tbuckley/cabot-search huggingface dataset:
Cysteine and Cystine Depletion Targets Leukemia Stem Cells
Authors: Courtney L Jones, Brett M Stevens, Angelo D'Alessandro, Rachel Culp-Hill, Julie Reisz, Haobin Ye, Nabilah Khan, Mohd Minhajuddin, James DeGregori, Daniel A Pollyea, Craig T Jordan
Journal: Blood (2018)
Abstract 14500: Impact of Glucose Variability on Vulnerability of Non-Culprit Plaque in Non-Diabetic Patients With Acute Coronary Syndrome
Authors: Junya Harada, Kazumasa Sugimoto, Yo Iwata, Tadayuki Kadohira, Yoshihide Fujimoto, Yoshio Kobayashi
Journal: Circulation (2013)

Background: Attention has been paid to the effect of glucose variability on cardiovascular disease. The present study evaluated relation between glucose variability and plaque composition of nonculprit lesions in nondiabetic patients with acute coronary syndrome (ACS). Methods: A total of 75 ACS patients (25 patients with diabetes mellitus (DM) and 50 patients without DM) who underwent intravascular ultrasound (IVUS)-guided percutaneous coronary intervention were enrolled. IVUS and integrated backscatter (IB)-IVUS measurements were performed in the 10-mm segment with largest plaque volume in nonculprit lesion. Tissue components were classified into 4 categories: calcification, dense fibrosis, fibrosis, and lipid according to signal level. During hospitalization, all patients were equipped with a continuous glucose monitoring device while they were in stable condition, and were monitored at least 48 hours. Nondiabetic patients were classified into 2 groups according to above or below median of the mean amp...
Adoption of clinical trial results as a novel institutional quality metric: Sentinel lymph node biopsy and early-stage breast cancer.
Authors: John Bainbridge, Stephanie B. Wheeler, Eun-Sil Shelley Hwang
Journal: Journal of Clinical Oncology (2014)

e17607 Background: Clinical trials produce information which enables evidence-based change in practice, but to our knowledge, no metrics quantify the pattern of adoption. A class of institutional quality metrics has been developed quantifying the trajectory of use of new evidence-based procedures. Rogers’ theory of diffusion of innovation and adopter types informs this characterization of institutional culture in implementing clinical trial results. These metrics could be used by patients, payers, and quality initiatives to inform decisions and in research to identify factors associated with adoption rate. Methods: An evidence-based medical implementation index (EMII) was developed using treatment patterns of selected procedures during adoption periods. Specific metrics are based upon procedures relevant to a given disease. Trajectories of rates of use for the indicated patient population are derived using a generalized linear mixed model. Area under the curve (AUC) is calculated for these trajectories. Procedure AUCs are combined to create an EMII from 0-100 via an item response theory approach. To evaluate the EMII, based on a single procedure, is the use case of adoption of sentinel lymph node biopsy (SLNB) in early stage BC treatment using 1999-2007 SEER-Medicare data. Results: Differences in adoption patterns were found for SEER regions and institutions (p< .001 for each effect). For SEER regions (n=15) the SLNB EMII range was 33 (New Mexico) to 66 (Seattle). For all institutions: n = 720, range = 4 - 87, mean = 46, S.D. = 20, bell shaped distribution. Conclusions: Use of historical practice patterns in the adoption of clinical trial results differentiates behaviors at the region and institution levels. Use of the AUC of adoption trajectories is a simple way to characterize these variations. Further research is needed to calibrate specific EMIIs to determine values considered desirable in evaluating institutional behavior. Region N Min Max Avg SFO 27 9 76 46 CT 34 29 81 56 DTW 34 11 73 40 HI 14 13 79 38 IA 69 7 86 38 NM 23 10 84 37 SEA 33 41 87 66 UT 24 17 69 45 GA 24 25 81 51 SJC 15 15 72 50 LAX 60 12 77 45 CA 152 4 87 48 KY 60 14 82 43 LA 64 7 86 39 NJ 87 11 83 49
Abstract 5877: Regulation of Signal Transducer and Activator of Transcription 3 Signaling Pathway by AP-endonuclease 1 in Vascular Inflammation
Authors: Sutapa Ray
Journal: Circulation (2009)

