tbuckley/cabot-search huggingface dataset:
Abstract 2950: Development of a 4-aminopyrazolo[3,4-<i>d</i>]pyrimidine-based dual IGF1R/Src inhibitor as a novel anticancer agent with minimal toxicity
Authors: Ho-Jin Lee, Hye-Young Min, Phuong Chi Pham, Byungyeob Baek, Byungjin Kim, Yunha Kim, Jeeyeon Lee, Ho-Young Lee
Journal: Cancer Research (2018)

Abstract Both the type I insulin-like growth factor receptor (IGF1R) and Src pathways are associated with the development and progression of numerous types of human cancer, and Src activation confers resistance to anti-IGF1R therapies. Hence, targeting both IGF1R and Src concurrently is one of the main challenges in combating resistance to the currently available anti-IGF1R-based anticancer therapies. However, the enhanced toxicity from this combinatorial treatment could be one of the main hurdle for this strategy, suggesting the necessity of developing a novel strategy for co-targeting IGF1R and Src to meet an urgent clinical need. In the present study, We synthesized a series of 4-aminopyrazolo[3,4-d]pyrimidine-based dual IGF1R/Src inhibitors, selected LL28 as an active compound, and evaluated its potential antitumor effects in vitro and in vivo. LL28 markedly suppressed the activation of IGF1R and Src and significantly inhibited the viability of several NSCLC cell lines in vitro by inducing apoptosis. Administration of mice with LL28 significantly suppressed the growth of H1299 NSCLC xenograft tumors without overt toxicity and substantially reduced the multiplicity, volume, and load of lung tumors in the KrasG12D/+-driven lung tumorigenesis model. These results suggest the potential of LL28 as a novel anticancer drug candidate targeting both IGF1R and Src, providing a new avenue to efficient anticancer therapies. Further investigation is warranted in advanced preclinical and clinical settings. Citation Format: Ho-Jin Lee, Hye-Young Min, Phuong Chi Pham, Byungyeob Baek, Byungjin Kim, Yunha Kim, Jeeyeon Lee, Ho-Young Lee. Development of a 4-aminopyrazolo[3,4-d]pyrimidine-based dual IGF1R/Src inhibitor as a novel anticancer agent with minimal toxicity [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 2950.
Abstract 412: 8p12 amplification pattern dictates FGFR1 dependency in squamous cell lung cancer
Authors: Florian Malchers, Martijn Henricus van Attekum, Martin Peifer, Roman Kurt Thomas
Journal: Cancer Research (2018)

Abstract Squamous cell lung cancer (SQLC) is the second most common lung cancer subtype after adenocarcinoma and accounts for 30% of all lung cancer cases. However, in contrast to adenocarcinoma, SQLC lacks therapeutic targets like activating EGFR mutations, ALK or ROS translocations. Besides immune-checkpoint-inhibition a promising treatment option in SQLC is the recurrent amplification of the tyrosine kinase fibroblast growth factor receptor 1 (FGFR1) within the 8p12-p11 region. Thus, small molecules inhibiting FGFRs have been employed to treat FGFR1-amplified SQLC. However, only about 10% of such FGFR1-amplified tumors respond to single agent inhibitor therapy. To investigate the mechanism of FGFR inhibitor resistance in 8p12-p11 amplified SQLC we performed deep genomic and transcriptome sequencing on 53 FGFR1 amplified samples including primary tumors (n=33), patient derived xenografts (n=13) and cell lines (n=7). For 22 of these samples the response to FGFR inhibition was known. We detected frequent breaks within NSD3 (n=3), also known as WHSC1L1, favoring the expression of NSD3-short, which is known to enhance MYC expression. Furthermore, the amplification pattern for all samples was compatible with a breakage-fusion-bridge (BFB) mechanism, showing chromosomal telomeric losses, copy number, and frequent intrachromosomal head to head and tail to tail breaks. Genomic reconstruction of one sample suggests a tandem duplication followed by a BFB mechanism, implying that the BFB mechanism is a later event in tumor genesis. Intrachromosomal tail to tail fusions within a 400kb region close to the FGFR1 open reading frame, have been detected in 75% of patients with a partial response to FGFR inhibitor therapy (3 of 4 patients). A similar break was detected in the FGFR inhibitor sensitive cell line H1581. All samples, which responded to FGFR inhibition (n=9), demonstrated a centered amplification pattern on NSD3 / FGFR1 and excluded amplification of the adjacent disintigrin and metalloproteinase family members (ADAM) genes. In contrast, the main amplification peak of the non-responding samples (n = 13) was centered on ADAM family members, corresponding to an increase in ADAM expression. These data suggest strong relevance of these genes for tumor development and growth, and warrant further investigation. Citation Format: Florian Malchers, Martijn Henricus van Attekum, Martin Peifer, Roman Kurt Thomas. 8p12 amplification pattern dictates FGFR1 dependency in squamous cell lung 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 412.
Crosstalk Between Autophagy and Apoptosis in Heart Disease
Authors: KazuhikoNishida, OsamuYamaguchi, KinyaOtsu
Journal: Circulation Research (2008)

