tbuckley/cabot-search huggingface dataset:
Abstract 2537: Regulation of LMO2 oncogene expression in high-risk B-cell acute lymphoblastic leukemia
Authors: Yali Ding, Jonathon L. Payne, Shriya Kane, Elanora Dovat, Mario Soliman, Chunhua Song, Sinisa Dovat
Journal: Cancer Research (2018)

Abstract LIM domain only protein 2 (LMO2) is an oncogene that is overexpressed in a subset of B-cell acute lymphoblastic leukemia (B-ALL). The mechanisms that regulate LMO2 expression in B-ALL are still unknown. Here, we show that transcription of LMO2 in B-ALL is regulated by Ikaros, a tumor suppressor protein, which is encoded by the IKZF1 gene, and whose deletion is associated with development of high-risk B-ALL. The use of global chromatin immunoprecipitation coupled with the next-generation sequencing (ChIP-seq) studies in primary human B-ALL cells and in cell lines revealed a strong Ikaros occupancy at the promoter of the LMO2 gene. Ikaros binding to the LMO2 promoter was confirmed by quantitative chromatin immunoprecipitation (qChIP). We tested the role of Ikaros in regulating LMO2 transcription in B-ALL using gain-of-function and loss-of-function experiments. A luciferase reporter assay with the LMO2 promoter showed that Ikaros directly represses LMO2 transcription. Overexpression of Ikaros in B-ALL via retroviral transduction was associated with strongly reduced expression of LMO2. Furthermore, Ikaros knock-down with shRNA, resulted in increased transcription of LMO2 in B-ALL cells. These results suggest that Ikaros represses transcription of LMO2 in B-ALL. Since Ikaros' function in B-ALL is negatively regulated by pro-oncogenic Casein Kinase II (CK2), we tested whether CK2 inhibition affects Ikaros-mediated repression of LMO2. Both molecular inhibition with shRNA, and pharmacological inhibition of CK2 with a specific CK2 inhibitor, CX-4945, resulted in reduced expression of LMO2. Inhibition of CK2 was also associated with increased Ikaros occupancy at the LMO2 promoter. In high-risk B-ALL that have deletion of a single copy of the IKZF1 gene, Ikaros does not bind to the LMO2 promoter. Treatment of primary B-ALL cells that have IKZF1 haploinsufficiency restores Ikaros binding to the LMO2 promoter and results in reduced LMO2 expression. In conclusion, our data demonstrate that Ikaros and CK2 regulate transcription and overall expression of the LMO2 oncogene in B-ALL. Our results identify a novel mechanism of therapeutic action of CK2 inhibitors in high-risk B-ALL—repression of LMO2 expression via restoration of Ikaros' tumor suppressor function. Citation Format: Yali Ding, Jonathon L. Payne, Shriya Kane, Elanora Dovat, Mario Soliman, Chunhua Song, Sinisa Dovat. Regulation of LMO2 oncogene expression in high-risk B-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2537.
Abstract 19419: Novel Remodeling Mitral Annuloplasty Ring That Preserves Axial Dynamics of the Native Mitral Annulus
Authors: Søren N Skov, Diana M Røpcke, Marcell J Tjørnild, Christine Ilkjær, Jonas Rasmussen, Hans Nygaard, J M Hasenkam, Morten O Jensen, Sten L Nielsen
Journal: Circulation (2016)

Introduction: The design of mitral annuloplasty rings has evolved over the last decades with the introduction of flexible and semi-rigid rings. The rings have been developed to restore systolic saddle shaped annulus configuration while allowing mitral annular motion in specific directions. Despite acceptable results with annuloplasty rings there is still a need for innovations of annuloplasty devices that ensures a competent valve and maintains the natural out-of-annular-plane dynamics. In this study we tested a prototype of a novel remodeling annuloplasty ring with built-in septal-lateral annular fixation and commissural axial flexibility. The aim was to evaluate the biomechanical performance of the new remodeling annuloplasty ring compared to two common commercially available remodeling annuloplasty rings. Methods: The measurements were performed in-vivo in an 80 kg porcine model. 28 animals were randomized evenly in four groups: A No ring, a novel remodeling ring, a semi-rigid ring (CE Physio ITM Ring)...
Abstract 1430: Improved sample indexing for high fidelity demultiplexing to increase confidence in low frequency variant calling
Authors: Jonathan C. Irish, Jordan RoseFigura, Sukhinder K. Sandhu, Bita Carrion, Laurie Kurihara, Vladimir Makarov
Journal: Cancer Research (2018)

