tbuckley/cabot-search huggingface dataset:
Abstract 2498: Over-expression of dual-specificity phosphatase 4 (DUSP4) in multiple myeloma
Authors: Tian Xia, Kin-Mang Lau, Chi Keung Cheng, Nelson CN Chan, Margaret H. L. Ng
Journal: Cancer Research (2018)

Abstract Super-enhancers are unique genomic domains with dense binding of transcription factors (TFs)/cofactors that drive expression of genes defining cell identity. They also contribute to over-expression of oncogenes. The abundance of multiple TFs and coactivators at the super-enhancers favors their cooperative binding and synergistic gene activation. Thus, super-enhancers are more sensitive to perturbation of TF levels than typical enhancers, providing a therapeutic window for preferential targeting oncogenic expression in cancer cells. Recently, a list of super-enhancer associated genes (SEAG) was identified in a multiple myeloma (MM) cell line MM1S and inhibition of transcriptional coactivator BRD4 by JQ1 selectively repressed MYC oncogene expression through reduction of BRD4 binding at the associated super-enhancer. Significances of SEAG other than MYC in myeloma cells remains unclear. By unsupervised hierarchical clustering analysis of expression of 682 identified SEAG in 74 MM, 28 relapsed MM and 15 normal plasma cells (NPC) (GSE6477), distinct expression pattern of SEAG was associated with MM as compared to NPC, indicating their importance in MM. Among the upregulated genes, DUSP4 (Dual Specificity Phosphatase 4), an inducible phosphatase of MAPK (Mitogen-Activated Protein Kinases), was significantly overexpressed in MM and further upregulated in the relapsed MM. High expression was associated with inferior patient outcomes. The overexpression was confirmed in our patient cohort which includes CD138-immunosorted myeloma cells from 30 untreated and 3 relapsed MM patients, 6 smoldering MM patients and 5 MGUS patients, 5 sorted normal plasma cells (NPC) and 7 MM cell lines. Using the cutoff for over-expression as higher than the mean level of NPC plus 2X Standard Deviation, 10 out of 30 MM and all the 3 relapsed samples showed significant DUSP4 over-expression. Functional significance of DUSP4 in MM was explored by siRNA knockdown and the knockdown inhibited myeloma cell growth, implying an oncogenic role of DUSP4 in MM. To study the significances of super-enhancer in regulation of DUSP4 expression, JQ1 was used and inhibition of BRD4 by JQ1 in MM1S, L363 and OPM2 repressed both DUSP4 expression and MM cell growth. By ChIP-PCR, we demonstrated BRD4 specifically bound onto the proximal region of DUSP4 promoter and the binding was blocked by JQ1. Taken together, the oncogenic role of DUSP4 as SEAG in MM was revealed and the preferential targeting SEAG by BRD4 inhibitor could provide insights into further developments of effective therapeutic approaches for MM patients. Citation Format: Tian Xia, Kin-Mang Lau, Chi Keung Cheng, Nelson CN Chan, Margaret H. L. Ng. Over-expression of dual-specificity phosphatase 4 (DUSP4) in 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 2498.
Genotype-driven dosing of irinotecan and adverse events in patients receiving irinotecan with <i>UGT1A1</i> gene variants.
Authors: Candice Baldeo, Caren Hughes, Pashtoon Murtaza Kasi
Journal: Journal of Clinical Oncology (2018)

