tbuckley/cabot-search huggingface dataset:
The predictive role of ultrasound-detected tenosynovitis and joint synovitis for flare in patients with rheumatoid arthritis in stable remission. Results of an Italian multicentre study of the Italian Society for Rheumatology Group for Ultrasound: the STARTER study
Authors: Georgios Filippou, Garifallia Sakellariou, Carlo Alberto Scirè, Greta Carrara, Federica Rumi, Emanuela Bellis, Antonella Adinolfi, Alberto Batticciotto, Alessandra Bortoluzzi, Giovanni Cagnotto, Marta Caprioli, Marco Canzoni, Francesco Paolo Cavatorta, Orazio De Lucia, Valentina Di Sabatino, Antonella Draghessi, Ilaria Farina, Maria Cristina Focherini, Alessandra Gabba, Marwin Gutierrez, Luca Idolazzi, Filippo Luccioli, Pierluigi Macchioni, Marco Sergio Massarotti, Claudio Mastaglio, Luana Menza, Maurizio Muratore, Simone Parisi, Valentina Picerno, Matteo Piga, Roberta Ramonda, Bernd Raffeiner, Daniela Rossi, Silvia Rossi, Paola Rossini, Crescenzio Scioscia, Carlo Venditti, Alessandro Volpe, Annamaria Iagnocco
Journal: Annals of the Rheumatic Diseases (2018)

Objective To define the role of ultrasound (US) for the assessment of patients with rheumatoid arthritis (RA) in clinical remission, including joint and tendon evaluation. Methods A multicentre longitudinal study has been promoted by the US Study Group of the Italian Society for Rheumatology. 25 Italian centres participated, enrolling consecutive patients with RA in clinical remission. All patients underwent complete clinical assessment (demographic data, disease characteristics, laboratory exams, clinical assessment of 28 joints and patient/physician-reported outcomes) and Power Doppler (PD) US evaluation of wrist, metacarpalphalangeal joints, proximal interphalangeal joints and synovial tendons of the hands and wrists at enrolment, 6 and 12 months. The association between clinical and US variables with flare, disability and radiographic progression was evaluated by univariable and adjusted logistic regression models. Results 361 patients were enrolled, the mean age was 56.20 (±13.31) years and 261 were women, with a mean disease duration of 9.75 (±8.07) years. In the 12 months follow-up, 98/326 (30.1%) patients presented a disease flare. The concurrent presence of PD positive tenosynovitis and joint synovitis predicted disease flare, with an OR (95% CI) of 2.75 (1.45 to 5.20) in crude analyses and 2.09 (1.06 to 4.13) in adjusted analyses. US variables did not predict the worsening of function or radiographic progression. US was able to predict flare at 12 months but not at 6 months. Conclusions PD positivity in tendons and joints is an independent risk factor of flare in patients with RA in clinical remission. Musculoskeletal ultrasound evaluation is a valuable tool to monitor and help decision making in patients with RA in clinical remission.
Overcoming imatinib resistance using Src inhibitor CGP76030, Abl inhibitor nilotinib, and Abl/Lyn inhibitor INNO-406 in newly established K562 variants with bcr-abl gene amplification.
Authors: Koji Morinaga, Takahiro Yamauchi, Shinya Kimura, Taira Maekawa, Takanori Ueda
Journal: Cancer Research (2007)

