tbuckley/cabot-search huggingface dataset:
Abstract 18849: Molecular Signature of Early Cardiovascular Lineages Revealed by Single Cell Transcriptomics
Authors: Wuming Gong, Satyabrata Das, Wei Pan, Naoko Koyano-Nakagawa, Daniel J Garry
Journal: Circulation (2015)

Background: The molecular definition of the differentiation process of cardiovascular lineages is of intense interest for developmental biologists. Recent studies have demonstrated that multipotent cardiac progenitors are capable of giving rise to multiple cardiovascular lineages such as endothelium, endocardium, epicardium and myocardium. Moreover, Nkx2-5 and Etv2 are two of the key genes that regulate the specification of the cardiac lineage. Understanding the global gene expression pattern and ontogeny of Nkx2-5 and Etv2 positive cells are critical steps for the decoding of the signaling cascade and the molecular mechanisms that govern mesodermal lineage differentiation. Methods: Using Etv2- and Nkx2-5-EYFP transgenic embryos, from which progenitors of cardiovascular/circulatory lineages can be isolated with high purity, we performed single cell transcriptome analysis. We used our recently developed single cell RNA-seq analysis pipeline, dpath, to decompose the transcriptome into seven major metagenes. Each gene and each cell was assigned the “metagene signature” based on its unique and robust features, which successfully captured their molecular dynamics and global expression patterns. Results: An unbiased clustering analysis using the metagene signature of 459 Etv2- and Nkx2-5 EYFP positive cells from E7.75 and E8.25 embryos revealed 16 mesodermal cell populations with distinct global gene expression patterns. The metagene entropy analysis revealed distinct differentiation potential and mesodermal lineage coverage among Etv2-EYFP + and Nkx2-5-EYFP + cells. Two major Nkx2-5 + cell populations were significantly associated with the first and second heart fields and novel gene markers for each heart fields were identified. We also discovered multiple types of endocardial populations from different sources and with distinct global gene expression patterns. Conclusions: We report the analysis of complete gene expression profiles during mesodermal lineage specification at a single cell resolution. These results demonstrate the power of combining machine learning algorithms and single cell RNA-seq for discovering hidden cell types from mixed cell population and novel lineage markers.
Hearing Impairment and Type 1 Diabetes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Cohort
Authors: David S. Schade, Gayle M. Lorenzi, Barbara H. Braffett, Xiaoyu Gao, Kathleen E. Bainbridge, Annette Barnie, Karen J. Cruickshanks, Dayna Dalton, Lisa Diminick, Rose Gubitosi-Klug, John R. Kramer, John M. Lachin, Mary E. Larkin, Catherine C. Cowie
Journal: Diabetes Care (2018)

OBJECTIVE To evaluate the prevalence of hearing impairment in participants with type 1 diabetes enrolled in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study and compare with that of a spousal control group without diabetes. Among participants with type 1 diabetes, to evaluate the association of hearing impairment with prior DCCT therapy and overall glycemia. RESEARCH DESIGN AND METHODS DCCT/EDIC participants (n = 1,150) and 288 spouses without diabetes were recruited for the DCCT/EDIC Hearing Study. All subjects completed a self-administered questionnaire, medical history, and physical measurements. Audiometry was performed by study-certified personnel; audiograms were assessed centrally. Speech-frequency (pure-tone average [PTA] thresholds at 500, 1,000, 2,000, and 4,000 Hz) and high-frequency impairment (PTA thresholds at 3,000, 4,000, 6,000, and 8,000 Hz) were defined as PTA &amp;gt;25 dB hearing loss. Logistic regression models were adjusted for age and sex. RESULTS DCCT/EDIC participants and spousal control subjects were similar in age, race, education, smoking, and systolic blood pressure. There were no statistically significant differences between groups in the prevalence or adjusted odds of speech- or high-frequency impairment in either ear. Among participants with type 1 diabetes, for every 10% increase in the time-weighted mean HbA1c, there was a 32% (95% CI 1.15–1.50) and 19% (95% CI 1.07–1.33) increase in speech- and high-frequency hearing impairment, respectively. CONCLUSIONS We found no significant difference in the prevalence of hearing impairment between the group with type 1 diabetes and the spousal control group. Among those with type 1 diabetes, higher mean HbA1c over time was associated with hearing impairment.
Sensitivity of gemtuzumab ozogamicin can be predicted by the amount of DNA strand breaks despite different mechanisms of resistance including the CD33 expression, membrane transporters, and DNA damage response in leukemic cells.
Authors: Takahiro Yamauchi, Yoshimasa Urasaki, Haruyuki Takemura, Takanori Ueda
Journal: Cancer Research (2008)

