tbuckley/cabot-search huggingface dataset:
EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs
Authors: Josef S Smolen, Robert Landewé, Ferdinand C Breedveld, Maxime Dougados, Paul Emery, Cecile Gaujoux-Viala, Simone Gorter, Rachel Knevel, Jackie Nam, Monika Schoels, Daniel Aletaha, Maya Buch, Laure Gossec, Tom Huizinga, Johannes W J W Bijlsma, Gerd Burmester, Bernard Combe, Maurizio Cutolo, Cem Gabay, Juan Gomez-Reino, Marios Kouloumas, Tore K Kvien, Emilio Martin-Mola, Iain McInnes, Karel Pavelka, Piet van Riel, Marieke Scholte, David L Scott, Tuulikki Sokka, Guido Valesini, Ronald van Vollenhoven, Kevin L Winthrop, John Wong, Angela Zink, Désirée van der Heijde
Journal: Annals of the Rheumatic Diseases (2010)

Treatment of rheumatoid arthritis (RA) may differ among rheumatologists and currently, clear and consensual international recommendations on RA treatment are not available. In this paper recommendations for the treatment of RA with synthetic and biological disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) that also account for strategic algorithms and deal with economic aspects, are described. The recommendations are based on evidence from five systematic literature reviews (SLRs) performed for synthetic DMARDs, biological DMARDs, GCs, treatment strategies and economic issues. The SLR-derived evidence was discussed and summarised as an expert opinion in the course of a Delphi-like process. Levels of evidence, strength of recommendations and levels of agreement were derived. Fifteen recommendations were developed covering an area from general aspects such as remission/low disease activity as treatment aim via the preference for methotrexate monotherapy with or without GCs vis-à-vis combination of synthetic DMARDs to the use of biological agents mainly in patients for whom synthetic DMARDs and tumour necrosis factor inhibitors had failed. Cost effectiveness of the treatments was additionally examined. These recommendations are intended to inform rheumatologists, patients and other stakeholders about a European consensus on the management of RA with DMARDs and GCs as well as strategies to reach optimal outcomes of RA, based on evidence and expert opinion.
Functionally distinct subgroups of oligodendrocyte precursor cells integrate neural activity and execute myelin formation
Authors: Roberta Marisca, Tobias Hoche, Eneritz Agirre, Laura Jane Hoodless, Wenke Barkey, Franziska Auer, Gonçalo Castelo-Branco, Tim Czopka
Journal: Nature Neuroscience (2020)
Distinct cardiac energy metabolism and oxidative stress adaptations between obese and non-obese type 2 diabetes mellitus
Authors: Xinghui Li, Yandi Wu, Jingjing Zhao, Haiping Wang, Jing Tan, Ming Yang, Yuanlong Li, Shijie Deng, Saifei Gao, Hui Li, Zhenyu Yang, Fengmin Yang, Jianxing Ma, Jianding Cheng, Weibin Cai
Journal: Theranostics (2020)