Background: Signal transducer and activator of transcription-3 (STAT3) is a latent interleukin-6 (IL-6) inducible transcription factor that mediates hepatic and vascular inflammation including athe...
Analysis of circulating tumor cells for monitoring treatment response in triple-negative breast cancer.
Authors: Arturo Ramirez, Daniel Campton, Elisabeth Mahen, C. Anthony Blau, Eric Peter Kaldjian, Jackie L. Stilwell
Journal: Journal of Clinical Oncology (2014)

e22017 Background: The University of Washington Center for Cancer Innovation is intensively studying triple-negative breast cancer (TNBC) at the individual patient level. We used a high-recovery rare cell analysis system to count and characterize circulating tumor cells (CTCs) from advanced TNBC patients treated with cis-platinum. Methods: Two patients have been studied to date. Blood was collected from patients prior to treatment and regularly thereafter. Density-based enrichment of blood cells was performed using the AccuCyte tube, float and collector system. Collected cells were processed and applied to microscopic slides. Fluorescently labeled antibodies to cytokeratin, CD45 and EpCAM, and a nuclear dye were applied to samples using an automated slide stainer. Slides were scanned on a digital microscope and candidate CTCs identified using image analysis software. CTCs were verified by appropriate morphology and expression of epithelial and nuclear stains without CD45 expression. Other antibodies used to characterize cells included Her2, EGFR, and Ki-67. Results: CTC levels before cis-platinum treatment in a patient with extensive bone-only metastatic disease were extremely high (1,500 cells/mL) and she was thrombocytopenic and short of breath. One week after treatment CTC levels spiked (5670 cells/mL) and high numbers of non-nucleated cells and fragments were observed. CTC counts dropped exponentially after the spike to 21 cells/mL after 3 months. CTC clusters and Ki-67 positive cells have decreased during therapy. Clinical response to treatment has paralleled the reduction in CTC levels, with elimination of oxygen therapy and normalization of platelet count. In the second patient, CTCs have decreased from approximately 4 cells/mL to 0.5 over 3 months with generalized reduction in size and number of positive lymph nodes as measured by imaging. Conclusions: Analysis of CTCs may provide a non-invasive measure of cancer progression/response and the molecular evolution of tumor cells in TNBC.
Abstract 18413: Salacia Chinensis and Metabolic Risk Factors: in vivo Model
Authors: Vijaya Juturu, Kazim Sahin, Cemal Orhan, Mehmet Tuzcu, Fusun Erten, Nurhan Sahin
Journal: Circulation (2017)

Introduction: We recently demonstrated that Salacia Chinensis Extract (SCE) inhibits alpha-glucosidase, pancreatic lipase and HMG CoA reductase. Hypothesis: We hypothesized that SCE may regulate gl...
VTD (Bortezomib/Thalidomide/Dexamethasone) As Pretransplant Induction Therapy for Multiple Myeloma: Definitive Results of a Randomized Phase 3 Pethema/GEM Study
Authors: Laura Rosinol Dachs, Albert Oriol, Ana Isabel Teruel, Ana López de la Guía, M Jesús Blanchard, Isidro Jarque, Miquel Granell, Antonia Sampol, Luis Palomera, Yolanda Gonzalez-Montes, Enrique Bengoechea, Rafael Martínez-Martínez, Miguel T Hernández, Felipe De Arriba, Maria Luisa Martin-Ramos, Norma C. Gutierrez, Maria Teresa Cibeira, Maria-Victoria Mateos, Joaquin Martinez-Lopez, Adrián Alegre, Juan Jose Lahuerta, Jesus F San-Miguel, Joan Blade
Journal: Blood (2018)
A comparison of cardiac event rates in patients with or without multiple myeloma in the United States.
Authors: Kristin D Kistler, Brian Murphy, Jill Kalman, Gagan Sahni, Winifred Werther, Kanya Rajangam, Ajai Chari
Journal: Journal of Clinical Oncology (2014)