4059   Gemtuzumab ozogamicin (GO) consists of the CD33 antibody linked to calicheamicin. Binding of GO to the CD33 antigen of leukemic cells results in internalization followed by the release of calicheamicin. Calicheamicin induces DNA strand breaks and subsequently apoptosis. Because GO sensitivity varies widely among patients, GO-based chemotherapy should be optimized by predicting the drug sensitivity. Here, we hypothesized that GO-induced DNA strand breaks are the surrogate marker of GO efficacy. To test this hypothesis, we investigated factors that affect GO sensitivity using various CD33-positive leukemic cells, and sought for the relationship between the amount of DNA strand breaks and the sensitivity to GO. First, two GO-resistant variants were established from HL-60 cells as HL/GO/CYA and HL/GO, by incubation of the cells with GO in the presence of P-glycoprotein (PGP) inhibitor cyclosporine A (CYA) or not, respectively. Both HL/GO/CYA and HL/GO cells were comparably 200-fold more GO-resistant than HL-60 cells. The CD33 positivity were 40% in HL/GO/CYA cells and 6% in HL/GO cells despite the 99% positivity in HL-60 cells. HL/GO/CYA alone exhibited an increased mRNA level of multidrug resistance protein (MRP) although both variants did not possess PGP overexpression, suggesting different mechanisms of resistance between the two variants. An MRP inhibitor MK571 reversed GO resistance partially in HL/GO/CYA cells but not in HL/GO cells while CYA had no effects on both cell lines. The microarray analysis demonstrated elevated levels of GADD45, XRCC5, and PARP1 commonly in both variants, suggesting participation of DNA damage response in GO resistance. Next, different HL-60 variants, HL/D-1-9 exhibiting PGP overexpression and HL/AD exhibiting MRP overexpression were used. Both variants were also more resistant to GO than HL-60 cells. CYA and MK571 sensitized HL/D-1-9 and HL/AD, respectively, confirming an important role of membrane transporters in GO sensitivity. Finally, the amount of DNA strand breaks was quantitated in cells after treatment with GO using the Comet assay. Compared with HL-60 cells, the amounts of GO-induced DNA strand breaks were equally small in HL/GO/CYA and HL/GO cells. Moreover, HL/D-1-9 and HL/AD cells exhibited smaller amounts of DNA strand breaks than HL-60 cells. These results suggested that regardless of the mechanisms of GO resistance, the sensitivity to GO was closely associated with the amount of DNA strand breaks. In conclusion, the CD33 positivity, membrane transporters, and DNA damage response were associated with GO resistance. Nevertheless, GO-induced DNA strand breaks were most related to the cellular sensitivity to GO. The Comet assay will be useful for predicting GO sensitivity and optimizing GO-containing leukemia therapy.
Comprehensive literature search for animal studies may have saved STRIDER trial
Authors: Michael E Symonds, Helen Budge
Journal: BMJ (2018)

Symonds and Budge 1 are raising a classic but important and neglected concern on how a proper systematic review could prevent waste in trials and add value to the research. 2,3A living systematic review is required alongside each clinical trial.This review should start with the raising of a clinical question and continue to be updated during the protocol/grant application writing, and designing, conducting, recording, and reporting the trial to safeguard every research project from reinventing the wheel or worse a flat tire. 4ile the involvement of librarians and information specialists could avoid the similar waste caused by missing literature, 5 research teams constantly resist involving a search expert in their team.Clinical trials require daily, weekly and monthly updates from the literature which could be achieved through designing, running, and updating the rigor search strategies in bibliographic databases.Librarians and information specialists are equipped with the information skills to avoid preventable waste in research.Furthermore, their efforts on systematic reviewing for ongoing trials could result in added value such as a secondary updateable and shareable bibliographic database of literature per clinical question for the research team and audiences who could use it in writing the report or updating the literature review in a faster and more accurate way.
Abstract 12766: Long Term Outcome of Patients With Complete Revascularization
Authors: Jeehoon Kang, Kyung Woo Park, Si-Hyuck Kang, Hyun-Jae Kang, Hae-Young Lee, Bon-Kwon Koo, In-Ho Chae, Tae-Jin Youn, Byung-Hee Oh, Young-Bae Park, Hyo-soo Kim
Journal: Circulation (2014)