Background: Little is known about the pathophysiological diversity of myocardial injury in type 2 diabetes mellitus (T2DM), but analyzing these differences is important for the accurate diagnosis and precise treatment of diabetic cardiomyopathy. This study aimed to elucidate the key cardiac pathophysiological differences in myocardial injury between obese and non-obese T2DM from mice to humans. Methods: Obese and non-obese T2DM mouse models were successfully constructed and observed until systolic dysfunction occurred. Changes in cardiac structure, function, energy metabolism and oxidative stress were assessed by biochemical and pathological tests, echocardiography, free fatty acids (FFAs) uptake fluorescence imaging, transmission electron microscopy, etc. Key molecule changes were screened and verified by RNA sequencing, quantitative real-time polymerase chain reaction and western blotting. Further, 28 human heart samples of healthy population and T2DM patients were collected to observe the cardiac remodeling, energy metabolism and oxidative stress adaptations as measured by pathological and immunohistochemistry tests. Results: Obese T2DM mice exhibited more severe cardiac structure remodeling and earlier systolic dysfunction than non-obese mice. Moreover, obese T2DM mice exhibited severe and persistent myocardial lipotoxicity, mainly manifested by increased FFAs uptake, accumulation of lipid droplets and glycogen, accompanied by continuous activation of the peroxisome proliferator activated receptor alpha (PPARα) pathway and phosphorylated glycogen synthase kinase 3 beta (p-GSK-3β), and sustained inhibition of glucose transport protein 4 (GLUT4) and adipose triglyceride lipase (ATGL), whereas non-obese mice showed no myocardial lipotoxicity characteristics at systolic dysfunction stage, accompanied by the restored PPARα pathway and GLUT4, sustained inhibition of p-GSK-3β and activation of ATGL. Additionally, both obese and non-obese T2DM mice showed significant accumulation of reactive oxygen species (ROS) when systolic dysfunction occurred, but the NF-E2-related factor 2 (Nrf2) pathway was significantly activated in obese mice, while was significantly inhibited in non-obese mice. Furthermore, the key differences found in animals were reliably verified in human samples. Conclusion: Myocardial injury in obese and non-obese T2DM may represent two different types of complications. Obese T2DM individuals, compared to non-obese individuals, are more prone to develop cardiac systolic dysfunction due to severe and persistent myocardial lipotoxicity. Additionally, anti-oxidative dysfunction may be a key factor leading to myocardial injury in non-obese T2DM.
Age‐related prevalence and clinical significance of neutropenia ‐ isolated or combined with other cytopenias: Real world data from 373 820 primary care individuals
Authors: Jan Palmblad, Volkert Siersma, Bent Lind, Ole Weis Bjerrum, Hans Hasselbalch, Christen Lykkegaard Andersen
Journal: American Journal of Hematology (2020)

Neutropenia (NP), that is, an absolute blood neutrophil count (ANC) <1.5 g/L, accompanies various diseases. However, the clinical significance of NP, detected in routine complete blood cell counts (CBC) in primary care, is poorly characterized. Here, from a primary care resource with ANCs from >370 000 individuals, we identified and followed neutropenic subjects for the next 4 years for novel ICD-10 based diagnoses of viral infections and hematological malignancies (ie, previously identified major outcomes in NP individuals) in Danish nationwide health registers. Risk estimates were assessed for children/adolescents (1-18 years) and adults (19-90 years) in relation to NP severity, and for isolated NP, bi- or pancytopenias. We found that NP was observed in 4.9% of children and in 1.9% of adults. The lower the ANC, the likelier was a diagnosis of viral infections or hematological malignancies established during the ensuing 4 years. Among neutropenic children, unspecified viral infections predominated, followed by mononucleosis (with other cytopenias in only 7% and 25% of the cases, respectively). All NP children with acute leukemia presented with bi- or pancytopenia from start of follow-up. In NP adults, hepatitis, followed by HIV, were the most common infections, and acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDSs) the predominating hematological malignancies. Adult NP patients, subsequently diagnosed with hepatitis, HIV or AML, MDS, were bi- or pancytopenic in 42%, 47%, 90% and 91% of cases, respectively. Thus, presence of NP in even one CBC may be the first sign of a latent viral or hematological disorder requiring careful follow-up.
Repression of Wnt signaling inhibits prostate cancer cell proliferation
Authors: Wenyan Lu, Heather Tinsley, Zhican Qu, Gary Piazza, Yonghe Li
Journal: Cancer Research (2008)

