tbuckley/cabot-search huggingface dataset:
Role of the interactions between the chemokine CX3CL1/fractalkine and its receptor CX3CR1 in cell-adhesion and extravasation during the early arrival of circulating cancer cells to the skeleton.
Authors: Whitney Jamieson, Michael Russell, Alessandro Fatatis
Journal: Cancer Research (2008)

5328   Advanced prostate cancer shows an overwhelming propensity to metastasize to the skeleton, causing patients to experience extreme pain and eventually leading to death in the vast majority of cases. Unfortunately, only palliative treatments for clinically established skeletal metastases are available. It is therefore essential that the mechanisms involved in the initial colonization of the bone marrow by cancer cells are fully understood in order to develop effective preventive treatments.  We have previously shown that the chemokine fractalkine promotes the adhesion of human prostate cancer (PCa) cells to bone marrow endothelial cells (BMEC) as well as their migration toward human osteoblasts  in vitro . We were therefore the first to hypothesize that fractalkine expressed on the surface of BMEC as well as secreted by the cells of the bone microenvironment recruits the CX 3 CR1 receptor expressed by prostate cancer cells to mediate early metastatic events and contributes to their selective colonization of the skeleton.  To further test this hypothesis, we injected green-fluorescent cancer cells in the left cardiac ventricle of immunocompromised mice that were successively sacrificed between 1 and 72 hours following the injection. A red-fluorescent marker was used to visualize the endothelium in tissue sections of bones that are common sites of secondary tumors in our mouse model of experimental metastases. The correct execution of cell- injection was validated by the inclusion of blue-fluorescent polystyrene beads in the cancer cell suspension. We found that a blocking antibody against CX 3 CR1 significantly reduced the arrival of cells at the bone tissue following their injection in the blood circulation. The blockade of this chemokine receptor was less determinant for counteracting the location of cancer cells to soft tissues. Finally, the role of CX 3 CR1 in skeletal metastasis was confirmed by the alteration of its expression by cancer cells followed by their injection in our animal model.In conclusion, our present data further support the idea that the CX 3 CR1-fractalkine pair is centrally involved in the arrival of prostate cancer cells to the bone and represents an attractive therapeutic target in the prevention of skeletal metastasis from prostate adenocarcinoma.
A Phase 2 Study of the Safety and Efficacy of INCB050465, a Selective PI3Kδ Inhibitor, in Combination with Ruxolitinib in Patients with Myelofibrosis
Authors: Naval G. Daver, Marina Kremyanskaya, Casey O'Connell, Kim-Hien Dao, Stephen T Oh, Aaron T. Gerds, Srdan Verstovsek, Sue Erickson-Viitanen, Feng Zhou, Albert Assad, Abdulraheem Yacoub
Journal: Blood (2018)
Abstract 12471: Optimal Prediction of Atrial Fibrillation Recurrence After Ablation: A Computational Anatomy Study
Authors: Marta Varela, Felipe Bisbal, Ernesto Zacur, Esther Guiu, Antonio Berruezo, Marta Sitges, Susana Prat, Oleg V Aslanidi, Lluis Mont, Pablo Lamata
Journal: Circulation (2015)