Introduction: Complete revascularization (CR) is considered as a goal for percutaneous coronary intervention (PCI). Previous studies have proved that achieving CR is beneficial compared to incomplete CR. However there has been no research about the long term outcome within CR patients. Hypothesis: The SS has predictive value in CR patients. Methods: From patients enrolled in the Efficacy of Xience/Promus versus Cypher in rEducing Late Loss after stENTing (EXCELLENT) registry, the SYNTAX score was checked before and after PCI. The primary clinical outcome was 3-year patient-oriented composite endpoint (POCE), which was a composite of all cause death, any myocardial infarction, and any revascularization. Secondary outcomes were the individual components of 3-year POCE and 3-year target lesion failure (TLF). For calculation of the clinical SS, the SS was multiplied with the value of the ‘Age, Creatinine, and Ejection Fraction’ score. Results: Among 5102 patients from the EXCELLENT registry, 2112 patients achieved CR by PCI. 3-year POCE was less common in CR patients (10.0% vs. 16.9%, p&lt;0.001) and CR was an independent predictor of adverse outcomes (Hazard ratio (HR) 1.326, 95% Confidence Interval (CI) 1.108-1.587, p=0.002). Patients who achieved CR were divided into 3 groups, according to the pre-PCI SYNTAX score (SS); 1≤low-SS&lt;6: 771 patients, 6≤mid-SS&lt;10: 692 patients, and high-SS≥10: 649 patients. 3-year POCE increased significantly along with increasing baseline SS tertiles (7.5% vs. 8.4% vs. 14.8%, p&lt;0.001) and secondary outcomes also showed similar tendency. Multivariate analysis showed that baseline SS was an independent predictor of 3-year POCE (HR 1.032, 95% CI 1.011-1.053, p=0.003 per SS point). The clinical SS was superior to baseline SS in predicting 3-year POCE (AUC: 0.595 vs. 0.649, p=0.008). In subgroup analysis, baseline SS was a predictor for POCE only in multi-vessel diseases (HR 1.027, 95% CI 1.001-1.054, p=0.042 per SS point). Conclusions: CR is an independent predictor of 3-year POCE in patients receiving PCI. However, even after CR is achieved to make the post-PCI SS zero, baseline SS still has predictive value of 3-year clinical outcomes. Moreover, the predictivity is was superior in multi-vessel diseases.
Pharmacogenomic landscape of patient-derived tumor cells informs precision oncology therapy
Authors: Jin-Ku Lee, Zhaoqi Liu, Jason K. Sa, Sang Shin, Jiguang Wang, Mykola Bordyuh, Hee Jin Cho, Oliver Elliott, Timothy Chu, Seung Won Choi, Daniel I. S. Rosenbloom, In-Hee Lee, Yong Jae Shin, Hyun Ju Kang, Donggeon Kim, Sun Young Kim, Moon-Hee Sim, Jusun Kim, Taehyang Lee, Yun Jee Seo, Hyemi Shin, Mijeong Lee, Sung Heon Kim, Yong-Jun Kwon, Jeong-Woo Oh, Minsuk Song, Misuk Kim, Doo-Sik Kong, Jung Won Choi, Ho Jun Seol, Jung-Il Lee, Seung Tae Kim, Joon Oh Park, Kyoung-Mee Kim, Sang-Yong Song, Jeong-Won Lee, Hee-Cheol Kim, Jeong Eon Lee, Min Gew Choi, Sung Wook Seo, Young Mog Shim, Jae Ill Zo, Byong Chang Jeong, Yeup Yoon, Gyu Ha Ryu, Nayoung K. D. Kim, Joon Seol Bae, Woong-Yang Park, Jeongwu Lee, Roel G. W. Verhaak, Antonio Iavarone, Jeeyun Lee, Raul Rabadan, Do-Hyun Nam
Journal: Nature Genetics (2018)
Impact of nontreatment oncology research trials on physician engagement in clinical research in an oncology community practice setting.
Authors: Susan S. Night, Juston S. Roemisch, David A. Smith
Journal: Journal of Clinical Oncology (2018)