e19563 Background: Multiple myeloma (MM) patients have age-, disease-, and treatment-related risk factors for cardiac events; it is unknown if this risk is greater than in non-MM patients. Methods: Two cohorts were identified in the 2006–2011 MarketScan database: 1) MM patients treated with corticosteroids and ≥3 drugs (bortezomib, IMiDs, and alkylating agents or anthracyclines), where the index date (ID) was the date criteria of exposure to the 3 drugs was met; and 2) age and sex matched No-MM patients (5:1); the distribution of No-MM patients’ IDs matched MM patients. Baseline was 6 months prior to the ID. Patients were followed from ID to study end. Baseline variables included age, sex, geographic area, comorbidities (e.g., cardiac events), and Charlson Comorbidity Index. Incidence was calculated for patients without the event(s) at baseline. Hazard ratios (HR) and 95% confidence intervals (CI) were adjusted for baseline variables when univariate analyses showed a 10% difference. Results: 1,723 MM patients and 8,615 comparators were analyzed. Median (range) months of observation were: MM cohort, 9 (0–60); no-MM, 19 (0–66). The prevalence of cardiac events was greater in the MM (52%) vs. no-MM group (35%), P<0.0001. Incidence of any cardiac event, arrhythmia, congestive heart failure (CHF), cardiomyopathy and conduction disorders was also significantly greater among MM vs. no-MM patients; the incidence of hypertensive/arterial events and ischemic heart disease was similar for MM and no-MM patients (Table). Conclusions: This study provides the first comparison of cardiac event risk in MM patients vs. age- and gender-matched patients without MM. Cardiac event prevalence and risk was greater in MM patients with ≥3 prior drugs for any cardiac event, arrhythmia, CHF, cardiomyopathy, and conduction disorders compared to patients with no MM. Hazard ratios for incidence of cardiac events in treated MM patients versus no-MM patients. Cardiac event Adjusted hazard ratio (95% confidence interval) Any 2.2 (1.9–2.5) Cardiac arrhythmia 4.1 (3.5–4.8) Congestive heart failure 2.9 (2.2–3.7) Cardiomyopathy 2.6 (1.8–3.8) Conduction disorders 1.7 (1.2–2.5) Hypertensive/arterial 1.1 (1.0–1.3) Ischemic heart disease 1.0 (0.8–1.3)
Dynamics of Genetic Landscapes and Clonal Evolution between Patients and PDX Models in Acute Myeloid Leukemia
Authors: Naomi Kawashima, Yuichi Ishikawa, Akimi Akashi, Hikaru Hattori, Yohei Yamaguchi, Takahiro Nishiyama, Rika Kihara, Yukiyasu Ozawa, Hitoshi Kiyoi
Journal: Blood (2018)
Population-based analysis of treatment receipt in prostate cancer patients who initially pursued active surveillance (AS).
Authors: Nathan Christopher Sheets, Laura H. Hendrix, Ronald C. Chen
Journal: Journal of Clinical Oncology (2014)

6517 Background: Active surveillance for early prostate cancer may reduce over-treatment based on publications of patients managed in clinical trials or at high volume academic centers. In these selected reports, up to 30% of AS patients receive treatment (prostatectomy, radiation, hormone therapy) within 3 years due to cancer progression or patient anxiety. However, no study has examined receipt of treatment in AS patients in the community. Methods: Patients diagnosed from 2004-7 in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database with low or intermediate risk prostate cancer were included; claims were available through 2010. AS was defined as a repeat prostate biopsy between 2-24 months after diagnosis with no treatment prior to repeat biopsy. We report the proportion of AS patients who received treatment within 3 years. Logistic regression examined factors associated with treatment receipt. Results: 737 low-risk and 618 intermediate-risk prostate cancer patients were analyzed. At 3 years, 64% of low-risk and 76% of intermediate-risk patients received treatment (Table). On multivariate analysis, being married (odds ratio [OR]=1.45; 95% CI 1.1-1.9), later year of diagnosis (2007 vs 2004, OR=1.73; 95% CI 1.2-2.5) and intermediate risk disease (vs. low-risk, OR=2.0; 95% CI 1.5-2.5) were associated with increased odds of treatment. Older patients had lower odds of treatment (age 76-79 vs 66-69, OR=0.6; 95% CI 0.4-0.9). Conclusions: On a population level, two-thirds (low-risk) to three-fourths (intermediate-risk) of early prostate cancer patients who initially chose AS converted to treatment within 3 years. These rates are twice that of published studies from trials or academic centers. This information may be informative to patients and physicians in the treatment decision-making process. Studies are needed to discern the reasons for this high rate of treatment, potentially due to suboptimal patient selection for AS or anxiety. Treatment by 3 years in AS patients. Low risk Intermediate risk N (%) N (%) Prostatectomy 61 (8) 76 (12) External beam RT 174 (24) 152 (25) Brachytherapy 219 (30) 204 (33) Hormone 14 (2) 39 (6) No treatment 269 (36) 147 (24)
A population-based comparison of outcomes among screening, symptom, and emergently-detected colorectal cancer (CRC).
Authors: McKyla McIntyre, Gillian Gresham, Pierre Y. Cheung, Matthew Chan, Jenny J. Ko, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2014)