Autophagy is a cell survival mechanism that involves degradation and recycling of cytoplasmic components, such as long-lived proteins and organelles. In addition, autophagy mediates cell death under specific circumstances. Apoptosis, a form of programmed cell death, has been well characterized, and the molecular events involved in apoptotic death are well understood. Damaged cardiomyocytes that show characteristics of autophagy have been observed during heart failure. However, it remains unclear whether autophagy is a sign of failed cardiomyocyte repair or is a suicide pathway for the failing cardiomyocytes. Although autophagy and apoptosis are markedly different processes, several pathways regulate both autophagic and apoptotic machinery and autophagy can cooperate with apoptosis. This review summarizes the evidence for crosstalk between autophagy and apoptosis.
Abstract 1112: AKT2 loss impairs BRAF mutant melanoma metastasis
Authors: Siobhan K. McRee, Jodie R. Pietruska, Philip N. Tsichlis, Phil W. Hinds
Journal: Cancer Research (2018)

Abstract Despite recent advances in treatment, melanoma remains the deadliest form of skin cancer, due to its highly metastatic nature. Many melanomas with oncogenic BRAFV600E lose the tumor suppressor PTEN, leading to unconstrained PI3K/AKT signaling and a drastic increase in melanoma invasiveness, but the contribution of AKT to melanoma metastasis has not been fully explored. Differential roles for AKT1 and AKT3 have been suggested in many cancers, but a requirement for AKT2 has not been described in melanoma. We report here that shRNA-mediated, conditional knockdown of AKTs in a variety of human melanoma cell lines reveals that selective AKT2 depletion inhibits migratory and invasive phenotypes in vitro, and prevents metastasis in vivo. Our results support a critical role for AKT2 in stimulating melanoma cell migration and invasion and in supporting growth of metastatic lesions. As AKT inhibitors advance in clinical trials for melanoma, our findings could inform therapeutic strategies to improve treatment options and outcome for this devastating disease. Citation Format: Siobhan K. McRee, Jodie R. Pietruska, Philip N. Tsichlis, Phil W. Hinds. AKT2 loss impairs BRAF mutant melanoma metastasis [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 1112.
Volatile Organic Compounds: Chemically Modified Polyaniline for the Detection of Volatile Biomarkers of Minimal Sensitivity to Humidity and Bending (Adv. Healthcare Mater. 15/2018)
Authors: Yunfeng Deng, Jiaxing Sun, Han Jin, Muhammad Khatib, Xianhui Li, Zongsu Wei, Feng Wang, Yehu David Horev, Weiwei Wu, Hossam Haick
Journal: Advanced Healthcare Materials (2018)

In article number 1800232 by Weiwei Wu, Hossam Haick, and co-workers, a strategy of oleic acid molecular layer assembly on PANI-based flexible sensors, is proposed to achieve tolerance of mechanical bending and humidity effects, up to 350 ppm. These results trigger the real application of flexible sensor applications in wearable devices for disease diagnostics.
Abstract 11228: The Endothelial Nitric Oxide Synthase Gene -786T/C Polymorphism is a Significant Predictive Factor for Myocardial Lactate Production During Acetylcholine-Provoked Coronary Spasm
Authors: KoichiKaikita, KojiSato, MasafumiNakayama, KenichiTsujita, SunaoKojima, SeijiHokimoto, HisaoOgawa
Journal: Circulation (2014)