Abstract Due to recent scientific advances, there is a growing demand for new indices with high fidelity to eliminate errors associated with certain index combinations and sequencing chemistries. These errors are due to insufficient edit distances (the minimum number of changes required to transform one index sequence to the other) between index sequences or index hopping. Recent publications have highlighted how sequencing reads are misassigned due to "index hopping" on Illumina patterned flow cells, such as the recently launched Illumina Novaseq which can generate billions of reads (&amp;gt;100 exomes) in a single run. This misassignment canlead to false positives in ultra-sensitive assays where low frequency variants or nucleic acid species are monitored. We have observed misassignment due to insufficient edit distance among Illumina TruSeq HT i7 indices at a frequency up to 1.5%. Therefore, we developed 968nt i7 indices that can be paired with the existing TruSeq HT i5 indices to achieve 768 high throughput dual combinations, which were validated using a novel method on both Illumina's 2- and 4-channel technologies as both single and dual indices. This method involved thepreparation of 96 libraries with unique, non-overlapping inserts to facilitate tracking of index misassignment. This allowed us to assess not only which index has misassigned library molecules, but also pinpoint the origin and rate of misassignment within a single run. With our 96 i7 indices, misassignment was observed at rates &amp;lt;0.1%. For even higher fidelity de-multiplexing, we have paired our 96 indices in a non-tandem manner for single use in both the i5 and i7 positions, known as Unique Dual Indices (UDIs). The use of UDIs further eliminates index read errors that misassign reads, enabling increased confidence in calling low frequency variants. UDIs can also eliminate PCR-induced chimerisms, which can significantly improve data from a variety of assays. We are validating 96 new indices as UDIs for avoidance of index hopping and for eliminating PCR-induced chimerism during multiplexed library amplification. Citation Format: Jonathan C. Irish, Jordan RoseFigura, Sukhinder K. Sandhu, Bita Carrion, Laurie Kurihara, Vladimir Makarov. Improved sample indexing for high fidelity demultiplexing to increase confidence in low frequency variant calling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1430.
Abstract 4276: Analysis of sensitivity of genomic signatures of therapeutic responses of non-small cell lung cancer in patient-derived xenograft models
Authors: Iman Tavassoly, Ravi Iyengar
Journal: Cancer Research (2018)

Abstract Genomic alterations are important characteristics of therapeutic responses and therapeutic-resistance phenotype in cancer. These genomic alterations are complex and are determinants of aberrations in signaling pathways and their dynamics. A genomic signature includes a set of genomic alterations like gene expressions, mutations, copy number variations, etc. These genomic signatures are used as biomarkers for assigning treatment to individuals benefiting from a specific treatment plan and are validated using preclinical models such as patient-derived xenograft models (PDX models). We have proposed a methodology to optimize these genomic signatures in silico and evaluate their accuracy in vivo using PDX models of non-small cell lung cancer (NSCLC). Our integrative analysis has shown that different sizes and complexities of gene sets provide different layers of information applicable in designing therapeutic regimens. To eliminate sloppy signatures, it is possible to find optimized and sensitive genomic signatures for precision oncology. Citation Format: Iman Tavassoly, Ravi Iyengar. Analysis of sensitivity of genomic signatures of therapeutic responses of non-small cell lung cancer in patient-derived xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4276.
Abstract 14832: Immunologic Targeting of CD30 Eliminates Tumorigenic Human Pluripotent Stem Cells (iPSC) Allowing Safer Clinical Application of hiPSC-Based Therapy
Authors: NagakoSougawa, ShigeoMasuda, ShigeruMiyagawa, SatsukiFukushima, EmikoIto, AtsuhiroSaito, YoshikiSawa
Journal: Circulation (2014)

