tbuckley/cabot-search huggingface dataset:
Executive summary from American Radium Society’s appropriate use criteria on neurocognition after stereotactic radiosurgery for multiple brain metastases
Authors: Michael T Milano, Veronica L S Chiang, Scott G Soltys, Tony J C Wang, Simon S Lo, Alexandria Brackett, Seema Nagpal, Samuel Chao, Amit K Garg, Siavash Jabbari, Lia M Halasz, Melanie Hayden Gephart, Jonathan P S Knisely, Arjun Sahgal, Eric L Chang
Journal: Neuro-Oncology (2020)

The American Radium Society (ARS) Appropriate Use Criteria brain malignancies panel systematically reviewed (PRISMA [Preferred Reporting Items for Systematic Reviews and Meta-Analyses]) published literature on neurocognitive outcomes after stereotactic radiosurgery (SRS) for patients with multiple brain metastases (BM) to generate consensus guidelines.The panel developed 4 key questions (KQs) to guide systematic review. From 11 614 original articles, 12 were selected. The panel developed model cases addressing KQs and potentially controversial scenarios not addressed in the systematic review (which might inform future ARS projects). Based upon quality of evidence, the panel confidentially voted on treatment options using a 9-point scale of appropriateness.The panel agreed that SRS alone is usually appropriate for those with good performance status and 2-10 asymptomatic BM, and usually not appropriate for >20 BM. For 11-15 and 16-20 BM there was (between 2 case variants) agreement that SRS alone may be appropriate or disagreement on the appropriateness of SRS alone. There was no scenario (among 6 case variants) in which conventional whole-brain radiotherapy (WBRT) was considered usually appropriate by most panelists. There were several areas of disagreement, including: hippocampal sparing WBRT for 2-4 asymptomatic BM; WBRT for resected BM amenable to SRS; fractionated versus single-fraction SRS for resected BM, larger targets, and/or brainstem metastases; optimal treatment (WBRT, hippocampal sparing WBRT, SRS alone to all or select lesions) for patients with progressive extracranial disease, poor performance status, and no systemic options.For patients with 2-10 BM, SRS alone is an appropriate treatment option for well-selected patients with good performance status. Future study is needed for those scenarios in which there was disagreement among panelists.
Care Gaps in Adherence to Heart Failure Guidelines
Authors: Marilyne Jarjour, Christine Henri, Simon de Denus, Annik Fortier, Nadia Bouabdallaoui, Anil Nigam, Eileen O’Meara, Charaf Ahnadi, Michel White, Patrick Garceau, Normand Racine, Marie-Claude Parent, Mark Liszkowski, Geneviève Giraldeau, Jean-Lucien Rouleau, Anique Ducharme
Journal: JACC Heart Failure (2020)
Efficient elimination of primary B-ALL cells in vitro and in vivo using a novel 4-1BB-based CAR targeting a membrane-distal CD22 epitope
Authors: Talia Velasco-Hernandez, Samanta Romina Zanetti, Heleia Roca-Ho, Francisco Gutierrez-Aguera, Paolo Petazzi, Diego Sánchez-Martínez, Oscar Molina, Matteo Libero Baroni, Jose Luis Fuster, Paola Ballerini, Clara Bueno, Narcis Fernandez-Fuentes, Pablo Engel, Pablo Menendez
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background There are few therapeutic options available for patients with B-cell acute lymphoblastic leukemia (B-ALL) relapsing as CD19 – either after chemotherapy or CD19-targeted immunotherapies. CD22-chimeric antigen receptor (CAR) T cells represent an attractive addition to CD19-CAR T cell therapy because they will target both CD22 + CD19 – B-ALL relapses and CD19 – preleukemic cells. However, the immune escape mechanisms from CD22-CAR T cells, and the potential contribution of the epitope binding of the anti-CD22 single-chain variable fragment (scFv) remain understudied. Methods Here, we have developed and comprehensively characterized a novel CD22-CAR (clone hCD22.7) targeting a membrane-distal CD22 epitope and tested its cytotoxic effects against B-ALL cells both in in vitro and in vivo assays. Results Conformational epitope mapping, cross-blocking, and molecular docking assays revealed that the hCD22.7 scFv is a high-affinity binding antibody which specifically binds to the ESTKDGKVP sequence, located in the Ig-like V-type domain, the most distal domain of CD22. We observed efficient killing of B-ALL cells in vitro, although the kinetics were dependent on the level of CD22 expression. Importantly, we show an efficient in vivo control of patients with B-ALL derived xenografts with diverse aggressiveness, coupled to long-term hCD22.7-CAR T cell persistence. Remaining leukemic cells at sacrifice maintained full expression of CD22, ruling out CAR pressure-mediated antigen loss. Finally, the immunogenicity capacity of this hCD22.7-scFv was very similar to that of other CD22 scFv previously used in adoptive T cell therapy. Conclusions We report a novel, high-affinity hCD22.7 scFv which targets a membrane-distal epitope of CD22. 4-1BB-based hCD22.7-CAR T cells efficiently eliminate clinically relevant B- CD22 high and CD22 low ALL primary samples in vitro and in vivo. Our study supports the clinical translation of this hCD22.7-CAR as either single or tandem CD22–CD19-CAR for both naive and anti-CD19-resistant patients with B-ALL.
Variation in Provider Connectedness Associates With Outcomes of Inflammatory Bowel Diseases in an Analysis of Data From a National Health System
Authors: Shirley Cohen-Mekelburg, Xianshi Yu, Deena Costa, Timothy P. Hofer, Sarah Krein, John Hollingsworth, Wyndy Wiitala, Sameer Saini, Ji Zhu, Akbar Waljee
Journal: Clinical Gastroenterology and Hepatology (2020)
Abstract 12243: Relationship Between Nitric Oxide Bioavailability and Modified Low Density Lipoproteins and Their Impact on Vascular Outcome in African Americans With Type Ii Diabetes
Authors: Ahmed Bakillah, Ajibola M Adedayo, Ayobami Eluwole, Fasika Tedla, Arye Kremer, Mastrogiovanni Nicole, Muhammad Khan, Carl Rosenberg, Dreizen Paul, John C LaRosa, Louis Salciccioli, Mohamed Boutjdir, Mary Ann Banerji, Clinton D Brown, Moro Salifu, Jason Lazar
Journal: Circulation (2019)