e15544 Background: Pharmacogenomic testing can be used to optimize drug doses and increase tolerability.The main adverse effects of irinotecan include gastrointestinal toxicity such as nausea,vomiting and diarrhea.It can also result in cytopenias including neutropenia requiring growth factor support.There has been a correlation between UGT1A1 gene mutations and irinotecan toxicity.The focus of our study was to identify the hematological and symptomatic effects of irinotecan in patients with UGT1A1 gene variant and to evaluate if pre-planned dose reductions of irinotecan can reduce these adverse effects. Methods: A retrospective chart review was done on patients between October 2017- February 2018,who had metastatic colorectal cancer and were tested for UGT1A1 gene mutation and received irinotecan-based therapy,in Mayo Clinic Florida.Testing was done by blood sample or buccal swab.We compared patients who had UGT1A1 gene variant, and receiving full dose or dose reduced irinotecan, with patients with no UGT1A1 mutation and on irinotecan.We looked at symptoms of nausea, vomiting, diarrhea, constipation, mucositis and pain that were documented after the first cycle of irinotecan and prior to the second cycle of irinotecan.We also looked at new or worsening anemia, thrombocytopenia, neutropenia and liver function tests documented after the first cycle and prior to the second cycle of irinotecan. Results: There were 15 patients with UGT1A1 gene variant on irinotecan(9 patients on dose reduced irinotecan and 6 patients on full dose irinotecan) and 9 patients with no UGT1A1 variant on irinotecan.The presence of any symptoms was twice as high in the UGT1A1 variant population (67%), as compared to the population without a variant (33%), and this was seen regardless of dose reduction of irinotecan.There was a new grade 3 neutropenia in UGT1A1 variant group on full dose irinotecan dose,while none was documented in patients with normal variant or patients with variant receiving dose reductions. Conclusions: A higher prevalence of symptoms was reported in patients with a UGT1A1 variant. Genotype-driven dosing can help prevent serious adverse events and is feasible given the fast turnaround.
Significance of the Initial R Wave in Lead aVR of the Electrocardiogram in the Diagnosis of Myocardial Infarction
Authors: Noboruokamoto, Ernstsimonson, Surajahuja, Georgemanning
Journal: Circulation (1967)

Distribution, means, and standard deviations of the initial R wave in lead aVR of the electrocardiogram are investigated in 1,563 healthy U.S.A., Canadian, and Japanese men, ages 18 to 60 years, and on 448 healthy U.S.A., Canadian, and Japanese women, ages 17 to 51 years, and in samples of cardiac pathology. Findings in the normal group included an initial R wave in about 50% of the group, no significant effect of age, sex, or race on the mean initial R-wave amplitude in lead aVR or its distribution, or on the upper 98% normal limit of the initial R wave, a decrease of the mean R amplitude in aVR with clockwise rotation of the transitional zone, and a highly significant correlation of R amplitude in aVR to that of R in V1, Q3, and Q in aVF, but too low for reliable prediction. Right ventricular hypertrophy, anterior wall myocardial infarction, and hypertensive heart disease have no effect on the amplitude or prevalence of the initial R in aVR. Posterior and anterior plus posterior wall infarction signific...
Novel Mechanism of HERG Current Suppression in LQT2
Authors: TadashiNakajima, TetsushiFurukawa, ToshihiroTanaka, YoshifumiKatayama, RyozoNagai, YusukeNakamura, MasayasuHiraoka
Journal: Circulation Research (1998)

Abstract—In a Xenopus oocyte heterologous expression system, we characterized the electrophysiology of 3 novel missense mutations of HERG identified in Japanese LQT2 families: T474I (within the S2-S3 linker), A614V, and V630L (in the outer mouth of pore-forming region). For each of the 3 mutations, injection of mutant cRNA alone did not express detectable currents. Coinjection of wild-type (WT) along with each mutant cRNA (T474I/WT, A614V/WT, and V630L/WT) suppressed HERG current in a dominant-negative manner, and the order of magnitude of current suppression was V630L/WT>A614V/WT>T474I/WT. In addition to decreases in slope conductance for all 3 mutants, the voltage dependence of steady-state inactivation was shifted to negative potentials for V630L/WT and A614V/WT. Consequently, channel availability at positive potentials was diminished, and inward rectification was enhanced for these 2 mutants. Thus, missense mutations of HERG caused dominant-negative suppression through multiple mechanisms. The shift i...
Abstract 11423: Mitochondrial Calcium Flux Modulates Pacemaker Activity in Mouse Stem Cell Derived Cardiomyocytes
Authors: An Xie, Anyu Zhou, Hong Liu, Guangbin Shi, Kenneth R Boheler, Samuel C Dudley
Journal: Circulation (2014)