3246   The treatment of chronic myeloid leukemia has recently been revolutionized by the introduction of imatinib mesylate (IM), a selective inhibitor of Bcr-Abl tyrosine kinase. Although IM is effective against chronic-phase chronic myeloid leukemia, only a half of blast-crisis patients respond to IM, and the majority relapses due to acquired drug resistance. Because IM resistance is primarily caused by the re-establishment of Abl kinase activity, new inhibitors need to be developed. Here, we evaluated three new agents, the Src kinase inhibitor CGP76030, the highly specific Abl kinase inhibitor nilotinib, and the dual Abl/Lyn inhibitor INNO-406 (formerly NS-187) against IM resistance. Two new K562 cell lines, IM-R1 and IM-R2 cells, were developed having 7- and 27-fold more resistance towards IM, respectively than the parental K562 cells, determined using the XTT assay. These variants were also refractory to IM-induced apoptosis, which were evaluated using Hoechst 33342 staining of nuclei. Cytogenetic and fluorescence in situ hybridization analyses demonstrated that in both cell lines  bcr-abl  gene was amplified, although to a greater extent in IM-R2 cells than IM-R1 cells. Real-time RT-PCR and Western blot analyses revealed that transcript and protein levels were elevated and Abl kinase were enhanced to a greater extent in IM-R2 cells than MI-R1 cells. Mutation was not found in the kinase domain of both resistant variants. P-glycoprotein was not overexpressed, although the increased efflux of IM by this protein was reported in clinic. The degree of  bcr-abl  gene amplification appeared to be associated with the extent of IM-resistance. IM-resistant variants did not acquire Lyn overexpression, which also was reported to be associated with IM resistance of CML in some patients. Nevertheless, CGP76030 showed positive cooperability with IM in enhancing growth inhibition. Nilotinib inhibited the growth of IM-R2 cells much more potently than IM, but the combination of nilotinib with CGP76030 showed little additivity. The growth-inhibitory effect of INNO-406 was a little more potent than nilotinib against K562 and IM-R1 cells, and as potent as nilotinib against IM-R2 cells. Because Bcr-Abl overexpression is found in blast crisis, the present findings suggest that these new inhibitors might have potential to overcome IM resistance.
A SEER-based multiethnic picture of cholangiocarcinoma in the United States pre and post the advent of gemcitabine/cisplatin.
Authors: Kabir Mody, Samuel O Antwi, David O Hodge, Zahara Meghji, Sikander Ailawadhi, Tanios S. Bekaii-Saab, Lewis R. Roberts
Journal: Journal of Clinical Oncology (2018)

448 Background: Cholangiocarcinoma (CCA) is a rare, lethal cancer with five-year survival of less than 10%. Although incidence rates have been increasing in the United States, ethnic variations in survival have not been investigated. We examined multi-ethnic variation in overall survival (OS) and CCA-specific survival (CSS) using data from the population-based Surveillance Epidemiology and End Results (SEER) program in the four year periods before and after introduction of gemcitabine/cisplatin as treatment for CCA. Methods: The study included data from 9,975 CCA cases reported in SEER between 2006 and 2013. Multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CIs) were calculated to examine overall and cholangiocarcinoma-specific survival by ethnicity, age, gender and in the pre- and post- gemcitabine/cisplatin era (2006-2009 vs. 2010-2013). Results: Compared to non-Hispanic Whites, Hispanics had poorer 3-year OS (HR = 1.18, 95% CI = 1.10-1.26) and 3-year CCA-specific survival (HR = 1.25, 95% CI = 1.16-1.35). Similarly, non-Hispanic Blacks had 3-year OS (HR = 1.22, 95% CI = 1.12-1.30) and 3-year CCA-specific survival (HR = 1.24, 95% CI = 1.13-1.37). Males and older patients also were found to have shorter survival compared to females and younger patients. Also noted was an increase in CCA incidence rate over time (2006-2013) of 5.93%. Among those &lt; 50 versus ≥50 years old, a 23% higher rate of incidence in those &lt; 50 was noted. Overall survival and CSS were both significantly improved for patients post-advent of Gemcitabine/Cisplatin. Statistically significant improvement in CSS pre- and post-advent of Gemcitabine/Cisplatin was noted in non-hispanic whites (p &lt; 0.001) and Hispanics (p = 0.02). Conclusions: Hispanics and non-Hispanic Blacks have worse survival after diagnosis with CCA. Further studies are needed to determine the determinants of poor survival among these groups toward targeted intervention. Significant improvements in OS and CSS have been seen after the advent of Gemcitabine/Cisplatin. The incidence of CCA is rising faster in young persons, under the age of 50, compared with older patients.
Tobacco Product Use Among Youths With and Without Lifetime Asthma — Florida, 2016
Authors: Keshia M. Reid, Jamie R. Forrest, Lauren Porter
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