Background: Left atrial structural remodelling, assessed by left atrial (LA) sphericity or antero-posterior diameter, has been shown to predict recurrence after atrial fibrillation (AF) ablation. The study aimed to perform a computational shape analysis of the LA to quantitatively characterise the LA shape remodelling process and identify metrics that optimally predict recurrence. Methods: Pre-procedural bright-blood MRIs of the LA of patients undergoing AF ablation were segmented. Patient-specific smooth 3D meshes were fitted to the segmentations. A statistical shape model of the LA was created and the global features underpinning the observed shape variation extracted as principal components (PCs). PCs were optimally combined to create non-empirical atlas-based metrics using linear discriminant analysis. Meshes depicting mean and extreme recurrent and non-recurrent LA shapes were also synthetized. The capability of different metrics to predict recurrence was evaluated using the area under the ROC curve (AUC) of a leave 1 out cross validation test. Results: In total, 111 patients were included. At 12 months follow-up, LA sphericity was the best predictor of recurrence (AUC: 0.66) over novel atlas-based metrics (AUC: 0.65). At 24 months, atlas-based metrics were the best predictors of recurrence (AUC: 0.66), outperforming a combination of sphericity and volume (AUC: 0.64), sphericity alone (AUC: 0.63) and any other traditional metric. Conclusions: Novel atlas-based metrics improve the prediction of recurrence at 2 years post-AF ablation. They allow a more complete characterization of the LA shape remodelling process, for example by allowing the synthesis of recurrent and non-recurrent LA shapes, which may contribute to patient stratification for AF ablation.
Prognostic Value of Thoracic Aorta Calcification Burden in Patients Treated With TAVR
Authors: Tea Gegenava, E. Mara Vollema, Rachid Abou, Laurien Goedemans, Alexander van Rosendael, Frank van der Kley, Arend de Weger, Nina Ajmone Marsan, Jeroen J. Bax, Victoria Delgado
Journal: JACC. Cardiovascular imaging (2018)
Chimeric antigen receptor-modified T cell therapy in chronic lymphocytic leukemia
Authors: Yixin Zou, Wei Xu, Jianyong Li
Journal: Journal of Hematology & Oncology (2018)

Chronic lymphocytic leukemia (CLL), a common type of B cell chronic lymphoproliferative disorder in adults, has witnessed enormous development in its treatment in recent years. New drugs such as ibrutinib, idelalisib, and venetoclax have achieved great success in treating relapsed and refractory (R/R) CLL. In addition, with the development of immunotherapy, chimeric antigen receptor-engineered T cells (CAR-T) therapy, a novel adoptive immune treatment, has also become more and more important in treating R/R CLL. It combines the advantages of T cells and B cells via ex vivo gene transfer technology and is able to bind targets recognized by specific antibodies without antigen presentation, thus breaking the restriction of major histocompatibility complex. So far, there have been lots of studies exploring the application of CAR-T therapy in CLL. In this review, we describe the structure of chimeric antigen receptor, the preclinical, and clinical results of CAR-T therapy against CLL, along with its adverse events and advances in efficacy.
Preclinical antitumor activity of oral silibinin-meglumine in combination with erlotinib or gefitinib in the treatment of erlotinib- and gefitinib-resistant EGFR-mutant NSCLC mouse xenografts.
Authors: Joaquim Bosch-Barrera, Silvia Cufi, Alejandro Vazquez-Martin, Cristina Oliveras-Ferraros, Bruna Corominas-Faja, Rosa Bonavia, Joana Visa, Begoña Martin-Castillo, Enrique Barrajon-Catalan, Enric Carcereny, Vicente Micol, Javier A. Menendez
Journal: Journal of Clinical Oncology (2013)

