tbuckley/cabot-search huggingface dataset:
Factors Associated With and Prognostic Implications of Cardiac Troponin Elevation in Decompensated Heart Failure With Preserved Ejection Fraction
Authors: Ambarish Pandey, Harsh Golwala, Shubin Sheng, Adam D. DeVore, Adrian F. Hernandez, Deepak L. Bhatt, Paul A. Heidenreich, Clyde W. Yancy, James A. de Lemos, Gregg C. Fonarow
Journal: JAMA Cardiology (2016)

<h3>Importance</h3> Elevated levels of cardiac troponins are associated with adverse clinical outcomes among patients with heart failure (HF) and reduced ejection fraction. However, the clinical significance of troponin elevation in the setting of decompensated HF with preserved ejection fraction (HFpEF) is not well established. <h3>Objective</h3> To determine the clinical predictors of troponin elevation and its association with in-hospital and long-term outcomes among patients with decompensated HFpEF. <h3>Design, Setting, and Participants</h3> Observational analysis of Get With The Guidelines–HF registry participants who were admitted for decompensated HFpEF (ejection fraction ≥50%) from January 2009 through December 2014 and who had quantitative or categorical (elevated vs normal based on institution’s reference laboratory) measures of troponin level (troponin T or troponin I, as available). <h3>Main Outcomes and Measures</h3> In-hospital outcomes (mortality, length of stay, and discharge destination) and postdischarge outcomes (30-day mortality, 30-day readmission rate, 1-year mortality). <h3>Results</h3> We included 34 233 patients with HFpEF from 224 sites with measured troponin levels (33.4% men; median age, 79 years): 78.6% (n = 26 896) with troponin I and 21.4% (n = 7319) with troponin T measurements. Among these, 22.6% (n = 7732) had elevation in troponin levels. In adjusted analysis, higher serum creatinine level, black race, older age, and ischemic heart disease were associated with troponin elevation. Elevated troponin was associated with higher odds of in-hospital mortality (odds ratio [OR], 2.19; 95% CI, 1.88-2.56), greater length of stay (length of stay &gt;4 days OR, 1.38; 95% CI, 1.29-1.47), and lower likelihood of discharge to home (OR, 0.65; 95% CI, 0.61-0.71) independent of other clinical predictors and measured confounders. Presence of elevated troponin I levels was also significantly associated with increased risk of 30-day mortality (hazard ratio [HR], 1.59; 95% CI, 1.42-1.80), 30-day all-cause readmission (HR, 1.12; 95% CI, 1.01-1.25), and 1-year mortality HR, 1.35; 95% CI, 1.26-1.45). <h3>Conclusions and Relevance</h3> Troponin elevation among patients with acutely decompensated HFpEF is associated with worse in-hospital and postdischarge outcomes, independent of other predictive variables. Future studies are needed to determine if measurement of troponin levels among patients with decompensated HFpEF may be useful for risk stratification.
Inflammation and elevated levels of fibroblast growth factor 23 are independent risk factors for death in chronic kidney disease
Authors: Jair Munoz Mendoza, Tamara Isakova, Xuan Cai, Liz Y. Bayes, Christian Faul, Julia J. Scialla, James P. Lash, Jing Chen, Jiang He, Sankar Navaneethan, Lavinia Negrea, Sylvia E. Rosas, Matthias Kretzler, Lisa Nessel, Dawei Xie, Amanda Hyre Anderson, Dominic S. Raj, Myles Wolf, Lawrence J. Appel, Harold I. Feldman, Alan S. Go, Jiang He, John W. Kusek, James P. Lash, Akinlolu Ojo, Raymond R. Townsend
Journal: Kidney International (2016)
154. Targeting Hypoxic and Angiogenic Tumor Microenvironment with pH-Sensitive Oncolytic Adenovirus
Authors: Joung-Woo Choi, Soo-Jung Jung, Kasala Dayananda, June Kyu Hwang, Jun Hu, You Han Bae, Chae-Ok Yun
Journal: Molecular Therapy (2015)