2342  Mounting evidence has demonstrated an important role of Wnt/β-catenin signaling in the development and progression of cancer, although the therapeutic potential of small molecules that target this pathway for prostate cancer remains largely unknown. In the present study, we found that the human prostate cancer cell lines PC-3, LNCaP and DU 145 exhibited higher levels of Wnt/β-catenin signaling and were more sensitive to Wnt3a stimulation compared with the non-cancerous prostate cell lines, PZ-HPV-7 and PWR-1E. The androgen-independent PC-3 and DU 145 lines exhibited the highest level of Wnt/β-catenin signaling and displayed the most significant increase of Wnt/β-catenin signaling after Wnt3A stimulation compared with the androgen-dependent LNCaP line. Furthermore, we demonstrated that the non-steroidal anti-inflammatory drug sulindac sulfide, the COX-2 selective inhibitor, celecoxib and the nitric oxide-donating aspirin derivative, NO-ASA reduced the level of cytosolic free β-catenin and blocked the expression of Wnt/β-catenin signaling targets, Axin2 and Cyclin D1, in PC-3 cells. These effects occurred at concentrations comparable to those required to inhibit proliferation, indicating that the inhibitory effect of NO-ASA, celecoxib and sulindac sulfide on PC-3 cell proliferation may involve the suppression of Wnt/β-catenin signaling. Finally, we showed that a small molecule inhibitor of Wnt/β-catenin signaling, PKF118 310 inhibited PC-3 cell proliferation. Together, these results suggest that small molecules that inhibit Wnt/β-catenin signaling have therapeutic potential for the prevention or treatment of prostate cancer.
Major Strides in HER2 Blockade for Metastatic Breast Cancer
Authors: Priyanka Sharma
Journal: New England Journal of Medicine (2020)

Breast cancer that is characterized by amplification or overexpression of human epidermal growth factor receptor 2 (HER2) accounts for 15 to 20% of all forms of the disease. The advent of HER2-targeted drugs, such as trastuzumab, pertuzumab, lapatinib, and the antibody-drug conjugate trastuzumab emtansine, has revolutionized the treatment of both early-stage and metastatic HER2-positive breast cancer.1-4 The increasing availability of HER2-targeted agents has led to improved outcomes for patients with HER2-positive metastatic breast cancer, as reported in a study in which overall survival rose from a median of 38.7 months to 51.1 months from 2008 through 2012.5 The standard first-line . . .
Author Correction: On-chip recapitulation of clinical bone marrow toxicities and patient-specific pathophysiology
Authors: David B. Chou, Viktoras Frismantas, Yuka Milton, Rhiannon David, Petar Pop-Damkov, Douglas Ferguson, Alexander MacDonald, Özge Vargel Bölükbaşı, Cailin E. Joyce, Liliana S. Moreira Teixeira, Arianna Rech, Amanda Jiang, Elizabeth Calamari, Sasan Jalili-Firoozinezhad, Brooke A. Furlong, Lucy R. O’Sullivan, Carlos F. Ng, Youngjae Choe, Susan Marquez, Kasiani C. Myers, Olga K. Weinberg, Robert P. Hasserjian, Richard Novak, Oren Levy, Rachelle Prantil-Baun, Carl D. Novina, Akiko Shimamura, Lorna Ewart, Donald E. Ingber
Journal: Nature Biomedical Engineering (2020)
Lead-Time Bias Confounds Association Between Duration of Untreated Psychosis and Illness Course in Schizophrenia
Authors: Katherine G. Jonas, Laura J. Fochtmann, Greg Perlman, Yuan Tian, John M. Kane, Evelyn J. Bromet, Roman Kotov
Journal: American Journal of Psychiatry (2020)