Myocardial lactate production (MLP) in the coronary circulation is a supporting diagnostic marker useful in the evaluation of coronary spasm-induced myocardial ischemia during acetylcholine (ACh)-provocation test. We previously found a -786T/C polymorphism in the 5’-flanking region of the endothelial nitric oxide synthase (eNOS) gene and reported that this polymorphism is strongly associated with coronary spasm. However, there is no report showing the relation between MLP induced by ACh-provocation test and eNOS gene -786T/C polymorphism in the large study population. We examined 712 consecutive patients who underwent myocardial lactate measurement during ACh-provocation test and agreed with genetic screening test of eNOS gene -786T/C polymorphism between January 1991 and December 2010. ACh-provoked MLP was observed in 252 out of 712 patients included in the present analysis [252 MLP-positive and 460 MLP-negative patients]. MLP-positive patients were more likely to be female, diabetic, non-smokers, had ep...
Abstract 2754: NT219, a novel dual inhibitor of STAT3 and IRS1/2, converts immuno-oncology resistant tumors to responders
Authors: Lana Kuperschmidt, Hadas Reuveni, Shani Carmi, Neta Moskovits, Netta R. Shraga, Evgeny Solomonov, Ohad Ronen, Salomon Stemmer, Izhak Haviv
Journal: Cancer Research (2018)

Abstract Feedback activation of STAT3 and IGF1R/IRS plays a prominent role in mediating drug resistance to a broad spectrum of targeted cancer therapies and chemotherapies. Both the IRS1/2 and STAT3 are major signaling junctions regulated by various oncogenes, and altered during EMT and drug resistance. STAT3 has also been known to play an active role in immune-evasion of tumors and inhibition of STAT3, both in the tumor, as well as in the tumor's microenvironment, may therefore potentiate immune attack on the tumor. NT-219 is a dual inhibitor of STAT3 and IRS1/2 developed by TyrNovo Ltd. to overcome cancer drug resistance. NT-219 inhibits STAT3 phosphorylation and eliminates IRS1/2 in a unique 3-step mechanism: dissociation of IRS1/2 from the IGF1 receptor, induction of IRS1/2 serine phosphorylation, and subsequent degradation by the proteasome. We recently demonstrated that the inhibition of both IRS and STAT3 are required and essential for overcoming drug resistance. NT-219 efficacy was demonstrated in Patient-Derived tumor Xenograft (PDX) models of multiple cancer types: melanoma, sarcoma, pancreatic, colon, lung, and head &amp; neck, when added-on to the approved therapies. In these models, NT-219 overcame acquired resistance to several oncology drug families: inhibitors of EGFR (Tarceva®, Erbitux®, Tagrisso®), MEK (Mekinist®), mutated-BRAF (Zelboraf®), mTOR (Afinitor®) as well as with chemotherapy agents (Gemzar®, 5FU, Oxaliplatin). We recently demonstrated that NT-219 works in synergy also with immune-oncology therapies. By using double autologous PDX models we demonstrated that NT-219 converted non-responding tumors to responders to Keytruda®. It also enhanced the immunotherapeutic potential of Cetuximab. The unique mode of action of NT219 may open a new avenue of combined targeted therapies in a wide range of malignancies, and has the potential to expand response duration and target patient population to the applicable drugs. Citation Format: Lana Kuperschmidt, Hadas Reuveni, Shani Carmi, Neta Moskovits, Netta R. Shraga, Evgeny Solomonov, Ohad Ronen, Salomon Stemmer, Izhak Haviv. NT219, a novel dual inhibitor of STAT3 and IRS1/2, converts immuno-oncology resistant tumors to responders [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 2754.
The Transient Receptor Potential Protein Homologue TRP6 Is the Essential Component of Vascular α1-Adrenoceptor–Activated Ca2+-Permeable Cation Channel
Authors: RyujiInoue, TakaharuOkada, HitoshiOnoue, YujiHara, ShunichiShimizu, ShinjiNaitoh, YushiIto, YasuoMori
Journal: Circulation Research (2001)