Background: Endothelial dysfunction in diabetes has been attributed to lack of nitric oxide (NO) bioavailability. Oxidized LDL (OxLDL) and NO play antagonist roles in endothelium dysfunction. OxLDL...
Case of adult large vessel vasculitis after SARS-CoV-2 infection
Authors: Ryohei Oda, Takeshi Inagaki, Masahiro Ishikane, Masatoshi Hotta, Akira Shimomura, Mitsuhiro Sato, Takato Nakamoto, Yutaro Akiyama, Kei Yamamoto, Ryogo Minamimoto, Hiroshi Kaneko, Norio Ohmagari
Journal: Annals of the Rheumatic Diseases (2020)

We read with great interest the article ‘Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry’ by Gianfrancesco et al .1 This study showed that glucocorticoid exposure of ≥10 mg/day was associated with higher odds of hospitalisation and anti-TNF with a decreased odds of hospitalisation in patients with COVID-19 with rheumatic disease. Like this report, studies on the relationship between COVID-19 and rheumatic diseases are needed. Although several cases of vasculitis, such as large vessel vasculitis (LVV) and Kawasaki disease, have been reported among patients with COVID-19,2 3 there are no recorded cases of adult LVV developing after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We report a case of this development.

A 71-year-old Japanese man was admitted to our hospital with complaints of fever and productive cough for 12 days. He was referred to our hospital after a chest X-ray at a private clinic revealed ground glass opacity (GGO) in bilateral lung fields. He had no history of vasculitis or arteriosclerosis. Two days after admission, PCR was positive for SARS-CoV-2 RNA. …
Effects of Metformin Exposure on Survival in a Large National Cohort of Patients With Diabetes and Cirrhosis
Authors: David E. Kaplan, Marina Serper, Binu V. John, Kristen M. Tessiatore, Renata Lerer, Rajni Mehta, Rena Fox, Ayse Aytaman, Michelle Baytarian, Kristel Hunt, Jeffrey Albrecht, Tamar H. Taddei
Journal: Clinical Gastroenterology and Hepatology (2020)
YTHDF1 Promotes Gastric Carcinogenesis by Controlling Translation of <i>FZD7</i>
Authors: Jingnan Pi, Wen Wang, Ming Ji, Xiaoshuang Wang, Xueju Wei, Jing Jin, Tao Liu, Jiaqi Qiang, Zhihong Qi, Feng Li, Yue Liu, Yanni Ma, Yanmin Si, Yue Huo, Yufeng Gao, Yiying Chen, Lei Dong, Rui Su, Jianjun Chen, Shuan Rao, Ping Yi, Shuyang Yu, Fang Wang, Jia Yu
Journal: Cancer Research (2020)

