tbuckley/cabot-search huggingface dataset:
Enhancing anticancer activity of checkpoint immunotherapy by targeting RAS
Authors: Antonio B. Ward, Adam B. Keeton, Xi Chen, Tyler E. Mattox, Alex B. Coley, Yulia Y. Maxuitenko, Donald J. Buchsbaum, Troy D. Randall, Gang Zhou, Gary A. Piazza
Journal: MedComm (2020)

Abstract Approximately 30% of human cancers harbor a gain‐in‐function mutation in the RAS gene , resulting in constitutive activation of the RAS protein to stimulate downstream signaling, including the RAS‐mitogen activated protein kinase pathway that drives cancer cells to proliferate and metastasize. RAS‐driven oncogenesis also promotes immune evasion by increasing the expression of programmed cell death ligand‐1, reducing the expression of major histocompatibility complex molecules that present antigens to T‐lymphocytes and altering the expression of cytokines that promote the differentiation and accumulation of immune suppressive cell types such as myeloid‐derived suppressor cells, regulatory T‐cells, and cancer‐associated fibroblasts. Together, these changes lead to an immune suppressive tumor microenvironment that impedes T‐cell activation and infiltration and promotes the outgrowth and metastasis of tumor cells. As a result, despite the growing success of checkpoint immunotherapy, many patients with RAS‐driven tumors experience resistance to therapy and poor clinical outcomes. Therefore, RAS inhibitors in development have the potential to weaken cancer cell immune evasion and enhance the antitumor immune response to improve survival of patients with RAS‐driven cancers. This review highlights the potential of RAS inhibitors to enhance or broaden the anticancer activity of currently available checkpoint immunotherapy.
A Prospective Safety and Feasibility Study of Metered CryoSpray (MCS) for Patients with Chronic Bronchitis in COPD
Authors: Justin L. Garner, Tawimas Shaipanich, Jorine E. Hartman, Christopher M. Orton, Cielito Caneja, Karin Klooster, John Thornton, Don D. Sin, Dirk-Jan Slebos, Pallav L. Shah
Journal: European Respiratory Journal (2020)

