tbuckley/cabot-search huggingface dataset:
Abstract 5326: Differential methylation observed in cancer related genes between DNA samples from normal and obese individuals
Authors: Ryan Drennan, Nicolas Culhane, Matthew L. Poulin, Zhenhua Liu, Liying Yan
Journal: Cancer Research (2018)

Abstract Based on research funded by The American Institute for Cancer Research, evidence is clear that weight can affect your risk of developing cancer. It is estimated that close to 1/3 of cancers that occur every year in the U.S. could be prevented by maintaining a healthy weight, being physically active and eating a nutritious diet. The body mass index (BMI) is defined as the body mass divided by the square of the body height and is typically expressed in kg/m2. BMI between 18.5 and 25 are considered normal while BMI of 25 to 30 is overweight and greater than 30 is considered obese. We have analyzed the DNA methylation levels of 18 individuals with BMI &amp;gt;30, and compared them to 7 individuals with BMI between 18.5 and 25 utilizing three targeted Next-Gen Bisulfite Sequencing (tNGBS) panels that we have developed as well as with individual pyrosequencing assays. The three panels, FOXP3, Immunology and Cancer Panels, cover regulatory regions of 44 genes that include over 400 CpG sites in addition to a global methylation assay to the LINE1 promoter. The results show that seven gene regulatory regions and the LINE1 global methylation assay show significant differential methylation between the obese and the normal BMI samples. ESR1, PAPR1, EN1, LXH2, TFF1, FOXP3 and LINE1 were shown to be hypermethylated and CD3G was hypomethylated, with p-values ranging between 0.08 and 0.005. Larger sample cohorts can now be examined more thoroughly with individual pyrosequencing assays to further validate the findings. Citation Format: Ryan Drennan, Nicolas Culhane, Matthew L. Poulin, Zhenhua Liu, Liying Yan. Differential methylation observed in cancer related genes between DNA samples from normal and obese individuals [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 5326.
Abstract 11333: Identifying Patients at Low Risk for Ventricular Tachycardia After Cardiac Resynchronisation
Authors: MartinGrett, Hans-JoachimTrappe
Journal: Circulation (2014)

Introduction: Ruling out scar as a substrate and ischemia as a trigger of ventricular tachyarrhythmia could define patients (pts) at low risk for adequate ICD-therapies despite poor left ventricular ejection fraction (LVEF). The modified Selvester-ECG-score (MSES) correlates with the LV scar burden. Every 1 point raise counts for 3% additional scar. In a retrospective analysis of SCD-HeFT it has shown a value in describing pts at high vs low risk for ICD-therapy. Its value in pts with non-ischemic cardiomyopathy and indication for CRT has not yet been described. Hypothesis:A low MSES, non-ischemic cardiomyopathy and CRT can define pts at low risk for adequate ICD-therapies Methods: We studied 54 pts who underwent primary prophylactic CRT-D implantation at our department, had non-ischemic cardiomyopathy and complete follow up of device interrogation for 1 year. For 44 of these pts a complete follow up of 2 years was obtainable. Pts with upgrade from existing devices were not studied. Results: Mean LVEF was...
Abstract 2382: In silico/in vitro studies of novel hot spot mutations in BCR-ABL1: A multidisciplinary approach to shed a new light on TKI resistance
Authors: Erik Laurini, Suzana Aulic, Natasa Skoko, Sulena Polez, Marco Baralle, Maurizio Romano, Sabrina Pricl
Journal: Cancer Research (2018)