The increasing availability of diverse tobacco products has led to complex tobacco product use patterns among youths (1). Use by youths of products containing nicotine in any form is unsafe (2); among young persons with asthma, use of combustible tobacco products, particularly cigarettes, is associated with worsening symptoms, poor asthma control, and an increased need for medical management (3,4). Studies suggest that youths with asthma adopt health risk behaviors, including tobacco product use, at rates similar to or higher than those of youths without asthma (3-7); however, these studies are often limited to a partial list of tobacco product types among high school students. To assess current use (≥1 days during the past 30 days) of one or more of five tobacco product types (cigarettes, electronic cigarettes [defined as e-cigarettes, e-cigars, vape pipes, vaping pens, e-hookah, and hookah pens], hookah, smokeless tobacco, or cigars) among Florida middle school (grades 6-8) and high school (grades 9-12) students with or without a previous medical diagnosis of asthma, the Florida Department of Health analyzed data from the 2016 Florida Youth Tobacco Survey (FYTS). In 2016, 11.1% of middle school and 27.9% of high school students with asthma, and 7.9% of middle school and 24.2% of high school students without asthma, reported any current tobacco product use. Current use of each tobacco product type was considerably higher among students with asthma than among those without asthma. E-cigarettes were the most commonly used tobacco product type reported by middle and high school students with asthma (7.9% and 19.6%, respectively) and without asthma (5.8% and 17.2%, respectively). Statewide tobacco prevention strategies could help reduce all forms of tobacco product use among youths, particularly among those with asthma.
Abstract 19664: Pharmacological Induction of Torpor/Hypothermia as a Novel Strategy for Improving Cardiac Arrest Resuscitation Outcomes
Authors: Willard W Sharp, Lin Piao, Yong hu Fang
Journal: Circulation (2016)

Introduction:  Torpor is the process by which some small species of animals induce a state of hypo-metabolism/hypothermia by decreasing their metabolic rate in order to increase their chances of survival during periods of increased environmental stress. Recently it has been demonstrated that a state of torpor can be induced rapidly and reversibly by 5’adenosine monophosphate (5’AMP) injection in mice. We hypothesized that torpor induction by 5’AMP is a promising therapy for reducing ischemic cellular injury and improving survival following sudden cardiac arrest.   Methods and Results:  C57BL/6 wild type mice injected intraperitoneal with 0.5 mg/g or 0.7 mg/g 5’AMP demonstrated a rapid lowering of core body temperature from 37°C to 32°C within 20 minutes and reached a nadir of 28°C by 60 minutes. The duration of this effect was dose dependent lasting 2.5 hours (0.5 mg/g) and 3.5 hours (0.7 mg/g). Mice remained awake but were lethargic during this time, showed no ill effects, and completely recovered following treatment. Next, we tested 5’AMP pre-treatment in a murine model of asystolic cardiac arrest. Anesthetized and ventilated adult female C57BL/6 wild-type mice were injected 30 min prior to cardiac arrest (CA) with 5’AMP or PBS (control). Mice underwent a 16 min KCl-induced CA followed by cardiopulmonary resuscitation. 5’AMP (0.5mg/g) treated mice demonstrated improved myocardial function (%Fractional Shortening (%FS), 45% vs. 28%) and increased survival (100% vs. 30% at 2 hours, n=10, p   Conclusions:  Induction of torpor by 5’AMP is protective against ischemic injury and improves survival following sudden cardiac arrest. Torpor induction is promising as a therapeutic strategy for improving post-cardiac arrest outcomes.
CD4 <sup>+</sup> T cell–mediated HLA class II cross-restriction in HIV controllers
Authors: Moran Galperin, Carine Farenc, Madhura Mukhopadhyay, Dhilshan Jayasinghe, Amandine Decroos, Daniela Benati, Li Lynn Tan, Lisa Ciacchi, Hugh H. Reid, Jamie Rossjohn, Lisa A. Chakrabarti, Stephanie Gras
Journal: Science Immunology (2018)

Rare individuals, termed HIV controllers, spontaneously control HIV infection by mounting efficient T cell responses against the virus. Protective CD4+ T cell responses from HIV controllers involve high-affinity public T cell receptors (TCRs) recognizing an immunodominant capsid epitope (Gag293) presented by a remarkably broad array of human leukocyte antigen (HLA) class II molecules. Here, we determine the structures of a prototypical public TCR bound to HLA-DR1, HLA-DR11, and HLA-DR15 molecules presenting the Gag293 epitope. TCR recognition was driven by contacts with the Gag293 epitope, a feature that underpinned the extensive HLA cross-restriction. These high-affinity TCRs promoted mature immunological synapse formation and cytotoxic capacity in both CD4+ and CD8+ T cells. The public TCRs suppressed HIV replication in multiple genetic backgrounds ex vivo, emphasizing the functional advantage conferred by broad HLA class II cross-restriction.
Association of Daily Intellectual Activities With Lower Risk of Incident Dementia Among Older Chinese Adults
Authors: Allen T. C. Lee, Marcus Richards, Wai C. Chan, Helen F. K. Chiu, Ruby S. Y. Lee, Linda C. W. Lam
Journal: JAMA Psychiatry (2018)

