tbuckley/cabot-search huggingface dataset:
Transcriptome based individualized therapy of refractory pediatric cancer in adolescents and young adults.
Authors: Bushra Weidenbusch, Guenther H.S. Richter, Uta Dirksen, Thomas G. P. Grunewald, Lars Lindner, Irene Teichert von Luettichau, Ulrich Robert Mansmann, Stefan Burdach
Journal: Journal of Clinical Oncology (2015)

10060 Background: Progress in pediatric oncology had little impact on adolescents and young adults (AYAs). Survival rates stagnated and are even worse than in younger and older age groups. Tumor biology in refractory patients is highly heterogeneous inter- and even intra-individually .New approaches are therefore urgently needed. Gene expression analysis may aid in medical decision making in this setting. Methods: We enrolled patients aged 10-40 years for whom standard of care and current clinical trials provided no further treatment options in a one arm open label prospective study to assess survival. Tumor samples obtained for diagnosis underwent transcriptome analysis with Affymetrix arrays. We focused on genes with > 1.5 fold expression vs. normal tissue, identified as drivers by TARGETgene. Targets ranked between 1-100 were considered for therapy. Drug selection criteria were: delivery, no previous use in the patient, citations related to disease, citations related to other cancers, side effects, drug interactions, oral application, approval by German authorities. Results: From 12/12-01/15, 18 biopsies were obtained after informed consent from 16 eligible patients at a single institution (TUM) with a mean age of 15.8 years. Diagnosis was sarcoma in 14 (6 Ewing sarcomas, 4 soft tissue sarcomas, 4 osteosarcoma), and embryonal tumor in 2. Targeted therapy was administered in 10, while in 5 no druggable targets could be identified. One patient was noncompliant. Mean druggable targets per patient was 7.6, with 462 medications assessed. 18 different drugs were recommended with an average of 3 drugs per patient, including PKIs, TKIs, TOP2Is, nucleoside analogs, arsenic trioxide and ATRA. Therapy was well tolerated with no adverse reactions and no side effect-related discontinuation of treatment. In this pilot study survival was at least not inferior to best medical care. Conclusions: Targeted therapy is a feasible alternative to best medical care in refractory cancer in AYAs. In the majority of patients druggable targets can be identified and therapy typically does not cause side effects. Prospective studies to determine potential overall survival benefit are ongoing within the INFORM consortium.
Role of PECAM-1 in Arteriogenesis and Specification of Preexisting Collaterals
Authors: ZhongmingChen, JanetRubin, EllieTzima
Journal: Circulation Research (2010)

Rationale:Hemodynamic forces caused by the altered blood flow in response to an occlusion lead to the induction of collateral remodeling and arteriogenesis. Previous work showed that platelet endothelial cell adhesion molecule (PECAM)-1 is a component of a mechanosensory complex that mediates endothelial cell responses to shear stress. Objective:We hypothesized that PECAM-1 plays an important role in arteriogenesis and collateral remodeling. Methods and Results:PECAM-1 knockout (KO) and wild-type littermates underwent femoral artery ligation. Surprisingly, tissue perfusion and collateral-dependent blood flow were significantly increased in the KO mice immediately after surgery. Histology confirmed larger caliber of preexisting collaterals in the KO mice. Additionally, KO mice showed blunted recovery of perfusion from hindlimb ischemia and reduced collateral remodeling, because of deficits in shear stress–induced signaling, including activation of the nuclear factor κB pathway and inflammatory cell accumul...
Inhibition of Protein Kinase C Prevents Rapid Desensitization of Type 1B Angiotensin II Receptor
Authors: HuaTang, HeigoroShirai, TadashiInagami
Journal: Circulation Research (1995)

