tbuckley/cabot-search huggingface dataset:
Molecular landscape and prognostic impact of FLT3-ITD insertion site in acute myeloid leukemia: RATIFY study results
Authors: Frank G. Rücker, Ling Du, Tamara J. Luck, Axel Benner, Julia Krzykalla, Insa Gathmann, Maria Teresa Voso, Sergio Amadori, Thomas W. Prior, Joseph M. Brandwein, Frederick R. Appelbaum, Bruno C. Medeiros, Martin S. Tallman, Lynn Savoie, Jorge Sierra, Celine Pallaud, Miguel A. Sanz, Joop H. Jansen, Dietger Niederwieser, Thomas Fischer, Gerhard Ehninger, Michael Heuser, Arnold Ganser, Lars Bullinger, Richard A. Larson, Clara D. Bloomfield, Richard M. Stone, Hartmut Döhner, Christian Thiede, Konstanze Döhner
Journal: Leukemia (2021)

Abstract In acute myeloid leukemia (AML) internal tandem duplications of the FLT3 gene ( FLT3- ITD) are associated with poor prognosis. Retrospectively, we investigated the prognostic and predictive impact of FLT3 -ITD insertion site (IS) in 452 patients randomized within the RATIFY trial, which evaluated midostaurin additionally to intensive chemotherapy. Next-generation sequencing identified 908 ITDs, with 643 IS in the juxtamembrane domain (JMD) and 265 IS in the tyrosine kinase domain-1 (TKD1). According to IS, patients were categorized as JMDsole ( n = 251, 55%), JMD and TKD1 (JMD/TKD1; n = 117, 26%), and TKD1sole ( n = 84, 19%). While clinical variables did not differ among the 3 groups, NPM1 mutation was correlated with JMDsole ( P = 0.028). Overall survival (OS) differed significantly, with estimated 4-year OS probabilities of 0.44, 0.50, and 0.30 for JMDsole, JMD/TKD1, and TKD1sole, respectively ( P = 0.032). Multivariate (cause-specific) Cox models for OS and cumulative incidence of relapse using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable identified TKD1sole as unfavorable and HCT as favorable factors. In addition, Midostaurin exerted a significant benefit only for JMDsole. Our results confirm the distinct molecular heterogeneity of FLT3 -ITD and the negative prognostic impact of TKD1 IS in AML that was not overcome by midostaurin.
Abstract 17213: Role of Protein Aggregation in Ischemic Cardiomyopathy
Authors: Moydul Islam, Xiucui Ma, Layla Foroughi, Babak Razani, Abhinav Diwan, Kartik Mani
Journal: Circulation (2019)

Background: Unlike the protective role of protein aggregates in lower species, their appearance in mammalian hearts, associated with rare proteotoxic mutations, result in fatal cardiomyopathy. Impr...
P15-10 Relationship between Tumor Infiltrating Lymphocytes and clinicopathological factors in luminal type breast cancer
Authors: I Gusti Ayu Stiti Sadvika, I Gede Wikania Wira Wiguna, Ni Putu Sri Indrani Remitha, Putu Anda Tusta Adiputra, Desak Wihandani, I Gede Supadmanaba
Journal: Annals of Oncology (2021)
Abstract 18088: The Geriatric Assessment Score is a Proper Clinical Tool to Stratify Older Old Patients Admitted with Heart Failure for In-Hospital and Two-Year Survival
Authors: Carlos Rodriguez-Pascual, Emilio Paredes-Galan, Daniel Perez-Soto, Arturo Vilches-Moraga, Ana I Ferrero-Martinez, Marta Torrente-Carballido, Jose Antonio Lazarini, Fernando Rodriguez-Artalejo
Journal: Circulation (2011)

