tbuckley/cabot-search huggingface dataset:
Abstract 18954: Novel Role of De Novo Matricellular Protein Cyr61 in Bridging Lysophosphatidic Acid and Integrin Pathways Leading to Smooth Muscle Cell Migration
Authors: Mei-Zhen Cui, Fuqiang Zhang, Daniel D Wu, Feng Hao, Xuemin Xu
Journal: Circulation (2013)

Lysophosphatidic acid (LPA), a potent bioactive lipid, markedly induces smooth muscle cell (SMC) migration, which is one of the important processes involved in atherosclerotic lesion development. In order to search for key molecules that control LPA-induced SMC migration, we performed gene microarray analysis and attempted to identify LPA-induced extracellular molecules responsible for LPA-triggered cell migration. We observed that LPA selectively induced the expression of the matricellular protein Cyr61, a multifunctional matrix-related protein, which has been implicated in cell angiogenesis, proliferation, adhesion and migration. We hypothesize that Cyr61 mediates LPA-induced cell migration. Our data show that LPA induces temporal and spatial expression of Cyr61 protein in SMCs. LPA-induced de novo Cyr61 proteins promptly accumulate in the Golgi apparatus and then translocate to the extracellular matrix. Cyr61 specific siRNAs diminishes LPA-induced cell migration, indicating the novel regulatory role of the induced matricellular protein Cyr61 in LPA-induced cell migration. Using primary SMCs derived from LPA receptor 1 (LPA1) knockout and LPA2 knockout mice, our data reveal that LPA1 is required for LPA-induced Cyr61 expression in SMCs and cell migration. Furthermore, LPA induces profound activation of focal adhesion kinase (FAK) in SMCs in later time points, coinciding with the accumulation of Cyr61in the extracellular matrix. FAK is an intracellular kinase important in regulating cell migration. Our data demonstrated that knockdown of de novo Cyr61 expression blocked LPA-induced cellular FAK activation and cell migration. Integrin alpha6 and beta1 have been reported to interact with Cyr61 in SMCs. We found that knockdown of the expression of integrin alpha6 or beta1 prevented LPA-induced FAK activation and cell migration. Taken together, these data reveal that a novel LPA/Cyr61 pathway controls cell migration and that de novo Cyr61 in extracellular matrix bridges LPA and integrin signaling, which in turn, activates FAK leading to cell migration. Understanding this novel pathway will provide new insights into mechanisms underlying the development of cell migration related disorders including atherosclerosis and restenosis.
Abstract 3447: APC truncating mutations in Middle Eastern population: Tankyrase inhibitor is an effective strategy to sensitize APC mutant CRC to 5-FU chemotherapy
Authors: Sandeep K. Parvathareddy, Abdul K. Siraj, Rong Bu, Prateeshkumar Poyil, Tariq Masoodi, Divya Sasidharan Padmaja, Rica Concepcion, Rafia Begum, Maria A. Sabido, Roxanne Melosantos, Nasser Al-Sanea, Fouad Al-Dayel, Khawla S. Al-Kuraya
Journal: Cancer Research (2019)