Although oncolytic adenoviruses (Ads) are an attractive option for cancer gene therapy, the intravenous administration of naked Ad still encounters unfavorable host responses, non-specific interactions, and heterogeneity in targeted cancer cells. To overcome these obstacles and achieve specific targeting of the tumor microenvironment, Ad was coated with the pH-sensitive block copolymer, methoxy poly(ethylene glycol)-b-poly(L-histidine-co-L-phenylalanine) (PEGbPHF). The physicochemical properties of the generated nanocomplex, Ad/PEGbPHF, were assessed. At pH 6.4, GFP-expressing Ad/PEGbPHF induced significantly higher GFP expression than naked Ad in both coxsackie and adenovirus receptor (CAR)-positive and -negative cells. To assess the therapeutic efficacy of the Ad/PEGbPHF complex platform, VEGF promoter-targeting transcriptional repressor zinc-finger protein-expressing oncolytic Ad (KOX) was used to form complexes. At pH 6.4, KOX/PEGbPHF significantly suppressed VEGF gene expression, cancer cell migration, vessel sprouting, and cancer cell killing effect compared to naked KOX or KOX/PEGbPHF at pH 7.4, demonstrating that KOX/PEGbPHF can overcome the lack of CAR that is frequently observed in tumor tissues. The antitumor activity of KOX/PEGbPHF systemically administered to a tumor xenograft model was significantly higher than that of naked KOX. Furthermore, KOX/PEGbPHF showed lower hepatic toxicity and did not induce an innate immune response against Ad. Altogether, these results demonstrate that pH sensitive polymer coated Ad complex significantly increase net positive charge upon exposure to hypoxic tumor microenvironment, allowing it to passive target to tumor site. It may offer superior potential for systemic therapy, due to its improved tumor selectivity, increased therapeutic efficacy, and lower toxicity compared to naked KOX.
Abstract AS18: The somatic mutational landscape of endometriosis associated ovarian cancers and precursor lesions
Authors: Michael S Anglesio, Ali Bashashati, Yikan Wang, Gavin Ha, Janine Senz, Winnie Yang, Steve E Kalloger, Leah M Prentice, Satoshi Yanagida, Clara Salamanca, Galina Soukhatcheva, Anthony Kazernis, Hector Chang, Anne-Marie Mes-Mason, Aikou Okamoto, Marco A Marra, Blake Gilks, Sohrab P Shah, David G Huntsman
Journal: Clinical Cancer Research (2015)

Abstract Introduction: Clear Cell ovarian carcinomas (CCC) represent 10% of ovarian carcinomas, with outcomes for high-stage significantly worse than high-grade serous form. The complete mutational landscape, the molecular basis of the transformation of endometriosis, the putative precursor, and patterns of clonal evolution in CCC are not well understood. Methods: Whole genome sequencing and gene expression profiling was done to uncover somatic alterations and measure effects on transcriptional networks. Targeted deep sequencing of primary tumors, metastases and endometriosis was also performed and statistical modeling approaches were used to validate mutations, quantify clonal diversity, and trace patterns of selection. Results: Mutations in ARID1A (11/19) and PIK3CA (8/19) were by far the most frequent aberrations seen. Three other SWI/SNF components also showed somatic alteration: two in non-ARID1A mutant cases and a truncating mutation of ARID1B in an ARID1A-null case. Amongst 24 significant “candidate drivers” impacting expression, five “cancer genes” have been previously described: PIK3CA, ARID1A, CTNNB1, TP53, and PPP2R1A. We observed no association between PIK3CA or ARID1A status with disease stage, genomic instability, or mutation load. Deep sequencing data suggested multiple clones in every case. In cases with matching precursor lesions, we observed multiple mutations in at least one such lesion. In precursor lesions where tumor-matched somatic mutations were observed, ARID1A and PIK3CA mutations were also always present, if observed in the matched tumor. Conclusions: ARID1A and PIK3CA mutations appear as early and histo-type defining events in CCC. Pattern of endometriosis transformation can be associated with somatic mutations in all cases, including histologically “Atypical” and non-atypical endometriosis. Finally, patterns of mutational conservation across the series of precursor lesions may present an opportunity for early screening of endometriosis tissues as an indicator of transformation potential. Citation Format: Michael S Anglesio, Ali Bashashati, Yikan Wang, Gavin Ha, Janine Senz, Winnie Yang, Steve E Kalloger, Leah M Prentice, Satoshi Yanagida, Clara Salamanca, Galina Soukhatcheva, Anthony Kazernis, Hector Chang, Anne-Marie Mes-Mason, Aikou Okamoto, Marco A Marra, Blake Gilks, Sohrab P Shah, David G Huntsman. The somatic mutational landscape of endometriosis associated ovarian cancers and precursor lesions [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS18.
The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis
Authors: Clair Crewe, Yu Aaron An, Philipp E. Scherer
Journal: Journal of Clinical Investigation (2017)