Background No currently approved intervention counteracts airway metaplasia and mucus hypersecretion of chronic bronchitis in COPD. However, metered cryospray (MCS) delivering liquid nitrogen to the tracheobronchial airways ablates abnormal epithelium and facilitates healthy mucosal regeneration. The objective of this study was to evaluate the feasibility, efficacy and safety of MCS in chronic bronchitis. Methods Patients with a forced expiratory volume in 1 s of 30–80% predicted who were taking optimal medication were recruited. Primary outcomes were feasibility (completion of treatments), efficacy (3-month change in St George's Respiratory Questionnaire (SGRQ)) and safety (incidence of adverse events). Secondary outcomes were lung function, exercise capacity and additional patient-reported outcomes. Results 35 patients, 19 male/16 female, aged 47–76 years, Global Initiative for Chronic Obstructive Lung Disease grade I (n=3), II (n=10) and III (n=22), underwent staggered liquid nitrogen treatments to the tracheobronchial tree. 34 patients completed three treatments, each lasting 34.3±12.1 min, separated by 4–6 weeks; one withdrew after the first treatment. ∼1800 doses of MCS were delivered. Clinically meaningful improvements in patient-reported outcomes were observed at 3 months: change in SGRQ −6.4 (95% CI −11.4 to −1.3; p=0.01), COPD Assessment Test (CAT) −3.8 (95% CI −6.4 to −1.3; p&lt;0.01) and Leicester Cough Questionnaire (LCQ) 21.6 (95% CI 7.3 to 35.9; p&lt;0.01). Changes in CAT were durable to 6 months (−3.4, 95% CI −5.9 to −0.9; p=0.01); changes in SGRQ and LCQ were durable to 9 months (−6.9, 95% CI −13.0 to −0.9; p=0.03 and 13.4, 95% CI 2.1 to 24.6; p=0.02, respectively. At 12 months, 14 serious adverse events were recorded in 11 (31.4%) subjects; six (43%) moderate and eight (57%) severe. Nine were respiratory-related: six exacerbations of COPD, two pneumonias and one case of increased coughing; all recovered without sequelae. None were serious device- or procedure-related adverse events. Conclusion MCS is safe, feasible and associated with clinically meaningful improvements in multidimensional patient-reported outcomes.
COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study
Authors: Florian Götzinger, Begoña Santiago-García, Antoni Noguera-Julián, Miguel Lanaspa, Laura Lancella, Francesca I Calò Carducci, Natalia Gabrovska, Svetlana Velizarova, Petra Prunk, Veronika Osterman, Uros Krivec, Andrea Lo Vecchio, Delane Shingadia, Antoni Soriano-Arandes, Susana Melendo, Marcello Lanari, Luca Pierantoni, Noémie Wagner, Arnaud G L'Huillier, Ulrich Heininger, Nicole Ritz, Srini Bandi, Nina Krajcar, Srđan Roglić, Mar Santos, Christelle Christiaens, Marine Creuven, Danilo Buonsenso, Steven B Welch, Matthias Bogyi, Folke Brinkmann, Marc Tebruegge, Jasmin Pfefferle, Angela Zacharasiewicz, Angelika Berger, Roland Berger, Volker Strenger, Daniela S. Kohlfürst, Anna Zschocke, Benoît Bernar, Burkhard Simma, Edda Haberlandt, Christina Thir, Ariane Biebl, Koen Vanden Driessche, Tine Boiy, Daan Van Brusselen, An Bael, Sara Debulpaep, Petra Schelstraete, Ivan Pavic, Ulrikka Nygaard, Jonathan P. Glenthoej, Lise Heilmann Jensen, Ilona Lind, Mihhail Tistsenko, Ülle Uustalu, Laura Buchtala, Stephanie Thee, Robin Kobbe, Cornelius Rau, Nicolaus Schwerk, Michael Barker, Maria Tsolia, Irini Eleftheriou, Patrick Gavin, Oksana Kozdoba, Borbàla Zsigmond, Piero Valentini, Inga Ivaškeviciene, Rimvydas Ivaškevicius, Valentina Vilc, Elisabeth Schölvinck, Astrid Rojahn, Anastasios Smyrnaios, Claus Klingenberg, Isabel Carvalho, Andreia Ribeiro, Anna Starshinova, Ivan Solovic, Lola Falcón, Olaf Neth, Laura Minguell, Matilde Bustillo, Aida M. Gutiérrez-Sánchez, Borja Guarch Ibáñez, Francesc Ripoll, Beatriz Soto, Karsten Kötz, Petra Zimmermann, Hanna Schmid, Franziska Zucol, Anita Niederer, Michael Buettcher, Benhur S. Cetin, Olga Bilogortseva, Vera Chechenyeva, Alicia Demirjian, Fiona Shackley, Lynne McFetridge, Lynne Speirs, Conor Doherty, Laura Jones, Paddy McMaster, Clare Murray, Frances Child, Yvonne Beuvink, Nick Makwana, Elisabeth Whittaker, Amanda Williams, Katy Fidler, Jolanta Bernatoniene, Rinn Song, Zoe Oliver, Andrew Riordan
Journal: The Lancet Child & Adolescent Health (2020)
COVID-19 and pulmonary rehabilitation: preparing for phase three
Authors: Massimiliano Polastri, Stefano Nava, Enrico Clini, Michele Vitacca, Rik Gosselink
Journal: European Respiratory Journal (2020)

<b>Considering the expected high burden of respiratory, physical and psychological impairment following the acute phase of COVID-19, a huge number of patients should be referred early to a rehabilitation programme</b>https://bit.ly/3d0s0hu
Identification of the SRC-family tyrosine kinase HCK as a therapeutic target in mantle cell lymphoma
Authors: Hildo C. Lantermans, Marthe Minderman, Annemieke Kuil, Marie-José Kersten, Steven T. Pals, Marcel Spaargaren
Journal: Leukemia (2020)

Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma subtype arising from naïve B cells. Although novel therapeutics have improved patient prognosis, drug resistance remains a key problem. Here, we show that the SRC-family tyrosine kinase hematopoietic cell kinase (HCK), which is primarily expressed in the hematopoietic lineage but not in mature B cells, is aberrantly expressed in MCL, and that high expression of HCK is associated with inferior prognosis of MCL patients. HCK expression is controlled by the toll-like receptor (TLR) adaptor protein MYD88 and can be enhanced by TLR agonists in MCL cell lines and primary MCL. In line with this, primary MCL with high HCK expression are enriched for a TLR-signaling pathway gene set. Silencing of HCK expression results in cell cycle arrest and apoptosis. Furthermore, HCK controls integrin-mediated adhesion of MCL cells to extracellular matrix and stromal cells. Taken together, our data indicate that TLR/MYD88-controlled aberrant expression of HCK plays a critical role in MCL proliferation and survival as well as in retention of the malignant cells in the growth- and survival-supporting lymphoid organ microenvironment, thereby contributing to lymphomagenesis. These novel insights provide a strong rationale for therapeutic targeting of HCK in MCL.
Response to: ‘Comment on ‘Successful remission with tofacitinib in a patient with refractory Takayasu arteritis complicated by ulcerative colitis’ by Kuwabara<i>et al</i>’ by Rios Rodriguez<i>et al</i>
Authors: Shun Tanimura, Hiroyuki Nakamura, Tetsuya Horita
Journal: Annals of the Rheumatic Diseases (2020)

Response to: 'Comment on: 'Successful remission with tofacitinib in a patient with refractory Takayasu arteritis complicated by ulcerative colitis' by
Publisher Correction: Building an international consortium for tracking coronavirus health status
Authors: Eran Segal, Feng Zhang, Xihong Lin, Gary King, Ophir Shalem, Smadar Shilo, William E. Allen, Faisal Alquaddoomi, Han Altae-Tran, Simon Anders, Ran Balicer, Tal Bauman, Ximena Bonilla, Gisel Booman, Andrew T. Chan, Ori Cohen, Silvano Coletti, Natalie Davidson, Yuval Dor, David A. Drew, Olivier Elemento, Georgina Evans, Phil Ewels, Joshua Gale, Amir Gavrieli, Benjamin Geiger, Yonatan H. Grad, Casey S. Greene, Iman Hajirasouliha, Roman Jerala, Andre Kahles, Olli Kallioniemi, Ayya Keshet, Ljupco Kocarev, Gregory Landua, Tomer Meir, Aline Muller, Long H. Nguyen, Matej Oresic, Svetlana Ovchinnikova, Hedi Peterson, Jana Prodanova, Jay Rajagopal, Gunnar Rätsch, Hagai Rossman, Johan Rung, Andrea Sboner, Alexandros Sigaras, Tim Spector, Ron Steinherz, Irene Stevens, Jaak Vilo, Paul Wilmes
Journal: Nature Medicine (2020)

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Glycated milk protein fermented with <i>Lactobacillus rhamnosus</i> ameliorates the cognitive health of mice under mild-stress condition
Authors: Nam Su Oh, Jae Yeon Joung, Ji Young Lee, Jae Gwang Song, Sangnam Oh, Younghoon Kim, Hyung Wook Kim, Sae Hun Kim
Journal: Gut Microbes (2020)

This study aimed to investigate the effects of glycated milk casein (Gc) fermented with Lactobacillus rhamnosus 4B15 (FGc) on the intestinal microbiota and physiological and behavioral properties in mice under chronic stress. Mice were administered Gc or FGc for 10 weeks and then exposed to unpredictable chronic mild stress (UCMS) for 7 weeks. FGc administration restored alterations of gut microbiota induced by UCMS. Moreover, FGc significantly reduced the stress-induced increase in serum corticosterone and decrease in serotonin levels. Anxiety-like behaviors induced by UCMS were also significantly decreased in the FGc group. UCMS-induced dysregulation of gene and protein expression related to neuroendocrine function, neuronal development, and inflammation, and gut-blood-brain barrier function was controlled by FGc pre-treatment. These results strongly suggest the protective effects of FGc targeting of intestinal microbiota for abnormal brain activity, which is consistent with the view that FGc plays an important role in regulating stress-related gut-brain axis disorders.
Heparin‐Coated Albumin Nanoparticles for Drug Combination in Targeting Inflamed Intestine
Authors: Sufeng Zhang, Won Joon Cho, Amy T. Jin, Lie Yun Kok, Yunhua Shi, David E. Heller, Young‐Ah Lucy Lee, Yixuan Zhou, Xi Xie, Joshua R. Korzenik, Jochen K. Lennerz, Giovanni Traverso
Journal: Advanced Healthcare Materials (2020)