Abstract Colorectal Cancer (CRC) is the leading cause of cancer related death and the most common cancer affecting Saudi males. Mutation of the adenomatous polyposis coli (APC) gene is considered as the initiating step of transformation in familial and sporadic CRC. The prevalence and prognostic role of APC mutation spectra are not well established in Middle Eastern CRC. Next generation sequencing of 412 CRC tumors was performed to determine mutations in APC. Association with protein expression and clinico-pathological correlation was performed. APC truncating mutation is found at a frequency of 58.2% (240/412) and is significantly associated with superior overall survival, whereas no difference in survival between short truncating and long truncating APC was noted. To test the hypothesis that APC mutations might influence 5- Fluorouracil (5-FU) therapy, which is the first line chemotherapy used in CRC, we compared CRC cell lines and showed that those expressing truncated APC exhibit limited response to 5-FU, unlike cells which were APC wild type. In COLO-320 DM and HCT-15, APC mutated CRC cells, we were able to increase sensitivity of APC truncated cells to 5-FU by inhibiting Tankyrase (TNKs) which are members of PARP family, using XAV939. In conclusion, the study identified the prognostic value of APC truncating mutation in Middle Eastern ethnicity. In vitro data further showed that APC mutation can be used as a molecular biomarker to predict response to 5-FU. Furthermore, Tankyrase inhibitor XAV939 selectively targeting APC-mutated CRC cells can be an effective strategy to overcome 5-FU resistance in these cells. Note: This abstract was not presented at the meeting. Citation Format: Sandeep K. Parvathareddy, Abdul K. Siraj, Rong Bu, Prateeshkumar Poyil, Tariq Masoodi, Divya Sasidharan Padmaja, Rica Concepcion, Rafia Begum, Maria A. Sabido, Roxanne Melosantos, Nasser Al-Sanea, Fouad Al-Dayel, Khawla S. Al-Kuraya. APC truncating mutations in Middle Eastern population: Tankyrase inhibitor is an effective strategy to sensitize APC mutant CRC to 5-FU chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3447.
Deregulated Expression of EVI1 Defines a Poor Prognostic Subset of MLL-Rearranged Acute Myeloid Leukemias
Authors: Gröschel Stefan, Richard F. Schlenk, Karina Eiwen, Jan Engelmann, Michael Luebbert, Ulrich Germing, Ingo Schmidt-Wolf, Brigitte Schlegelberger, Jürgen Krauter, Arnold Ganser, Ruud Delwel, Bob Lowenberg, Konstanze Döhner, Hartmut Döhner
Journal: Blood (2011)
<i>Withdrawn:</i>Skin fragility caused by biallelic<i>KRT10</i>mutations: an intriguing form of self‐improving epidermolytic ichthyosis
Authors: L. Frommherz, J. Küsel, A. Zimmer, J. Fischer, C. Has
Journal: British Journal of Dermatology (2019)

Autosomal recessive epidermolytic ichthyosis is a rare skin condition associated with KRT10 loss-of-function mutations. It presents with severe life-threatening clinical manifestations. Here we describe a case of autosomal recessive epidermolytic ichthyosis with an unusually mild, spontaneously improving phenotype. Erythroderma and superficial blistering were present at birth, but the skin recovered and remained almost intact at the age of 1 year. Mild scaling on the neck and skin fragility manifesting as superficial erosions after scratching were the only clinical features as the child grew. As a cause, previously unreported compound heterozygous KRT10 pathogenic variants were found: a nonsense mutation leads to mRNA decay, while the other synonymous variant induces a leaky splice site, explaining the residual keratin 10 expression and mild clinical phenotype. What's already known about this topic? Autosomal recessive epidermolytic ichthyosis is a rare skin condition caused by loss-of-function KRT10 mutations. The clinical phenotype is severe with superficial skin blistering, scaling and hyperkeratosis. What does this study add? Here we extend the mutational and phenotypic spectrum of autosomal recessive epidermolytic ichthyosis. Our case presented with erythroderma and superficial blistering at birth, but the skin recovered and was almost intact at the age of 1 year. The only disease manifestations were mild scaling on the neck and skin fragility appearing as superficial erosions after scratching. The causative factors were found to be one nonsense mutation in KRT10 that leads to mRNA decay, and one synonymous variant that affects the donor splice site of exon 3. We hypothesize that this leaky splice site explains the residual keratin 10 expression and self-improving clinical phenotype.
CFTR-PTEN–dependent mitochondrial metabolic dysfunction promotes <i>Pseudomonas aeruginosa</i> airway infection
Authors: Sebastián A. Riquelme, Carmen Lozano, Ahmed M. Moustafa, Kalle Liimatta, Kira L. Tomlinson, Clemente Britto, Sara Khanal, Simren K. Gill, Apurva Narechania, Jose M. Azcona-Gutiérrez, Emily DiMango, Yolanda Saénz, Paul Planet, Alice Prince
Journal: Science Translational Medicine (2019)

Excess succinate due to CFTR-PTEN dysfunction selects for Pseudomonas aeruginosa mutants adapted to the airway.
Ixazomib and dexamethasone in high risk smoldering multiple myeloma: A clinical and correlative pilot study.
Authors: Sham Mailankody, Meghan Salcedo, Elizabet Tavitian, Neha Korde, Nikoletta Lendvai, Hani Hassoun, Alexander M. Lesokhin, Oscar Boutros Lahoud, Eric L. Smith, Malin Hultcrantz, Sean M. Devlin, Ola Landgren
Journal: Journal of Clinical Oncology (2019)

