tbuckley/cabot-search huggingface dataset:
Combined Menin and EGFR Inhibitors Synergize to Suppress Colorectal Cancer via EGFR-Independent and Calcium-Mediated Repression of SKP2 Transcription
Authors: Bryson W. Katona, Rebecca A. Glynn, Kayla E. Paulosky, Zijie Feng, Caroline I. Davis, Jian Ma, Corbett T. Berry, Katherine M. Szigety, Smita Matkar, Yuanyuan Liu, Haoren Wang, Yuan Wu, Xin He, Bruce D. Freedman, Donita C. Brady, Xianxin Hua
Journal: Cancer Research (2019)

Menin is a nuclear epigenetic regulator that can both promote and suppress tumor growth in a highly tissue-specific manner. The role of menin in colorectal cancer, however, remains unclear. Here, we demonstrate that menin was overexpressed in colorectal cancer and that inhibition of menin synergized with small-molecule inhibitors of EGFR (iEGFR) to suppress colorectal cancer cells and tumor xenografts in vivo in an EGFR-independent manner. Mechanistically, menin bound the promoter of SKP2, a pro-oncogenic gene crucial for colorectal cancer growth, and promoted its expression. Moreover, the iEGFR gefitinib activated endoplasmic reticulum calcium channel inositol trisphosphate receptor 3 (IP3R3)-mediated release of calcium, which directly bound menin. Combined inhibition of menin and iEGFR-induced calcium release synergistically suppressed menin-mediated expression of SKP2 and growth of colorectal cancer. Together, these findings uncover a molecular convergence of menin and the iEGFR-induced, IP3R3-mediated calcium release on SKP2 transcription and reveal opportunities to enhance iEGFR efficacy to improve treatments for colorectal cancer. SIGNIFICANCE: Menin acts as a calcium-responsive regulator of SKP2 expression, and small molecule EGFR inhibitors, which induce calcium release, synergize with Menin inhibition to reduce SKP2 expression and suppress colorectal cancer.
Altered cognitive function in systemic lupus erythematosus and associations with inflammation and functional and structural brain changes
Authors: Michelle Barraclough, Shane McKie, Ben Parker, Alan Jackson, Philip Pemberton, Rebecca Elliott, Ian N Bruce
Journal: Annals of the Rheumatic Diseases (2019)

Objectives Cognitive dysfunction (CD) is common in systemic lupus erythematosus (SLE) but the cause remains unclear and treatment options are limited. We aimed to compare cognitive function in SLE and healthy controls (HCs) using both behavioural and neuroimaging techniques. Methods Patients with SLE with stable disease and HCs were recruited. Clinical and psychological data were collected along with a blood sample for relevant biomarkers. Neurocognitive function was assessed using tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and functional magnetic resonance imaging (fMRI) was used to examine brain responses to working memory (WM) and emotional processing (facial emotional recognition task, FERT) tasks. Results Compared with HCs (n=30), patients with SLE (n=36) scored higher on measures of depression, fatigue and had higher hsCRP (p=0.013), IL-6 (p=0.003) and B lymphocyte stimulator (p&lt;0.001). Patients with SLE had poorer performance on a task of sustained attention (p=0.002) and had altered brain responses, particularly in default mode network (DMN) regions and the caudate, during the WM task. Higher organ damage and higher VCAM-1 were associated with less attenuation of the DMN (p=0.005 and p=0.01, respectively) and lower BOLD signal in the caudate areas (p=0.005 and p=0.001, respectively). Increased IL-6 was also associated with lower BOLD signal in caudate areas (p=0.032). Conclusions Sustained attention was impaired in patients with SLE. Poor attenuation of the DMN may contribute to cognitive impairments in SLE and our data suggest that in addition to mood and fatigue inflammatory mechanisms and organ damage impact cognitive functioning in SLE. The multifaceted nature of CD in SLE means any therapeutic interventions should be individually tailored.
Multi-Omic Biomarker Signatures Are Predictive Of The Allergen-Induced Late Phase Asthmatic Response
Authors: A Singh, CP Shannon, Y Kim, M DeMarco, K-A Le Cao, G Gauvreau, JM Fitzgerald, L-P Boulet, P O'Byrne, SJ Tebbutt
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
Abstract P115: Prevalence of Undiagnosed Diabetes Decreases by Eighty Percent When A1C Replaces the OGTT: The Africans in America Study
Authors: Sara M Briker, Regine Mugeni, Margrethe F Horlyck-Romanovsky, Jessica Y Aduwo, Christopher W DuBose, Lilian S Mabundo, Joon Ha, Arthur Sherman, David B Sacks, Anne E Sumner
Journal: Circulation (2019)