Abstract Acquisition of mutations in the BCR-ABL1 kinase domain (KD) is frequently associated with tyrosine kinase inhibitor (TKI) failure in CML. Recently, we revealed a novel mutation “hot- spot” in the BCR-ABL1 KD region (residues 295 - 312), associated with high resistance and poor clinical outcomes [1]. Some of these new BCR-ABL1 variants locate in a protein region, which might not be directly involved in TKI interaction. Therefore, we hypothesized that some of these mutations might be linked to TKI resistance via a direct mechanism while others might exert an indirect effect on drug resistance. The present contribution integrates molecular, computational, and structural biology techniques to understand the eventual role of the newly reported hot-spot mutations of the BCR-ABL1 KD in TKI resistance observed in CML patients using a "two-tier level" investigation: isolated KDs and SH2-linker-SH3-KD BCR- ABL1 constructs. Molecular Modeling will assess in silico whether the clinically observed “hot-spot” BCR-ABL1 mutations might be directly related to a change in the thermodynamic stability and/or protein structure and how these modifications could be involved in the BCR-ABL1 binding profile to specific TKIs (e.g., imatinib, dasatinib, and ponatinib) compared with wild-type (WT) systems and “prototypical” BCR-ABL1 mutations (e.g. T315I). In parallel, in vitro analysis will evaluate the effects exerted by the selected mutations on the intrinsic activity of the kinase and to determine the inhibition activity of the selected drugs on these BCR-ABL1 variants. Specifically, direct drug binding to both KD and SSK constructs will be measured using isothermal titration calorimetry and in vitro kinase assays will monitor the ability of these mutant isoforms to auto-phosphorylate and to phosphorylate a substrate peptide. Finally, structural biology (e.g., SAXS and far-UV CD) evidences of WT and mutant isolated KDs and SH2-linker-SH3-KD (SSK) constructs (per se and in complex with TKIs) will be discussed to support in silico predictions. [1] Gibbons DL, Pricl S et al., Molecular dynamics reveal BCR-ABL1 polymutants as a unique mechanism of resistance to PAN-BCR-ABL1 kinase inhibitor therapy. Proc Natl Acad Sci U S A. 2014 Mar 4;111(9):3550-5. doi: 10.1073/pnas.1321173111. Citation Format: Erik Laurini, Suzana Aulic, Natasa Skoko, Sulena Polez, Marco Baralle, Maurizio Romano, Sabrina Pricl. In silico/in vitro studies of novel hot spot mutations in BCR-ABL1: A multidisciplinary approach to shed a new light on TKI resistance [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 2382.
Abstract 1468: ZBTB48 is both a vertebrate telomere-binding protein and a transcriptional activator
Authors: Arne Jahn, Grishma Rane, Maciej Paszkowski-Rogacz, Sergi Sayols, Alina Bluhm, Chung-Ting Han, Irena Draškovič, Arturo Londoño, Alan Prem Kumar, Frank Buchholz, Falk Butter, Dennis Kappei
Journal: Cancer Research (2018)

Abstract Telomeres consist of repetitive TTAGGG repeats and together with the shelterin complex protect the ends of linear chromosomes from DNA repair mechanisms. Due to telomere shortening with every cell division proliferating cells need to ensure telomere maintenance by telomerase or in about 15% of cancer cells via the recombination based alternative lengthening of telomeres. Recently ZBTB48 was identified as a novel telomere-associated factor throughout the vertebrate lineage. Here we show that ZBTB48 binds directly to telomeres in vitro and in vivo, independently of the telomere maintenance mechanism. Loss of the protein leads to longer telomeres indicating a role as negative regulator of telomere length. Furthermore RNAseq, ChIPseq and quantitative expression proteomics demonstrate a function as transcriptional activator for a small set of target genes, including mitochondrial fission process 1 (MTFP1). This regulatory role links its telomeric function to mitochondrial metabolism and might play a role in cancer development. In summary ZBTB48 is a novel telomere binding protein which regulates telomere length and transcriptional activity. Citation Format: Arne Jahn, Grishma Rane, Maciej Paszkowski-Rogacz, Sergi Sayols, Alina Bluhm, Chung-Ting Han, Irena Draškovič, Arturo Londoño, Alan Prem Kumar, Frank Buchholz, Falk Butter, Dennis Kappei. ZBTB48 is both a vertebrate telomere-binding protein and a transcriptional activator [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 1468.
Abstract 1322: A systems-level approach identifies novel links between iron and fatty acid metabolism in high-grade serous ovarian cancer
Authors: Anna Konstorum, Miranda L. Lynch, Suzy V. Torti, Frank M. Torti, Reinhard C. Laubenbacher
Journal: Cancer Research (2018)

