tbuckley/cabot-search huggingface dataset:
Circulating Tumor DNA Genomics Reveal Potential Mechanisms of Resistance to BRAF-Targeted Therapies in Patients with<i>BRAF</i>-Mutant Metastatic Non–Small Cell Lung Cancer
Authors: Sandra Ortiz-Cuaran, Laura Mezquita, Aurélie Swalduz, Mihalea Aldea, Julien Mazieres, Camille Leonce, Cecile Jovelet, Anne Pradines, Virginie Avrillon, Washington R. Chumbi Flores, Ludovic Lacroix, Yohann Loriot, Virginie Westeel, Maud Ngo-Camus, Claire Tissot, Christine Raynaud, Radj Gervais, Etienne Brain, Isabelle Monnet, Etienne Giroux Leprieur, Caroline Caramella, Celine Mahier-Aït Oukhatar, Natalie Hoog-Labouret, Frank de Kievit, Karen Howarth, Clive Morris, Emma Green, Luc Friboulet, Sylvie Chabaud, Jean-François Guichou, Maurice Perol, Benjamin Besse, Jean-Yves Blay, Pierre Saintigny, David Planchard
Journal: Clinical Cancer Research (2020)

Abstract Purpose: The limited knowledge on the molecular profile of patients with BRAF-mutant non–small cell lung cancer (NSCLC) who progress under BRAF-targeted therapies (BRAF-TT) has hampered the development of subsequent therapeutic strategies for these patients. Here, we evaluated the clinical utility of circulating tumor DNA (ctDNA)-targeted sequencing to identify canonical BRAF mutations and genomic alterations potentially related to resistance to BRAF-TT, in a large cohort of patients with BRAF-mutant NSCLC. Experimental Design: This was a prospective study of 78 patients with advanced BRAF-mutant NSCLC, enrolled in 27 centers across France. Blood samples (n = 208) were collected from BRAF-TT–naïve patients (n = 47), patients nonprogressive under treatment (n = 115), or patients at disease progression (PD) to BRAF-TT (24/46 on BRAF monotherapy and 22/46 on BRAF/MEK combination therapy). ctDNA sequencing was performed using InVisionFirst-Lung. In silico structural modeling was used to predict the potential functional effect of the alterations found in ctDNA. Results: BRAFV600E ctDNA was detected in 74% of BRAF-TT–naïve patients, where alterations in genes related with the MAPK and PI3K pathways, signal transducers, and protein kinases were identified in 29% of the samples. ctDNA positivity at the first radiographic evaluation under treatment, as well as BRAF-mutant ctDNA positivity at PD were associated with poor survival. Potential drivers of resistance to either BRAF-TT monotherapy or BRAF/MEK combination were identified in 46% of patients and these included activating mutations in effectors of the MAPK and PI3K pathways, as well as alterations in U2AF1, IDH1, and CTNNB1. Conclusions: ctDNA sequencing is clinically relevant for the detection of BRAF-activating mutations and the identification of alterations potentially related to resistance to BRAF-TT in BRAF-mutant NSCLC.