Abstract N6-methyladenosine (m6A) is the most prevalent internal RNA modification in mammals that regulates homeostasis and function of modified RNA transcripts. Here, we aimed to investigate the role of YTH m6A RNA-binding protein 1 (YTHDF1), a key regulator of m6A methylation in gastric cancer tumorigenesis. Multiple bioinformatic analyses of different human cancer databases identified key m6A-associated genetic mutations that regulated gastric tumorigenesis. YTHDF1 was mutated in about 7% of patients with gastric cancer, and high expression of YTHDF1 was associated with more aggressive tumor progression and poor overall survival. Inhibition of YTHDF1 attenuated gastric cancer cell proliferation and tumorigenesis in vitro and in vivo. Mechanistically, YTHDF1 promoted the translation of a key Wnt receptor frizzled7 (FZD7) in an m6A-dependent manner, and mutated YTHDF1 enhanced expression of FZD7, leading to hyperactivation of the Wnt/β-catenin pathway and promotion of gastric carcinogenesis. Our results demonstrate the oncogenic role of YTHDF1 and its m6A-mediated regulation of Wnt/β-catenin signaling in gastric cancer, providing a novel approach of targeting such epigenetic regulators in this disease. Significance: This study provides a rationale for controlling translation of key oncogenic drivers in cancer by manipulating epigenetic regulators, representing a novel and efficient strategy for anticancer treatment.
CCL21-loaded 3D hydrogels for T cell expansion and differentiation
Authors: Eduardo Pérez del Río, Fabião Santos, Xavier Rodriguez Rodriguez, Marc Martínez-Miguel, Ramon Roca-Pinilla, Anna Arís, Elena Garcia-Fruitós, Jaume Veciana, Joachim P. Spatz, Imma Ratera, Judith Guasch
Journal: Biomaterials (2020)

Recent achievements in the field of immunotherapy, such as the development of engineered T cells used in adoptive cell therapy, are introducing more efficient strategies to combat cancer. Nevertheless, there are still many limitations. For example, these T cells are challenging to manufacture, manipulate, and control. Specifically, there are limitations in producing the large amounts of therapeutic T cells needed for these therapies in a short period of time and in an economically viable manner. In this study, three-dimensional (3D) poly(ethylene) glycol (PEG) hydrogels covalently combined with low molecular weight heparin are engineered to resemble the lymph nodes, where T cells reproduce. In these hydrogels, PEG provides the needed structural and mechanical properties, whereas heparin is used as an anchor for the cytokine CCL21, which is present in the lymph nodes, and can affect cell migration and proliferation. The 3D structure of the hydrogel in combination with its loading capacity result in an increased primary human CD4+ T cell proliferation compared to the state-of-the-art expansion systems consisting of artificial antigen presenting cells. Thus, we present a new tool for adoptive cell therapy to help achieving the large numbers of cells required for therapy of selected phenotypes targeted against cancer cells, by mimicking the lymph nodes.
A cognitive transition underlying both technological and social aspects of cumulative culture
Authors: Liane Gabora, Cameron M. Smith
Journal: Behavioral and Brain Sciences (2020)

Abstract The argument that cumulative technological culture originates in technical-reasoning skills is not the only alternative to social accounts; another possibility is that accumulation of both technical-reasoning skills and enhanced social skills stemmed from the onset of a more basic cognitive ability such as recursive representational redescription. The paper confuses individual learning of pre-existing information with creative generation of new information.
Phase II Open Label Study of Anakinra in Intravenous Immunoglobulin–Resistant Kawasaki Disease
Authors: Isabelle Koné‐Paut, Stéphanie Tellier, Alexandre Belot, Karine Brochard, Corinne Guitton, Isabelle Marie, Ulrich Meinzer, Bilade Cherqaoui, Caroline Galeotti, Nadja Boukhedouni, Helene Agostini, Moshe Arditi, Virginie Lambert, Céline Piedvache
Journal: Arthritis & Rheumatology (2020)