Abstract Targeting areas of inflammation offers potential therapeutic and diagnostic benefits by maximizing drug and imaging marker on‐target effects while minimizing systemic exposure that can be associated with adverse side effects. This strategy is particularly beneficial in the management of inflammatory bowel disease (IBD). Here an inflammation‐targeting (IT) approach based on heparin‐coated human serum albumin nanoparticles (HEP‐HSA NPs) that utilize the increased intestinal permeability and changes in electrostatic interaction at the site of intestinal inflammation is described. Using small‐molecule and biologic drugs as a model for drug combination, the HEP‐HSA NPs demonstrate the capacity to load both drugs simultaneously; the dual‐drug loaded HEP‐HSA NPs exhibit a higher anti‐inflammatory effect than both of the single‐drug loaded NPs in vitro and selectively bind to inflamed intestine after enema administration in vivo in a murine model of colitis. Importantly, analyses of the physicochemical characteristics and targeting capacities of these NPs indicate that HEP coating modulates NP binding to the inflamed intestine, providing a foundation for future IT‐NP formulation development.
Extreme Risk Protection Orders in Washington
Authors: Ali Rowhani-Rahbar, M. Alex Bellenger, Lauren Gibb, Heather Chesnut, Madison Lowry-Schiller, Emma Gause, Miriam J. Haviland, Frederick P. Rivara
Journal: Annals of Internal Medicine (2020)

In the United States, 74% of homicides and 51% of suicides involve firearms. Using extreme risk protection order (ERPO) laws, petitioners can request restricting firearm access for individuals (known as "respondents") who pose a risk to themselves or others.To characterize respondents and circumstances of ERPOs.Descriptive study.State of Washington.All ERPO respondents during 8 December 2016 to 10 May 2019.Reason for filing the ERPO; characteristics of respondents; respondent's reported history of domestic violence perpetration, mental illness, substance misuse, and suicide ideation or attempt; number and type of firearms removed; and ERPO petition outcome (granted or not granted).The ERPOs were filed for concerns about harm to self (n = 67), harm to others (n = 86), or harm to both self and others (n = 84). Of all ERPOs, 87% were filed by law enforcement and 81% were granted. At least 1 firearm was removed from 64% of respondents, with a total of 641 firearms removed. The petitioner reported prior domestic violence perpetration by the respondent in 24% of cases, and a prior diagnosis of a mental health condition and substance misuse for the respondent in 40% and 47% of cases, respectively. Of all respondents, 62% had a history of suicidal ideation or attempt according to the petitioner. As part of the ERPO process, the court ordered mental health evaluation in 30% of cases.Filing of the forms was inconsistent.Laws regarding ERPOs are a potential tool to help protect patients or family members from harming themselves or others by restricting firearm possession and purchase. Further studies are needed to determine the long-term effects of these laws and identify approaches to increase their use.State of Washington.
Salt causes aging-associated hypertension via vascular Wnt5a under Klotho deficiency
Authors: Wakako Kawarazaki, Risuke Mizuno, Mitsuhiro Nishimoto, Nobuhiro Ayuzawa, Daigoro Hirohama, Kohei Ueda, Fumiko Kawakami-Mori, Shigeyoshi Oba, Takeshi Marumo, Toshiro Fujita
Journal: Journal of Clinical Investigation (2020)