THU0018 Differential chloroquine sensitivity of human cem (t) cells with various mechanisms of resistance to methotrexate
Authors: G Jansen, RJ Scheper, B Dijkmans
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Methotrexate (MTX) is the anchor drug in rheumatoid arthritis treatment, either as monotherapy or in combination with other antirheumatics, e.g. chloroquine (CHQ). <h3>Objectives</h3> Does resistance to MTX influence sensitivity to CHQ, and if so, by what mechanism? <h3>Methods</h3> <i>In vitro</i> CHQ sensitivity was evaluated in human CEM (T) cell lines, wild type CEM (CEM<sup>wt</sup>) and 3 CEM sublines resistant to MTX due to reduced cellular uptake (CEM/MTX-transport<sup>low</sup>), elevated levels of dihydrofolate reductase (CEM/MTX-DHFR<sup>up</sup>) or impaired polyglutamylation (CEM/MTX-FPGS<sup>low</sup>). <h3>Results</h3> CEM/MTX-transport<sup>low</sup> cells were 1.5-fold more sensitive to CHQ than CEM<sup>wt</sup> cells (IC<sub>50</sub>: 25 μM vs 39 μM, respectively, after 72 h drug exposure). However, CEM/MTX-DHFR<sup>up</sup> and CEM/MTX-FPGS<sup>low</sup> cells were 2.3-fold (IC<sub>50</sub>: 89 μM) and 1.9-fold (IC<sub>50</sub>: 74 μM) resistant to CHQ, respectively, compared to CEM<sup>wt</sup> cells. The mechanism of CHQ resistance in CEM/MTX-DHFR<sup>up</sup> and CEM/MTX-FPGS<sup>low</sup> cells is likely due to overexpression of multidrug resistance protein 1 (MRP1). This was suggested by a low level (1.5–2-fold) cross-resistance to doxorubicin and daunorubicin, and observations that an inhibitor of MRP1, MK571, was able to reverse CHQ resistance. The same phenotypic changes were noted in CEM/MTX-transport<sup>low</sup> cells with acquired resistance to CHQ (4-fold) after <i>in vitro</i> exposure to stepwise increasing extracellular CHQ concentrations. <h3>Conclusion</h3> Development of MTX resistance can be associated with up regulated expression of MRP1, which, concomitantly, can confer cross-resistance to CHQ. Analysis of MRP1 expression in inflammatory cells should therefore be considered as an important parameter determining the efficacy of anti-rheumatic (combination) therapy.
Safe scarless cassette-free selection of genome-edited human pluripotent stem cells using temporary drug resistance
Authors: Keun-Tae Kim, Ju-Chan Park, Hyeon-Ki Jang, Haeseung Lee, Seokwoo Park, Jumee Kim, Ok-Seon Kwon, Young-Hyun Go, Yan Jin, Wankyu Kim, Jeongmi Lee, Sangsu Bae, Hyuk-Jin Cha
Journal: Biomaterials (2020)
Abstract 5350: RBE, <i>in vivo</i>, for a 212Pb-conjugated anti-HER2/neu antibody
Authors: Ioanna Liatsou, Anders Josefsson, Angel Cortez, Robert F. Hobbs, Cory Brayton, Julien Torgue, George Sgouros
Journal: Cancer Research (2020)

Abstract The relative biological effectiveness is defined as the absorbed dose ratio (Dref(x)/Dtest(x)) of a reference radiation, Dref, to a test radiation, Dtest, that leads to a particular biological end-point, x. The majority of reported RBE values are obtained from in vitro irradiation of cells in monolayer culture wherein clonogenic survival is the end-point. As alpha-particle emitter radiopharmaceutical therapy (RPT) becomes a viable cancer therapy modality, RBE determinations, in vivo, are essential to assessing the potential efficacy and toxicity of alpha-emitter RPT. The aim of the study was to obtain the relative biological effectiveness, RBE, for alpha-particle emissions delivered by Bi-212, following the decay of Pb-212, conjugated onto an anti-HER2/neu antibody. Photon irradiation (200 kVp, 13 mA, 4 Gy/min, 10 × 10 mm2 collimator), delivered by a small animal radiation research platform (SARRP) was used as the reference radiation to irradiate the femurs of 6-8 weeks old female, neu/N transgenic mice (MMTV-neu). The biological endpoint was the reduction in hematopoietic cells in the region of the femur used for the RBE calculation. Alpha-particle emissions were delivered to this region by administering 325 kBq (8.8 μCi) of 212Pb-TCMC-7.16.4 intravenously (tail vein). Mice were sacrificed (n=3) at 1-7 days post-212Pb-TCMC-7.16.4 antibody administration. The long bones (femurs) were harvested, fixed with formalin and counted for radioactivity. The samples were also examined for histopathologic changes to assess the marrow cellularity. Clinical chemistry and hematological analysis were also performed on blood collected by cardiac puncture. The nadir in blood counts was observed 5 days after radiolabeled antibody injection. An absorbed dose to the marrow from the 212Bi alpha-particle emissions of 1.6 Gy yielded a marrow cellularity reduction of 50 %. The absorbed dose from XRT to achieve the same reduction in marrow cellularity was 5.7 Gy. This gives an RBE of 3.6 for a 212Pb-anti-HER2/neu antibody. Since hematologic toxicity is dose-limiting in almost all antibody-based RPT, in vivo measurements of RBE are critical to avoiding it. 2 Gy to the red marrow of low LET radiation is a threshold between low platelet toxicity grades (1 and 2) vs high (3 and 4) grade toxicity. These results suggest that the toxicity threshold for a 212Pb-antibody would be less than 1 Gy. Citation Format: Ioanna Liatsou, Anders Josefsson, Angel Cortez, Robert F. Hobbs, Cory Brayton, Julien Torgue, George Sgouros. RBE, in vivo, for a 212Pb-conjugated anti-HER2/neu antibody [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5350.