OBJECTIVES. - To determine the influence of physical, cognitive function and other comprehensive geriatric assessment (CGA) components on in-hospital and two-year mortality of older adults admitted with acute heart failure (HF). METHODS - Prospective study of 581 individuals aged &gt;75 years admitted due to HF. Demographic, clinical, echocardiographic and analytical data were recorded. CGA included dependence in activities of daily living (ADL), mobility, cognitive status, screening for depression, comorbidity and pharmachological prescriptions. A Geriatric Assessment Score (range 0-10 p) was constructed. Mean follow-up of 533 hospitalization survivors was 77+52 weeks. A logistic regression model to determine factors independently related with in-hospital mortality and a Cox regression model to identify those related with two years mortality were constructed. RESULTS - Mean age 85.8±5.8 y., 67% women, 75% preserved ejection fraction, mean comorbidity index 3.97±3.01. Cognitive impairment was present in 45%, depression in 49%, 66% had mobility problems and 50% dependence in &gt;1 ADL. In-hospital fatality was 8.2%. Variables associated with in-hospital mortality included NYHA class III (OR 4.1, 95% CI 1.5-10.8) or IV (OR 19.6, 95% CI 6.3-60.9), pulmonary oedema (OR 3, 95% CI 1.3-6.6), renal failure (OR 2.8, 95% CI 1.2-6.2) and the Geriatric Assessment Score (OR per point of increment 1.2, 95% CI 1-1.4). Two-year mortality related factors included age (OR 1.06, 95% CI 1.03-1.09), Geriatric Assessment Score (OR 1.17, 95% CI 1.09-1.27), NYHA functional class III (OR 1.62, 95% CI 1.18-2.23) or IV (OR 3.02, 95% CI 1.49-6.10), left ventricle systolic dysfunction (OR 1.67, 95% CI 1.20-2.31), comnorbidity index (OR 1.07, 95% CI 1.02-1.12), AF (OR 1.57, 95% CI 1.15-2.15), ACEI or ARB treatment (OR 0.66, 95% CI 0.49-0.90) and renal failure (OR 1.01, 95% CI 1.00-1.01). COCNLUSIONS - In very elderly heart failure patients, an index incorporating comorbidities, total number of prescription drugs, cognitive, functional and mobility status predicts in-hospital and two-year survival. In addition to other variables previously known, these should be considered for a better stratification of elderly patients admitted with HF.
Racial, Rural, and Regional Disparities in Diabetes-Related Lower-Extremity Amputation Rates, 2009–2017
Authors: Marvellous A. Akinlotan, Kristin Primm, Jane N. Bolin, Abdelle L. Ferdinand Cheres, JuSung Lee, Timothy Callaghan, Alva O. Ferdinand
Journal: Diabetes Care (2021)

OBJECTIVE To examine the racial/ethnic, rural-urban, and regional variations in the trends of diabetes-related lower-extremity amputations (LEAs) among hospitalized U.S. adults from 2009 to 2017. RESEARCH DESIGN AND METHODS We used the National Inpatient Sample (NIS) (2009–2017) to identify trends in LEA rates among those primarily hospitalized for diabetes in the U.S. We conducted multivariable logistic regressions to identify individuals at risk for LEA based on race/ethnicity, census region location (North, Midwest, South, and West), and rurality of residence. RESULTS From 2009 to 2017, the rates of minor LEAs increased across all racial/ethnic, rural/urban, and census region categories. The increase in minor LEAs was driven by Native Americans (annual percent change [APC] 7.1%, P &amp;lt; 0.001) and Asians/Pacific Islanders (APC 7.8%, P &amp;lt; 0.001). Residents of non-core (APC 5.4%, P &amp;lt; 0.001) and large central metropolitan areas (APC 5.5%, P &amp;lt; 0.001) experienced the highest increases over time in minor LEA rates. Among Whites and residents of the Midwest and non-core and small metropolitan areas there was a significant increase in major LEAs. Regression findings showed that Native Americans and Hispanics were more likely to have a minor or major LEA compared with Whites. The odds of a major LEA increased with rurality and was also higher among residents of the South than among those of the Northeast. A steep decline in major–to–minor amputation ratios was observed, especially among Native Americans. CONCLUSIONS Despite increased risk of diabetes-related lower-limb amputations in underserved groups, our findings are promising when the major–to–minor amputation ratio is considered.
Acquired <i>RAD51C</i> Promoter Methylation Loss Causes PARP Inhibitor Resistance in High-Grade Serous Ovarian Carcinoma
Authors: Ksenija Nesic, Olga Kondrashova, Rachel M. Hurley, Cordelia D. McGehee, Cassandra J. Vandenberg, Gwo-Yaw Ho, Elizabeth Lieschke, Genevieve Dall, Nirashaa Bound, Kristy Shield-Artin, Marc Radke, Ashan Musafer, Zi Qing Chai, Mohammad Reza Eftekhariyan Ghamsari, Maria I. Harrell, Damien Kee, Inger Olesen, Orla McNally, Nadia Traficante, Australian Ovarian Cancer Study, Anna DeFazio, David D.L. Bowtell, Elizabeth M. Swisher, S. John Weroha, Katia Nones, Nicola Waddell, Scott H. Kaufmann, Alexander Dobrovic, Matthew J. Wakefield, Clare L. Scott
Journal: Cancer Research (2021)