Aging is associated with a high prevalence of hypertension due to elevated susceptibility of BP to dietary salt, but its mechanism is unknown. Serum levels of Klotho, an anti-aging factor, decline with age. We found that high salt (HS) increased BP in aged mice and young heterozygous Klotho-knockout mice and was associated with increased vascular expression of Wnt5a and p-MYPT1, which indicate RhoA activity. Not only the Wnt inhibitor LGK974 and the Wnt5a antagonist Box5 but Klotho supplementation inhibits HS-induced BP elevation, similarly to the Rho kinase inhibitor fasudil, associated with reduced p-MYPT1 expression in both groups of mice. In cultured vascular smooth muscle cells, Wnt5a and angiotensin II (Ang II) increased p-MYPT1 expression but knockdown of Wnt5a with siRNA abolished Ang II-induced upregulation of p-MYPT1, indicating that Wnt5a is indispensable for Ang II-induced Rho/ROCK activation. Notably, Klotho inhibited Wnt5a- and Ang II-induced upregulation of p-MYPT1. Consistently, Klotho supplementation ameliorated HS-induced augmentation of reduced renal blood flow (RBF) response to intra-arterial infusion of Ang II and the thromboxane A2 analog U46619, which activated RhoA in both groups of mice and were associated with the inhibition of BP elevation, suggesting that abnormal response of RBF to Ang II contributes to HS-induced BP elevation. Thus, Klotho deficiency underlies aging-associated salt-sensitive hypertension through vascular non-canonical Wnt5a/RhoA activation.
Measurement Tool of Chemotherapy Sensitivity in Advanced Ovarian Cancer
Authors: Taymaa May, Amit M. Oza
Journal: Clinical Cancer Research (2020)

The modeled Ca125 ELIMination rate constant K (KELIM) can be used as a measure of chemotherapy sensitivity in women with newly diagnosed advanced epithelial ovarian cancer who are being treated with neoadjuvant chemotherapy. This marker may aid in decision-making regarding surgical resection and alternate systemic treatments in this cohort.See related article by You et al., p. 4625.
Publisher Correction: Personalized early detection and prevention of breast cancer: ENVISION consensus statement
Authors: Nora Pashayan, Antonis C. Antoniou, Urska Ivanus, Laura J. Esserman, Douglas F. Easton, David French, Gaby Sroczynski, Per Hall, Jack Cuzick, D. Gareth Evans, Jacques Simard, Montserrat Garcia-Closas, Rita Schmutzler, Odette Wegwarth, Paul Pharoah, Sowmiya Moorthie, Sandrine De Montgolfier, Camille Baron, Zdenko Herceg, Clare Turnbull, Corinne Balleyguier, Paolo Giorgi Rossi, Jelle Wesseling, David Ritchie, Marc Tischkowitz, Mireille Broeders, Dan Reisel, Andres Metspalu, Thomas Callender, Harry de Koning, Peter Devilee, Suzette Delaloge, Marjanka K. Schmidt, Martin Widschwendter
Journal: Nature Reviews Clinical Oncology (2020)

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
One-year results of gastric peroral endoscopic myotomy for refractory gastroparesis: a French multicenter study
Authors: Olivier Ragi, Jérémie Jacques, Julien Branche, Sarah Leblanc, Geoffroy Vanbiervliet, Romain Legros, Mathieu Pioche, Jérôme Rivory, Stanislas Chaussade, Maximilien Barret, Timothée Wallenhorst, Marc Barthet, Sébastien Kerever, Jean-Michel Gonzalez
Journal: Endoscopy (2020)

Data on the long-term outcomes of gastric peroral endoscopic myotomy (G-POEM) for refractory gastroparesis are lacking. We report the results of a large multicenter long-term follow-up study of G-POEM for refractory gastroparesis.This was a retrospective multicenter study of all G-POEM operations performed in seven expert French centers for refractory gastroparesis with at least 1 year of follow-up. The primary endpoint was the 1-year clinical success rate, defined as at least a 1-point improvement in the Gastroparesis Cardinal Symptom Index (GCSI).76 patients were included (60.5 % women; age 56 years). The median symptom duration was 48 months. The median gastric retention at 4 hours (H4) before G-POEM was 45 % (interquartile range [IQR] 29 % - 67 %). The median GCSI before G-POEM was 3.6 (IQR 2.8 - 4.0). Clinical success was achieved in 65.8 % of the patients at 1 year, with a median rate of reduction in the GCSI score of 41 %. In logistic regression analysis, only a high preoperative GCSI satiety subscale score was predictive of clinical success (odds ratio [OR] 3.41, 95 % confidence interval [CI] 1.01 - 11.54; P = 0.048), while a high rate of gastric retention at H4 was significantly associated with clinical failure (OR 0.97, 95 %CI 0.95 - 1.00; P = 0.03).The results confirm the efficacy of G-POEM for the treatment of refractory gastroparesis, as evidenced by a 65.8 % clinical success rate at 1 year. Although G-POEM is promising, prospective sham-controlled trials are urgently needed to confirm its efficacy and identify the patient populations who will benefit most from this procedure.
A phase 1b study of dual PD-1 and CTLA-4 or KIR blockade in patients with relapsed/refractory lymphoid malignancies
Authors: Philippe Armand, Alexander Lesokhin, Ivan Borrello, John Timmerman, Martin Gutierrez, Lili Zhu, Mihaela Popa McKiver, Stephen M. Ansell
Journal: Leukemia (2020)