Background: Human induced pluripotent stem cells (hiPSCs) are considered to be invaluable for regenerative medicine. However, they carry the risk of teratoma formation by residual undifferentiated cells, and it is important to develop a means of eliminating all residual tumorigenic cells before clinical application. Cell surface markers of hiPSCs can be useful for selective removal of undifferentiated hiPSCs from differentiated cultures. Although cell sorting strategies may be feasible, they are time-consuming and reduce cell viability. In this study, we hypothesized that cell selection using an antibody-cytotoxic drug conjugate may be clinically useful for immunologic targeting of undifferentiated cells. Methods and Results: We first compared CD antigen expression patterns between undifferentiated and differentiated cells and found that CD30, CD50, TRA-1-60, and TRA-1-81 were highly expressed on undifferentiated cells. The CD30-negative fraction was less positive for Lin28, a pluripotent marker. To elimi...
The Expanding Complexity of Estrogen Receptor Signaling in the Cardiovascular System
Authors: SaraMenazza, ElizabethMurphy
Journal: Circulation Research (2016)

Estrogen has important effects on cardiovascular function including regulation of vascular function, blood pressure, endothelial relaxation, and the development of hypertrophy and cardioprotection. However, the mechanisms by which estrogen mediates these effects are still poorly understood. As detailed in this review, estrogen can regulate transcription by binding to 2 nuclear receptors, ERα and ERβ, which differentially regulate gene transcription. ERα and ERβ regulation of gene transcription is further modulated by tissue-specific coactivators and corepressors. Estrogen can bind to ERα and ERβ localized at the plasma membrane as well as G-protein–coupled estrogen receptor to initiate membrane delimited signaling, which enhances kinase signaling pathways that can have acute and long-term effects. The kinase signaling pathways can also mediate transcriptional changes and can synergize with the ER to regulate cell function. This review will summarize the beneficial effects of estrogen in protecting the car...
Activated Forms of VEGF-C and VEGF-D Provide Improved Vascular Function in Skeletal Muscle
Authors: AndreyAnisimov, AnnamariAlitalo, PetraKorpisalo, JarkkoSoronen, SeppoKaijalainen, Veli-MattiLeppänen, MichaelJeltsch, SeppoYlä-Herttuala, KariAlitalo
Journal: Circulation Research (2009)

The therapeutic potential of vascular endothelial growth factor (VEGF)-C and VEGF-D in skeletal muscle has been of considerable interest as these factors have both angiogenic and lymphangiogenic activities. Previous studies have mainly used adenoviral gene delivery for short-term expression of VEGF-C and VEGF-D in pig, rabbit, and mouse skeletal muscles. Here we have used the activated mature forms of VEGF-C and VEGF-D expressed via recombinant adeno-associated virus (rAAV), which provides stable, long-lasting transgene expression in various tissues including skeletal muscle. Mouse tibialis anterior muscle was transduced with rAAV encoding human or mouse VEGF-C or VEGF-D. Two weeks later, immunohistochemical analysis showed increased numbers of both blood and lymph vessels, and Doppler ultrasound analysis indicated increased blood vessel perfusion. The lymphatic vessels further increased at the 4-week time point were functional, as shown by FITC-lectin uptake and transport. Furthermore, receptor activatio...
Intracoronary Thrombectomy With the X-Sizer Catheter System Improves Epicardial Flow and Accelerates ST-Segment Resolution in Patients With Acute Coronary Syndrome
Authors: GilbertBeran, IreneLang, WolfgangSchreiber, StefanDenk, ThomasStefenelli, BonniSyeda, GeraldMaurer, DietmarGlogar, PeterSiostrzonek
Journal: Circulation (2002)

Background— In patients with acute coronary syndrome (ACS), percutaneous coronary intervention (PCI) may cause thrombus dislodgment followed by reduced flow and impaired microcirculatory function. We prospectively compared conventional PCI to a strategy of additional pretreatment using the X-sizer thrombectomy system. Methods and Results— Sixty-six patients (51 [77%] men; 54.9±9.9 years) with ACS (49 with ST-elevation infarction [STEMI]) and suspected intracoronary thrombus were randomized 1:1 to pretreatment with X-sizer and conventional PCI alone. Various aspects of epicardial flow and microvascular function were studied. Baseline data were similar in both groups. Postprocedural TIMI 3 flow was obtained in 90% of X-sizer–treated patients and in 84% of controls (NS); however, corrected TIMI frame count was lower in X-sizer– treated patients (18.3±10.2 versus 24.7±14.1; P<0.05). No significant group differences were observed in final coronary flow reserve, myocardial blush grade, and myocardial dye intens...
Abstract LB-117: Role of ectoenzymes CD39 and CD73 in the immune response to multiple myeloma
Authors: Rui Yang, Samah Elsaadi, Kristine Misund, Geir Slupphaug, Eline Menu, Carl Hay, Zac Cooper, Karin Vanderkerken, Magne Børset, Anne Marit Sponaas
Journal: Cancer Research (2018)