There are three dominant contributors to the pathogenesis of dysfunctional adipose tissue (AT) in obesity: unresolved inflammation, inappropriate extracellular matrix (ECM) remodeling and insufficient angiogenic potential. The interactions of these processes during AT expansion reflect both a linear progression as well as feed-forward mechanisms. For example, both inflammation and inadequate angiogenic remodeling can drive fibrosis, which can in turn promote migration of immune cells into adipose depots and impede further angiogenesis. Therefore, the relationship between the members of this triad is complex but important for our understanding of the pathogenesis of obesity. Here we untangle some of these intricacies to highlight the contributions of inflammation, angiogenesis, and the ECM to both "healthy" and "unhealthy" AT expansion.
[<sup>68</sup>Ga]Pentixafor-PET/CT for imaging of chemokine receptor CXCR4 expression in multiple myeloma - Comparison to [<sup>18</sup>F]FDG and laboratory values
Authors: Constantin Lapa, Martin Schreder, Andreas Schirbel, Samuel Samnick, Klaus Martin Kortüm, Ken Herrmann, Saskia Kropf, Herrmann Einsele, Andreas K. Buck, Hans-Jürgen Wester, Stefan Knop, Katharina Lückerath
Journal: Theranostics (2016)

Chemokine (C-X-C motif) receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer including multiple myeloma (MM). Proof-of-concept of CXCR4-directed radionuclide therapy in MM has recently been reported. This study assessed the diagnostic performance of the CXCR4-directed radiotracer [68Ga]Pentixafor in MM and a potential role for stratifying patients to CXCR4-directed therapies. Thirty-five patients with MM underwent [68Ga]Pentixafor-PET/CT for evaluation of eligibility for endoradiotherapy. In 19/35 cases, [18F]FDG-PET/CT for correlation was available. Scans were compared on a patient and on a lesion basis. Tracer uptake was correlated with standard clinical parameters of disease activity. [68Ga]Pentixafor-PET detected CXCR4-positive disease in 23/35 subjects (66%). CXCR4-positivity at PET was independent from myeloma subtypes, cytogenetics or any serological parameters and turned out as a negative prognostic factor. In the 19 patients in whom a comparison to [18F]FDG was available, [68Ga]Pentixafor-PET detected more lesions in 4/19 (21%) subjects, [18F]FDG proved superior in 7/19 (37%). In the remaining 8/19 (42%) patients, both tracers detected an equal number of lesions. [18F]FDG-PET positivity correlated with [68Ga]Pentixafor-PET positivity (p=0.018). [68Ga]Pentixafor-PET provides further evidence that CXCR4 expression frequently occurs in advanced multiple myeloma, representing a negative prognostic factor and a potential target for myeloma specific treatment. However, selecting patients for CXCR4 directed therapies and prognostic stratification seem to be more relevant clinical applications for this novel imaging modality, rather than diagnostic imaging of myeloma.
Intermediate Dose Cyclophosphamide Followed by Sequential GM-CSF and G-CSF: An Efficient and Predictable PBPC Mobilization Regimen for Autografting: A Single Center Study of Two Hundred and Thirty Patients.
Authors: Thomas A. Lane, Lin Liu, Anita Ihasz, Bridget Medina, Sue Corringham, Peter Holman, Ewa Carrier, Januario Castro, Edward D. Ball, Asad Bashey
Journal: Blood (2005)