Replacement of Red and Processed Meat With Other Food Sources of Protein and the Risk of Type 2 Diabetes in European Populations: The EPIC-InterAct Study
Authors: Daniel B. Ibsen, Marinka Steur, Fumiaki Imamura, Kim Overvad, Matthias B. Schulze, Benedetta Bendinelli, Marcela Guevara, Antonio Agudo, Pilar Amiano, Dagfinn Aune, Aurelio Barricarte, Ulrika Ericson, Guy Fagherazzi, Paul W. Franks, Heinz Freisling, Jose R. Quiros, Sara Grioni, Alicia K. Heath, Inge Huybrechts, Verena Katze, Nasser Laouali, Francesca Mancini, Giovanna Masala, Anja Olsen, Keren Papier, Stina Ramne, Olov Rolandsson, Carlotta Sacerdote, Maria-José Sánchez, Carmen Santiuste, Vittorio Simeon, Annemieke M.W. Spijkerman, Bernard Srour, Anne Tjønneland, Tammy Y.N. Tong, Rosario Tumino, Yvonne T. van der Schouw, Elisabete Weiderpass, Clemens Wittenbecher, Stephen J. Sharp, Elio Riboli, Nita G. Forouhi, Nick J. Wareham
Journal: Diabetes Care (2020)

OBJECTIVE There is sparse evidence for the association of suitable food substitutions for red and processed meat on the risk of type 2 diabetes. We modeled the association between replacing red and processed meat with other protein sources and the risk of type 2 diabetes and estimated its population impact. RESEARCH DESIGN AND METHODS The European Prospective Investigation into Cancer (EPIC)-InterAct case cohort included 11,741 individuals with type 2 diabetes and a subcohort of 15,450 participants in eight countries. We modeled the replacement of self-reported red and processed meat with poultry, fish, eggs, legumes, cheese, cereals, yogurt, milk, and nuts. Country-specific hazard ratios (HRs) for incident type 2 diabetes were estimated by Prentice-weighted Cox regression and pooled using random-effects meta-analysis. RESULTS There was a lower hazard for type 2 diabetes for the modeled replacement of red and processed meat (50 g/day) with cheese (HR 0.90, 95% CI 0.83–0.97) (30 g/day), yogurt (0.90, 0.86–0.95) (70 g/day), nuts (0.90, 0.84–0.96) (10 g/day), or cereals (0.92, 0.88–0.96) (30 g/day) but not for replacements with poultry, fish, eggs, legumes, or milk. If a causal association is assumed, replacing red and processed meat with cheese, yogurt, or nuts could prevent 8.8%, 8.3%, or 7.5%, respectively, of new cases of type 2 diabetes. CONCLUSIONS Replacement of red and processed meat with cheese, yogurt, nuts, or cereals was associated with a lower rate of type 2 diabetes. Substituting red and processed meat by other protein sources may contribute to the prevention of incident type 2 diabetes in European populations.
Matt Morgan: Standing in the shoes of a relative may complicate decision making
Authors: Matt Morgan
Journal: BMJ (2020)

Matt Morgan: Standing in the shoes of a relative may complicate decision making Matt Morgan intensive care consultantThe family room hangs in silence.I've explained the science, the medicine, and the human costs.It was a near impossible decision to make, with no right or wrong answer.An operation will probably kill her.Without an operation, she's likely to die.Then came the familiar question relatives often ask: "If it were your daughter, what would you do?"