In high-grade serous ovarian carcinoma (HGSC), deleterious mutations in DNA repair gene RAD51C are established drivers of defective homologous recombination and are emerging biomarkers of PARP inhibitor (PARPi) sensitivity. RAD51C promoter methylation (meRAD51C) is detected at similar frequencies to mutations, yet its effects on PARPi responses remain unresolved.In this study, three HGSC patient-derived xenograft (PDX) models with methylation at most or all examined CpG sites in the RAD51C promoter show responses to PARPi. Both complete and heterogeneous methylation patterns were associated with RAD51C gene silencing and homologous recombination deficiency (HRD). PDX models lost meRAD51C following treatment with PARPi rucaparib or niraparib, where a single unmethylated copy of RAD51C was sufficient to drive PARPi resistance. Genomic copy number profiling of one of the PDX models using SNP arrays revealed that this resistance was acquired independently in two genetically distinct lineages.In a cohort of 12 patients with RAD51C-methylated HGSC, various patterns of meRAD51C were associated with genomic "scarring," indicative of HRD history, but exhibited no clear correlations with clinical outcome. Differences in methylation stability under treatment pressure were also observed between patients, where one HGSC was found to maintain meRAD51C after six lines of therapy (four platinum-based), whereas another HGSC sample was found to have heterozygous meRAD51C and elevated RAD51C gene expression (relative to homozygous meRAD51C controls) after only neoadjuvant chemotherapy.As meRAD51C loss in a single gene copy was sufficient to cause PARPi resistance in PDX, methylation zygosity should be carefully assessed in previously treated patients when considering PARPi therapy. SIGNIFICANCE: Homozygous RAD51C methylation is a positive predictive biomarker for sensitivity to PARP inhibitors, whereas a single unmethylated gene copy is sufficient to confer resistance.
MO5-2 Retrospective study of nivolumab monotherapy for advanced esophageal squamous cell carcinoma
Authors: Hayato Mikuni, Shun Yamamoto, Kotoe Oshima, Hidekazu Hirano, Natsuko Okita, Hirokazu Shoji, Yoshitaka Honma, Satoru Iwasa, Atsuo Takashima, Narikazu Boku, Ken Kato
Journal: Annals of Oncology (2021)
Targeting central nervous system extracellular vesicles enhanced triiodothyronine remyelination effect on experimental autoimmune encephalomyelitis
Authors: Yun Xiao, Jing Tian, Wen-Cheng Wu, Yu-Han Gao, Yu-Xin Guo, Sheng-Jiao Song, Rui Gao, Li-Bin Wang, Xiao-Yu Wu, Yuan Zhang, Xing Li
Journal: Bioactive Materials (2021)

The lack of targeted and high-efficiency drug delivery to the central nervous system (CNS) nidus is the main problem in the treatment of demyelinating disease. Extracellular vesicles (EVs) possess great promise as a drug delivery vector given their advanced features. However, clinical applications are limited because of their inadequate targeting ability and the "dilution effects" after systemic administration. Neural stem cells (NSCs) supply a plentiful source of EVs on account of their extraordinary capacity for self-renewal. Here, we have developed a novel therapeutic system using EVs from modified NSCs with high expressed ligand PDGF-A (EVPs) and achieve local delivery. It has been demonstrated that EVPs greatly enhance the target capability on oligodendrocyte lineage. Moreover, EVPs are used for embedding triiodothyronine (T3), a thyroid hormone that is critical for oligodendrocyte development but has serious side effects when systemically administered. Our results demonstrated that systemic injection of EVPs + T3, versus EVPs or T3 administration individually, markedly alleviated disease development, enhanced oligodendrocyte survival, inhibited myelin damage, and promoted myelin regeneration in the lesions of experimental autoimmune encephalomyelitis mice. Taken together, our findings showed that engineered EVPs possess a remarkable CNS lesion targeting potential that offers a potent therapeutic strategy for CNS demyelinating diseases as well as neuroinflammation.
日本における医薬およびPCIによる以前の治療を受けた安定な低危険度の冠状動脈疾患患者の結果 J-SAP研究1-1
Authors: Tanihata Shintaro, Nishigaki Kazuhiko, Kawasaki Masanori, Takemura Genzou, Minatoguchi Shinya, Fujiwara Hisayoshi
Journal: Circulation (2006)
P26-6 Pharmacokinetic advantage of HIPEC with cisplatin over systemic administration of cisplatin
Authors: Galina S. Kireeva, Mikhail A. Maydin, Stepan A. Kruglov, Ekaterina A. Gubareva, Ekaterina A. Zubakina, Marina M. Bezruchko, Natalia B. Ivanenko, Vladislav K. Osetnik, Elena I. Fedoros
Journal: Annals of Oncology (2021)
Uncertainty in Medicine
Authors: Jayshil J. Patel, Rachel Goodman
Journal: JAMA Internal Medicine (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Management of the Axilla in Early-Stage Breast Cancer: Ontario Health (Cancer Care Ontario) and ASCO Guideline
Authors: Muriel Brackstone, Fulvia G. Baldassarre, Francisco E. Perera, Tulin Cil, Mariana Chavez Mac Gregor, Ian S. Dayes, Jay Engel, Janet K. Horton, Tari A. King, Anat Kornecki, Ralph George, Sandip K. SenGupta, Patricia A. Spears, Andrea F. Eisen
Journal: Journal of Clinical Oncology (2021)