e19003 Background: Silibinin (SLB), a bioactive flavonolignan isolated from the dried fruits of milk thistle (Silybum marianum), suppresses the resistance to erlotinib (ERL) caused by the EGFR T790M mutation in NSCLC xenograft models. Poor water solubility and low bioavailability might severely limit the efficacy of SLB. The ability of SLB to overcome ERL resistance attributed to mechanisms other than the second-site EGFR mutations remains completely unexplored. Methods: Using PC-9 cells harboring the ERL-sensitizing EGFR exon 19-mutation ΔE746-A750, we developed ERL-refractory derivatives (PC-9 ERL-R) that lacked EGFR T790M mutation. An oral formulation of milk thistle extract enriched (30%) with a water-soluble form of SLB complexed with the excipient amino-sugar meglumine (SLB-m) was explored for its ability to inhibit the growth of PC-9 ERL-R xenografts. Results: In the absence of second-site EGFR mutations or the alternative activation of MET or AXL, acquired cross-resistance to ERL and GEF correlated with enhanced epithelial-to-mesenchymal transition (EMT) features. Single-agent SLB-m significantly decreased the overall tumor volumes of PC-9 ERL-R xenografts, which exhibited enhanced engraftment and faster growth compared with the ERL-/GEF-sensitive PC-9 parental xenografts. Combination treatment with ERL + SLB-m or GEF + SLB-m significantly suppressed tumor growth (&gt; 90%) compared with single-agent treatment. The SLB-m treatment fully inhibited the development of an EMT phenotype in the ERL-/GEF-refractory cells in vitro. Systemic SLB-m treatment significantly affected the expression of EMT-related transcription factors in the ERL-/GEF-refractory xenografts. Conclusions: The oral administration of SLB-m delays tumor progression in ERL-/GEF-refractory EGFR-mutant NSCLC mouse xenografts. Given that the EMT phenomenon is required by a multiplicity of mechanisms of acquired resistance mechanisms to ERL, our data might facilitate the design of clinical trials to test the administration of SLB-m in combination with ERL or GEF in patients with EGFR-mutated tumors that progress to these drugs.
Adult Patients with ALL Treated with CD62L+ T Naïve/Memory-Enriched T Cells Expressing a CD19-CAR Mediate Potent Antitumor Activity with a Low Toxicity Profile
Authors: Samer K. Khaled, Suzette Blanchard, Xiuli Wang, Jamie Wagner, Araceli Naranjo, Jennifer Simpson, Sandra Thomas, Julie Ostberg, Christine Brown, Stephen J Forman
Journal: Blood (2018)
The Physical Activity Guidelines for Americans
Authors: Katrina L. Piercy, Richard P. Troiano, Rachel M. Ballard, Susan A. Carlson, Janet E. Fulton, Deborah A. Galuska, Stephanie M. George, Richard D. Olson
Journal: JAMA (2018)

Approximately 80% of US adults and adolescents are insufficiently active. Physical activity fosters normal growth and development and can make people feel, function, and sleep better and reduce risk of many chronic diseases.
Effect of a Program Combining Transitional Care and Long-term Self-management Support on Outcomes of Hospitalized Patients With Chronic Obstructive Pulmonary Disease
Authors: Hanan Aboumatar, Mohammad Naqibuddin, Suna Chung, Hina Chaudhry, Samuel W. Kim, Jamia Saunders, Lee Bone, Ayse P. Gurses, Amy Knowlton, Peter Pronovost, Nirupama Putcha, Cynthia Rand, Debra Roter, Carol Sylvester, Carol Thompson, Jennifer L. Wolff, Judith Hibbard, Robert A. Wise
Journal: JAMA (2018)