Abstract The type 1B angiotensin II (AT1B) receptor cloned from rat kidney was stably expressed in Chinese hamster ovary cells. The stably expressed receptor was characterized by radioligand binding studies and functional coupling to inositol 1,4,5-triphosphate (IP3) formation. Exposure of cells expressing the AT1B receptor to angiotensin II (Ang II) resulted in a rapid and dose-dependent homologous desensitization of receptor-mediated production of IP3, with an essentially complete desensitization at an agonist concentration >10 nmol/L. Binding studies revealed no significant change in the number of AT1B receptors in transfected cells exposed to 1 nmol/L Ang II, whereas exposure to 100 nmol/L Ang II caused a rapid decrease of cell surface receptors, with a 75% loss of receptor number seen at 1 hour. Rapid desensitization occurred in the absence of receptor internalization. Blockade of receptor internalization with concanavalin A had at most only a slight effect on the agonist-induced desensitization. Thi...
Abstract 17539: IGF promotes Cardiac Lineage Induction by Selective Expansion of Mesoderm in vitro
Authors: Marc C Engels, Kuppusamy Rajarajan, Rebecca Feistritizer, Arun Sharma, Ulrik B Nielsen, Martin J Schalij, Antoine A de Vries, Daniel A Pijnappels, Sean M Wu
Journal: Circulation (2013)

Purpose: A thorough understanding of the developmental processes that direct embryonic stem cells (ESCs) towards a cardiac fate is essential for translational application of ESCs in cardiac disease modeling and therapy. Methods: This study set out to identify, by high throughput screening, key signaling pathways that regulate early cardiac lineage formation. Results: A panel of 44 signaling molecules was tested for ability to induction of Nkx2.5+ cardiac progenitor cell (CPC) formation during ESC in vitro differentiation. Consistent with previous reports, treatment with insulin-like growth factor (IGF) family of ligands (e.g. IGF1, IGF2, insulin) resulted in expansion of Nkx2.5+ CPCs by 7.4-fold ± 0.79 (IGF1; 2.71%±0.27 vs. 0.37%±0.03); 6.3-fold ± 0.46 (IGF2; 2.96%±0.25 vs. 0.47%±0.07) and 6.3-fold ± 0.35 (insulin; 2.85%±0.01 vs. 0.45%±0.03), respectively. To examine the mechanism of IGF-mediated cardiac lineage expansion, we quantified the abundance of endoderm, ectoderm, and mesoderm populations after I...
Abstract 17341: Comparing the Kansas City Cardiomyopathy Questionnaire and New York Heart Association in Assessing Functional Capacity and Outcomes
Authors: Nael Hawwa, Amanda Vest, Rahul Kumar, James Young, Yuping Wu, Eiran Gorodeski, Leslie Cho
Journal: Circulation (2015)

Background: The Kansas City Cardiomyopathy Questionnaire (KCCQ) has emerged as a patient-centered, heart failure-specific health status measure. This study examined the correlation between KCCQ and cardiopulmonary exercise testing (CPET) parameters and clinical outcomes, in comparison to the physician-derived New York Heart Association (NYHA) functional class. Methods and Results: We performed a single-centered, observational prospective analysis of 432 outpatients who presented to the Heart Failure Department, completed the KCCQ, and underwent CPET. Outcomes assessed included 30-day heart failure hospitalization and all-cause mortality. Among the KCCQ scores, the physical limitation domain had similar correlations as NYHA with peak oxygen consumption (r = 0.48 for both, p &lt; 0.001) and ventilatory threshold (r = 0.42 versus r = 0.40, respectively, p &lt; 0.001). The KCCQ overall score predicted 30-day hospitalization (OR 0.77, 95% CI 0.66 to 0.88, p &lt; 0.001) and mortality (HR 0.91, 95% CI 0.88 to 0.95, p &lt; 0.0001). NYHA could not differentially predict mortality between functional class II and III patients who comprised the majority of our cohort, although it did predict 30-day heart failure hospitalization in this group. Using model validation, NYHA was the best predictor of peak VO 2 (r 2 = 0.36), KCCQ total symptom score the best predictor of 30-day heart failure hospitalization (AUC = 0.724), and KCCQ physical limitation score the best predictor of mortality (AUC = 0.671). Conclusions: KCCQ and NYHA provide a reasonable assessment of functional capacity, the latter being more predictive. KCCQ is superior to NYHA in its ability to predict clinical outcomes. These findings support its routine use in clinical care, as well as its potential to serve as a measure in clinical trials.
Abstract 1262: Type-2 cGMP-dependent protein kinase has a tumor-suppressive role in the colon epithelium
Authors: Bianca N. Islam, Sarah K. Sharman, Yali Hou, Justin Ashby, Rui Wang, Subbaramiah Sridhar, Ravindra Kolhe, Darren D. Browning
Journal: Cancer Research (2018)