INTRODUCTION: Ca2+ release from sarcoplasmic reticulum (SR) is known to contribute to the pacemaker activity in embryonic stem cells (ESC) derived cardiomyocytes (CMs). Mitochondria are known to participate in Ca2+ cycling. Nevertheless, the role of mitochondria in pacemaker activity is unclear. We studied the role of mitochondrial Ca2+ flux in spontaneously activity of ESC derived CMs. METHODS: CMs were derived from Wt and ryanodine receptor type 2 knockout (RYR2-/-) mouse ESC. Action potentials (APs) were recorded by perforated whole-cell current-clamp. Cytoplasmic and mitochondrial Ca2+ transients were determined by Fluo-4 and Rhod-2 respectively. Mitochondrial Ca2+ uniporter (MCU) siRNA was used. The mRNA level was evaluated by qPCR. RESULTS: As predicted, SR Ca2+ handling inhibitors, 10 μM ryanodine and 2 μM 2-APB, reduced spontaneous beating rate to 56% and 73% respectively in Wt CMs. Inhibition of mitochondrial Ca2+ flux by 10 μM Ru360 showed a similar inhibition effect on the pacemaker activity as 2 μM 2-APB in Wt CMs. To isolate the mitochondrial component, we used RYR2-/- CMs. In these cells, MCU inhibition by pharmacological or molecular biological means reduced beating rate. The MCU mRNA decreased by 96% after MCU siRNA silence 72 hrs (p&lt;0.01). AP and mitochondrial Ca2+ transient synchronous recording revealed that the reduction of spontaneous beating rate accompanied with the depressed mitochondrial Ca2+ uptaking and releasing. In RyR2-/- CMs, 2 μM 2-APB could significantly lower the spontaneous beating rate. While 2 μM 2-APB was applied to MCU silenced RyR2-/- CMs, the beating rate couldn’t be slowed down further. This indicated IP3 receptors reduced spontaneous beating rate via MCU. Thapsigargin could substantially slow down beating rate like 2-APB. Caffeine depletion experiments showed other ryanodine receptor subtypes didn’t contribute Ca2+ release in RyR2-/- CMs. A L-type Ca2+ channel block, 10 μM nifedipine, couldn’t reduce beating frequency. This indicated spontaneous beating rate is Ca2+ influx independent in RyR2-/- CMs. CONCLUSIONS: Mitochondrial Ca2+ handling plays an important role in decreasing spontaneous beating rate. IP3R reduced spontaneous beating rate through MCU.
Abstract 44: Characterization and targeting of a temporal micro-metastatic signature in human brain metastases
Authors: Mohini Singh, Chitra Venugopal, Tomas Tokar, Nicole McFarlane, Minomi Subhapanditha, David Bakhshinyan, Maleeha Qazi, Parvez Vora, Neil Savage, Naresh K. Murty, Igor Jurisica, Sheila K. Singh
Journal: Cancer Research (2018)

Abstract Metastases to the brain (BM) are the most common neoplasms to affect the adult central nervous system, arising in 40% of cancer patients and at a rate 10 times greater than primary brain tumors. Despite the prevalence and poor survival rates, therapeutic strategies for BM remain limited, and a substantial cause is the lack of proper preclinical models available to interrogate the intricacies of BM development. Previous work in our lab utilized BM samples from patient-derived lung-to-brain metastases to successfully establish clinically relevant in vivo models of BM. Here we further characterized the cells responsible for BM, termed brain metastasis initiation cells (BMIC). Patient-derived BMICs were injected via intracranial (BT), intracardiac (IC) and intrathoracic (IT) routes into NOD/SCID mice and re-isolated at different stages of metastatic progression. We isolated cells from primary lung tumors (LT), cells injected via intra-thoracic route that crossed the blood brain barrier to seed the brain forming micro-metastases (BMIT), and cells injected via intracardiac route that seeded large macro-metastases (BMIC). Through RNA sequencing we determined cells from BMIT (micro-metastasis stage) to retain a vastly different genetic profile compared to BMICs isolated at other stages of metastasis. Several of these genes belonged to pathways implicated in autonomic central nervous system neoplasms and neural development. Through connectivity mapping of BMIT profiles we discovered drugs that could inhibit the micro-metatsasis signature, and further in vitro validation revealed apomorphine to reduce BMIC sphere formation and proliferation. In vivo treatment with apomorphine blocked both micro- and macro-metastatic stages of our BMIC model. Of 5 BMIT genes identified to be specifically targeted by apomorphine, KIF16B, TESK2 and SEPW1 were shown to have significant value when applied as an independent prognostic signature in a cohort of lung adenocarcinoma patients. Future work will further validate the efficacy of apomorphine in targeting BMICs in primary lung cancer patient samples. With this work we present a possible new avenue for therapeutic targeting toward the prevention of BM development, where it is anticipated to transform a uniformly fatal disease into one that is eminently more treatable. Citation Format: Mohini Singh, Chitra Venugopal, Tomas Tokar, Nicole McFarlane, Minomi Subhapanditha, David Bakhshinyan, Maleeha Qazi, Parvez Vora, Neil Savage, Naresh K. Murty, Igor Jurisica, Sheila K. Singh. Characterization and targeting of a temporal micro-metastatic signature in human brain metastases [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 44.
Medically Expulsive Therapy (MET) Has No Benefit in Improving Spontaneous Stone Passage (SSP) in Patients Presenting with Acute Ureteric Colic: Results from the MIMIC Study
Authors: S. Khadhouri, T. Shah, C. Gao, A. O'Keefe, T. Manning, A. Peacocke, S. Cashman, A. Nambiar, B. Lamb, R. Pickard, P. Erotocritou, D. Smith, V. Kasivisvanathan
Journal: International Journal of Surgery (2018)
Abstract 4504: Functional roles of KRT6-KRT14 fusion variant 7 in desmosome remodeling and cell spreading/migration
Authors: Jim J. Sheu, Brian Y. Kuo, Chia-Cheng Wu, Jacky Yang, Chih-Mei Chen
Journal: Cancer Research (2018)