Patients hospitalized for chronic obstructive pulmonary disease (COPD) exacerbations have high rehospitalization rates and reduced quality of life.
MMR deficiency(d) in an unselected cohort of endometrial cancer (EC) patients, the Royal Marsden experience
Authors: C.M.A. Orbegoso Aguilar, K. Vroobel, A. Attygalle, S. Lalondrelle, A. Taylor, M. Nobbenhuis, S. Banerjee, A. George
Journal: Annals of Oncology (2018)
AB1228 Sonoelastography of quadriceps is more accuracy than grip strength to predict low muscle mass
Authors: Y.-C. Chen
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Reduced muscle mass had associated with higher mortality. So it is mandatory for simple techniques to early detection sof arcopenia. However, some patients with low grip strength had normal muscle mass, especially those with rheumatoid arthritis. <h3>Objectives</h3> Our objective was to examine the validity of sonoelastography to predict sarcopenia in osteoporotic patients. <h3>Methods</h3> We conducted an observational study in Kaohsiung Chang Gang Memorial Hospital. Low muscle mass was determined using a dual-energy X-ray absorptiometry. Sonoelastography was performed over mid thigh over quadriceps muscle. We measure grip strength and hardness and elastography ratio of quadriceps over subcutaneous fat tissue. Logistical regression was used to find the factors to predict low muscle mass. While ROC analysis was used to find best cut-off point. <h3>Results</h3> A total 122 (68 low muscle mass, 54 normal muscle mass) patients were enrolled. The mean age was 79.26±6.77 years in low muscle mass group and 74.7±13.49 in normal muscle mass group(p=0.017). Most patients (86.9%) were women. Sonoelastography showed low muscle mass patients had more soft than normal muscle mass patients, furthermore the elastography ratio of quadriceps over subcutaneous tissue was lower than normal muscle mass patients. Using logistical regression, grip strength, sex and age cannot be used to predict low muscle mass, while the hardness and ratio had statistically significant to predict low muscle mass (p=0.001). When the cut points determined by receiver operating characteristic (ROC) curve analysis were applied, The best cut-point of hardness was 64.79%(sensitivity, 0.741; 1-specificity, 0.147), while the best cut-point of quadriceps over subcutaneous tissue was 0.81 (sensitivity, 0.815; 1-specificity, 0.118). <h3>Conclusions</h3> Our findings indicate that sonoelastography is more accurate to predict low muscle mass. The measurement include quadriceps over subcutaneous tissue and hardness of the quadriceps. Although, grip strength is less expensive for evaluation of muscular weakness, from this findings, it is not a reliable method for evaluation of low muscle mass. The possible reason is that sarcopenia initial occur at thigh muscle and then spread up to upper limb. So grip strength is not a accurate method to screen sarcopenia. <h3>Reference</h3> [1] Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, Landi F, Martin FC, Michel JP, Rolland Y, Schneider SM, et al: Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age and ageing2010, 39(4):412–423. <h3>Acknowledgements</h3> This study was supported by Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung grant<b> CMRP</b> <h3>Disclosure of Interest</h3> None declared
Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study
Authors: Peter Ueda, Henrik Svanström, Mads Melbye, Björn Eliasson, Ann-Marie Svensson, Stefan Franzén, Soffia Gudbjörnsdottir, Kristian Hveem, Christian Jonasson, Björn Pasternak
Journal: BMJ (2018)

Abstract Objective To assess the association between the use of sodium glucose cotransporter 2 (SGLT2) inhibitors and seven serious adverse events of current concern. Design Register based cohort study. Setting Sweden and Denmark from July 2013 to December 2016. Participants A propensity score matched cohort of 17 213 new users of SGLT2 inhibitors (dapagliflozin, 61%; empagliflozin, 38%; canagliflozin, 1%) and 17 213 new users of the active comparator, glucagon-like peptide 1 (GLP1) receptor agonists. Main outcome measures The primary outcomes were lower limb amputation, bone fracture, diabetic ketoacidosis, acute kidney injury, serious urinary tract infection, venous thromboembolism, and acute pancreatitis, as identified from hospital records. Hazard ratios and 95% confidence intervals were estimated by using Cox proportional hazards models. Results Use of SGLT2 inhibitors, as compared with GLP1 receptor agonists, was associated with an increased risk of lower limb amputation (incidence rate 2.7 v 1.1 events per 1000 person years, hazard ratio 2.32, 95% confidence interval 1.37 to 3.91) and diabetic ketoacidosis (1.3 v 0.6, 2.14, 1.01 to 4.52) but not with bone fracture (15.4 v 13.9, 1.11, 0.93 to 1.33), acute kidney injury (2.3 v 3.2, 0.69, 0.45 to 1.05), serious urinary tract infection (5.4 v 6.0, 0.89, 0.67 to 1.19), venous thromboembolism (4.2 v 4.1, 0.99, 0.71 to 1.38) or acute pancreatitis (1.3 v 1.2, 1.16, 0.64 to 2.12). Conclusions In this analysis of nationwide registers from two countries, use of SGLT2 inhibitors, as compared with GLP1 receptor agonists, was associated with an increased risk of lower limb amputation and diabetic ketoacidosis, but not with other serious adverse events of current concern.
Mosunetuzumab, a Full-Length Bispecific CD20/CD3 Antibody, Displays Clinical Activity in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma (NHL): Interim Safety and Efficacy Results from a Phase 1 Study
Authors: Lihua E Budde, Laurie H Sehn, Sarit Assouline, Ian W. Flinn, Iris Isufi, Sung-Soo Yoon, Won-Seog Kim, Matthew J Matasar, Loretta J. Nastoupil, Raoul Santiago, Youngil Koh, Genevive Hernandez, Chi-Chung Li, Priya R Kulkarni, Bruce McCall, Scott McClellan, Shen Yin, Vinita Gupta, Yu-Waye Chu, Nancy L. Bartlett
Journal: Blood (2018)
A Young Woman With Chest Pain
Authors: Quentin R. Youmans, Erin D. Unger, Keith H. Benzuly
Journal: JAMA (2018)