Abstract The low survival rate for high-grade serous ovarian cancer (HGSOC) motivates novel approaches to identify causative and therapeutically targetable factors involved in HGSOC initiation and progression. Cancer cells are known to sequester iron, which can potentiate cancer progression via mechanisms that have not yet been completely elucidated. In order to uncover novel, and potentially therapeutically tractable links, between iron and HGSOC, we developed an algorithm to identify perturbed regulatory pathways containing differentially expressed iron-related genes in microarray data from clinical sources and an experimental model of HGSOC. Used in tandem with over-representation analysis for iron-related genes, the algorithm led us to uncover an iron dependence of fatty acid import and synthesis pathways, which are upregulated in HGSOC and other cancers, and to develop a network synthesizing the relationship between iron, fatty acid metabolism, and HGSOC. We use the network to derive specific hypotheses of mechanisms by which iron impacts fatty acid metabolic pathways to promote tumorigenesis. We have thus shown that a systems-level approach to identifying novel regulatory links between iron and HGSOC has yielded a previously unappreciated association between iron and fatty acid metabolism that may be exploited for therapeutic potential. This work has been supported in part by NIH grants F32CA214030 to AK, R01CA188025 to SVT, and RO1CA171101 to FMT. Citation Format: Anna Konstorum, Miranda L. Lynch, Suzy V. Torti, Frank M. Torti, Reinhard C. Laubenbacher. A systems-level approach identifies novel links between iron and fatty acid metabolism in high-grade serous ovarian cancer [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 1322.
Abstract 5416: Isolation of the PAX8 transcriptional complex to identify novel therapeutic vulnerabilities for ovarian cancer
Authors: Daniele Chaves-Moreira, Marilyn Mitchell, Simone Sidoli, Benjamin Garcia, Ronny Drapkin
Journal: Cancer Research (2018)

Abstract A central problem in the treatment of ovarian cancer remains the heterogeneity among ovarian tumors. DNA and RNA sequencing studies have demonstrated both intertumoral and intratumoral genetic variation. Despite efforts to elucidate common signaling pathways among various ovarian cancer subtypes, few have led to meaningful patient stratification or to truly individualized targeted molecular therapies. Our proposed set of experiments is a radical departure from the conventional approach to treating ovarian cancer. PAX8, a transcription factor that identifies nearly all high-grade serous ovarian cancers (HGSOCs), is also the master regulator of fallopian tube development. Building off observations pointing to the fallopian tube epithelium as a major site of origin for HGSOCs, we propose targeting the fallopian tube developmental program as the basis for new therapies. This possibility is supported by the observation that knockdown of PAX8 leads to apoptosis in ovarian cancer cells. We hypothesize that blocking the ability of PAX8 to influence its gene targets, either by interrupting PAX8 protein-protein interactions or by inhibiting the products of PAX8-driven signaling, has the potential to eliminate the primary growth stimulus for high-grade serous tumors. In order to achieve that goal, we have identified candidate PAX8-interacting partners using gel filtration chromatography and tandem-affinity immunopurification coupled with mass spectrometry analyses. Interactions have been validated by Western blot, immunofluorescence, and proximity ligation assay. We used ovarian cancer (KURAMOCHI, OVSAHO and OVCAR4) and fallopian tube (FT189, FT194 and FT246) cell lines to determine whether PAX8 protein partners changed between benign and malignant cells. Our preliminary results suggest that PAX8 interacts with other transcription factors such as TEAD4 and components of chromatin-remodeling complexes (RUVBL1, RUVBL2 and CHD4). Many of these factors are known to mediate the effects of oncogenes such as YAP, β-catenin and c-Myc. Further studies will be done in order to decipher the functional contribution of each candidate PAX8-interacting protein. Our ultimate goal is to determine how PAX8 regulates expression of its target genes and how PAX8-interacting proteins influence that function. Inhibition of certain protein-protein interactions may provide novel avenues to abrogate PAX8 function in ovarian cancer cells. Citation Format: Daniele Chaves-Moreira, Marilyn Mitchell, Simone Sidoli, Benjamin Garcia, Ronny Drapkin. Isolation of the PAX8 transcriptional complex to identify novel therapeutic vulnerabilities for ovarian cancer [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 5416.
Abstract 5541: Clinical impact of hypothyroidism and PD-L1 SNPs in patients having non-small cell lung cancer treated with nivolumab
Authors: Tomoko Funazo, Hiroaki Ozasa, Takashi Nomizo, Takahiro Tsuji, Yuto Yasuda, Hironori Yoshida, Yuichi Sakamori, Hiroki Nagai, Toyohiro Hirai, Young Hak Kim
Journal: Cancer Research (2018)