Associations between late-life participation in intellectual activities and decreased odds of developing dementia have been reported. However, reverse causality and confounding effects due to other health behaviors or problems have not been adequately addressed.To examine whether late-life participation in intellectual activities is associated with a lower risk of incident dementia years later, independent of other lifestyle and health-related factors.A longitudinal observational study was conducted at all Elderly Health Centres of the Department of Health of the Government of Hong Kong among 15 582 community-living Chinese individuals age 65 years or older at baseline who were free of dementia, with baseline evaluations performed January 1 to June 30, 2005, and follow-up assessments performed from January 1, 2006, to December 31, 2012. Statistical analysis was performed from January 1, 2015, to December 31, 2016.The main outcome was incident dementia as diagnosed by geriatric psychiatrists in accordance with the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, or a Clinical Dementia Rating of 1 to 3. At baseline and follow-up interviews, self-reported information on participation in intellectual activities within 1 month before assessment was collected. Examples of intellectual activities, which were described by a local validated classification system, were reading books, newspapers, or magazines; playing board games, Mahjong, or card games; and betting on horse racing. Other important variables including demographics (age, sex, and educational level), physical and psychiatric comorbidities (cardiovascular risks, depression, visual and hearing impairments, and poor mobility), and lifestyle factors (physical exercise, adequate fruit and vegetable intake, smoking, and recreational and social activities) were also assessed.Of the 15 582 individuals in the study, 9950 (63.9%) were women, and the median age at baseline was 74 years (interquartile range, 71-77 years). A total of 1349 individuals (8.7%) developed dementia during a median follow-up period of 5.0 years. Multivariable logistic regression analysis showed that the estimated odds ratio for incident dementia was 0.71 (95% CI, 0.60-0.84; P < .001) for those with intellectual activities at baseline, after excluding those who developed dementia within 3 years after baseline and adjusting for health behaviors, physical and psychiatric comorbidities, and sociodemographic factors.Active participation in intellectual activities, even in late life, might help delay or prevent dementia in older adults.
Natural language generation for electronic health records
Authors: Scott H. Lee
Journal: npj Digital Medicine (2018)

A variety of methods existing for generating synthetic electronic health records (EHRs), but they are not capable of generating unstructured text, like emergency department (ED) chief complaints, history of present illness or progress notes. Here, we use the encoder-decoder model, a deep learning algorithm that features in many contemporary machine translation systems, to generate synthetic chief complaints from discrete variables in EHRs, like age group, gender, and discharge diagnosis. After being trained end-to-end on authentic records, the model can generate realistic chief complaint text that preserves much of the epidemiological information in the original data. As a side effect of the model's optimization goal, these synthetic chief complaints are also free of relatively uncommon abbreviation and misspellings, and they include none of the personally-identifiable information (PII) that was in the training data, suggesting it may be used to support the de-identification of text in EHRs. When combined with algorithms like generative adversarial networks (GANs), our model could be used to generate fully-synthetic EHRs, facilitating data sharing between healthcare providers and researchers and improving our ability to develop machine learning methods tailored to the information in healthcare data.
Staging comparison on a series of 1,106 breast cancer patients, according to the 8<sup>TH</sup> VS the 7<sup>TH</sup> AJCC criteria.
Authors: Bruno Alberto Bustos, Sabrina Barchuk, Giselle Pizarro, Federico Leroux, María Florencia Marchetta, Marcela Yoshida, Pablo Rodriguez, Anibal Nuñez de Pierro
Journal: Journal of Clinical Oncology (2018)