Objective: At first hospitalization, a long duration of untreated psychosis (DUP) predicts illness severity and worse treatment outcomes. The mechanism of this association, however, remains unclear. It has been hypothesized that lengthy untreated psychosis is toxic or that it reflects a more severe form of schizophrenia. Alternatively, the association may be an artifact of lead-time bias. These hypotheses are tested in a longitudinal study of schizophrenia with 2,137 observations spanning from childhood to 20 years after first admission. Methods: Data were from the Suffolk County Mental Health Project. The cohort included 287 individuals with schizophrenia or schizoaffective disorder. DUP was defined as days from first psychotic symptom to first psychiatric hospitalization. Psychosocial function was assessed using the Premorbid Adjustment Scale and the Global Assessment of Functioning Scale. Psychosocial function trajectories were estimated using multilevel spline regression models adjusted for gender, occupational status, race, and antipsychotic medication. Results: Both long- and short-DUP patients experienced similar declines in psychosocial function, but declines occurred at different times relative to first admission. Long-DUP patients experienced most of these declines prior to first admission, while short-DUP patients experienced declines after first admission. When psychosocial function was analyzed relative to psychosis onset, DUP did not predict illness course. Conclusions: The association between DUP and psychosocial function may be an artifact of early detection, creating the illusion that early intervention is associated with improved outcomes. In other words, DUP may be better understood as an indicator of illness stage than a predictor of course.
HDL-related biomarkers are robust predictors of survival in patients with chronic liver failure
Authors: Markus Trieb, Florian Rainer, Vanessa Stadlbauer, Philipp Douschan, Angela Horvath, Lukas Binder, Athina Trakaki, Eva Knuplez, Hubert Scharnagl, Tatjana Stojakovic, Ákos Heinemann, Mattias Mandorfer, Rafael Paternostro, Thomas Reiberger, Carla Pitarch, Alex Amorós, Alexander Gerbes, Paolo Caraceni, Carlo Alessandria, Richard Moreau, Joan Clària, Gunther Marsche, Rudolf E. Stauber
Journal: Journal of Hepatology (2020)

High-density lipoprotein cholesterol (HDL-C) levels are reduced in patients with chronic liver disease and inversely correlate with disease severity. During acute conditions such as sepsis, HDL-C levels decrease rapidly and HDL particles undergo profound changes in their composition and function. We aimed to determine whether indices of HDL quantity and quality associate with progression and survival in patients with advanced liver disease.
Allele-specific expression changes dynamically during T cell activation in HLA and other autoimmune loci
Authors: Maria Gutierrez-Arcelus, Yuriy Baglaenko, Jatin Arora, Susan Hannes, Yang Luo, Tiffany Amariuta, Nikola Teslovich, Deepak A. Rao, Joerg Ermann, A. Helena Jonsson, Cristina Navarrete, Stephen S. Rich, Kent D. Taylor, Jerome I. Rotter, Peter K. Gregersen, Tonu Esko, Michael B. Brenner, Soumya Raychaudhuri
Journal: Nature Genetics (2020)
Abstract 15637: Exposure to Traffic-Generated Air Pollutants Results in Disruption of the Blood Brain Barrier through Altered Expression of Tight Junction Proteins
Authors: Amie K Lund, Hannah Oppenheim, JoAnn Lucero, Lindsay Herbert, Jacob McDondald
Journal: Circulation (2012)

In addition to its harmful effects in the pulmonary and cardiovascular systems, several recent studies have implicated environmental air pollution exposure in deleterious effects on the central ner...
Abstract P4-03-04: Stereotactic vaccum-assisted breast biopsy: A cost effective diagnostic method for suspicious calcifications investigation in Brazil
Authors: Andressa Amorim, Marcellus N. M. Ramos, Maria Isabela B. A. C. Sawada, André Mattar, Jorge Y. Shida, Luiz H. Gebrim
Journal: Cancer Research (2020)