A 36-year-old gravida 3, para 3 woman who had elective cesarean delivery 11 days prior presented with 3 days of exertional chest pain, an elevated troponin I level, ST-segment depression on electrocardiography, and coronary artery dissection on angiography. What would you do next?
GIP regulates inflammation and body weight by restraining myeloid-cell-derived S100A8/A9
Authors: Fernanda Dana Mantelmacher, Isabel Zvibel, Keren Cohen, Alona Epshtein, Metsada Pasmanik-Chor, Thomas Vogl, Yael Kuperman, Shai Weiss, Daniel J. Drucker, Chen Varol, Sigal Fishman
Journal: Nature Metabolism (2018)
GPs are being “emotionally blackmailed” to prescribe outside competency, conference hears
Authors: Gareth Iacobucci
Journal: BMJ (2018)

GP are increasingly being put under pressure to prescribe beyond their clinical competency because of a lack of specialist service provision, local medical committees have warned.

The annual conference of England’s LMCs, which represent GPs, heard on 23 November in London that there were particular problems accessing services for gender identity and eating disorders, putting pressure on GPs to prescribe outside their clinical competency. The conference unanimously backed calls for the BMA’s General Practitioners Committee to negotiate for “safe and effective secondary care high risk medical monitoring” for patients with eating disorders to be available everywhere in England.

A separate section of the motion, calling …
Modulation of Host Immunity by Helminths: The Expanding Repertoire of Parasite Effector Molecules
Authors: Rick M. Maizels, Hermelijn H. Smits, Henry J. McSorley
Journal: Immunity (2018)

Helminths are extraordinarily successful parasites due to their ability to modulate the host immune response. They have evolved a spectrum of immunomodulatory molecules that are now beginning to be defined, heralding a molecular revolution in parasite immunology. These discoveries have the potential both to transform our understanding of parasite adaptation to the host and to develop possible therapies for immune-mediated disease. In this review we will summarize the current state of the art in parasite immunomodulation and discuss perspectives on future areas for research and discovery.
Distinct Compartmentalization of the Chemokines CXCL1 and CXCL2 and the Atypical Receptor ACKR1 Determine Discrete Stages of Neutrophil Diapedesis
Authors: Tamara Girbl, Tchern Lenn, Lorena Perez, Loïc Rolas, Anna Barkaway, Aude Thiriot, Carlos del Fresno, Eleanor Lynam, Elin Hub, Marcus Thelen, Gerard Graham, Ronen Alon, David Sancho, Ulrich H. von Andrian, Mathieu-Benoit Voisin, Antal Rot, Sussan Nourshargh
Journal: Immunity (2018)