8051 Background: Patients with high risk smoldering multiple myeloma (HR-SMM) have an increased risk of progression to multiple myeloma (MM)- median time &lt; 2 years. The standard management of these patients currently is close clinical monitoring; however, randomized trials show longer progression-free and overall survival in in HR-SMM patients treated with the oral immunomodulatory drug lenalidomide. We report the use ixazomib, the first oral proteasome inhibitor, in combination with dexamethasone in the setting of HR-SMM. Because proteasome inhibitors can provide deep clinical responses in patients with MM, we set the pre-specified threshold for efficacy high (overall response rate of ≥75%). Methods: In this single arm pilot trial of ixazomib/dexamethasone, patients received 12 4-week cycles of ixazomib/dexamethasone followed by ixazomib maintenance for 24 cycles. The primary endpoint is best overall response after 12 cycles and second objectives include duration of response, safety, and progression free survival. Results: 14 patients with HR-SMM were enrolled between 06/2016 and 03/2018. The median age is 65 years and 10 (71%) of patients were male. 11 (79%) patients were high-risk by the PETHEMA criteria, 2 (14%) by the Mayo Clinic criteria and 1 (7%) by both. At data cut-off (02/07/2019), patients completed a median of 17 cycles and 10 (71%) are continuing treatment. 4 patients have stopped treatment (2 patients for raise in serum markers without progression to MM, and 1 each for toxicities, and co-morbidities unrelated to treatment). 9 (64%) achieved an objective response (8 PR, and 1 VGPR) and no patient has progressed to MM. Non-heme adverse events included 3 grade 1 GI events, 2 grade 3 lung infection, 1 grade 2 acute kidney injury, and 1 had grade 1 fatigue that was possibly related to treatment. Conclusions: Ixazomib/dexamethasone appears well tolerated with high overall response (9/14; 64%) in patients with HR-SMM. Although the trial does not meet our pre-specified threshold for efficacy (i.e. best overall response rate of 75%), with a median follow-up of 17 months, no patient progressed to MM and only 2 patients had serologic progression. These results support further evaluation of ixazomib/dexamethasone alone and in combination with other agents as treatment for patients with HR-SMM. Clinical trial information: NCT02697383.
Abstract P108: Genome-wide Association Study of Activated Partial Thromboplastin Time in Multi-Ethnic Populations
Authors: Amanda A Seyerle, Saonli Basu, Christian Fuchsberger, Marine Germain, Weihua Guan, Tim Kacprowski, Andreas Greinacher, Marcus E Kleber, Graciela Delgado, Winfried März, Pierre-Emmanuel Morange, Nathan Pankratz, David-Alexandre Tregouet, James S Pankow, Weihong Tang
Journal: Circulation (2017)

Background: Activated partial thromboplastin time (aPTT) is a clinical test used to measure the clotting time between the activation of factor XII and the formation of a fibrin clot. Prolonged aPTT indicates a deficiency in the coagulation pathway while shortened aPTT is associated with prothrombotic risk factors and venus thromboembolism. Despite the high heritability of aPTT (40-80%), previous genome-wide association studies (GWAS) of aPTT have been limited to European descent populations, with only a smaller candidate gene study conducted in African Americans. Methods: We included 13,803 participants of European ancestry (EU) and 2,724 participants of African American ancestry (AA) from the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) consortium. aPTT, in seconds (s), was measured using standard protocols in plasma with the use of automated coagulometers. Genotype data were imputed to the 1000 Genomes Phase 1 reference panel, and associations were examined using linear regression assuming an additive genetic model and adjusting for global ancestry, age, sex, and study design. Study-specific results were combined using a fixed-effects, inverse variance weighted meta-analysis. Results: We identified seven loci associated with aPTT in EU populations ( F5, FRMD5, KNG1, F11, F12, HLA, ABO ) and three loci associated with aPTT in AA populations ( KNG1, F12, ABO ) at genome-wide significant levels ( P &lt; 5x10 -8 ). These results are consistent with previously reported genetic studies in EU and AA populations. Effect sizes were larger in AA populations (1.08 to 1.32 s) than in EU populations (0.40 to 1.00 s). Conclusions: We successfully replicated associations with aPTT at seven loci in EU populations and three loci in AA populations. Our results suggest that genetic determinants of aPTT are consistent across race/ethnicity but that studies in AA populations are currently underpowered relative to EU populations. Future work in aPTT genetics should consider more diverse populations.
Abstract 17640: Prolongation of High Tricuspid Regurgitation Pressure Gradient After Exercise in Patients With Exercise-Induced Pulmonary Hypertension: Stress Echocardiographic Study
Authors: Michiyo Yamano, Tetsuhiro Yamano, Tomonori Miki, Naohiko Nakanishi, Kan Zen, Takeshi Nakamura, Hirokazu Shiraishi, Takeshi Shirayama, Satoaki Matoba
Journal: Circulation (2017)