Introduction: Africa has the highest prevalence of undiagnosed diabetes (DM) in the world. It is unknown whether programs designed to screen for DM in Africa should rely on hemoglobin A 1C (A1C) or the 2h oral glucose tolerance test (OGTT). In general, the prevalence of undiagnosed DM is lower when detection is based on A1C rather than the OGTT. However, the degree to which the prevalence of undiagnosed DM would be lower in Africans if A1C rather than the OGTT was used is unknown. Heterozygous hemoglobinopathies such as sickle cell trait (SCT) and hemoglobin C (HbC) trait may lower A1C independent of the degree of glycemia, potentially compromising the ability of A1C to detect DM. Objective: Our goals were to determine in Africans the rate of detection and reproducibility of the diagnosis of DM by both A1C and OGTT. Methods: Ninety African-born blacks (66% (59/90) male, age 40±11y (mean±SD), BMI 27.6±4.6 kg/m 2 ) who self-identified as healthy, currently live in the Washington DC area and enrolled in the Africans in America study had two OGTT performed 10±8 days apart. At both visits A1C was assayed by HPLC from whole blood and glucose from plasma samples taken at -15, 0, 30, 60, 90 and 120 minutes. For A1C, DM was diagnosed by levels ≥6.5%. For the OGTT, fasting glucose ≥126 mg/dL or 2h glucose≥200 mg/dL was required to diagnose DM. The κ-statistic was used to evaluate reproducibility. Hemoglobin electrophoresis was performed. Results: At Visit 1: DM was diagnosed by A1C in 4% (4/90) and by OGTT in 26% (23/90). At Visit 2: DM was diagnosed by A1C in 3% (3/89) and by OGTT in 21% (19/90). Diagnosis by A1C and OGTT displayed substantial (κ=0.74) and almost perfect (κ=0.88) reproducibility, respectively. All persons with DM diagnosed by A1C criteria at either visit were also diagnosed by OGTT. However, 83% (19/23) of people with DM diagnosed by OGTT were not detected by A1C. In the entire cohort the combined prevalence of HbS and HbC trait was 14% (13/90). However, the prevalence of SCT and HbC trait in people with DM diagnosed by OGTT was 42% (8/19), but no one with SCT or HbC trait had an A1C level≥6.5%. Conclusion: Diagnosis of DM by both A1C and OGTT are highly reproducible in African immigrants. However, A1C detects 80% fewer people with DM than does the glucose criteria for the OGTT. The clinical consequences of this lower rate of detection of DM by A1C remains to be determined in prospective studies.
Comparison of breast cancer risk in women with and without systemic lupus erythematosus in a Medicare population.
Authors: Waseem Khaliq, Rehan Qayyum, Jeffrey Clough, Dhananjay Vaidya, Diane M Becker
Journal: Journal of Clinical Oncology (2015)

1576 Background: Studies have suggested a decreased breast cancer risk in patients with systemic lupus erythematosus (SLE). However, these studies enrolled primarily younger patients at lower risk of breast cancer identified from lupus clinics. Therefore, we examined a large population-based cohort assembled from a Medicare beneficiary population to compare the incidence of breast cancer among women with SLE with women without a diagnosis of SLE. Methods: We used 20% sample from 2006 Medicare claims data to assemble a cohort of women (N = 3,670,138), 84% of whom were ≥ 65 years. Women with a SLE diagnosis (ICD-9-CM 710.0) and population-based controls were identified and the incidence of breast cancer for women with and without SLE was determined during the following 5 years. Results: Of the 18,423 women with SLE who met inclusion criteria, 21% were African Americans and 53% were ≥ 65 years. Among women with SLE and without SLE the age adjusted risk for breast cancer was 2.23 (95% CI, 1.94-2.55) and 2.14 (95% CI, 1.96-2.34) per 100 women over five years respectively. The age and race adjusted incidence ratio for breast cancer was 1.04 (95% CI 0.90-1.21). Stratification by age and race showed no difference in the incidence ratio for breast cancer among women with SLE compared to their respective age-group controls. Conclusions: In contrast to clinic based cohorts, we found a similar risk of breast cancer in women with and without SLE in a population based cohort. Because the presence of SLE may affect breast cancer therapies, early detection is critical, so that optimal screening recommendations should be followed.
Evaluation of preoperative prostate magnetic resonance imaging for cancer control and neurovascular tissue preservation during robotic radical prostatectomy.
Authors: Samuel A Gold, Amir H Lebastchi, Jonathan Bloom, Sherif Mehralivand, Patrick H Gomella, Thomas Sanford, Graham Hale, Vladimir Valera, Mark Wayne Ball, Maria J Merino, Peter L. Choyke, Baris Turkbey, Peter A. Pinto
Journal: Journal of Clinical Oncology (2019)