Abstract—The Drosophila transient receptor potential protein (TRP) and its mammalian homologues are thought to be Ca2+-permeable cation channels activated by G protein (Gq/11)–coupled receptors and are regarded as an interesting molecular model for the Ca2+ entry mechanisms associated with stimulated phosphoinositide turnover and store depletion. However, there is little unequivocal evidence linking mammalian TRPs with particular native functions. In this study, we have found that heterologous expression of murine TRP6 in HEK293 cells reproduces almost exactly the essential biophysical and pharmacological properties of α1-adrenoceptor–activated nonselective cation channels (α1-AR–NSCC) previously identified in rabbit portal vein smooth muscle. Such properties include activation by diacylglycerol; S-shaped current-voltage relationship; high divalent cation permeability; unitary conductance of 25 to 30 pS and augmentation by flufenamate and Ca2+; and blockade by Cd2+, La3+, Gd3+, SK&F96365, and amiloride. R...
Abstract 9949: Prognostic Value of Longitudinal Strain of Right Ventricle in Patients With Stable Coronary Artery Disease
Authors: Wei-TingChang, Wei-ChuanTsai, Yen-WenLiu, Cheng-HanLee, Ping-YenLiu, Ju-YiChen, Yi-HengLi, Liang-MiinTsai
Journal: Circulation (2013)

Background: Regional strain by speckle tracking echocardiography is an emerging technique and can be used for assessment of right ventricle (RV). The aims of this study were to validate the prognostic value of RV strain as a new index of RV systolic function in patients with stable coronary artery disease. Methods and Results: We recruited 142 patients receiving elective coronary angiography for suspected coronary artery disease (mean age 64 ± 11 years, 113 men). RV lateral wall strain was measured by using speckle tracking echocardiography from apical 4 chamber view. The median follow-up duration for the entire patient population was 23.07 ± 6.58 months. During the follow-up, 21 patients died and 39 patients reached major adverse cardiovascular events. After excluding non-cardiovascular death, patients who died (18, 12.6%) had lower left ventricular ejection fraction (53.61±12.29 vs. 61.13± 14.27 %, p = 0.03 or greater impairment of RV lateral wall strain (-12.29 ±3.26 vs. -17.42± 5.12%, p = 0.01) compar...
Permanent Cardiac Pacing Versus Medical Treatment for the Prevention of Recurrent Vasovagal Syncope
Authors: FabrizioAmmirati, FurioColivicchi, MassimoSantini
Journal: Circulation (2001)

Background—This clinical investigation was performed to compare the effects of permanent dual-chamber cardiac pacing with pharmacological therapy in patients with recurrent vasovagal syncope. Methods and Results—Patients from 14 centers were randomized to receive either a DDD pacemaker provided with rate-drop response function or the β-blocker atenolol at the dosage of 100 mg once a day. Inclusion criteria were age >35 years, ≥3 syncopal spells in the preceding 2 years, and positive response to tilt table testing with syncope occurring in association with relative bradycardia. The primary outcome was the first recurrence of syncope after randomization. Enrollment was started in December 1997, and the first formal interim analysis was performed on July 30, 2000. By that time, 93 patients (38 men and 55 women; mean age, 58.1±14.3 years) had been enrolled and randomized, although follow-up data were available for all patients (46 patients in the pacemaker arm, 47 patients in the pharmacological arm). The int...
Abstract 1958: Benztropine enhances temozolomide sensitivity by restricting the growth of drug-resistant glioma stem cells
Authors: Damian A. Almiron Bonnin, Myung Chang Lee, Joseph M. Howard, Alison L. Young, Matthew C. Havrda
Journal: Cancer Research (2018)

Abstract Glioblastomas (GBMs) are the most aggressive type of primary brain tumor in adults, the second leading cause of cancer-related death in children, and are incurable using currently available treatment modalities. GBMs are characterized by the presence of primitive glioma stem-like cell subpopulations that resist chemotherapy and sustain disease progression. In this study, we found that Benztropine, a muscarinic acetylcholine receptor (mAChR) inhibitor, suppresses glioma cell proliferation and sensitizes these cells to treatment with Temozolomide. Modeling the development of Temozolomide resistance in vitro, we identified a subpopulation of glioma cells, defined by the co-expression of CD44, CD15, and PDGFRa that was resistant to Temozolomide. This chemo-resistant subpopulation was phenotypically similar to oligodendroglial progenitor cells (OPC-like); a stem-like cell population important in the initiation and progression of glioblastoma known to be modulated by mAChR signaling. The addition of the mAChR inhibitor, benztropine, dramatically reduced the emergence of this Temozolomide-resistant sub-population. To begin understanding the mechanism of action of benztropine on GBM cells, we analyzed the effect of this drug on a panel of mitotic drivers that have been implicated in glioma initiation and progression. Sub-lethal doses of Benztropine alone or in combination with temozolomide repressed the PDGF-signaling axis as characterized by a significant reduction of PDGFA secretion and PDGFRA activation. We also developed an in vivo model of Temozolomide resistance to determine whether Benztropine could improve the survival of animals harboring glioma xenografts that had recurred following treatment with Temozolomide. These in vivo studies demonstrated that Benztropine alone improves animal survival as compared with vehicle controls and that Benztropine combined with Temozolomide reduces glioma growth following initial Temozolomide treatment and improves survival in mice xenografted with human GBM cells. Taken together, our results suggest that Benztropine might be targeting glioma stem cells by altering the glioma stem cell microenvironment. These findings support a potential role for the use of adjuvant Benztropine for the clinical management of GBM. Citation Format: Damian A. Almiron Bonnin, Myung Chang Lee, Joseph M. Howard, Alison L. Young, Matthew C. Havrda. Benztropine enhances temozolomide sensitivity by restricting the growth of drug-resistant glioma stem cells [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 1958.
Epigenetic Modifications of Stem Cells
Authors: YonggangZhou, JohnnyKim, XuejunYuan, ThomasBraun
Journal: Circulation Research (2011)