1567 Background: CRC screening is recommended in average-risk individuals aged 50 years or older. Our aims were 1) to evaluate the proportion of CRC in a large population-based setting that were diagnosed by screening, symptoms, or emergent presentation; and 2) to examine the characteristics and outcomes of CRC based on their method of detection. Methods: All sporadic CRC cases diagnosed and referred in 2008 to any 1 of 5 regional cancer centers in British Columbia, Canada were reviewed and analyzed. Screening-eligible patients were classified into CRC diagnosed by 1) screening endoscopies or stool tests; (2) symptoms prompting outpatient workup; and (3) emergent presentations to the hospital. Using Kaplan-Meier methods and Cox regression, 5-year CRC-specific survival (CRC-SS) and overall survival (OS) were compared. Results: A total of 992 CRC patients were included: median age was 69 years (range 50-95), 58% were men, and 54% were colon. Among them, 12% were diagnosed by screening, 75% by symptoms, and 13% by emergent presentation. Comparing across the 3 cohorts, patients who presented emergently tended to be older (p=0.06), women (p=0.02) and have colonic tumors (p<0.001) while individuals with either emergently or symptom-detected tumors were more likely to manifest with metastatic disease (p<0.001). In the group that underwent screening, stool tests were the most frequent screening modality. Compared to CRC diagnosed by screening, emergently detected disease showed worse CRC-SS (HR 1.34), but symptom-detected disease showed better CRC-SS (HR 0.66) (p for trend =0.0095). Both emergently and symptom-detected CRC were correlated with worse OS relative to screening-detected disease (HRs 2.28 and 1.25, respectively) (p for trend<0.001). Conclusions: Despite screening guidelines, CRC was more commonly diagnosed by symptoms or emergent presentations. Screening was associated with improved OS, but its impact on CRC-SS was variable. Thus, the observed benefits of screening may be more strongly driven by the presence of other associated preventive or healthy behaviors. Interventions that harness these healthy behaviors may be more effective in improving CRC screening uptake and outcomes.
In vitro antimyeloma activity of pixantrone (PIX).
Authors: Ella Willenbacher, Wolfgang Willenbacher, Brigitte Kircher
Journal: Journal of Clinical Oncology (2014)

e19569 Background: Despite considerable clinical progress has been made by the implementation of proteasome inhibitors and immuno-modulatory drugs with respect to Multiple Myeloma (MM) therapy efficiency, all patients will finally relapse. New and better myeloma drugs thus represent a major unmet clinical need. PIX is a Mitoxantrone analog with fewer cardiac side effects, newly registered for the treatment of relapsed/refractory aggressive NHL. PIX seems to have a unique mechanism of action inducing cell death by mitotic perturbations and subsequent aberrant cell divisions, making the drug a logic partner for combination therapies. The aim of this research was to investigate the anti-MM properties of Pixantrone (PIX) and its effects on MM cells. Methods: 5 MM cell lines (KMS-12-PE, KMS-12-BM, AMO-1, U266, LP1) and PBMC from healthy donors, as well as the stromal cell line HS-5 were cultivated and exposed with pharmacologically realistic doses of PIX (0.01 – 5 µM). These cultures were analyzed for proliferation (H3-thymidine incorporation), metabolic activity (EZ4you assay), and apoptosis induction (PI, Annexin). Furthermore these assays were reproduced with primary samples from a plasma cell leukemia (PCL). Results: PIX dose-dependently inhibits the proliferation and metabolic activity of MM cell lines, and increases apoptosis, at relatively low concentrations achievable with standard dose PIX in humans. The IC50 for proliferation inhibition was found to lie inbetween 0.1 – 0.25 µM in all cell lines, while the IC50 for the inhibition of metabolic activity was in the range of 0.5 – 5µM with a more variant pattern. These effects are more pronounced in MM cell lines compared to the stromal cell line HS-5 and PBMC. The in-vitro anti-MM activity of PIX could be readily reproduced in primary samples from a refractory PCL with respect to inhibition of proliferation and metabolic activity, as well as the induction of apoptosis (at 1.0 – 2.5 µM). Conclusions: Our results indicate a potential role of PIX for the treatment of MM. Further in-vitro studies of PIX-anti-MM drug combinations and possible synergistic strategies are ongoing, both with MM cell lines and primary patient material.
Pleiotropy Modulates the Efficacy of Selection in<i>Drosophila melanogaster</i>
Authors: Christelle Fraïsse, Gemma Puixeu Sala, Beatriz Vicoso
Journal: Molecular Biology and Evolution (2018)