Abstract Simultaneously targeting other pathways could increase the activity of PD-1 blockade in lymphoid malignancies not sensitive to single-agent blockade. We explored the safety and efficacy of combined PD-1 and CTLA-4 or KIR blockade in patients with relapsed/refractory (R/R) lymphoid malignancies. This phase 1b trial enrolled adult patients with R/R classical Hodgkin lymphoma (cHL), non-Hodgkin lymphoma (NHL), or multiple myeloma (MM). Patients received nivolumab plus ipilimumab (nivo/ipi) or lirilumab (nivo/liri) until complete response (CR), progression, or unacceptable toxicity. The primary endpoint was safety and tolerability, while secondary endpoints included overall (ORR) and CR rates (CRR), progression-free and overall survival. Sixty-five patients were treated with nivo/ipi, and 72 with nivo/liri. Twenty-nine percent of patients experienced grade 3–4 treatment-related adverse events with nivo/ipi, and 15% with nivo/liri. In cHL, ORR was 74% for nivo/ipi and 76% for nivo/liri, CRRs were 23% and 24%, respectively. In B-NHL and T-NHL, ORR range was 9–22% and CRR was 0–6%. No patient with MM had an objective response. While both combinations were active in cHL, the toxicity of nivo/ipi was higher than expected from nivolumab alone. These data suggest no meaningful improvement in the efficacy of the combinations over single-agent nivolumab in the diseases studied.
Biology of antimicrobial resistance and approaches to combat it
Authors: Sarah M. Schrader, Julien Vaubourgeix, Carl Nathan
Journal: Science Translational Medicine (2020)

Insufficient development of new antibiotics and the rising resistance of bacteria to those that we have are putting the world at risk of losing the most widely curative class of medicines currently available. Preventing deaths from antimicrobial resistance (AMR) will require exploiting emerging knowledge not only about genetic AMR conferred by horizontal gene transfer or de novo mutations but also about phenotypic AMR, which lacks a stably heritable basis. This Review summarizes recent advances and continuing limitations in our understanding of AMR and suggests approaches for combating its clinical consequences, including identification of previously unexploited bacterial targets, new antimicrobial compounds, and improved combination drug regimens.
Fetal growth and gestational age prediction by machine learning
Authors: Cande V Ananth, Justin S Brandt
Journal: The Lancet Digital Health (2020)

Current strategies to identify fetuses with pathological fetal growth restriction are inadequate. Conventionally, fetal growth restriction is defined as an estimate of fetal size at a specific gestational age that is below a predefined threshold, usually the bottom 10th percentile, based on a specific growth standard or population reference.1 By this definition, most fetuses diagnosed with fetal growth restriction are constitutionally small but not at increased risk for adverse outcomes due to hypoxic-ischaemic stress, and instead are at high risk for interventions such as iatrogenic preterm birth due to false-positive antenatal testing.
Unroofing technique: effective “incomplete” endoscopic resection of large esophageal lymphangiomas
Authors: Mitsunobu Matsushita, Takayuki Ueshima, Shuhei Nishimon, Mio Takahashi, Toshiki Asayama, Nobuyuki Shibatani, Kazuyo Fujimura
Journal: Endoscopy (2020)

Letter to:Endoscopic submucosal dissection as a diagnostic procedure for a giant submucosal "sausage" causing dysphagiaEndoscopy 2019; 51(12): E368-E369DOI: 10.1055/a-0929-3072See also:Reply to Matsushita et al.Endoscopy 2020; 52(07): 622-622DOI: 10.1055/a-1167-8295