44 Background: The rapid development of new oncology drugs has created a significant increase in the number of clinical research studies. This underscores the need for greater participation in research by physicians as well as patients. Many physicians hesitate to participate in oncology clinical trials that provide treatment options for their patients given the complexity of the protocols. Non-treatment clinical trials may serve as a bridge for engaging physicians in clinical research and enhance the culture of research in community oncology practices. Methods: A large non-treatment oncology clinical trial was opened in a network of community oncology practices with approximately 1,000 physicians. We evaluated the number of physicians who did not enroll a patient onto a clinical trial in Year 1 but did enroll patients onto the non-treatment study. We further examined the number of physicians who enrolled a patient onto the non-treatment study that also enrolled patients onto a treatment clinical trial. Overall physician engagement in clinical research was measured by comparing practices where non-treatment study was offered to locations that did not participate in the non-treatment study. Negative impact on treatment accruals was also evaluated. Results: There were 105 physicians that practice at a site with the non-treatment study who had 0 accruals in Year 1 but enrolled a patient to any clinical trial in Year 2. Ninety-two of those physicians were responsible for enrolling over 900 patients to the non-treatment study in Year 2. Additionally, 46 of the 0 accruing physicians in Year 1, enrolled a patient to the non-treatment study also enrolled a patient to a treatment clinical trial. We also found that 24 physicians who did not did not enroll a patient in Year 1 and did not enroll a patient to the non-treatment study did enroll patients to a treatment clinical trial in Year 2. Conclusions: Participation in oncology treatment clinical trials can be difficult in the community oncology setting. Participation in a non-treatment study may serve as a bridge to engage more physicians in clinical research and enhance the culture of research within a community oncology practice.
Patterns in breast cancer staging imaging: Are we choosing wisely?
Authors: Brett Barlow, Courtney Williams, Aidan Gilbert, Stacey M Watkins, Gabrielle Betty Rocque
Journal: Journal of Clinical Oncology (2018)

51 Background: The American Society of Clinical Oncology’s Choosing Wisely guidelines recommend no staging imaging in early stage breast cancer (ESBC) patients with low risk of metastasis, as it is potentially harmful and provides no survival benefit. This study evaluates local adherence to this recommendation and identifies factors contributing to unnecessary staging imaging. Methods: This retrospective cohort study included patients with AJCC stage 0-II BC diagnosed from 2013-2015 at a single-site, academic medical center. Data was abstracted from chart review. Imaging included computed tomography, positron emission tomography, or bone scans. Imaging for documented symptoms was considered appropriate. Abstracted patient data included demographics, medical oncologist, and clinical characteristics. To evaluate factors influencing inappropriate screening imaging, risk ratios (RR) and corresponding 95% confidence intervals (CI) were estimated using generalized linear models with a log link and Poisson distribution with robust variance estimates. Results: Of the 872 ESBC patients, 262 (30%) underwent staging imaging. Median diagnosis age of patients receiving imaging was 55 (IQR 48-63) compared to 60 (IQR 52-68) for patients with no or appropriate imaging. Risk of inappropriate screening imaging was increased for patients who were younger (RR 0.98, 95% CI 0.97-0.98), had triple negative disease vs any hormone receptor positive (RR 2.98, 95% CI 2.25-3.95), had higher stage BC (I vs. 0, RR 3.58, 95% CI 2.05-6.25; II vs. 0, RR 10.86, 95% CI 6.43-18.33), and did not have Medicare insurance (RR 1.52, 95% CI 1.22-1.89). Rates of imaging did not vary by race (non-white vs. white: RR 0.98, 95% CI 0.78-1.23). For medical oncologists with at least 15 patients, prevalence of inappropriate imaging varied from 26-68%. Conclusions: A substantial proportion of ESBC patients received unnecessary and potentially harmful staging imaging inconsistent with guidelines. Staging imaging was associated with patient demographic and clinical characteristics related to increased recurrence risk, suggesting a need for further physician education about the low-risk nature of this ESBC population to ensure high value oncologic care.
A description of the free text word choices physicians use to describe prognosis in over 50,000 electronic treatment plans.
Authors: Lalan S. Wilfong, Mark Ferencik, Marcus A. Neubauer
Journal: Journal of Clinical Oncology (2018)