101 Background: Prostate multi-parametric magnetic resonance imaging (mpMRI) can precisely depict prostate cancer (PCa) location and adverse pathologic features. Surgeons can utilize this information to maximize sparing of the neurovascular bundles (NVBs) during radical prostatectomy (RP) while avoiding a positive surgical margin (PSM). We detail the technique of using preoperative mpMRI to quantify its effect regarding nerve-sparing and rates of PSMs. Methods: A prospectively maintained database was queried for robotic-assisted RPs (RARPs) with preoperative mpMRI between 2007-2017. Imaging margin risk factors (iMRF) were defined on mpMRI as frank extraprostatic extension (EPE), possible EPE, and capsular irregularity (capsular bulge, lesion-capsule contact, or lesion adjacency to the neurovascular bundles). Surgical adjustments to nerve-sparing technique (full sparing, partial sparing, and wide excision) were made based on these findings. Results: Five hundred thirty-two patients comprising 1041 prostate sides were included for analysis. Overall, PSM rate was found in 80/1041 (7.7%) sides of the prostate. iMRF were seen in 313/1041 (30.1%) prostate sides, for which adjustments were made in 244/313 (78.0%) of these. In the 69/244 (22.0%) cases where full nerve-sparing was performed despite iMRF, PSM rate was 20/69 (29%) compared to 33/244 (13.5%), p = 0.002. MRI-guided surgical adjustments decreased PSM risk by 68% and 15% in pT3 and pT2 cases, respectively. On multivariable analysis, log PSA (odds ratio [OR] 4.06, [95% CI 2.40-12.3], p &lt; 0.001) and iMRF (OR 1.78, [95% CI 1.01-3.16], p = 0.047) were significantly associated with PSM while nerve-sparing adjustment was significantly associated with decreased risk of PSM (OR 0.38 [95% CI 0.22-0.66], p = 0.001). Conclusions: MRI effectively detects risks for PSM and guides surgical adjustments to decrease PSM rates. As prostate MRI is more frequently acquired for PCa screening and biopsy, we show its additional value for RP planning and potentially improved outcomes.
Implementing personalized pathways for cancer follow‐up care in the United States: Proceedings from an American Cancer Society–American Society of Clinical Oncology summit
Authors: Catherine M. Alfano, Deborah K. Mayer, Smita Bhatia, Jane Maher, Jessica M. Scott, Larissa Nekhlyudov, Janette K. Merrill, Tara O. Henderson
Journal: CA A Cancer Journal for Clinicians (2019)

Abstract A new approach to cancer follow‐up care is necessary to meet the needs of cancer survivors while dealing with increasing volume and provider shortages, knowledge gaps, and costs to both health care systems and patients. An approach that triages patients to personalized follow‐up care pathways, depending on the type(s) and level(s) of resources needed for patients’ long‐term care, is in use in the United Kingdom and other countries and has been shown to meet patients’ needs, more efficiently use the health care system, and reduce costs. Recognizing that testing and implementing a similar personalized approach to cancer follow‐up care in the United States will require a multipronged strategy, the American Cancer Society and the American Society of Clinical Oncology convened a summit in January 2018 to identify the needed steps to move this work from concept to implementation. The summit identified 4 key strategies going forward: 1) developing a candidate model (or models) of care delivery; 2) building the case for implementation by conducting studies modeling the effects of personalized pathways of follow‐up care on patient outcomes, workforce and health care resources, and utilization and costs; 3) creating consensus‐based guidelines to guide the delivery of personalized care pathways; and 4) identifying and filling research gaps to develop and implement needed care changes. While these national strategies are pursued, oncology and primary care providers can lay the groundwork for implementation by assessing their patients’ risk of recurrence and the chronic and late effects of cancer as well as other health care needs and resources available for care and by considering triaging patients accordingly, referring patients to appropriate specialized survivorship clinics as these are developed, helping to support patients who are capable of self‐managing their health, setting expectations with patients from diagnosis onward for the need for follow‐up in primary care and/or a survivorship clinic, and improving coordination of care between oncology and primary care.
Quality of care for the initial management of stage IB1-IIA2 invasive cervical carcinomas.
Authors: Gina Mantia-Smaldone, Elizabeth Handorf, Angela Jain, Lainie P. Martin, Stephen C. Rubin
Journal: Journal of Clinical Oncology (2015)