Abstract The cGMP level plays a central role in regulating homeostasis in the colon epithelium and is emerging as a potential target for colon cancer prevention. The signaling components downstream of cGMP, and the tumor suppressive mechanism remain poorly understood. The present study has examined the expression of cGMP-dependent protein kinase isoforms (PKG1, PKG2) in normal intestinal mucosa and in colon cancer from human specimens. Immunohistochemical analysis detected PKG1 in supportive cells in the lamina propria and in smooth-muscle tissue, but not in the epithelium of normal intestine and colon. In contrast, PKG2 was detected exclusively in the epithelium. In colon cancer, PKG1 was restricted to the stroma where it colocalized with vimentin, whereas PKG2 was only detected in the tumor epithelium where it colocalized with cytokeratin. This pattern of PKG isoform expression was similar in the mouse intestine and colon, where only PKG2 was detected in purified colonic crypts. PKG2 knockout (KO) mice were used interrogate possible anti-carcinogenic roles in the colon epithelium. When subjected to the AOM/DSS model of colon carcinogenesis, the PKG2 KO animals produced significantly more polyps than wild type controls (1.75-fold, p=0.0037). While the polyps from PKG2 KO animals were slightly smaller than those from wild type, the trend was not significant (p=0.13). Wild type and PKG2 KO mice responded equally to DSS treatment, but the PKG2-deficient animals exhibited crypt hyperplasia and increased apoptosis in luminal epithelium relative to wild type animals. Taken together these findings suggest that PKG2 has a tumor suppressive role in the colon epithelium, and that reducing the proliferative compartment may be part of the mechanism. Citation Format: Bianca N. Islam, Sarah K. Sharman, Yali Hou, Justin Ashby, Rui Wang, Subbaramiah Sridhar, Ravindra Kolhe, Darren D. Browning. Type-2 cGMP-dependent protein kinase has a tumor-suppressive role in the colon epithelium [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 1262.
Abstract 5291: Professional nurses' awareness and practice with sexual concerns of the oncology patient
Authors: Maurel C. Emeagi, Hester Rina De Swardt, Martjie De Villiers
Journal: Cancer Research (2018)

Abstract Sexuality is an important aspect of quality of life (QOL). QOL after cancer therapy is an important aspect of patient care of which sexual wellbeing forms part of the holistic nursing care although sexuality assessment is recognized as an important part of nursing care, in practice it has been observed that professional nurses may experience some difficulties to this aspect. Purpose: The purpose of this study was to gain a deeper understanding of the awareness, practice and possible barriers of professional nurses when engaging in conversation about sexuality with patients receiving cancer treatment in a private oncology care setting in Pretoria, South Africa. Objectives: The research objectives were: Ø To explore and describe the awareness and practice of professional nurses to engage in conversation about sexuality with the patient receiving cancer treatment in a private oncology setting in Pretoria. Ø To describe possible barriers that prohibit professional nurses to engage in conversation with patients receiving cancer treatment in a private oncology setting regarding sexuality Ø To make recommendations to improve nursing practice with regard to nursing care related to sexuality in the private oncology care setting. Method: An exploratory, descriptive and qualitative design was followed. A convenient purposive sample consisting of nine participants who met the inclusion criteria participated. Data were gathered through semi-structured interviews, while Creswell's method of data analysis was applied. Trustworthy measures included credibility, transferability, dependability and confirmability. This study obtained ethical clearance from all stakeholders. Results: The themes embarrassment, cultural beliefs and values emerged as barriers to engage in conversation about sexuality while, referring to a specialist in the field as suggested support to cancer treated patients arose. Limited knowledge about intensive therapy featured as the last theme. The data revealed that professional nurses themselves had restricted views on sexuality and very often would see the patient's body image and associated sexuality as not their responsibility. The concept intensive therapy was not fully understood which led to limited referral to various specialist. Conclusions: Professional nurses should be sensitized and empowered with the skills and knowledge on how patients' perception of their body image changed when been treated with cancer and the effect thereof. Reflective conversations about this sensitive topic could assist in this regard. Citation Format: Maurel C. Emeagi, Hester Rina De Swardt, Martjie De Villiers. Professional nurses' awareness and practice with sexual concerns of the oncology patient [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 5291.
Abstract LB-200: A pan-cancer analysis of stage-dependent gene expression program
Authors: Man-Sun Kim, Dongsan Kim, Jeong-Rae Kim, Yong Pyo Lim
Journal: Cancer Research (2018)