219 Background: Fourteen practices within the US Oncology Network are participating in the Center for Medicare and Medicaid Innovation’s (CMMI) Oncology Care Model. To meet the requirement of documenting a care plan that contains the 13 components in the Institute of Medicine Care Management Plan, an electronic treatment plan was developed which incorporates core elements from our EMR, IKnowMed, supplemented by additional physician documentation. Physicians must document in their own words the prognosis section of the care plan. Methods: To better understand the word choices physicians use for prognosis, we evaluated the word choices used in over 50,000 treatment plans. Using an excel based word count macro, all contents of the free text entry “prognosis” field were sorted based on frequency of the same answer and were then ranked from most common use to least common. A word count method was applied to determine and rank the most commonly used words across all answers. The “current status of disease” field in the treatment plan was used to divide the prognosis answers into those that mentioned “Metastatic” and “Not Metastatic” so that prognosis wording trends could be compared using pivot tables and data filters. Results: 70% of prognosis word choices were single words: “excellent, good, fair, poor, or guarded” were the most common. 20% of phrases were multi-word that appeared repeatedly such as “will depend on the response to therapy.” Only 10% of answers were uniquely worded per treatment plan and felt to be personal to the patient’s situation. Additionally, the number of words did not differ between metastatic and non-metastatic disease. Conclusions: To our knowledge, this is the largest cohort of treatment plans where the word choices used by physicians are described to document prognosis to patients. The results indicate that single words or short phrases are commonly used to describe prognosis when the treatment plan is shared with patients. The data set has high potential for further study to better understand the role and impact of written treatment plans (including downstream events) to help physicians refine this documentation for better patient understanding of this important topic.
Variation in Survival After Out-of-Hospital Cardiac Arrest Between Emergency Medical Services Agencies
Authors: Masashi Okubo, Robert H. Schmicker, David J. Wallace, Ahamed H. Idris, Graham Nichol, Michael A. Austin, Brian Grunau, Lynn K. Wittwer, Neal Richmond, Laurie J. Morrison, Michael C. Kurz, Sheldon Cheskes, Peter J. Kudenchuk, Dana M. Zive, Tom P. Aufderheide, Henry E. Wang, Heather Herren, Christian Vaillancourt, Daniel P. Davis, Gary M. Vilke, Frank X. Scheuermeyer, Myron L. Weisfeldt, Jonathan Elmer, Riccardo Colella, Clifton W. Callaway
Journal: JAMA Cardiology (2018)

Emergency medical services (EMS) deliver essential initial care for patients with out-of-hospital cardiac arrest (OHCA), but the extent to which patient outcomes vary between different EMS agencies is not fully understood.To quantify variation in patient outcomes after OHCA across EMS agencies.This observational cohort study was conducted in the Resuscitation Outcomes Consortium (ROC) Epistry, a prospective multicenter OHCA registry at 10 sites in North America. Any adult with OHCA treated by an EMS from April 2011 through June 2015 was included. Data analysis occurred from May 2017 to March 2018.Treating EMS agency.The primary outcome was survival to hospital discharge. Secondary outcomes were return of spontaneous circulation at emergency department arrival and favorable functional outcome at hospital discharge (defined as a modified Rankin scale score ≤3). Multivariable hierarchical logistic regression models were used to adjust confounders and clustering of patients within EMS agencies, and calculated median odds ratios (MORs) were used to quantify the extent of residual variation in outcomes between EMS agencies.We identified 43 656 patients with OHCA treated by 112 EMS agencies. At EMS agency level, we observed large variations in survival to hospital discharge (range, 0%-28.9%; unadjusted MOR, 1.43 [95% CI, 1.34-1.54]), return of spontaneous circulation on emergency department arrival (range, 9.0%-57.1%; unadjusted MOR, 1.53 [95% CI, 1.43-1.65]), and favorable functional outcome (range, 0%-20.4%; unadjusted MOR, 1.54 [95% CI, 1.40-1.73]). This variation persisted despite adjustment for patient-level and EMS agency-level factors known to be associated with outcomes (adjusted MOR for survival 1.56 [95% CI 1.44-1.73]; adjusted MOR for return of spontaneous circulation at emergency department arrival, 1.50 [95% CI, 1.41-1.62]; adjusted MOR for functionally favorable survival, 1.53 [95% CI, 1.37-1.78]). After restricting analysis to those who survived more than 60 minutes after hospital arrival and including hospital treatment characteristics, the variation persisted (adjusted MOR for survival, 1.49 [95% CI, 1.36-1.69]; adjusted MOR for functionally favorable survival, 1.34 [95% CI, 1.20-1.59]).We found substantial variations in patient outcomes after OHCA between a large group of EMS agencies in North America that were not explained by documented patient-level and EMS agency-level variables.