To provide recommendations on the best strategies for the management and on the best timing and treatment (surgical and radiotherapeutic) of the axilla for patients with early-stage breast cancer.Ontario Health (Cancer Care Ontario) and ASCO convened a Working Group and Expert Panel to develop evidence-based recommendations informed by a systematic review of the literature.This guideline endorsed two recommendations of the ASCO 2017 guideline for the use of sentinel lymph node biopsy in patients with early-stage breast cancer and expanded on that guideline with recommendations for radiotherapy interventions, timing of staging after neoadjuvant chemotherapy (NAC), and mapping modalities. Overall, the ASCO 2017 guideline, seven high-quality systematic reviews, 54 unique studies, and 65 corollary trials formed the evidentiary basis of this guideline.Recommendations are issued for each of the objectives of this guideline: (1) To determine which patients with early-stage breast cancer require axillary staging, (2) to determine whether any further axillary treatment is indicated for women with early-stage breast cancer who did not receive NAC and are sentinel lymph node-negative at diagnosis, (3) to determine which axillary strategy is indicated for women with early-stage breast cancer who did not receive NAC and are pathologically sentinel lymph node-positive at diagnosis (after a clinically node-negative presentation), (4) to determine what axillary treatment is indicated and what the best timing of axillary treatment for women with early-stage breast cancer is when NAC is used, and (5) to determine which are the best methods for identifying sentinel nodes.Additional information is available at www.asco.org/breast-cancer-guidelines.
Multivariable clinical-genetic model for predicting dyskinesia in early-onset Parkinson’s disease
Authors: Yong-Ping Chen, Ru-Wei Ou, Xiao-Jing Gu, Ling-Yu Zhang, Bei Cao, Yan-Bing Hou, Kun-Cheng Liu, Jun-Yu Lin, Qian-Qian Wei, Bi Zhao, Ying Wu, Hui-Fang Shang
Journal: Translational Neurodegeneration (2021)

Background: Levodopa-induced dyskinesias (LIDs) is one of important motor complications, which negatively affect the quality of life of patients with Parkinson disease (PD).Objects: This study aims to establish clinical-genetic models of LIDs prediction and explore clinical and genetic predictors of LIDs in early-onset PD (EOPD).

Methods: A prospective cohort design including 279 EOPD patients were followed-up about 9.2 years. Clinical and genetic data were investigated. LIDs prediction was evaluated by the area under the curve (AUC) of receiver operating characteristic (ROC) curve. A multivariable logistic regression model was conducted to discriminate the independent predictive factors of LIDs incident. An independent cohort including 144 EOPD was used as the validation group to confirm the developed prediction models.

Results: The incidence of LIDs in EOPD at the first 5 years of duration and at the first 5 years after receiving dopamine replacement therapy (DRT) were 15.4% and 29.7%, respectively. In two clinical-genetic models, adding genotypes from 11 candidate variants significantly increased LIDs predictability compared to prediction based on clinical variables only (p<0.005), which were confirmed in the validation group. Importantly, the AUCs of clinical or clinical-genetic model for predicting LIDs incident were not significantly different when patients carrying seven PD causative genes were excluded or not. In addition, LEDD, DRD3 rs6280, SLC6A3 rs460000 and COMT rs4680 , were the strongest independent predictive factors.

Conclusion: LIDs incident was common in the early stage of EOPD, established clinical-genetic models and identified independent predictive factors have good application prospects to LIDs prediction and DRT management.

Funding: This study was supported the National Key Research and Development Program of China (grant no. 2016YFC0901504 and 2018YFC1312001), the National Natural Science Fund of China (Grant No. 81571247) and the 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (Grant No. ZYJC18038, Grant No. ZYJC18003 and Grant No. 2019HXFH046).

