts in a bacterial nanocellulose hydrogel is designed and synthesized. Osteogenic, neuronal cells are successfully differentiated on this hybrid membrane. Based on the multi‐lineage differentiation property of the membrane, a bioactive 3D osteoid tissue (osteogenic, neural, and ECs) is mimetically constructed in vitro using layer‐by‐layer culture and integration. The bone regeneration ability of the as‐prepared bioactive osteoid tissue is assessed in vivo via heterotopic osteogenesis experiments for eight weeks. The rapid new bone growth and formation of blood capillaries and nerve fibers prove that the hybrid membrane can be universally applied as a stem cell multi‐lineage differentiation platform, which has significant applications in bone tissue engineering.
Radiation-induced abscopal effect and its enhancement by programmed cell death 1 blockade in the hepatocellular carcinoma: A murine model study
Authors: Gyu Sang Yoo, Won-Gyun Ahn, Shin-Yeong Kim, Wonseok Kang, Changhoon Choi, Hee Chul Park
Journal: Clinical and Molecular Hepatology (2020)

Background/Aims: The abscopal effect, a rare phenomenon induced by radiation, can be reinforced by immunotherapy. Although radiation therapy and immunotherapy are increasingly being utilized for the treatment of hepatocellular carcinoma (HCC), whether immunotherapy could boost the abscopal effect remains unclear. In this study, we aimed to elucidate the immunological mechanisms underlying the abscopal effect induced by the combination of irradiation and immunotherapy in a murine HCC model.Methods: A syngeneic HCC mouse model was established by transplanting murine Hepa 1–6 HCC cells into both hind legs of immunocompetent C57BL/6 mice. The tumors on the right hind legs were irradiated, and abscopal effects were observed in the non-irradiated tumors on the left hind leg with or without the coadministration of anti-programmed cell death 1 (PD-1) antibodies. Flow cytometric analyses were performed to analyze the distributions of immune cells infiltrating both irradiated and non-irradiated tumors and the tumor-draining lymph nodes (TDLNs).Results: Administration of 16 Gy in two fractions more effectively inhibited the growth of both irradiated and nonirradiated tumors with higher tumor infiltration of cytotoxic T cells than 8 Gy did in a single fraction. The higher dose also increased activated dendritic cells in TDLNs, which had higher expression of the programmed cell death ligand 1. Coadministration of anti-PD-1 antibodies significantly enhanced the abscopal effect and increased infiltration of activated cytotoxic T cells in both irradiated and non-irradiated tumors.Conclusions: Our findings show that adding anti-PD-1 therapy to radiation enhanced the abscopal effect in a syngeneic murine model of HCC.
G9a/GLP-Sensitivity of H3K9me2 Demarcates Two Types of Genomic Compartments
Authors: Zixiang Yan, Luzhang Ji, Xiangru Huo, Qianfeng Wang, Yuwen Zhang, Bo Wen
Journal: Genomics Proteomics & Bioinformatics (2020)

In the nucleus, chromatin is folded into hierarchical architecture that is tightly linked to various nuclear functions. However, the underlying molecular mechanisms that confer these architectures remain incompletely understood. Here, we investigated the functional roles of H3 lysine 9 dimethylation (H3K9me2), one of the abundant histone modifications, in three-dimensional (3D) genome organization. Unlike in mouse embryonic stem cells, inhibition of methyltransferases G9a and GLP in differentiated cells eliminated H3K9me2 predominantly at A-type (active) genomic compartments, and the level of residual H3K9me2 modifications was strongly associated with B-type (inactive) genomic compartments. Furthermore, chemical inhibition of G9a/GLP in mouse hepatocytes led to decreased chromatin-nuclear lamina interactions mainly at G9a/GLP-sensitive regions, increased degree of genomic compartmentalization, and up-regulation of hundreds of genes that were associated with alterations of the 3D chromatin. Collectively, our data demonstrated essential roles of H3K9me2 in 3D genome organization.
Aortic Stenosis Severity: Do We Need a New Concept?⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Helmut Baumgartner, Catherine M. Otto
Journal: Journal of the American College of Cardiology (2009)
Nonsensus in the treatment of proximal humerus fractures: uncontrolled, blinded, comparative behavioural analysis between Homo chirurgicus accidentus and Macaca sylvanus
Authors: Sam Razaeian, Birgitt Wiese, Dafang Zhang, Afif Harb, Christian Krettek, Nael Hawi
Journal: BMJ (2020)

Abstract Objective To investigate the inter-rater reliability of Barbary macaques compared with an expert group of surgeons for the choice of treatment and predicted outcome of proximal humerus fractures. Design Uncontrolled, blinded, comparative behavioural analysis. Setting Germany and United States. Participants 10 blinded experts in the field of orthopaedic trauma surgery ( Homo chirurgicus accidentus ), with special focus on upper extremity surgery from Germany and the US, and five Barbary macaques ( Macaca sylvanus ) from a semi-free range enclosure. Main outcome measures The reliability of agreement between raters assessed with Fleiss’ ĸ. Results Barbary macaques seem to have inferior inter-rater reliability in comparison with experts for choice of treatment (non-surgical v surgical), but for the geriatric age group most frequently affected by proximal humeral fractures, they performed similarly to the experts in their choices of treatment and choice of surgical procedure. Agreement about predicted outcome was poor among the macaques and slight among the experts. All experts almost always predicted the outcome incorrectly and tended to underestimate it. While only 4 (4.4%) of 90 experts’ predictions were correct, 13 (28.9%) of 45 macaques’ predictions were correct. Conclusions Consensus on treatment and expected outcomes of proximal humeral fractures is lacking even beyond the human species. Although Barbary macaques tend to predict the clinical outcome more accurately, their reliability to assist surgeons in making a consistent decision is limited. Future high quality research is needed to guide surgeons’ decision making on the optimal treatment of this common injury.