Pleiotropy is the well-established idea that a single mutation affects multiple phenotypes. If a mutation has opposite effects on fitness when expressed in different contexts, then genetic conflict arises. Pleiotropic conflict is expected to reduce the efficacy of selection by limiting the fixation of beneficial mutations through adaptation, and the removal of deleterious mutations through purifying selection. Although this has been widely discussed, in particular in the context of a putative "gender load," it has yet to be systematically quantified. In this work, we empirically estimate to which extent different pleiotropic regimes impede the efficacy of selection in Drosophila melanogaster. We use whole-genome polymorphism data from a single African population and divergence data from D. simulans to estimate the fraction of adaptive fixations (α), the rate of adaptation (ωA), and the direction of selection (DoS). After controlling for confounding covariates, we find that the different pleiotropic regimes have a relatively small, but significant, effect on selection efficacy. Specifically, our results suggest that pleiotropic sexual antagonism may restrict the efficacy of selection, but that this conflict can be resolved by limiting the expression of genes to the sex where they are beneficial. Intermediate levels of pleiotropy across tissues and life stages can also lead to maladaptation in D. melanogaster, due to inefficient purifying selection combined with low frequency of mutations that confer a selective advantage. Thus, our study highlights the need to consider the efficacy of selection in the context of antagonistic pleiotropy, and of genetic conflict in general.
The Rate of Venous Thromboembolism in Cancer Patients Varies By Khorana Risk Category
Authors: Alok A. Khorana, Nicole M. Kuderer, Keith R. McCrae, Dejan Milentijevic, Guillaume Germain, François Laliberté, Nguyen Le, Patrick Lefebvre, Gary H. Lyman, Michael B. Streiff
Journal: Blood (2018)
TBK1/Ikkε Inhibitor Amlx Blocks Multiple Myeloma Cell Growth in Vitro and In Vivo
Authors: Quanhong Sun, Peng Zhang, Juraj Adamik, Konstantinos Lontos, Valentina Marchica, Nicola Giuliani, Rebecca W. Silbermann, G. David Roodman, Deborah Lynn Galson
Journal: Blood (2018)
Randomized controlled trial of a 12-week digital care program in improving low back pain
Authors: Raad Shebib, Jeannie F Bailey, Peter Smittenaar, Daniel A Perez, Gabriel Mecklenburg, Simon Hunter
Journal: npj Digital Medicine (2018)

Low back pain (LBP) is the leading cause of disability throughout the world and is economically burdensome. The recommended first line treatment for non-specific LBP is non-invasive care. A digital care program (DCP) delivering evidence-based non-invasive treatment for LBP can aid self-management by engaging patients and scales personalized therapy for patient-specific needs. We assessed the efficacy of a 12-week DCP for LBP in a two-armed, pre-registered, randomized, controlled trial (RCT). Participants were included based on self-reported duration of LBP, but those with surgery or injury to the lower back in the previous three months were excluded. The treatment group (DCP) received the 12-week DCP, consisting of sensor-guided exercise therapy, education, cognitive behavioral therapy, team and individual behavioral coaching, activity tracking, and symptom tracking - all administered remotely via an app. The control group received three digital education articles only. All participants maintained access to treatment-as-usual. At 12 weeks, an intention-to-treat analysis showed each primary outcome-Oswestry Disability Index (p < 0.001), Korff Pain (p < 0.001) and Korff Disability (p < 0.001)-as well as each secondary outcome improved more for participants in the DCP group compared to control group. For participants who completed the DCP (per protocol), average improvement in pain outcomes ranged 52-64% (Korff: 48.8-23.4, VAS: 43.6-16.5, VAS impact on daily life: 37.3-13.4; p < 0.01 for all) and average improvement in disability outcomes ranged 31-55% (Korff: 33.1-15, ODI: 19.7-13.5; p < 0.01 for both). Surgical interest significantly reduced in the DCP group. Participants that completed the DCP had an average engagement, each week, of 90%. Future studies will further explore the effectiveness of the DCP for long-term outcomes beyond 12 weeks and for a LBP patient population with possibly greater baseline pain and disability. In conclusion, the DCP resulted in improved LBP outcomes compared to treatment-as-usual and has potential to scale personalized evidence-based non-invasive treatment for LBP patients.