Inherited Rare, Deleterious Variants in ATM Increase Lung Adenocarcinoma Risk
Authors: Myvizhi Esai Selvan, Marjorie G. Zauderer, Charles M. Rudin, Siân Jones, Semanti Mukherjee, Kenneth Offit, Kenan Onel, Gad Rennert, Victor E. Velculescu, Steven M. Lipkin, Robert J. Klein, Zeynep H. Gümüş
Journal: Journal of Thoracic Oncology (2020)

IntroductionLung cancer is the leading cause of cancer deaths in the world, and lung adenocarcinoma (LUAD) is its most prevalent subtype. Symptoms are often found in advanced disease in which treatment options are limited. Identifying genetic risk factors will enable better identification of high-risk individuals.MethodsTo identify LUAD risk genes, we performed a case-control association study for gene-level burden of rare, deleterious variants (RDVs) in germline whole-exome sequencing data of 1083 patients with LUAD and 7650 controls, split into discovery and validation cohorts. Of these, we performed whole-exome sequencing on 97 patients and acquired the rest from multiple public databases. We annotated all rare variants for pathogenicity conservatively, using the guidelines of the American College of Medical Genetics and Genomics and ClinVar curation, and investigated gene-level RDV burden using penalized logistic regression. All statistical tests were two-sided.ResultsWe discovered and replicated the finding that the burden of germline ATM RDVs was significantly higher in patients with LUAD versus controls (combined cohort OR = 4.6; p = 1.7e−04; 95% confidence interval = 2.2–9.5; 1.21% of cases; 0.24% of controls). Germline ATM RDVs were also enriched in an independent clinical cohort of 1594 patients from the MSK-IMPACT study (0.63%). In addition, we observed that an Ashkenazi Jewish (AJ) founder ATM variant, rs56009889, was statistically significantly more frequent in AJ cases versus AJ controls in our cohort (combined AJ cohort OR = 2.7, p = 6.9e−03, 95% confidence interval = 1.3–5.3).ConclusionsOur results indicate that ATM is a moderate-penetrance LUAD risk gene and that LUAD may be a part of the ATM-related cancer syndrome spectrum. Individuals with ATM RDVs are at an elevated LUAD risk and can benefit from increased surveillance (particularly computed tomography scanning), early detection, and chemoprevention programs, improving prognosis.
The inflammation-resolution promoting molecule resolvin-D1 prevents atrial proarrhythmic remodelling in experimental right heart disease
Authors: Roddy Hiram, Feng Xiong, Patrice Naud, Jiening Xiao, Martin Sirois, Jean-François Tanguay, Jean-Claude Tardif, Stanley Nattel
Journal: Cardiovascular Research (2020)

Abstract Aims Inflammation plays a role in atrial fibrillation (AF), but classical anti-inflammatory molecules are ineffective. Recent evidence suggests that failure of inflammation-resolution causes persistent inflammatory signalling and that a novel drug-family called resolvins promotes inflammation-resolution. Right heart disease (RHD) is associated with AF; experimental RHD shows signs of atrial inflammatory-pathway activation. Here, we evaluated resolvin-therapy effects on atrial arrhythmogenic remodelling in experimental RHD. Methods and results Pulmonary hypertension and RHD were induced in rats with an intraperitoneal injection of 60 mg/kg monocrotaline (MCT). An intervention group received daily resolvin-D1 (RvD1), starting 1 day before MCT administration. Right atrial (RA) conduction and gene-expression were analysed respectively by optical mapping and qPCR/gene-microarray. RvD1 had no or minimal effects on MCT-induced pulmonary artery or right ventricular remodelling. Nevertheless, in vivo transoesophageal pacing induced atrial tachyarrhythmias in no CTRL rats vs. 100% MCT-only rats, and only 33% RvD1-treated MCT rats (P &amp;lt; 0.001 vs. MCT-only). Conduction velocity was significantly decreased by MCT, an effect prevented by RvD1. RHD caused RA dilation and fibrosis. RvD1 strongly attenuated RA fibrosis but had no effect on RA dilation. MCT increased RA expression of inflammation- and fibrosis-related gene-expression pathways on gene-microarray transcriptomic analysis, effects significantly attenuated by RvD1 (334 pathways enriched in MCT-rats vs. control; only 177 dysregulated by MCT with RvD1 treatment). MCT significantly increased RA content of type 1 (proinflammatory) CD68-positive M1 macrophages without affecting type 2 (anti-inflammatory) M2 macrophages. RvD1-treated MCT-rat RA showed significant reductions in proinflammatory M1 macrophages and increases in anti-inflammatory M2 macrophages vs. MCT-only. MCT caused statistically significant increases in protein-expression (western blot) of COL3A1, ASC, CASP1, CASP8, IL1β, TGFβ3, CXCL1, and CXCL2, and decreases in MMP2, vs. control. RvD1-treatment suppressed all these MCT-induced protein-expression changes. Conclusion The inflammation-resolution enhancing molecule RvD1 prevents AF-promoting RA remodelling, while suppressing inflammatory changes and fibrotic/electrical remodelling, in RHD. Resolvins show potential promise in combating atrial arrhythmogenic remodelling by suppressing ongoing inflammatory signalling.