Objective Anakinra has been shown to be successful in preventing and treating cardiovascular lesions both in experimental murine models of Kawasaki disease (KD) and in several studies on intravenous immunoglobulin (IVIG)– and steroid‐resistant patients with KD. This study was undertaken to determine the safety of blocking interleukin‐1 in patients with IVIG‐resistant KD. Methods Sixteen patients were included in the present study. Patients with KD who were not responsive to 1 or more courses of 2 mg/kg of IVIG received anakinra by subcutaneous daily injections. Starting doses were 2 mg/kg of IVIG (4 mg/kg in patients who were age &lt;8 months and who weighed ≥5 kilograms), and the dose was increased up to 6 mg/kg every 24 hours if the patient’s body temperature remained &gt;38°C, indicative of a fever. Treatment duration was 14 days. The last visit was on day 45. Primary outcome was abatement of fever. Secondary measures included disease activity, coronary artery Z score, and C‐reactive protein (CRP) levels. Results Seventy‐five percent of patients in the intention‐to‐treat group and 87.5% in the per‐protocol group became afebrile within 48 hours of the last escalation dose of anakinra. Reduction of disease activity by 50% was indicated on 93.3% (95% confidence interval [95% CI] 68.1–99.8%) of physician evaluations and on 100% (95% CI 73.5–100%) of parent evaluations. CRP values normalized by day 30. At the initial screening, 12 of 16 patients had a maximum coronary artery Z score of &gt;2, and 10 of 16 patients had a maximum Z score of &gt;2.5. At day 45, 5 of 10 patients (50% [95% CI 18.7–81.3%]) and 6 of 12 patients (50% [95% CI 21.1–78.9%]) had achieved coronary artery Z scores of &lt;2.5 and &lt;2, respectively. Five serious adverse events were observed in 3 patients, but no serious infections or deaths occurred. Conclusion Anakinra was well tolerated in the study patients and may have some efficacy in reducing fever, markers of systemic inflammation, and coronary artery dilatation in individuals with IVIG‐refractory KD.
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Authors: Raag Airan
Journal: Science Translational Medicine (2020)