Introduction: Exercise-induced pulmonary hypertension (ePH) must be a crucial finding for diagnosing etiology of exertional dyspnea on exercise stress echocardiography. Although it is indispensable...
Abstract 5024: Treatment with synthetic RIG-I agonist triphosphate RNA leads to local and systemic anti-tumor effects in a mouse melanoma tumor model
Authors: Mike W. Helms, Eric Parmantier, Kerstin Jahn-Hofmann, Felix Gnerlich, Lars König, Christiane Metz-Weidmann, Monika Braun, Gabriele Dietert, Kaj Grandien, Joachim Theilhaber, Hui Cao, Tim Wagenaar, Max Schnurr, Stefan Endres, Dmitri Wiederschain, Sabine Scheidler, Simon Rothenfusser, Bodo Brunner
Journal: Cancer Research (2019)

Abstract RIG-I is a highly important cytosolic pattern recognition receptor (PRR) involved in sensing RNA virus infection and inducing interferon (IFN) production. RIG-I’s natural ligand, triphosphate RNA (ppp-RNA), is proposed to be a valuable addition to the growing arsenal of cancer immunotherapy treatment options. This study validates the use of intratumoral treatment with synthetic RIG-I agonist ppp-RNA for the therapy of human cancer, with melanoma as potential entry indication amenable to intratumoral treatment. Firstly, we demonstrate that RIG-I expression is closely correlated to cellular and cytokine immune activation in a wide variety of tumor types. Secondly, cellular models of human melanoma confirm susceptibility of cancer cells to ppp-RNA treatment, revealing unexpected heterogeneity between cell lines in their selectivity for RNA features, including sequence, secondary structures and presence of triphosphate. Cellular RNA treatment responses (type I IFN, FasR, MHC-I, cytotoxicity) were demonstrated to be RIG-I dependent using RIG-I KO cells. Thirdly, we show that ppp-RNA treatment of a mouse melanoma tumor model, leads to significant local and systemic anti-tumor effects and survival benefits, associated with a type I IFN response, tumor cell apoptosis and innate and adaptive immune cell activation. For the first time, we demonstrate systemic presence of tumor antigen specific CTLs following treatment with RIG-I agonist. Overall our study demonstrates that ppp-RNA or analogs thereof have the potential to play an important role for cancer treatment in the next wave of immunotherapy. However, potential challenges in the generation and formulation of potent RIG-I agonists remain to be solved. Citation Format: Mike W. Helms, Eric Parmantier, Kerstin Jahn-Hofmann, Felix Gnerlich, Lars König, Christiane Metz-Weidmann, Monika Braun, Gabriele Dietert, Kaj Grandien, Joachim Theilhaber, Hui Cao, Tim Wagenaar, Max Schnurr, Stefan Endres, Dmitri Wiederschain, Sabine Scheidler, Simon Rothenfusser, Bodo Brunner. Treatment with synthetic RIG-I agonist triphosphate RNA leads to local and systemic anti-tumor effects in a mouse melanoma tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5024.
Abstract 798: Epithelial-mesenchymal transition directs stem cell polarity via regulation of mitofusin
Authors: Meng-Ju Wu, Mi Ran Kim, Silpa Gampala, Yingsheng Zhang, Yueyang Wang, Jer-Yen Yang, Chun-Ju Chang
Journal: Cancer Research (2019)