Role of interleukin-23/interleukin-17 axis in T-cell-mediated actions in hypertension
Authors: Akinori Higaki, Ahmad U M Mahmoud, Pierre Paradis, Ernesto L Schiffrin
Journal: Cardiovascular Research (2020)

Current knowledge suggests that hypertension is in part mediated by immune mechanisms. Both interleukin (IL)-23 and IL-17 are up-regulated in several experimental hypertensive rodent models, as well as in hypertensive humans in observational studies. Recent preclinical studies have shown that either IL-23 or IL-17A treatment induce blood pressure elevation. However, the IL-23/IL-17 axis has not been a major therapeutic target in hypertension, unlike in other autoimmune diseases. In this review, we summarize current knowledge on the role of these cytokines in immune mechanisms contributing to hypertension, and discuss the potential of IL-23/IL-17-targeted therapy for treatment of hypertension.
Bone marrow MSC from pediatric patients with B-ALL highly immunosuppress T-cell responses but do not compromise CD19-CAR T-cell activity
Authors: Samanta Romina Zanetti, Paola Alejandra Romecin, Meritxell Vinyoles, Manel Juan, José Luis Fuster, Mireia Cámos, Sergi Querol, Mario Delgado, Pablo Menendez
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Although adoptive transfer of CD19-directed chimeric antigen receptor (CAR) T-cells (CD19-CAR T-cells) achieves high rates of complete response in patients with B-cell acute lymphoblastic leukemia (B-ALL), relapse is common. Bone marrow (BM) mesenchymal stem/stromal cells (BM-MSC) are key components of the hematopoietic niche and are implicated in B-ALL pathogenesis and therapy resistance. MSC exert an immunosuppressive effect on T-cells; however, their impact on CD19-CAR T-cell activity is understudied. Methods We performed a detailed characterization of BM-MSC from pediatric patients with B-ALL (B-ALL BM-MSC), evaluated their immunomodulatory properties and their impact on CD19-CAR T-cell activity in vitro using microscopy, qRT-PCR, ELISA, flow cytometry analysis and in vivo using a preclinical model of severe colitis and a B-ALL xenograft model. Results While B-ALL BM-MSC were less proliferative than those from age-matched healthy donors (HD), the morphology, immunophenotype, differentiation potential and chemoprotection was very similar. Likewise, both BM-MSC populations were equally immunosuppressive in vitro and anti-inflammatory in an in vivo model of severe colitis. Interestingly, BM-MSC failed to impair CD19-CAR T-cell cytotoxicity or cytokine production in vitro using B-ALL cell lines and primary B-ALL cells. Finally, the growth of NALM6 cells was controlled in vivo by CD19-CAR T-cells irrespective of the absence/presence of BM-MSC. Conclusions Collectively, our data demonstrate that pediatric B-ALL and HD BM-MSC equally immunosuppress T-cell responses but do not compromise CD19-CAR T-cell activity.