Abstract Although Nivolumab is one of the immune-checkpoint inhibitors that improves the prognosis of lung cancer, it is known to cause immune-related adverse events (irAEs). It has recently been reported that patients with irAEs have a longer progression-free survival (PFS) than those without irAEs. However, there are few detailed reports on irAEs in patients with NSCLC. We previously reported the association between single nucleotide polymorphisms (SNPs) of programmed death ligand 1 (PD-L1) and PFS for nivolumab treatment. Therefore, we hypothesized that the SNPs of programed death 1 (PD-1) and PD-L1 were associated with irAEs and PFS. Between January 2016 and March 2017, 95 consecutive patients with advanced NSCLC were treated with nivolumab and 80 of these patients participated in this study. Patients who did not provide informed consent, patients without follow-up blood tests, patients with double cancer history, and patients diagnosed with disease progression within 15 days were excluded. The prevalence of genotypes between patients with adverse events and those without adverse events was evaluated. PFS was calculated in 59 out of 80 patients excluding liver metastasis at baseline imaging. The response rate was 15% and the median PFS was 85 days in this cohort. For all adverse events, hypothyroidism, which is defined as a low free T4 level, was associated with SNPs of PD-L1: rs1411262 and rs822339. Moreover, patients with hypothyroidism had a significantly longer PFS than those without hypothyroidism (67 days vs N.R.; P= 0.0055). The T/T genotype of rs1411262 and the A/A genotype of rs822339 were significantly associated with longer PFS than the C/T and C/C genotypes of rs1411262, and the A/G and G/G genotypes of rs822339, respectively (82 versus 175 days; P = 0.0468). In conclusion, the T allele of rs1411262 and the A allele of rs822339 were significantly associated with hypothyroidism and longer PFS. SNPs of PD-L1 may be associated with functions of the PD-1 and PD-L1 pathway. Hypothyroidism and SNPs of PD-L1hypothyroidism (-)hypothyroidism (+)P value(n=7)(n=73)rs14112620190.0386CC336CT418TTrs822339AA0190.0386AG336GG418 Citation Format: Tomoko Funazo, Hiroaki Ozasa, Takashi Nomizo, Takahiro Tsuji, Yuto Yasuda, Hironori Yoshida, Yuichi Sakamori, Hiroki Nagai, Toyohiro Hirai, Young Hak Kim. Clinical impact of hypothyroidism and PD-L1 SNPs in patients having non-small cell lung cancer treated with nivolumab [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 5541.
A factor VIII–nanobody fusion protein forming an ultrastable complex with VWF: effect on clearance and antibody formation
Authors: Vincent Muczynski, Caterina Casari, François Moreau, Gabriel Aymé, Charlotte Kawecki, Paulette Legendre, Valerie Proulle, Olivier D. Christophe, Cécile V. Denis, Peter J. Lenting
Journal: Blood (2018)
Abstract 121: Quality of Cardiopulmonary Resuscitation by Bystanders and Survival After Out-of-Hospital Cardiac Arrest
Authors: Chika Nishiyama, Tetsuhisa Kitamura, Tomonari Shimamoto, Takashi Kawamura, Tetsuya Sakamoto, Taku Iwami
Journal: Circulation (2014)