Abstract Mitochondria are dynamic organelles that have been linked to stem cell homeostasis. However, the mechanism involved in mitochondrial regulation of stem cell fate determination remain elusive. Here we discover that epithelial-mesenchymal transition (EMT), a key process in cancer progression, induces mitochondrial fusion through regulation of miR200c-PGC1a-MFN1 pathway. EMT-activated MFN1 forms a complex with PKCz and is required for PKCz-mediated NUMB phosphorylation and dissociation from the cortical membrane to direct asymmetric division of mammary stem cells, where fused mitochondria are tethered by MFN1-PKCz to the cortical membrane and asymmetrically segregated to the stem cell-like progeny with enhanced glutathione synthesis and reactive oxygen species scavenging capacities, allowing sustaining of a self-renewing stem cell pool. Suppression of MFN1 expression leads to equal distribution of the fragmented mitochondria in both progenies that undergo symmetric luminal cell differentiation. Together, this study elucidates a novel role of mitofusin in stem cell fate determination to mediate EMT-associated stemness and provides therapeutic implications for targeting EMT-induced tumor stem cell populations. Citation Format: Meng-Ju Wu, Mi Ran Kim, Silpa Gampala, Yingsheng Zhang, Yueyang Wang, Jer-Yen Yang, Chun-Ju Chang. Epithelial-mesenchymal transition directs stem cell polarity via regulation of mitofusin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 798.
Abstract 14501: Empagliflozin Improves 24-Hour Blood Pressure Profiles in Patients With Type 2 Diabetes and Hypertension
Authors: Ilkka Tikkanen, Kirsi Narko, Cordula Zeller, Alexandra Green, Afshin Salsali, Uli C Broedl, Hans J Woerle
Journal: Circulation (2013)

A Phase III randomized placebo (PBO)-controlled trial investigated the efficacy and safety of the SGLT2 inhibitor empagliflozin (EMPA) in patients with type 2 diabetes (T2DM) and hypertension. Pati...
Visualizing treatment delivery and deposition in mouse lungs using in vivo x-ray imaging
Authors: Regine Gradl, Martin Dierolf, Lin Yang, Lorenz Hehn, Benedikt Günther, Winfried Möller, David Kutschke, Tobias Stoeger, Bernhard Gleich, Klaus Achterhold, Martin Donnelley, Franz Pfeiffer, Otmar Schmid, Kaye Susannah Morgan
Journal: Journal of Controlled Release (2019)
Abstract 5245: Integrative analysis of KIF4A, 9, 18A, and 23 and their clinical significance in low-grade glioma and glioblastoma multiforme
Authors: SangYeon Cho, DongWoon Kim
Journal: Cancer Research (2019)

Abstract To determine the prognostic significance of kinesin superfamily gene (KIF) expression in patients with brain cancer, including low-grade glioma (LGG) and glioblastoma multiforme (GBM), we comprehensively analyzed KIFs in 515 LGG and 595 GBM patients. Among KIFs, KIF4A, 9, 18A, and 23 showed significant clinical implications in both LGG and GBM. The mRNA and protein expression levels of KIF4A, 9, 18A, and 23 were significantly increased in LGG and GBM compared with those in the normal control groups. The mRNA expression levels of KIF4A, 9, 18A, and 23 in LGG were significantly increased in the high-histologic-grade group compared with those with a low histologic grade. Genomic analysis showed that the percent of mRNA upregulation of KIF4, 9, 18A, and 23 was higher than that of other gene alterations, including gene amplification, deep deletion, and missense mutation. In addition, LGG patients with KIF4A, 18A, and 23 gene alterations were significantly associated with a poor prognosis. In survival analysis, the group with high expression of KIF4A, 9, 18A, and 23 mRNA was significantly associated with a poor prognosis in both LGG and GBM patients. Gene Set Enrichment Analysis (GSEA) revealed that high mRNA expression of KIF4A, 18A, and 23 in LGG and GBM patients showed significant positive correlations with the cell cycle, E2F targets, G2M checkpoint, Myc target, and mitotic spindle. By contrast, high mRNA expression of KIF9 in both LGG and GBM patients was significantly negatively correlated with the cell cycle, G2M checkpoint, and mitotic spindle pathway. However, it was significantly positively correlated with EMT and angiogenesis. This study has extended our knowledge of KIF4A, 9, 18A, and 23 in LGG and GBM and shed light on their clinical relevance, which should help to improve the treatment and prognosis of LGG and GBM. Citation Format: SangYeon Cho, DongWoon Kim. Integrative analysis of KIF4A, 9, 18A, and 23 and their clinical significance in low-grade glioma and glioblastoma multiforme [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5245.
Abstract 14191: Development of ex vivo Diagnostic Tool for Variant Angina Using Peripheral Blood-Derived iPS Cells
Authors: Han-Mo Yang, Joo-Eun Lee, Ju-Young Kim, Byung-Hee Oh, Hyo-Soo Kim
Journal: Circulation (2017)

Introduction: Although variant angina is known to be caused by coronary artery spasm, there have been no studies explaining the exact underlying mechanism of spasm. Moreover, in order to confirm va...