Use of Institutional Clinical Care Guidelines to Determine HA-VTE Risk Level for Consideration of Thromboprophylaxis in Hospitalized Children
Authors: Natalie Laing Smith, Kelsey Fowlkes, Beth Boulden Warren, Beth Wathen, Bryce Clark, Joanne M. Hilden, Daniel Hyman, Marilyn J. Manco-Johnson, Brian R. Branchford
Journal: Blood (2015)
Plerixafor Plus G-CSF Compared to Chemotherapy Plus G-CSF for Mobilization of Autologous CD34+ Cells Resulted in Similar Cost but More Predictable Days of Apheresis and Less Hospitalization.
Authors: Paul Shaughnessy, Miguel Islas-Ohlmayer, Julie Murphy, Maureen Hougham, Jill MacPherson, Kurt Winkler, Matthew Silva, Michael Steinberg, Jeffrey Matous, Sheryl Selvey, Michael Maris, Peter A. McSweeney
Journal: Blood (2009)
Abstract 4428: Metformin effects on ABCB1 expression and proliferation in pancreatic cancer cell lines with different ABCB1 genotypes/haplotypes
Authors: Beverly D. Lyn-Cook, Taylor Osborne, Stancy Joseph, Beverly Word, Li Pang, George Hammons
Journal: Cancer Research (2015)

Abstract Pancreatic cancer carries a poor prognosis and survival rate. Developing effective agents or repurposing agents with low toxicity, such as metformin, an insulin-lowering drug, has recently been investigated for pancreatic cancer. Metformin has long been associated with decreased cancer risk, particularly in diabetic patients. Although its major action is inhibiting hepatic glucose production, it also improves insulin sensitivity in peripheral tissues. This study demonstrates that metformin modulates the ATP-binding cassette gene, ABCB1, expression in pancreatic cancer cell lines with different ABCB1 genotypes. Metformin (100μM or 200μM) alone (p = 0.0212 or p = 0.0161) or in combination with gemcitabine (15nM) (p = 0.0248 or p = 0.0174) significantly decreased ABCB1 expression in Mia pancreatic cells after 24 hr and/or 72 hr treatments. This correlated to increased cell death. Metformin in combination with indole-3-carbinol also significantly (p = 0.0317) decreased ABCB1 expression. However, a sex or genotype difference was noted when two female pancreatic cell lines, SU86.86 and AsPC1, were used. Metformin did not down-regulate ABCB1 expression and was chemoresistance in these two cell lines. AsPC1 and SU86.86 both carry the 2677GG-3435CC ABCB1 haplotype compared to MiaPaca-2 which carries the 2677TT-3134TT ABCB1 haplotype. The 2677TT and 3435TT genotypes/haplotypes are known to be associated with lower risk of developing pancreatic cancer but these data demonstrate that these genotypes are also more sensitive to metformin treatment compared to the 2677GG or 3435CC genotypes. Further research is needed to ascertain whether sex or genotype is contributing to different efficacy of metformin in pancreatic cancer cells with different genotypes. Citation Format: Beverly D. Lyn-Cook, Taylor Osborne, Stancy Joseph, Beverly Word, Li Pang, George Hammons. Metformin effects on ABCB1 expression and proliferation in pancreatic cancer cell lines with different ABCB1 genotypes/haplotypes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4428. doi:10.1158/1538-7445.AM2015-4428
Abstract 1943: Integrin α6β4 promotes autocrine EGFR signaling to stimulate migration and invasion toward HGF
Authors: Brittany L. Carpenter, Min Chen, Teresa Knifley, Kelley A. Davis, Susan M. Harrison, Rachel L. Stewart, Kathleen L. O'Connor
Journal: Cancer Research (2015)