Introduction: Although quality of cardiopulmonary resuscitation (CPR) is a key to increase survival after out-of-hospital cardiac arrest (OHCA), little is known about the quality of bystander CPR and its association with survival outcomes after OHCA. Objective: To evaluate the association of quality of bystander CPR and patient outcomes after OHCA. Methods: Designs: Population-based cohort study. Cases: All OHCA cases treated by emergency medical services (EMS) personnel in Toyonaka city between September 2011 and August 2013. Data collection and analyses: EMS personnel assessed bystanders’ CPR quality including hand position, depth, and tempo of chest compressions using a specific data form at the scene. Fleiss’ Kappa statistics was used to assess the evaluation reliability among EMS personnel and the Kappa value was 0.81 before the study. The primary outcome was patient one-month survival with favorable neurological outcome and it was compared between the good-quality CPR group and the poor-quality CPR group. Results: Among 877 cases, bystander CPR was attempted in 429 (48.9%). Data on quality of CPR was applicable in 272 (63.4%) of them. In the good-quality CPR group, bystanders were younger, more likely to be health care provider, and have experience of CPR training than in the poor-quality of CPR group. The proportion of patients with neurologically favorable one-month survival was somewhat greater in the good-quality of CPR group (4.6% versus 3.0%), although it was statistically insignificant. Conclusions: Better quality of bystander chest compressions might increase OHCA patient survival. Further efforts to improve quality of CPR by general public are needed.
Dynamic Responses of the Right Ventricle following Extensive Damage by Cauterization
Authors: Abrahamkagan
Journal: Circulation (1952)

Previous observations that major destruction of the right ventricular walls causes but slight changes in venous and arterial pressures were confirmed. Furthermore, additional observations indicated that the compensatory reaction of the damaged ventricle to stress is diminished surprisingly little. The results are considered evidence that the cauterization procedure and others of a similar nature do not produce right heart failure and, therefore, would not be expected to cause venous congestion. The subsidiary muscular mechanism which maintains the right ventricular pump remains enigmatic; but evidence is submitted that the damaged right ventricle is regulated independently of the left.
Abstract 13767: Nitric Oxide Plays a Janus Role in the Pathogenesis of Tako-tsubo Cardiomyopathy
Authors: Thanh H Nguyen, Sven Surikow, Betty Raman, Matthew Chapman, Irene Stafford, John Horowitz
Journal: Circulation (2015)

Introduction: Tako-tsubo cardiomyopathy (TTC) is fundamentally a catecholamine-stimulated myocardial inflammatory state, initiated by aberrant β2-adrenoceptor signalling in susceptible (usually female) myocardium. We have recently reported that (i) TTC patients exhibit evidence of “supranormal” NO signalling, (ii) at post-mortem, heart of patients dying of TTC have increased content of 3-nitrotyrosine (3NT), a marker of nitrosative stress. Furthermore, in a rat model of TTC, isoproterenol (ISOP) induces increased myocardial expression of both 3NT and thioredoxin-interacting protein (TXNIP), a pro-inflammatory protein normally suppressed by NO. We therefore sought to determine the effects of suppression of NO generation in this rat model. Methods: Female Sprague-Dawley rats, aged 4-5 months, were randomly assigned to one of two groups: ISOP (5mg/kg) (n = 11) and L-NAME (50mg/kg) + ISOP (n = 14). Echocardiography was performed at baseline and after 24 hours. Animals were then sacrificed and immunoblotting was performed in both apical and basal samples to determine the extent of activation of both inducible NO synthase (iNOS) and endothelial NOS (eNOS). Expression of 3NT, TXNIP, and PARP1 as marker of DNA damage were also determined. Results: The results are summarized in the Table: mean ± SE are shown. Furthermore, L-NAME accentuated falls in LVEF and induced marked increases in intraventricular septal wall thickness (p &lt; 0.05 for both). Conclusions: NOS inhibition in this model of TTC limits PARP1 expression and thus potentially conserves energetics, but does not reduce overall nitrosative stress. Moreover, NOS inhibition worsens myocardial inflammation and impairment of LV function. Increased TXNIP expression may reflect withdrawal of NO-mediated inhibition.