Declaration of Interest: None to declare

Ethical Approval: This study was approved by the ethics committee of West China Hospital, Sichuan University.
Endogenous Retroviruses Drive Lineage-Specific Regulatory Evolution across Primate and Rodent Placentae
Authors: Ming-an Sun, Gernot Wolf, Yejun Wang, Anna D Senft, Sherry Ralls, Jinpu Jin, Caitlin E Dunn-Fletcher, Louis J Muglia, Todd S Macfarlan
Journal: Molecular Biology and Evolution (2021)

In mammals, the placenta mediates maternal-fetal nutrient and waste exchange and acts in an immunomodulatory way to facilitate maternal-fetal tolerance. The placenta is highly diverse across mammalian species, yet the molecular mechanisms that distinguish the placenta of human from other mammals are not fully understood. Using an interspecies transcriptomic comparison of human, macaque, and mouse late-gestation placentae, we identified hundreds of genes with lineage-specific expression-including dozens that are placentally enriched and potentially related to pregnancy. We further annotated the enhancers for different human tissues using epigenomic data and demonstrate that the placenta and chorion are unique in that their enhancers display the least conservation. We identified numerous lineage-specific human placental enhancers and found they highly overlap with specific families of endogenous retroviruses (ERVs), including MER21A, MER41A/B, and MER39B that were previously linked to immune response and placental function. Among these ERV families, we further demonstrate that MER41A/B insertions create dozens of lineage-specific serum response factor-binding loci in human, including one adjacent to FBN2, a placenta-specific gene with increased expression in humans that produces the peptide hormone placensin to stimulate glucose secretion and trophoblast invasion. Overall, our results demonstrate the prevalence of lineage-specific placental enhancers which are frequently associated with ERV insertions and likely facilitate the lineage-specific evolution of the mammalian placenta.
An Icteric Tongue
Authors: David Avelar Rodriguez, Julia Orkin
Journal: New England Journal of Medicine (2021)

A 12-year-old boy presented with a 4-day history of sore throat and dark urine. He was found to have jaundice with an icteric tongue, and the hemoglobin level was 6.1 g per deciliter. A diagnosis of cold agglutinin, EBV-induced acute hemolytic anemia was made.
Abstract 9133: Abnormal Response of Superior Sinoatrial Node to Sympathetic Stimulation is a Characteristic Finding in Patients with Atrial Fibrillation and Symptomatic Bradycardia
Authors: Boyoung Joung, Jaemin Shim, Hye jin Hwang, Hui-Nam Pak, Moon-Hyoung Lee, Changyu Shen, Shien-Fong Lin, Peng-Sheng Chen
Journal: Circulation (2011)

Introduction: We hypothesize that unresponsiveness of superior sinoatrial node (SAN) to sympathetic stimulation is strongly associated with the development of symptomatic bradycardia in patients with atrial fibrillation (AF). Methods and Results: We performed 3-dimensional endocardial mapping in healthy control (Group 1, n=10) and in patients with AF without (Group 2, n=57) or with (Group 3, n=15) symptomatic bradycardia at baseline and during isoproterenol infusion. Sympatomatic bradycardia includes cardiac syncope, presyncope or dizziness associated with either sinus bradycardia (&lt;40 bpm; n=7) or prolonged sinus pauses (&gt;3.0 seconds; n=8) Corrected SAN recovery time (CSNRT) was abnormal (&gt; 550ms) in 0%, 11% and 36% of groups 1, 2 and 3, respectively (p=0.02). At baseline, 90%, 36% and 7% (p&lt;0.001) of the patients had multicentric SAN activation patterns. For groups 1, 2 and 3, respectively, the median distance from the superior vena cava-right atrial junction to the most cranial earliest activation site (EAS) was 5.0 (25-75 percentile range, 3.5-21.3) mm, 10.0 (4-20) mm and 17.5 (12-34) mm at baseline (p=0.01), and was 4.0 (0-5) mm, 5.0 (1-10) mm and 15.0 (5.4-33.3) mm during isoproterenol infusion (p=0.01), suggesting upward shift of EAS during isoproterenol infusion. However, while the EAS during isoproterenol infusion was at the upper 1/3 of crista terminalis in 100% of Group 1 and 78% of Group 2 patients, only 20% of the groups 3 patients moved EAS to that region (p &lt; 0.001). We analyzed the comparative efficacy of CSNRT and 3D mapping in differentiating Group 2 and Group 3 patients. The sensitivity and specificity of CSNRT test are 35% and 89%, respectively, and of the 3D mapping test are 78% and 78%, respectively. Conclusions: Superior SAN serves as the EAS during sympathetic stimulation in normal patients and in most patients with AF without symptomatic bradycardia. In contrast, unresponsiveness of superior SAN to sympathetic stimulation is a characteristic finding in patients with AF and symptomatic bradycardia.