Abstract Background: Mammographic screening carried out in Brazil's Public Health System (SUS) is opportunistic and restricted to large cities mainly in the South and Southeast regions. However, only 30% of the suspicious calcifications are confirmed to be malignancy after the biopsy. The surgical procedure to investigate is still the routine in most centers in Brazil. A vacuum assisted stereotactic biopsy (VASB) is expensive and it is not available in most centers in the developing countries. Objective: To estimate saved values in SUS by performing VASB instead of performing classic surgical procedure in the investigation of suspicious calcifications. Methods: We’ve performed a retrospective and descriptive study from July, 2012 to June, 2019, in which 1,809 patients diagnosed with suspicious calcifications on mammography (BIRADS 4 and 5) had VASB performed at Hospital Estadual Pérola Byington. The device used was Surus Pearl (Hologic, Malbolrough, Massachusetts, USA) with probe gauge 9. The biopsy`s costs were calculated and estimated in terms of American Dollars (US$) in 2019. No direct medical and nonmedical or indirect costs have been evaluated. Results: the histopathological study of the lesions revealed benign alterations in 1,179 (65.1%) The findings were positive for malignancy in 533 (29.5%) and the precursor lesions were diagnosed in 97 (5.4%) VASB is an outpatient procedure; a single biopsy has an average cost of US$ 36. Instead, the classic surgical procedure is a procedure that requires hospitalization and general anesthesia with estimated cost of US$ 97 for every single procedure. The saved values in that time by SUS were US$ 29,077. Conclusion: we found a high economic impact of VASB in the SUS scenario. Lower costs than surgical procedures and being an outpatient procedure may indirectly increase hospital beds` supply for cancer treatment. Studies focusing on other direct and indirect costs are desirable, especially in developing countries. Keywords: calcifications; vacuum-assisted stereotactic biopsy; breast cancer. Citation Format: Andressa Amorim, Marcellus N. M. Ramos, Maria Isabela B. A. C. Sawada, André Mattar, Jorge Y. Shida, Luiz H. Gebrim. Stereotactic vaccum-assisted breast biopsy: A cost effective diagnostic method for suspicious calcifications investigation in Brazil [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-03-04.
Modulation of tumor microenvironment for immunotherapy: focus on nanomaterial-based strategies
Authors: Yun Liu, Jianfeng Guo, Leaf Huang
Journal: Theranostics (2020)

Recent advances in the field of immunotherapy have profoundly opened up the potential for improved cancer therapy and reduced side effects.However, the tumor microenvironment (TME) is highly immunosuppressive, therefore, clinical outcomes of currently available cancer immunotherapy are still poor.Recently, nanomaterial-based strategies have been developed to modulate the TME for robust immunotherapeutic responses.In this review, the immunoregulatory cell types (cells relating to the regulation of immune responses) inside the TME in terms of stimulatory and suppressive roles are described, and the technologies used to identify and quantify these cells are provided.In addition, recent examples of nanomaterial-based cancer immunotherapy are discussed, with particular emphasis on those designed to overcome barriers caused by the complexity and diversity of TME.
Abstract 11289: Outcomes of Transcatheter Aortic Valve Replacement vs. Surgical Aortic Valve Replacement in Patients With Cancer History and Chest Radiation Therapy
Authors: Dongfeng Zhang, Wei Guo, Abdallah El Sabbagh, Mohammed Al-Hijji, Herrmann Joerg
Journal: Circulation (2018)

Background: Transcatheter aortic valve replacement (TAVR) is considered an alternative to surgical aortic valve replacement (SAVR) in high and intermediate surgical risk patients with severe aortic...
Assessment of Treatment Effect With Multiple Outcomes in 2 Clinical Trials of Patients With Duchenne Muscular Dystrophy
Authors: Daniel Li, Craig M. McDonald, Gary L. Elfring, Marcio Souza, Joseph McIntosh, Dae Hyun Kim, Lee-Jen Wei
Journal: JAMA Network Open (2020)

This cohort study applies a heuristic, analytical procedure using z scores to data from 2 independent trials with multiple end points that examined whether ataluren is beneficial vs placebo for treating patients with Duchenne muscular dystrophy.
Selective inhibition of Ph-positive ALL cell growth through kinase-dependent and -independent effects by CDK6-specific PROTACs
Authors: Marco De Dominici, Patrizia Porazzi, Youcai Xiao, Allen Chao, Hsin-Yao Tang, Gaurav Kumar, Paolo Fortina, Orietta Spinelli, Alessandro Rambaldi, Luke F. Peterson, Svetlana Petruk, Camilla Barletta, Alexander Mazo, Gino Cingolani, Joseph M. Salvino, Bruno Calabretta
Journal: Blood (2020)
Integrin αvβ6-specific therapy for pancreatic cancer developed from foot-and-mouth-disease virus
Authors: Kate M. Moore, Ami Desai, Bea de Luxán Delgado, Sara Maria David Trabulo, Claire Reader, Nicholas F. Brown, Elizabeth R. Murray, Adam Brentnall, Philip Howard, Luke Masterson, Francesca Zammarchi, John A. Hartley, Patrick H. van Berkel, John F. Marshall
Journal: Theranostics (2020)