Neutrophils require directional cues to navigate through the complex structure of venular walls and into inflamed tissues. Here we applied confocal intravital microscopy to analyze neutrophil emigration in cytokine-stimulated mouse cremaster muscles. We identified differential and non-redundant roles for the chemokines CXCL1 and CXCL2, governed by their distinct cellular sources. CXCL1 was produced mainly by TNF-stimulated endothelial cells (ECs) and pericytes and supported luminal and sub-EC neutrophil crawling. Conversely, neutrophils were the main producers of CXCL2, and this chemokine was critical for correct breaching of endothelial junctions. This pro-migratory activity of CXCL2 depended on the atypical chemokine receptor 1 (ACKR1), which is enriched within endothelial junctions. Transmigrating neutrophils promoted a self-guided migration response through EC junctions, creating a junctional chemokine "depot" in the form of ACKR1-presented CXCL2 that enabled efficient unidirectional luminal-to-abluminal migration. Thus, CXCL1 and CXCL2 act in a sequential manner to guide neutrophils through venular walls as governed by their distinct cellular sources.
HCV Broadly Neutralizing Antibodies Use a CDRH3 Disulfide Motif to Recognize an E2 Glycoprotein Site that Can Be Targeted for Vaccine Design
Authors: Andrew I. Flyak, Stormy Ruiz, Michelle D. Colbert, Tiffany Luong, James E. Crowe, Justin R. Bailey, Pamela J. Bjorkman
Journal: Cell Host & Microbe (2018)
Sudden cardiac arrest in sports: a video analysis
Authors: Didrik Magnus Steinskog, Erik Ekker Solberg
Journal: British Journal of Sports Medicine (2018)

Objectives Information about sudden cardiac arrest (SCA) in sports arises from registries, insurance claims and various reports. Analysing video footage of SCA during sports for scientific purposes has scarcely been done. The objective of this study was to examine videotaped SCA in athletes to better understand the mechanisms of SCA. Methods Publicly available online video databases were searched for videos displaying SCA in athletes. Results Thirty-five online videos (26 from professional and 9 from amateur sport; 34 male victims) were obtained. Twenty-one events resulted in survival and 14 in sudden cardiac death. Level of physical activity prior to SCA was assessable in 28 videos; 19 events occurred during low-intensity, 6 during moderate-intensity and 3 during high-intensity activity. SCA predominately occurred during low-intensity compared with both moderate-intensity and high-intensity activities (p&lt;0.01). In 26/35 videos, it was possible to observe if resuscitation was provided. Resuscitation was carried out in 20 cases; cardiopulmonary resuscitation (CPR) alone (8 cases), CPR+defibrillation (10), cardiac thump (1) or shock from an implantable cardioverter defibrillator (1). Thirteen of the 20 cases with resuscitation received an intervention within 1 min after collapse. Survival was high when intervention occurred within 1 min (12/13) compared with those who received delayed (3/5) or no intervention (1/6). Associated signs of SCA such as agonal respirations and seizure-like movements were observed in 66% of the cases. Conclusions SCA during sport most often occurred during low-intensity activity. Prompt intervention within 1 min demonstrated a high survival rate and should be the standard expectation for witnessed SCA in athletes.
Autologous graft versus myeloma: it’s not a myth
Authors: Shuai Dong, Irene M. Ghobrial
Journal: Journal of Clinical Investigation (2018)

Graft-versus-tumor (GVT) effects have been thought to mostly result from allogeneic transplants; however, there is a growing body of research that supports a possible autologous GVT effect. In early clinical studies, a positive correlation between lymphocyte count recovery after autologous transplantation and overall survival has been observed. However, mechanistic studies to identify the mediators of autologous GVT responses have been lacking. In this issue of the JCI, Vuckovic et al. observed a T cell–dependent autologous GVT effect in the Vk*MYC myeloma model. Moreover, the authors showed that CD8+ T cells mediate myeloma control through IFN-γ secretion, which could be further augmented with a CD137 agonist, suggesting a therapeutic approach for enhancing autologous GVT.