Stem cells of all types are characterized by the ability to self-renew and to differentiate. Multiple lines of evidence suggest that both maintenance of stemness and lineage commitment, including determination of the cardiomyogenic lineage, are tightly controlled by epigenetic mechanisms such as DNA methylation, histone modifications, and ATP-dependent chromatin remodeling. Epigenetic mechanisms are intrinsically reversible, interdependent, and highly dynamic in regulation of chromatin structure and specific gene transcription programs, thereby contributing to stem cell homeostasis. Here, we review the current understanding of epigenetic mechanisms involved in regulation of stem cell self-renewal and differentiation and in the control of cardiac progenitor cell commitment during heart development. Further progress in this area will help to decipher the epigenetic landscape in stem and progenitor cells and facilitate manipulation of stem cells for regenerative applications.
Endoplasmic reticulum stress induces cardiac dysfunction through architectural modifications and alteration of mitochondrial function in cardiomyocytes
Authors: Alexandre Prola, Zuzana Nichtova, Julie Pires Da Silva, Jérôme Piquereau, Kevin Monceaux, Arnaud Guilbert, Mélanie Gressette, Renée Ventura-Clapier, Anne Garnier, Ivan Zahradnik, Marta Novotova, Christophe Lemaire
Journal: Cardiovascular Research (2018)

Endoplasmic reticulum (ER) stress has recently emerged as an important mechanism involved in the pathogenesis of cardiovascular diseases. However, the molecular mechanisms by which ER stress leads to cardiac dysfunction remain poorly understood. In this study, we evaluated the early cardiac effects of ER stress induced by tunicamycin (TN) in mice. Echocardiographic analysis indicated that TN-induced ER stress led to a significant impairment of the cardiac function. Electron microscopic observations revealed that ultrastructural changes of cardiomyocytes in response to ER stress manifested extensively at the level of the reticular membrane system. Smooth tubules of sarcoplasmic reticulum in connection with short sections of rough ER were observed. The presence of rough instead of smooth reticulum was increased at the interfibrillar space, at the level of dyads, and in the vicinity of mitochondria. At the transcriptional level, ER stress resulted in a substantial decrease in the expression of the major regulator of mitochondrial biogenesis PGC-1α and of its targets NRF1, Tfam, CS, and COXIV. At the functional level, ER stress also induced an impairment of mitochondrial Ca2+ uptake, an alteration of mitochondrial oxidative phosphorylation, and a metabolic remodelling characterized by a shift from fatty acid to glycolytic substrate consumption. Our findings show that ER stress induces cytoarchitectural and metabolic alterations in cardiomyocytes and provide evidences that ER stress could represent a primary mechanism that contributes to the impairment of energy metabolism reported in most cardiac diseases.
Abstract 14943: Comparison of Fasting and Nonfasting Lipoprotein Subfractions and Size in 13,460 Apparently Healthy Individuals
Authors: Zareen Farukhi, Olga Demler, Michael P Caulfield, Krishnaji Kulkarni, Jay Wohlgemuth, Michael Cobble, Heike Luttmann-Gibson, Nancy R Cook, Ronald M Krauss, JoAnn E Manson, Samia Mora
Journal: Circulation (2017)

Introduction: Elevated postprandial triglycerides (TGs) reflect a pro-atherogenic milieu but the underlying mechanisms are unclear. We examined differences between fasting and nonfasting plasma sam...