Abstract Integrin α6β4 is upregulated in pancreatic adenocarcinomas where it contributes to carcinoma cell invasion, in part, through its coordinated modulation of the transcriptome. Here, we find that integrin α6β4 signaling dramatically upregulates the expression of several genes involved in the epidermal growth factor receptor (EGFR) pathway, including amphiregulin (Areg), epiregulin (Ereg), and ectodomain cleavage protease MMP1. Notably, these genes correlate well with integrin α6β4 expression in publicly available pancreatic cancer databases. We previously reported that integrin α6β4 promotes HGF-stimulated migration and invasion; therefore, we tested the role of autocrine EGFR signaling in these processes. We discovered that blocking EGFR signaling with EGFR-specific blocking antibodies or an EGFR tyrosine kinase inhibitor hindered HGF-stimulated pancreatic carcinoma cell chemotaxis and invasive growth in three-dimensional culture. Furthermore, we found that both Areg and Ereg are required for these autocrine effects, as knocking down either ligand prevented migration and invasion. Notably, AsPC1 cells, isolated from abdominal metastases, are not dependent on EGFR signaling for migration or invasion; thus suggesting a mechanism exists for circumventing EGFR dependency. We also demonstrated that HGF stimulates the secretion of Areg, which is dependent on integrin signaling pathways including MAPK, PI3K and PKC and that Areg was transported to the leading edge of cells treated with HGF. Moreover, MMP activity and integrin α6β4 signaling are required for Areg secretion. Finally, we found that EGFR is phosphorylated in response to HGF stimulation which was dependent on EGFR protein kinase activity; however, Met phosphorylation in response to HGF was unaffected by EGFR signaling. Taken together, we show that integrin α6β4 stimulates invasion by promoting autocrine EGFR signaling through the upregulation of key genes and facilitating HGF-stimulated EGFR ligand secretion. Citation Format: Brittany L. Carpenter, Min Chen, Teresa Knifley, Kelley A. Davis, Susan M. Harrison, Rachel L. Stewart, Kathleen L. O'Connor. Integrin α6β4 promotes autocrine EGFR signaling to stimulate migration and invasion toward HGF. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1943. doi:10.1158/1538-7445.AM2015-1943
A gene expression inflammatory signature specifically predicts multiple myeloma evolution and patients survival
Authors: C Botta, M T Di Martino, D Ciliberto, M Cucè, P Correale, M Rossi, P Tagliaferri, P Tassone
Journal: Blood Cancer Journal (2016)

Multiple myeloma (MM) is closely dependent on cross-talk between malignant plasma cells and cellular components of the inflammatory/immunosuppressive bone marrow milieu, which promotes disease progression, drug resistance, neo-angiogenesis, bone destruction and immune-impairment. We investigated the relevance of inflammatory genes in predicting disease evolution and patient survival. A bioinformatics study by Ingenuity Pathway Analysis on gene expression profiling dataset of monoclonal gammopathy of undetermined significance, smoldering and symptomatic-MM, identified inflammatory and cytokine/chemokine pathways as the most progressively affected during disease evolution. We then selected 20 candidate genes involved in B-cell inflammation and we investigated their role in predicting clinical outcome, through univariate and multivariate analyses (log-rank test, logistic regression and Cox-regression model). We defined an 8-genes signature (IL8, IL10, IL17A, CCL3, CCL5, VEGFA, EBI3 and NOS2) identifying each condition (MGUS/smoldering/symptomatic-MM) with 84% accuracy. Moreover, six genes (IFNG, IL2, LTA, CCL2, VEGFA, CCL3) were found independently correlated with patients' survival. Patients whose MM cells expressed high levels of Th1 cytokines (IFNG/LTA/IL2/CCL2) and low levels of CCL3 and VEGFA, experienced the longest survival. On these six genes, we built a prognostic risk score that was validated in three additional independent datasets. In this study, we provide proof-of-concept that inflammation has a critical role in MM patient progression and survival. The inflammatory-gene prognostic signature validated in different datasets clearly indicates novel opportunities for personalized anti-MM treatment.
Alterations in a Panel of Serum Peptides Correlate with the Disease States of Multiple Myeloma
Authors: Ju Bai, Aili He, Wanggang Zhang, Yun Yang, Jianli Wang, Pengyu Zhang, Yuandong Feng, Lei Zhang, Hongli Chen, Xiaman Wang, Xiaoru Lei, Ying Shen, Lingjuan Huang
Journal: Blood (2015)
Swap pension pledges for guaranteed care in older age, says NHS boss
Authors: Matthew Limb
Journal: BMJ (2016)