e16596 Background: Due to available screening mechanisms, cervical cancer can be diagnosed at early stages. Our aim was to examine adherence to category 1 NCCN guidelines for the initial management of stage IB1-IIA2 cervical cancers using a large national cancer registry. Methods: Using the National Cancer Database (NCDB), patients with stage IB1-IIA2 cervical cancers were identified from 1998-2012. Category 1 recommendations were strictly defined as receipt of radical hysterectomy (RH+LN) with regional lymph node assessment (Stage IB1/IIA1) and chemoradiation (Stage IB/IIA2). Cochran-Armitage tests were used to examine trends over time and receipt of guideline recommended care was assessed using generalized estimating equations adjusting for patient and clinical characteristics. Results: 20,411 patients with Stage IB1-IIA2 cancers were identified (73.7% IB1/IIA1; 26.2% IB2/IIA2). Overall, 46% of women with IB1/IIA1 cancers received RH+LN, but there was a small but significant decrease in utilization noted from 1998-2012 (45.8 vs. 41.9%, -0.5% per year, p = 0.001). Patients least likely to receive RH+LN were age > 70 years (OR 0.32 [CI 0.31-0.45]), African American race (OR 0.67 [CI 0.56-0.79]), or have Medicare (OR 0.80 [CI 0.69-0.82]) or Medicaid (OR 0.90 [CI 0.81-0.99]) insurance, while patients were more likely to undergo RH+LN if treated at a comprehensive (OR 1.43 [CI 1.17-1.76]) or academic (OR 1.67 [CI 1.36-2.05]) center. For stage IB2/IIA2 cancers, there was a substantial increase in utilization of chemoradiation over time (51% to 72%; P < 0.001). Following adjustment, patients > 70 years were least likely to receive chemoradiation (OR 0.44 [CI 0.34-0.58]) while no other significant associations were demonstrated. Conclusions: In the NCDB, utilization of RH+LN for stage IB1/IIA1 cancers decreased from 1998-2012, while receipt of chemoradiation for stage IB2/IIA2 cancers significantly increased over the same period. Evaluating mechanisms to improve adherence to contemporary best practice guidelines should be for a priority for emerging quality of care initiatives.
A Novel ACKR2-Dependent Role of Fibroblast-Derived CXCL14 in Epithelial-to-Mesenchymal Transition and Metastasis of Breast Cancer
Authors: Elin Sjöberg, Max Meyrath, Laura Milde, Mercedes Herrera, John Lövrot, Daniel Hägerstrand, Oliver Frings, Margarita Bartish, Charlotte Rolny, Erik Sonnhammer, Andy Chevigné, Martin Augsten, Arne Östman
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Fibroblasts expressing the orphan chemokine CXCL14 have been previously shown to associate with poor breast cancer prognosis and promote cancer growth. This study explores the mechanism underlying the poor survival associations of stromal CXCL14. Experimental Design: Tumor cell epithelial-to-mesenchymal transition (EMT), invasion, and metastasis were studied in in vitro and in vivo models together with fibroblasts overexpressing CXCL14. An approach for CXCL14 receptor identification included loss-of-function studies followed by molecular and functional endpoints. The clinical relevance was further explored in publicly available gene expression datasets. Results: CXCL14 fibroblasts stimulated breast cancer EMT, migration, and invasion in breast cancer cells and in a xenograft model. Furthermore, tumor cells primed by CXCL14 fibroblasts displayed enhanced lung colonization after tail-vein injection. By loss-of function experiments, the atypical G-protein–coupled receptor ACKR2 was identified to mediate CXCL14-stimulated responses. Downregulation of ACKR2, or CXCL14-induced NOS1, attenuated the pro-EMT and migratory capacity. CXCL14/ACKR2 expression correlated with EMT and survival in gene expression datasets. Conclusions: Collectively, the findings imply an autocrine fibroblast CXCL14/ACKR2 pathway as a clinically relevant stimulator of EMT, tumor cell invasion, and metastasis. The study also identifies ACKR2 as a novel mediator for CXCL14 function and thereby defines a pathway with drug target potential. See related commentary by Zhang et al., p. 3476
Value of anticancer drugs in castrate-resistant prostate cancer: Hazard ratio and survival-based methodology.
Authors: Helmy M. Guirgis
Journal: Journal of Clinical Oncology (2015)