The glymphatics system of the brain rapidly clears organic nanoparticles commonly used for brain drug delivery. To enhance drug or gene delivery to the brain, investigators have proposed the use of nanoparticulate delivery vectors to improve pharmacokinetics and pharmacodistribution. Once blood-brain barrier crossing is achieved, it has been assumed that nanoparticles would have a relatively prolonged residence time in the central nervous system, long enough for the payload to reach the target cells of interest. Indeed, earlier pharmacokinetic studies with inorganic nanoparticles, such as iron oxide, supported this assumption of prolonged brain residence times of nanoparticulate agents. Recently, Gu et al. studied the residence time in the brain of organic, biodegradable nanoparticles that are more typically used for drug delivery. They found that nanoparticles composed of either lipoproteins or polymers cleared fairly rapidly from the mouse brain following direct intraparenchymal injection, with a clearance half-life of only a few hours. Moreover, they found that this clearance was mediated, for the most part, by the glymphatic system—a recently described mechanism by which the brain's interstitial fluid clears into the lymphatic system of the body via paravascular channels—with the resident immune cells of the brain playing a pivotal role. From a drug delivery perspective, this implies that bioengineers must not assume that delivery of a nanoparticle past the blood-brain barrier will be sufficient and instead consider that the glymphatic system could clear the nanoparticle nearly as fast as it is being delivered. Additionally, this implies that nanoparticles may be uniquely suited for studying how the glymphatic system clears different types of materials from the brain, as well as the role of immune cells in this process. Furthermore, given that they are selectively cleared by immune cells into the glymphatic system, this suggests that nanoparticles could be uniquely suited to treating neuroinflammatory and neurodegenerative disorders. Certainly, although these data are compelling, future studies will need to verify that these results translate to larger animals that better predict the human situation. Additionally, they will need to be realized in realistic models of the diseases the nanoparticles are intended to treat. Overall, this study underlines the importance of explicitly verifying the pharmacokinetics and pharmacodistribution of drug delivery technologies.
AB0029 CITRULLINE REACTIVE B CELLS ARE PRESENT IN THE LUNGS OF EARLY UNTREATED RA
Authors: Vijay Joshua, Malena Loberg-Haarhaus, Heidi Wähämaa, Aase Hensvold, Magnus Sköld, Johan Grunewald, Lars Klareskog, Vivianne Malmström, Anca Catrina
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> We have previously shown that structural changes, increased tissue citrullination, signs of local inflammation and ACPA are present in the pulmonary compartment of early seropositive RA. These findings suggest a potential role for the lungs in generation of RA-associated autoimmunity. <h3>Objectives</h3> To identify citrulline reactive B cells in the lung compartment of early untreated RA patients and to generate and characterize the corresponding monoclonal antibodies. <h3>Methods</h3> Bronchoalveolar lavage (BAL) fluid cells (13 and 22.5 million respectively) were obtained from two early untreated non-smoking ACPA positive RA patients and single CD19+ B cells were sorted by flow cytometry. Immunoglobulin variable region genes were sequenced and expressed to generate recombinant monoclonal antibodies (mAbs). The citrulline reactivity was determined by in-house ELISA against different citrullinated peptides and controls. <h3>Results</h3> Single sorted CD19+ B cells (n=768) from each patient (RA.1 and RA.2) were processed and the variable region amplification and sequencing yielded 192 (RA.1) and 213 (RA.2) paired heavy and light chain sequences. Based on previously published data showing SHM-introduced N-linked glycosylation in the Fab regions of ACPA [1], 22 sequences from each patient were pre-selected with such features, and monoclonal antibodies were expressed. Two antibodies from each patient were ACPAs as determined by their reactivity against CCP2. The 4 ACPAs have varying ACPA fine specificity against citrullinated enolase, filaggrin, vimentin and fibrinogen peptides (figure 1). Sequence analysis of the heavy chain variable region revealed unique V gene usage of the ACPAs arising from different patients, V4-39 for the 2 mAbs from RA.1 and V3-49 for RA.2. <h3>Conclusion</h3> We demonstrate for the first time that citrulline-reactive B cells are present in the lung compartment of early untreated RA. Further analysis and functional characterization are needed and ongoing to understand their role in RA. <h3>Reference</h3> [1] Lloyd, K.A., et al., Variable domain N-linked glycosylation and negative surface charge are key features of monoclonal ACPA: Implications for B-cell selection. Eur J Immunol, 2018. 48(6): p.1030-1045. <h3>Disclosure of Interests</h3> Vijay Joshua: None declared, Malena Loberg-Haarhaus: None declared, Heidi Wähämaa: None declared, Aase Hensvold: None declared, Magnus Sköld: None declared, Johan Grunewald: None declared, Lars Klareskog Grant/research support from: Yes, but not for the presented study., Vivianne Malmström: None declared, Anca Catrina Grant/research support from: Yes, but not for the presented study.
A pentapeptide enabled AL3810 liposome-based glioma-targeted therapy with immune opsonic effect attenuated
Authors: Jinyang Li, Jiasheng Lu, Haiyan Guo, Jianfen Zhou, Songli Wang, Kuan Jiang, Zhilan Chai, Shengyu Yao, Xiaoyi Wang, Linwei Lu, Cao Xie, Yi Chen, Weiyue Lu
Journal: Acta Pharmaceutica Sinica B (2020)

AL3810, a molecular dual inhibitor of the vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR), has earned the permission of phase II clinical trial for tumor treatment by China FDA. As a reversible ATP-competitive inhibitor, AL3810 targets ATP-binding site on intracellular region of VEGFR and FGFR, whereas, AL3810 lacking interplay with extracellular region of receptors rendered deficient blood–brain tumor barrier (BBTB) recognition, poor brain penetration and unsatisfactory anti-glioma efficacy. Integrin αvβ3 overexpressed on capillary endothelial cells of BBTB as well as glioma cells illuminated ligand-modified liposomes for pinpoint spatial delivery into glioma. The widely accepted peptide c(RGDyK)-modified liposome loading AL3810 of multiple dosing caused hypothermia, activated anti-c(RGDyK)-liposome IgG and IgM antibody and pertinent complements C3b and C5b-9, and experienced complement-dependent opsonization. We newly proposed a pentapeptide mn with superb αvβ3-binding affinity and tailored AL3810-loaded mn-modified liposome that afforded impervious blood circulation, targeting ability, and glioma therapeutic expertise as vastly alleviated immune opsonization on the underpinning of the finite antibodies and complements assembly. Stemming from attenuated immunogenicity, peptide mn strengthened liposome functions as a promising nanocarrier platform for molecular targeting agents.
Need for Additional Trials of Vitamin C for Sepsis—Reply
Authors: Andre C. Kalil
Journal: JAMA (2020)

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