Abstract Keratins are intermediate filament (IF) proteins with major functions in controlling/maintaining cell morphology and stiffness. Recent studies indicated possible involvement of keratin IFs in cancer developments. In our previous study, we have identified the existence of keratin fusions between KRT6 and KRT14 genes in oral squamous cell carcinoma (OSCC), and patients with the history of chewing betel nut showed higher frequency to harbor such fusions in their tumor tissues. In this study, we studied bio-functional roles of a major keratin fusion isotype K6-K14/V7, which correlated with bigger tumor size, in cell migration and invasion. We established a tet-off inducible gene expression system in OSCC cells. After gene being turned on, K6-K14/V7 formed a peripheral-dominant network that subsequently up-regulated genes related to actin filament remodeling via mechano-transduction. Actin-associated protrusion at cell leading edge was also increased by K6-K14/V7 to enhance cell migration and invasion. Interestingly, the desmosome junction was found to be dramatically reduced, leading to loss of cell-cell contact and stemness formation via epithelial-mesenchymal transition (EMT). The K6-K14/V7-expressing cells showed reduced drug sensitivity toward 5-FU and cisplatin treatment, and formed more colonies in vitro and bigger tumors in vivo. This study uncovers new functions/definitions for keratin IF in cancer development, Mechanisms revealed by this study can help us to design new strategies for new drug development and clinical treatments. Citation Format: Jim J. Sheu, Brian Y. Kuo, Chia-Cheng Wu, Jacky Yang, Chih-Mei Chen. Functional roles of KRT6-KRT14 fusion variant 7 in desmosome remodeling and cell spreading/migration [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 4504.
Abstract 572: Genome-scale CRISPR/Cas9 screen identifies factors required for sensitivity to pyrimidine nucleoside analogs
Authors: Awa SARR, Jennifer Bré, Peter Mullen, Sarah Blagden, In Hwa Um, David J. Harrison, Paul A. Reynolds
Journal: Cancer Research (2018)

Abstract NUC-1031 (NuCana plc), is a phosphoramidate transformation of gemcitabine, which bypasses cancer cell resistance mechanisms to gemcitabine. This compound showed promising results in clinical studies (phase I/II), demonstrating tumor reduction and durable disease control in patients who were refractory to or had relapsed on gemcitabine. Here, we adopted an unbiased approach to uncover genes and pathways involved in gemcitabine and NUC-1031 resistance. We performed a genome-wide knockdown screen using CRISPR/Cas9 technology in the pancreatic cancer cell line MiaPaCa2. Potential candidates from the screen were validated by gene inactivation using individual or combined single guide (sg)RNA targeting sequences. The effect of gene knockdown on NUC-1031 and gemcitabine resistance was assessed by monitoring cell survival after drug treatment using Celigo cytometry to assess cell number. EC50 values were determined using the resulting survival curves. This screen generated a list of 4 candidate genes potentially involved in NUC-1031 resistance. Two candidates were investigated further: DCK and DCTPP1, both involved in pyrimidine metabolism, especially in the maintenance of the dCMP/dCTP pool. DCK knockdown induced significant resistance to gemcitabine (EC50 350 times higher than in control cells) and a degree of resistance to NUC-1031 (EC50 7 times higher than in control cells). A less robust effect was observed when DCTPP1 was inactivated. DCTPP1 knockdown induced a small decrease in sensitivity to NUC-1031 (EC50 1.5 times higher than in control cells). These results highlight the potential role of dCMP/dCTP pool regulation by DCK and DCTPP1 in sensitivity to pyrimidine nucleoside analogs and may provide a useful biomarker for patient selection. Citation Format: Awa SARR, Jennifer Bré, Peter Mullen, Sarah Blagden, In Hwa Um, David J. Harrison, Paul A. Reynolds. Genome-scale CRISPR/Cas9 screen identifies factors required for sensitivity to pyrimidine nucleoside analogs [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 572.
Significance of Chymase-Dependent Angiotensin II–Forming Pathway in the Development of Vascular Proliferation
Authors: MasayoshiNishimoto, ShinjiTakai, ShokeiKim, DenanJin, AtsushiYuda, MasatoSakaguchi, MayumiYamada, YoshihideSawada, KeiichiroKondo, KunioAsada, HiroshiIwao, ShinjiroSasaki, MizuoMiyazaki
Journal: Circulation (2001)