e16013 Background: Survival is not reached at the end of some clinical studies and might vary along the time curve. Hazard ratio (HR) has rarely been integrated in cost and outcome evaluation. In the United States (US), the Department of Health and Human Services has set a goal of tying 85% of payments to quality and cost measures by 2016. Costly drugs are widely used in prostate cancer. The aim was to weigh drug cost in US$ against hazard ratio (HR) and survival (value) in chemo-naïve patients with castrate-resistant prostate cancer (CRPC). Methods: Overall survival gain over control in days (OSg) and HR were abstracted from previous reports. Cost/LYG were compared with cost/probability of survival (PoS) calculated as (1.0 - HR). Results: There were wide differences between cost/LYG and cost/HR (Table). Generic docetaxel demonstrated the lowest cost/LYG and lowest cost/PoS. Sipuleucel-T was the highest. Abiraterone and enzalutamide values were essentially comparable varying with HR and OS. Conclusions: The results suggest that parallel use of HR and survival could offer more balanced drug values.Cost/ outcome of docetaxel was the lowest as compared with other drugs. Differences in disease, populations and drugs preclude direct value comparison. Drug/combination OSg & HR Cost Cost/OSg Cost/LYG Cost/PoS Docetaxel iv + Ancillary costs 72 & 0.76 5,266 73 26,330 21,942 Sipuleucel-T iv, x 3 doses 123 & 0.78 93,000 756 272,195 422,727 Abiraterone 1000mg po x 6 months (m), (COU-AA-302) 132 & 0.80 37,200 282 101,455 186,000 Enzalutamide 160mg po x 6m, PREVAIL 66 & 0.70 44,700 677 243,818 149,000
Abstract 012: Performance of Polygenic Risk Scores for Coronary Artery Disease in the Million Veteran Program
Authors: Catherine Tcheandjieu, Xiang Zhu, Shining Ma, Austin Hilliard, Shoa L Clarke, Julie A Lynch, Scott M Damrauer, Amit V Khera, Sekar Kathiresan, Philip S Tsao, J. Michael Gaziano, Peter W Wilson, Christopher O’Donnell, Themistocles L Assimes
Journal: Circulation (2019)

Introduction: Recent studies suggest a substantial improvement in risk prediction of coronary artery disease (CAD) with polygenic risk scores (PRS). The degree to which this improvement is generalizable to other European (EUR) and non-EUR populations remains unclear. Hypothesis: We hypothesized that genome-wide PRSs trained and validated in the UK Biobank (UKBB) would perform best in external EUR populations and reduce the performance gap in prediction between EURs and African Americans (AA). Methods: We tested our hypothesis in ~91 000 EUR, AA, and Hispanic (HISP) Million Veteran Program (MVP) participants with CAD and ~225 000 non-cases as of July 2017. We created 5 separate weighted PRSs in all participants using: 1) 164 genome-wide significant SNPs for CAD (164SNPs), 2) 46 000 Metabochip SNPs (GRS46K), 3) 1.5 million (M) SNPs from standard pruning &amp; thresholding of CARDIOGRAM+C4D (Khera_P&amp;T), 4) 6.6M SNPs PRS created with LDpred (LDpred_Khera), and 5) 1.7M SNP PRS combining weights of 3 PRSs through meta-analysis (meta-GRS). We estimated age &amp; sex adjusted Odds Ratios (OR) of CAD per standard deviation increase in each PRS using logistic regression and performed sensitivity analyses in subgroups of cases and non-cases. Results: LDpred and meta-GRS performed best among EURs (figure). However, the point estimate of the OR for these PRSs in MVP was notably lower than that observed in the UKBB (1.36 vs. ~1.7). ORs in MVP were higher among participants with early-onset disease (1.39), myocardial infarction (1.52), and revascularization (1.56) but lower for incident events after enrollment (1.27). Performance in HISP was mildly diluted but all PRS performed poorly among AA (figure). Conclusion: Genome-wide PRSs developed in the UKBB transfer best to external EUR populations but may over-estimate risk and do not close the performance gap in prediction between EURs and AAs. Our findings highlight a need for better calibrated PRSs specific to the cohort and race/ethnic group being tested prior to implementation in clinical practice.
Health Status After Transcatheter Mitral-Valve Repair in Heart Failure and Secondary Mitral Regurgitation
Authors: Suzanne V. Arnold, Khaja M. Chinnakondepalli, John A. Spertus, Elizabeth A. Magnuson, Suzanne J. Baron, Saibal Kar, D. Scott Lim, Jacob M. Mishell, William T. Abraham, JoAnn A. Lindenfeld, Michael J. Mack, Gregg W. Stone, David J. Cohen
Journal: Journal of the American College of Cardiology (2019)