The head of the NHS in England has said that radical new guarantees on retirement security could form part of a new, long term funding settlement for older people’s care.

Simon Stevens, NHS chief executive, told MPs that current pensioner benefits, including the “triple lock” and free bus passes, may need to be reconsidered so that social care provision can be expanded.

Pensioners are currently protected by a triple lock that lifts pensions by either inflation, earnings, or 2.5%, whichever is highest. But a new “triple guarantee on retirement security” could instead cover people’s income, their ability to live at home, and adequate social care, Stevens told the Communities and Local Government Committee on 14 December. The committee is investigating the financial sustainability …
Do obese women benefit less from adjuvant endocrine therapy with aromatase inhibitors? Preliminary analysis on the association of BMI and aromatase inhibitor plasma levels.
Authors: D. Egle, A. Oberguggenberger, R. Achleitner, M. Sztankay, V. Meraner, J. Giesinger, B. Sperner-Unterweger, B. Holzner, B. Beer, H. Oberacher, C. Marth, M. Hubalek
Journal: Journal of Clinical Oncology (2011)

e11118 Background: The efficacy of adjuvant endocrine treatment with aromatase inhibitors (AI), inhibiting the conversion of androgens to estrogen in adipose tissue, might depend on the volume of adipose tissue. The scientific community recently even has discussed to recommend an increase of the AI dose for obese women. However, little evidence is available regarding the potential interactions among adjuvant antihormonal treatment and obesity. We aimed at investigating the association of BMI and anastrozole plasma levels adjusted for age. Methods: We prospectively included 114 postmenopausal early breast cancer patients undergoing aromatase inhibitor treatment with anastrozole at one of their regular after-care check-ups. Sociodemographic and clinical data as well as data on weight and size for the calculation of BMI were comprehensively assessed. Blood samples were collected within the routine blood collection and measurement of aromatase inhibitor plasma levels were performed by liquid chromatography–tandem mass spectrometry. The association of anastrozole plasma levels, BMI and age was analyzed using linear regression analysis. Results: We analyzed data of 109 postmenopausal patients. Non-adherent patients (n=5, no AI plasma concentration) were excluded from the analysis. 2.1% patients were underweight (defined BMI<19.5), 47.4% (defined BMI 20-25.5) had normal weight and 50.5 (defined BMI>25.5) patients were obese. Mean patient age was 64.7 (SD 8.6) years. Regression analysis revealed that age (t=2.850, p=0.005) was a stronger predictor of higher AI plasma level than BMI. Other variables had no impact on AI blood level. Conclusions: In this study, BMI did not serve as a predictor for anastrozole plasma concentrations. Analysis proved older age to be highly predictive of increased AI plasma levels. According to these finding, it is unclear whether AI dose recommendations have to be adjusted for obesity. However, the subject of age in terms of AI metabolization has to be enhanced. Further research in that matter is mandatory to clarify results on the association of obesity and AI therapy efficacy.