tbuckley/cabot-search huggingface dataset:
Abstract 2799: New-generation glucose transporter inhibitors targeting non-small cell lung cancer and triple-negative breast cancer
Authors: Pratik Shriwas, Yanrong Qian, Xuan Wang, Dennis Roberts, Stephen Bergmeier, Xiaozhuo Chen
Journal: Cancer Research (2018)

Abstract Cancer is a top killer second only to cardiovascular diseases. Cellular metabolic reprogramming and altered energetics are key features of cancer. Opportunistic uptake of extracellular nutrients has recently been named as an emerging hallmark of cancer metabolism. Glucose is a key nutrient taken in by cancer cells to meet their high energy and biosynthesis needs. Drastic upregulation of glucose uptake and glycolytic activity, a phenomenon called the Warburg effect, is prevalent in most cancers, including non-small cell lung cancer (NSCLC) and triple-negative breast cancer (TNBC). Cancer cells overexpress specific glucose transporters (GLUTs), particularly GLUT1, on their membranes to transport glucose via facilitated diffusion. Considering the addiction of cancer cells for glucose and their sensitivity and vulnerability to changes in glucose supply, GLUTs, especially GLUT1, have been recognized as an attractive anticancer target. We previously reported the identification of first-generation lead GLUT1 inhibitor WZB117. WZB117 treatment of human NSCLC A549 cells resulted in inhibition of glucose uptake, glycolysis and induction of apoptosis and necrosis (1). In addition, WZB-117 reduced tumor growth by more than 70% in an A549 tumor mouse model (1). Through a structure activity relationship (SAR) study of WZB117, a second-generation lead, DRB18, has been identified. DRB-18 is much more stable and 5 to 10 times more potent than WZB117 in inhibiting growth and proliferation in more than 90% of the 60 different cancer cell lines in 9 major cancer types as revealed by NCI-60 screenings. The compound shows particularly higher potency against cell lines with more metastatic potential such as HOP92 (NSCLC) and MDA-MB-231 (TNBC) with IC50 values in high nM range. DRB-18 also demonstrates a favorable liver microsomal metabolic profile and a maximal tolerance dose (MTD). All these indicate that DRB-18 is a potential therapeutic candidate for treating NSCLC and TNBC. Reference: 1. Liu Y, Cao Y, Zhang W, et al. A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycle arrest, and inhibits cancer cell growth in vitro and in vivo. Mol Cancer Ther 2012;11(8):1672-82. Citation Format: Pratik Shriwas, Yanrong Qian, Xuan Wang, Dennis Roberts, Stephen Bergmeier, Xiaozhuo Chen. New-generation glucose transporter inhibitors targeting non-small cell lung cancer and triple-negative breast 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 2799.
Abstract LB-139: Panel-based NGS identifies prognostic and actionable genes in childhood acute lymphoblastic leukemia and suits for clinical sequence
Authors: Hisashi Ishida, Akihiro Iguchi, Michinori Aoe, Takehiro Matsubara, Hirokazu Tsukahara, Akira Shimada
Journal: Cancer Research (2018)