e12560 Background: The AJCC TNM staging system describes breast cancer (BC) stages with different prognosis for each stage. Its 8th edition (ED) added to the usual anatomic criteria, tumor biological features such as Tumor Grade (G), Hormone-receptor (HR) status, Her2neu expression and genomic testing results, accounting for the importance of intrinsic tumor biology in disease prognosis. Methods: We performed a descriptive analysis on 1,106 patients with BC. Data collected from clinical records and database from patients treated between 2011 and 2017. We registered tumor size, G, nodal status, HR and Her2neu expression. Patients who received neoadjuvant chemotherapy or were initially Stage IV, or cases that did not fulfill all the data required were excluded. Initial staging was made according to the 7th ED, and these results were compared with the staging obtained using the 8th ED. Results: According to the 7th ED staging, 149 (13%) were stage 0, 434 (39%) stage I; 326 (29%) stage II; and 197 (18%) were stage III. Nineteen patients with Lobular Carcinoma In situ were excluded in the ulterior staging according to the 8th ED changes. Of the 1,087 remaining patients, 130 (12%) were stage 0, 579 (53%) stage I, 170 (15%) stage II, and 208 (19%) stage III. Seventy-seven percent of the patients that were 7thED stage IA remained unchanged, while 91% of patients that were 7thED stage IB were downstaged to IA and 63% of stage IIA patients were down-staged to IB. Conclusions: We observed a higher rate of stage I tumors and lower rate of stage II, with few changes in stages 0 and III. The higher impact of re-staging was observed in stages IB and IIA. The introduction of biologic features would allow a more homogeneous and accurate classification of BC patients.
Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer’s disease
Authors: Srikant Rangaraju, Eric B. Dammer, Syed Ali Raza, Priyadharshini Rathakrishnan, Hailian Xiao, Tianwen Gao, Duc M. Duong, Michael W. Pennington, James J. Lah, Nicholas T. Seyfried, Allan I. Levey
Journal: Molecular Neurodegeneration (2018)

Disease-associated-microglia (DAM) represent transcriptionally-distinct and neurodegeneration-specific microglial profiles with unclear significance in Alzheimer's disease (AD). An understanding of heterogeneity within DAM and their key regulators may guide pre-clinical experimentation and drug discovery.Weighted co-expression network analysis (WGCNA) was applied to existing microglial transcriptomic datasets from neuroinflammatory and neurodegenerative disease mouse models to identify modules of highly co-expressed genes. These modules were contrasted with known signatures of homeostatic microglia and DAM to reveal novel molecular heterogeneity within DAM. Flow cytometric validation studies were performed to confirm existence of distinct DAM sub-populations in AD mouse models predicted by WGCNA. Gene ontology analyses coupled with bioinformatics approaches revealed drug targets and transcriptional regulators of microglial modules predicted to favorably modulate neuroinflammation in AD. These guided in-vivo and in-vitro studies in mouse models of neuroinflammation and neurodegeneration (5xFAD) to determine whether inhibition of pro-inflammatory gene expression and promotion of amyloid clearance was feasible. We determined the human relevance of these findings by integrating our results with AD genome-wide association studies and human AD and non-disease post-mortem brain proteomes.WGCNA applied to microglial gene expression data revealed a transcriptomic framework of microglial activation that predicted distinct pro-inflammatory and anti-inflammatory phenotypes within DAM, which we confirmed in AD and aging models by flow cytometry. Pro-inflammatory DAM emerged earlier in mouse models of AD and were characterized by pro-inflammatory genes (Tlr2, Ptgs2, Il12b, Il1b), surface marker CD44, potassium channel Kv1.3 and regulators (NFkb, Stat1, RelA) while anti-inflammatory DAM expressed phagocytic genes (Igf1, Apoe, Myo1e), surface marker CXCR4 with distinct regulators (LXRα/β, Atf1). As neuro-immunomodulatory strategies, we validated LXRα/β agonism and Kv1.3 blockade by ShK-223 peptide that promoted anti-inflammatory DAM, inhibited pro-inflammatory DAM and augmented Aβ clearance in AD models. Human AD-risk genes were highly represented within homeostatic microglia suggesting causal roles for early microglial dysregulation in AD. Pro-inflammatory DAM proteins were positively associated with neuropathology and preceded cognitive decline confirming the therapeutic relevance of inhibiting pro-inflammatory DAM in AD.We provide a predictive transcriptomic framework of microglial activation in neurodegeneration that can guide pre-clinical studies to characterize and therapeutically modulate neuroinflammation in AD.