Abstract Cancer cells undergo diverse gene expression alterations according to their development and progression due to the accumulation of mutations. Understanding these phenomena not only provide us an insight into the underlying mechanisms of cancer development, but also offer useful information on the prediction of patient's prognosis. For some cancer types, previous studies attempted to identify key genes that change with the development of cancer. However, identification of cancer stage-dependent gene expression dysregulations based on pan-cancer dataset have not been addressed. Here, based on gene expression profiles and clinical data from 20 major cancer types and ~6,000 individual patients, we identified both gene expression programs that specifically change from each cancer-type and across all cancer types. Based on the pan-cancer analysis, we found that cell cycle and p53 dependent pathways are the most commonly dysregulated pathways across all cancer types according to cancer development. Next, we investigated whether the identified the stage-dependent gene expression programs from the pan-cancer analysis also hold from each cancer-type analysis. Interestingly, we identified that only about half cancer types also showed consistent gene expression alterations. These results suggest that although most cancer share common dysregulation mechanisms as cancer progress, also show that some cancer type have quite unique cancer development programs depending on the cancer type. Keywords: stage-dependent gene expression, systems biology, PANCANCER Citation Format: Man-Sun Kim, Dongsan Kim, Jeong-Rae Kim, Yong Pyo Lim. A pan-cancer analysis of stage-dependent gene expression program [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-200.
Abstract 3270: Pan-cancer analysis of 1,962 whole-genomes reveals significantly mutated CTCF/cohesin insulators
Authors: Eric Minwei Liu, Alexander Martinez-Fundichely, Tawny Cuykendall, Jason G. Dumelie, Matthew MacKay, Priyanka Dhingra, Samie R. Jaffrey, Ekta Khurana
Journal: Cancer Research (2018)

Abstract Recent studies have shown that mutations at non-coding elements, such as the TERT promoter and ESR1 enhancer, can act as cancer drivers. However, an important class of non-coding elements, namely CTCF/cohesin insulators, has been overlooked in the previous driver analyses. It is known that promoter and enhancer interactions are facilitated by partitioning of the human genome into DNA loops. These loops act as insulated neighborhoods preventing the interactions of enhancers and promoters across loops. They are held together by the binding of two CCCTCF binding factors (CTCF) and the cohesin complex, which consists of four core transcription factor subunits (SMC1, SMC3, RAD21 and either STAG2 or STAG1) at the loop ends. Disruption of the loop anchor regions, called CTCF/cohesin insulators, can lead to de novo enhancer-promoter interactions and subsequent dysregulation of associated genes. We used insulator annotations from cohesin ChIA-PET assays and analyzed somatic mutations in 1,962 whole-genomes from 21 cancer types. We find that the mutations predicted to disrupt DNA binding motifs of CTCF, RAD21 and SMC3 are enriched in many cancer types due to the sequence contexts of neutral mutational processes. Using a novel computational approach, CNCDriver (Cornell Non-Coding Driver), that balances the interplay between neutral mutational rate covariates of CTCF/RAD21/SMC3 motif loss and the stronger functional impact of motif-disrupting mutations, we identify the insulators that show signals of positive selection during tumor evolution. We find that the mutations in significantly mutated insulators are associated with differential expression of genes involved in multiple cancer pathways: TGF-β, Hedgehog and Wnt signaling. In particular, we find 16% of melanoma samples show mutations in an insulator that are associated with up-regulation of TGFB1, which is known to promote angiogenesis and tumor cell migration in melanoma. Thus, our study reveals insulators as a novel class of non-coding cancer drivers. Identification of significantly mutated insulators can complement the identification of other types of non-coding cancer drivers (promoters, enhancers and ncRNAs) to fully understand the role of non-coding alterations in tumorigenesis. Citation Format: Eric Minwei Liu, Alexander Martinez-Fundichely, Tawny Cuykendall, Jason G. Dumelie, Matthew MacKay, Priyanka Dhingra, Samie R. Jaffrey, Ekta Khurana. Pan-cancer analysis of 1,962 whole-genomes reveals significantly mutated CTCF/cohesin insulators [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 3270.
Abstract 17733: Some Epilepsy Patients Die Suddenly Without a Preceding Seizure Episode: What are the Mechanisms?
Authors: Eric C Stecker, Kelvin Chua, Audrey Uy-Evanado, Carmen Teodorescu, Kyndaron Reinier, Karen Gunson, Jonathan Jui, Sumeet S Chugh
Journal: Circulation (2015)