Abstract Multiple Myeloma is a cancer of the plasma cells in the bone marrow. Despite from the fact that new drugs have increased survival in the past decade, it is still an incurable cancer. It is therefore important to develop new drugs. Tumor immunosurveillance contributes to the control of cancer growth, but there many different escape mechanisms utilized by tumour to evade anti-tumour immune responses. One of the largely unexplored mechanisms of immune suppression in multiple myeloma is the role of adenosine in the bone marrow microenvironment, which now represents an attractive new therapeutic target for cancer therapy. 2 ectoenzymes, CD39 and CD73 are important for converting extracellular ATP to adenosine. When investigating the role of adenosine in the immune response to multiple myeloma, we found increased concentration of adenosine in the bone marrow plasma from myeloma patients compared with healthy controls. CD39 (ENTPD1) was expressed by myeloma cell lines and on myeloma cells from patients. CD73 was found on leukocytes and stromal cells in the bone marrow. Although very few cells expressed CD73 in the bone marrow, these cells could clearly convert AMP to adenosine. ATP was converted to AMP by CD39+ myeloma cell lines, and CD73+ stromal cells converted AMP to adenosine. Importantly, co-culture of CD39+ myeloma cells and CD73+ stromal cells catalyzed extracellular ATP to immunosuppressive adenosine. Indeed, we found that CD3 T cells stimulated with anti CD3/CD28 beads in the presence of supernatants from co-cultured cells did not proliferate as well as T cell culture without this supernatant. The fact that this proliferation was inhibited by the ZM241385 inhibitor, suggested that the suppression was mediated by the A2AR receptor. The CD39 inhibitor POM1 inhibited adenosine generation in the co-culture system as well as T cell proliferation in vitro. We have recently obtained the CD73 antibody MEDI199447 from MedImmune and are testing the ability of this antibody to prevent adenosine production and T cell proliferation in vitro, as well as the ability to reduce tumor growth in a mouse model of multiple myeloma. The clinical importance of the adenosine pathway in multiple myeloma found when analyzing patient data. Using the publicly available coMMpass database, we found that patients with high expression of CD39 had significantly reduced progression free and overall survival. Citation Format: Rui Yang, Samah Elsaadi, Kristine Misund, Geir Slupphaug, Eline Menu, Carl Hay, Zac Cooper, Karin Vanderkerken, Magne Børset, Anne Marit Sponaas. Role of ectoenzymes CD39 and CD73 in the immune response to multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-117.
Renal Venous Renin Determinations in the Diagnosis of Surgically Correctable Hypertension
Authors: Annettefitz
Journal: Circulation (1967)

Renin activity in renal vein plasma was measured in six normal subjects and 59 hypertensive patients. The average renin value in renal venous plasma in normal subjects was the same as that found in patients with essential hypertension and renal parenchymal hypertension. Renal venous renin levels were markedly elevated in patients with significant renal lesions who were improved by surgery but were normal in patients with insignificant renal artery stenosis. We defined an abnormal renal vein renin level as one which is higher than 4.1 ng/ml of plasma, the highest normal, and which is also more than twice as great as the level obtained from the opposite kidney. On 19 patients who were operated upon for renal hypertension, there were no false  tests, and two false  tests. One patient with essential hypertension had abnormal values by these standards. Since occasional false positive and false negative results occur, we presently recommend that this test be used with, but not to the exc...
Placebo Effects on the Neurologic Pain Signature
Authors: Matthias Zunhammer, Ulrike Bingel, Tor D. Wager
Journal: JAMA Neurology (2018)