Abstract 432: Development of a novel engineered B2M mouse strain on B-NDG background that specifically eliminates MHC I expression while retaining normal FcRn-mediated antibody retention
Authors: W. Frank An, Lan Gao, Xiaoen Wang, Shruti Sharma, Kaiqi Li, Xiqiang Gao, Chengzhang Shang, Yuting Hu
Journal: Cancer Research (2020)

Abstract Severely immunodeficient mouse strains, such as NOD.Cg-Prkdcscid Il2rg-/-, have been widely used to evaluate human immune responses, including applications in immuno-oncology in recent years. However, when human peripheral blood mononuclear cells (PBMCs) are engrafted in these mice, severe acute xenogeneic graft versus host disease (GvHD) arises due to engagement of human T cell receptors (TCRs) and murine major histocompatibility complex (MHC) I and II. GvHD shortens animal life span and results in only a brief window of evaluation of human immune cell functions in such mouse models. Efforts have been undertaken to reduce human PBMC-induced GvHD and to subsequently extend the window of human immunity assessment by eliminating mouse MHC I and MHC II. While these MHC deficient mice show few symptoms of GvHD, the use of beta-2-microglobulin (B2M) null allele in order to eliminate expression of all MHC I molecules resulted in an unintended consequence in that these mice had rapid antibody clearance. This is because B2M is also associated with neonatal Fc receptor (FcRn) and is important to FcRn-mediated in vivo antibody recycling and retention. Low half-lives of antibodies in B2M null mice render them unsuitable for antibody efficacy assessment. To overcome this undesired pharmacokinetic (PK) limitation of B2M null allele, while retaining its desired effect on eliminating MHC I expression and alleviating GvHD, we engineered a B2M knock-out strain in the background of B-NDG mice (NOD.Cg-Prkdcscid Il2rgtm1Wjl/Bcgen) that was deficient in MHC I expression but not antibody retention. In present study, we describe genetic, phenotypic, pharmacokinetic, and functional characterizations of the resulting mouse strain, which we believe will be a valuable addition to the collection of severely immunodeficient mouse models that permit extended and appropriate interrogation of antibody therapeutics on human immune cells. Citation Format: W. Frank An, Lan Gao, Xiaoen Wang, Shruti Sharma, Kaiqi Li, Xiqiang Gao, Chengzhang Shang, Yuting Hu. Development of a novel engineered B2M mouse strain on B-NDG background that specifically eliminates MHC I expression while retaining normal FcRn-mediated antibody retention [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 432.
Abstract 11423: Leveraging the Electronic Health Records for Population Health: A Case Study of Patients With Severe Hypertension
Authors: Yuan Lu, Chenxi Huang, Shiwani Mahajan, Erica S Spatz, Wade Schulz, Harlan M Krumholz
Journal: Circulation (2019)

Introduction: Despite the importance of achieving an optimal blood pressure, many patients with hypertension do not achieve this goal. Patients with severe hypertension who are at high risk for sho...
Indicators of profound hematologic response in AL amyloidosis: complete response remains the goal of therapy
Authors: Paolo Milani, Marco Basset, Mario Nuvolone, Francesca Benigna, Lara Rodigari, Francesca Lavatelli, Andrea Foli, Giampaolo Merlini, Giovanni Palladini
Journal: Blood Cancer Journal (2020)

Abstract In AL amyloidosis complete response (aCR) is defined as negative serum and urine immunofixation with normalized free light chain ratio (FLCR). However, achievement of low levels of involved FLC (iFLC) or difference between iFLC and uninvolved FLC (dFLC) are also relevant endpoints for treatment. We divided 434 consecutive patients with AL amyloidosis into five groups according to response 6 months after treatment initiation: aCR, iFLC &lt;20 mg/L, normalized-iFLC, dFLC &lt;10 mg/L, and normalized FLC ratio. Overall survival (OS) was similar (median not reached) in patients in aCR and in those who reached iFLC &lt;20 mg/L, while it was inferior in all other groups (medians ranging from 79 to 91 months). Time to next therapy or death (TNTD) was longer in subjects attaining aCR (median 69 months) than in subjects reaching any FLC endpoint (medians ranging from 18 to 39 months). The ability of discriminating patients who survived more than 2 years among all responders was greater for current definition of aCR compared to combination of negative serum and urine immunofixation with any low-FLC endpoint. Complete response predicts best outcomes in AL amyloidosis and should be the goal of therapy if tolerability allows.