Goals of investigation:The 5-year survival rate for pancreatic ductal adenocarcinoma (PDAC) has remained at <5% for decades because no effective therapies have been identified.Integrin αvβ6 is overexpressed in most PDAC and represents a promising therapeutic target.Thus, we attempted to develop an αvβ6-specific peptide-drug conjugate (PDC) for therapy of PDAC.Methodology: We conjugated the DNA-binding pyrrolobenzodiazepine (PBD)-based payload SG3249 (tesirine) to an αvβ6-specific 20mer peptide from the VP1 coat protein of foot-and-mouth-disease virus (FMDV) (forming conjugate SG3299) or to a non-targeting peptide (forming conjugate SG3511).PDCs were tested for specificity and toxicity on αvβ6-negative versus-positive PDAC cells, patient-derived cell lines from tumor xenografts, and on two different in vivo models of PDAC.Immunohistochemical analyses were performed to establish therapeutic mechanism.Results: The αvβ6-targeted PDC SG3299 was significantly more toxic (up to 78-fold) for αvβ6-expressing versus αvβ6-negative PDAC cell lines in vitro, and achieved significantly higher toxicity at equal dose than the non-targeted PDC SG3511 (up to 15-fold better).Moreover, SG3299 eliminated established (100mm 3 ) Capan-1 PDAC human xenografts, extending the lifespan of mice significantly (P=0.005).Immunohistochemistry revealed SG3299 induced DNA damage and apoptosis (increased γH2AX and cleaved caspase 3, respectively) associated with significant reductions in proliferation (Ki67), β6 expression and PDAC tumour growth. Conclusions:The FMDV-peptide drug conjugate SG3299 showed αvβ6-selectivity in vitro and in vivo and can specifically eliminate αvβ6-positive cancers, providing a promising new molecularspecific therapy for pancreatic cancer.
Distinct immune characteristics distinguish hereditary and idiopathic chronic pancreatitis
Authors: Bomi Lee, Julia Z. Adamska, Hong Namkoong, Melena D. Bellin, Josh Wilhelm, Gregory L. Szot, David M. Louis, Mark M. Davis, Stephen J. Pandol, Aida Habtezion
Journal: Journal of Clinical Investigation (2020)

Chronic pancreatitis (CP) is considered an irreversible fibroinflammatory pancreatic disease. Despite numerous animal model studies, questions remain about local immune characteristics in human CP. We profiled pancreatic immune cell characteristics in control organ donors and CP patients including those with hereditary and idiopathic CP undergoing total pancreatectomy with islet autotransplantation. Flow cytometric analysis revealed a significant increase in the frequency of CD68+ macrophages in idiopathic CP. In contrast, hereditary CP samples showed a significant increase in CD3+ T cell frequency, which prompted us to investigate the T cell receptor β (TCRβ) repertoire in the CP and control groups. TCRβ sequencing revealed a significant increase in TCRβ repertoire diversity and reduced clonality in both CP groups versus controls. Interestingly, we observed differences in Vβ-Jβ gene family usage between hereditary and idiopathic CP and a positive correlation of TCRβ rearrangements with disease severity scores. Immunophenotyping analyses in hereditary and idiopathic CP pancreases indicate differences in innate and adaptive immune responses, which highlights differences in immunopathogenic mechanisms of disease among subtypes of CP. TCR repertoire analysis further suggests a role for specific T cell responses in hereditary versus idiopathic CP pathogenesis, providing insights into immune responses associated with human CP.