<h3>Importance</h3> Placebo effects reduce pain and contribute to clinical analgesia, but after decades of research, it remains unclear whether placebo treatments mainly affect nociceptive processes or other processes associated with pain evaluation. <h3>Objective</h3> We conducted a systematic, participant-level meta-analysis to test the effect of placebo treatments on pain-associated functional neuroimaging responses in the neurologic pain signature (NPS), a multivariate brain pattern tracking nociceptive pain. <h3>Data Sources</h3> Medline (PubMed) was searched from inception to May 2015; the search was augmented with results from previous meta-analyses and expert recommendations. <h3>Study Selection</h3> Eligible studies were original investigations that were published in English in peer-reviewed journals and that involved functional neuroimaging of the human brain with evoked pain delivered under stimulus intensity-matched placebo and control conditions. The authors of all eligible studies were contacted and asked to provide single-participant data. <h3>Data Extraction and Synthesis</h3> Data were collected between December 2015 and November 2017 following the Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data guidelines. Results were summarized across participants and studies in a random-effects model. <h3>Main Outcomes and Measures</h3> The main, a priori outcome was NPS response; pain reports were assessed as a secondary outcome. <h3>Results</h3> We obtained data from 20 of 28 identified eligible studies, resulting in a total sample size of 603 healthy individuals. The NPS responses to painful stimulation compared with baseline conditions were positive in 575 participants (95.4%), with a very large effect size (<i>g</i> = 2.30 [95% CI, 1.92 to 2.69]), confirming its sensitivity to nociceptive pain in this sample. Placebo treatments showed significant behavioral outcomes on pain ratings in 17 of 20 studies (85%) and in the combined sample (<i>g</i> = −0.66 [95% CI, −0.80 to −0.53]). However, placebo effects on the NPS response were significant in only 3 of 20 studies (15%) and were very small in the combined sample (<i>g</i> = −0.08 [95% CI, −0.15 to −0.01]). Similarly, analyses restricted to studies with low risk of bias (<i>g</i> = −0.07 [95% CI, −0.15 to 0.00]) indicated very small effects, and analyses of just placebo responders (<i>g</i> = −0.22 [95% CI, −0.34 to −0.11]) indicated small effects, as well. <h3>Conclusions and Relevance</h3> Placebo treatments have moderate analgesic effects on pain reports. The very small effects on NPS, a validated measure that tracks levels of nociceptive pain, indicate that placebo treatments affect pain via brain mechanisms largely independent of effects on bottom-up nociceptive processing.
Abstract 1179: PAM50 subtype admixture in individual breast cancers and the relationship of this intratumoral heterogeneity to clinical variables
Authors: Peter H. Gann, Neeraj Kumar, Dan Zhao, Amit Sethi
Journal: Cancer Research (2018)

Abstract Classification of breast cancers by PAM50 gene profiling assigns each cancer to one of five intrinsic subtypes. However, individual cancers vary in their adherence to the assigned prototype, and some may exhibit expression patterns that indicate admixture with other subtypes. The prevalence of this intratumoral heterogeneity phenomenon and the relationship of subtype admixture to clinical endpoints has not been extensively studied. We obtained microarray data on 1,460 cases from the public Gene Expression Omnibus and processed the data to normalize and log-transform expression levels and control for batch effects. For each case, we extracted levels for PAM50 genes and computed the Mahalanobis distance in multidimensional space for each case from all five centroids, including the one assigned. This metric obtains the standardized distance from a centroid for a single case while accounting for correlation between genes. We then discriminated pure from admixed cases by setting criteria for distance from the assigned centroid as well as distance from nonassigned centroids. Using the criteria that pure cases are those within the 75th percentile of distance from the assigned centroid, while being greater than the 75th percentile from any other centroid, we found that 59% of basal cases were categorized as pure, versus luminal A 31%, luminal B 35%, HER2 34% and normal 27%. We used t-Distributed Stochastic Neighbor Embedding (t-SNE) plots to visualize these admixtures in two dimensions. This confirmed that basal cancers were more heterogeneous than the other types, and that LumA, LumB and normal were more frequently admixed than other combinations. Pure LumA cases were less likely to be high-grade than LumA cases admixed with LumB, basal, HER2 or null cases not near any other centroid (18.5% vs. 7.2%, P &amp;lt; 0.01). Pure basal cases were more likely to be high-grade than basal cases admixed with any other subtype. Kaplan-Meier curves for metastasis-free survival for pure LumA were very similar to admixed cases for the first 5 years, but then diverged, with worse survival when LumA was admixed with worse subtypes. These results support the hypothesis that subtype admixture, or at least the tendency for some breast cancers to exhibit this form of intratumoral heterogeneity, can be identified and that it should be explored for clinical consequences, including failure to respond to subtype-specific therapy. Citation Format: Peter H. Gann, Neeraj Kumar, Dan Zhao, Amit Sethi. PAM50 subtype admixture in individual breast cancers and the relationship of this intratumoral heterogeneity to clinical variables [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1179.