Background Vascular tissues of humans and dogs contain chymase as an angiotensin II–forming enzyme. In this study, we investigated whether chymase-dependent angiotensin II formation plays a crucial role in the development of vascular proliferation in dog grafted veins. Methods and Results The right external jugular vein of dogs was grafted to the ipsilateral carotid artery. As a control group, the right external jugular veins in dogs that had not received grafts were used. In the chymase inhibitor–treated group, the vein was infiltrated with 10 μmol/L Suc-Val-Pro-PheP(OPh)2 and was grafted to the carotid artery. In the placebo-treated group, ACE activity in the grafted veins was significantly lower than that in the control veins up to 7 days after the operation, whereas chymase activity was increased significantly. After 7 days, the mRNA levels of collagen I, collagen III, and fibronectin, all of which are induced by an increase of angiotensin II action, were significantly increased in the grafted veins, ...
Abstract LB-184: Core circadian clock component, PERIOD2, regulates adaptive radioprotection via PER2-β-Catenin controlled mitochondrial bioenergetics
Authors: Aris Alexandrou, Ming Fan, Shuaib Juma, Julian Perks, Andrew Vaughan, Clifford Tepper, Loning Fu, Gayle Woloschak, David Grdina
Journal: Cancer Research (2018)

Abstract Circadian clocks are intimately involved in the homeostatic maintenance of metabolic and physiological processes that may have increasingly important roles to enhance bone marrow transplantation success in cancer patients; to protect normal tissue surrounding tumors from the harmful effects of radio/chemotherapy; and to enhance the quality of diet and sleep for astronauts during space exploration. Herein, we report that expression of PERIOD2 (PER2; a core circadian clock component and “the inherent driver” of radioprotection) is required for adaptive protection against environmental radiation stress. PER2 expression is induced by exposure to low dose radiation (LDR; 10cGy) and siRNA blockade of PER2 ablates LDR-induced adaptive radioprotection. In addition, melatonin (N-acetyl-5-methoxytryptamine), a natural anti-oxidant and hypothalamic circadian synchronizer, stimulates PER2 expression and confers mice radioprotection through weight maintenance and increased survival. LDR-induced PER2 transcription is regulated by NF-κB and β-catenin and is released from phospho-glycogen synthase kinase-3ß (p-GSK3ß) in the WNT/β-catenin pathway. Unbound β-catenin interacts with the TCF/LEF domain on the Per2 promoter to promote feed-forward PER2-pGSK3β complex formation. Mitochondrial bioenergetics measured by oxygen consumption and ATP generation was attenuated in bone marrow isolated from PER2 mutant (Per2m/m) mice. Furthermore, RNA-seq profiling of bone marrow-derive progenitor hematopoietic stem cells (BM-pHSCs; Lin-/Sca1+/cKit+; LSK) cells isolated form LDR-treated wild-type (WT) versus Per2m/m mice showed a cluster of genes involved in mitochondrial bioenergetics and DNA repair capacity. These results demonstrate that a core circadian regulator plays an indispensable role in defending mammalian cells against environmental genotoxic stress through the PER2/β-catenin pathway, a potential therapeutic target to enhance cell survival under radiation. Citation Format: Aris Alexandrou, Ming Fan, Shuaib Juma, Julian Perks, Andrew Vaughan, Clifford Tepper, Loning Fu, Gayle Woloschak, David Grdina. Core circadian clock component, PERIOD2, regulates adaptive radioprotection via PER2-β-Catenin controlled mitochondrial bioenergetics [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-184.