Introduction: Epilepsy is associated with a significantly increased risk of sudden cardiac arrest (SCA), and we have previously reported that this devastating outcome does not always require a preceding seizure. Based on the hypothesis that the pathophysiology of SCA for epilepsy patients may be heterogeneous, we compared the clinical profile of epilepsy patients with and without seizure activity prior to SCA. Methods: Subjects of all ages with SCA occurring in the setting of prior documented epilepsy were identified from a large, ongoing, population-based study of SCA in the Northwest US (community pop. approx. 1 million). We explored the relationships between baseline demographics, lifetime medical history and SCA circumstances among those who had a witnessed seizure within 24 hours of the SCA event (seizure-dependent) and those who did not (seizure-independent). Data were obtained from multiple sources (first responders, medical practitioners and medical examiner) between 2002 and 2015. Patients with terminal illnesses and non-cardiac causes of arrest were excluded, as well as those with infantile febrile seizures or alcoholic withdrawal seizures. Results: Among 142 subjects with SCA and seizure disorder, 64 (45.1%) were witnessed during the event and, among these, 26 (40.6%) were seizure-dependent while 38 (59.4%) were seizure-independent. The seizure-independent subjects were significantly older (mean age 61.9 years; 95% CI, 43.1 to 80.7 years; vs 47.6 years; 95% CI, 27.0 to 68.2 years; p=0.006). However the younger seizure-dependent group had higher prevalence of cardiac arrest due to pulseless electrical activity (PEA) or asystole (81.0% vs 58.3%; p=0.081). There was no notable difference in the burden of comorbidities (Charlson index 1.92 vs 2.37; p=0.941), periarrest characteristics, ECG and echo parameters. Conclusions: Seizure-independent SCA occurs at an older age, supporting the hypothesis that over time, neuro-cardiac remodeling may lead to cardiac arrest in the absence of hypoxia. In younger, seizure-dependent patients hypoxia may be a pre-requisite, but both hypotheses warrant further detailed investigation.
Calcineurin Promotes the Expression of Monocyte Chemoattractant Protein-1 in Vascular Myocytes and Mediates Vascular Inflammation
Authors: HiroshiSatonaka, EtsuSuzuki, HiroakiNishimatsu, ShigeyoshiOba, RyoTakeda, AtsuoGoto, MasaoOmata, ToshiroFujita, RyozoNagai, YasunobuHirata
Journal: Circulation Research (2004)

Although the role of the calcineurin-dependent pathway in the development of cardiac hypertrophy has been intensively studied, little is known of its role in vascular inflammatory diseases such as atherosclerosis and restenosis after angioplasty. To help elucidate the role of calcineurin in vascular inflammation, we infected cultured vascular smooth muscle cells (VSMCs) with an adenovirus construct expressing a constitutively active mutant of calcineurin, and examined its effect on the expression of monocyte chemoattractant protein-1 (MCP-1). We also examined the role of calcineurin in vivo using a transluminal wire injury model of the rat femoral artery. Forced activation of calcineurin significantly increased the expression of MCP-1 both at the transcriptional and protein levels. Angiotensin II (Ang II) also significantly stimulated MCP-1 expression, and this increase was significantly inhibited by cyclosporin A (CyA). Constitutive activation of calcineurin stabilized MCP-1 mRNA without enhancing MCP-1 ...