Abstract Background: Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Whereas the cure rate has been much improved, considerable number of patients suffered from leukemia relapse. The cure rates of relapsed ALL patients remained poor as low as 40%, thus ALL is leading cause of cancer death during childhood. To improve the cure rates of these patients, precise re-stratification and newer targeted therapy are needed. For those reasons, detecting genes that had prognostic value and that are potentially actionable for in a short time is desired in clinical settings. Methods: We perform next generation sequence of matched diagnosis, remission, and relapse samples of eighteen relapsed ALL patients. We use the desktop sequencer MiSeq (Illumina, Inc., San Diego, CA, USA) and HaloPlex custom panels (Agilent Technologies, Santa Clara, CA, USA). These HaloPlex custom panels include more than 150 cancer-related genes. In the same sequencing run, we checked single nucleotide variations (SNV), insertion/deletion, and copy number variations (CNV) simultaneously. We also compare the genetic alterations between diagnosis and relapse samples, and presume the type of clonal evolutions. Results: We identified total 16 SNV and insertion/deletion and 19 CNV at diagnosis, and 28 SNV and insertion/deletion and 22 CNV at relapse. With these gene alterations, we could re-stratify many patients otherwise without any high-risk features (4/8 B-cell precursor ALL patients, 50%). We could also detect potentially actionable gene variants in most patients (13/17 of all patients, 76.5%). Among them, one patient harbored widely reported germline TP53 R248Q mutation, thus regarded as Li-Fraumeni syndrome. Most relapse samples (9/13 analyzed cases, 69.2%) acquire new lesions and lost some lesions present at diagnosis, suggesting their clonal evolution from ancestral clones. Remaining four cases (4/13 cases, 30.7 %) showed clonal evolution direct from diagnosis clones. Conclusion: This inexpensive, rapid, sequential next generation sequence method will immediately apply as clinical sequence, and lead to better management of these patients and potential improvement in survival rate in childhood ALL. Citation Format: Hisashi Ishida, Akihiro Iguchi, Michinori Aoe, Takehiro Matsubara, Hirokazu Tsukahara, Akira Shimada. Panel-based NGS identifies prognostic and actionable genes in childhood acute lymphoblastic leukemia and suits for clinical sequence [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-139.
Abstract 4457: Determining the role of novel GLI1 splice variants in breast cancer
Authors: Maria S. Dixon, Lhoucine Chdid, David Lamson, Michael Tarpley, Jodie M. Fleming, Jennifer A. Freedman, Gayathri R. Devi, Kevin P. Williams
Journal: Cancer Research (2018)

Abstract The purpose of this study is to investigate the biological significance of novel GLI1 splice variants in breast cancer. 15-20% of breast cancers are triple negative/basal-like, are associated with poor clinical outcomes and show disproportionately higher prevalence in younger women of African descent. The Hedgehog (Hh)/GLI1 developmental pathway has emerged as a therapeutic target in many cancers including studies on breast cancer such as those from our lab. Overexpression of the main Hh transcriptional mediator GLI1 correlates with poor patient prognosis and relapse. The human GLI1 transcript undergoes alternative splicing producing two shorter isoforms, an N-terminal deletion variant (GLI1ΔN) and a truncated GLI1 (tGLI1) which have been reported to have different patterns of tissue expression and function. tGLI1 has been identified as being highly expressed in several cancers, including in breast cancer. We undertook an in silico analysis of the NCBI database for evidence of additional human GLI1 transcripts and have identified novel GLI1 splice variants that we have subsequently shown to be highly expressed in breast cancer cell lines. Our objectives were to examine expression differences between GLI1 splice variants in basal-like and luminal breast cancer cell models, AA and White patient samples and to investigate the biological function of GLI1 splice variants in breast cancer. In our studies, we have utilized phenotypic and functional assays to examine the functional impact of these novel isoforms. Our preliminary data suggest that these newly identified GLI1 isoforms are expressed in basal-like breast cancers at substantially higher levels than GLI1, tGLI1 or GLI1ΔN. Previous studies assessing GLI1 expression have not considered these new isoforms and the relative contribution of each to breast cancer aggressiveness and require further investigation. Citation Format: Maria S. Dixon, Lhoucine Chdid, David Lamson, Michael Tarpley, Jodie M. Fleming, Jennifer A. Freedman, Gayathri R. Devi, Kevin P. Williams. Determining the role of novel GLI1 splice variants in breast 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 4457.
Spectral-Domain OCT Measurements in Alzheimer’s Disease
Authors: Victor T.T. Chan, Zihan Sun, Shumin Tang, Li Jia Chen, Adrian Wong, Clement C. Tham, Tien Y. Wong, Christopher Chen, M. Kamran Ikram, Heather E. Whitson, Eleonora M. Lad, Vincent C.T. Mok, Carol Y. Cheung
Journal: Ophthalmology (2018)
Abstract 1374: Modeling the CRISPR/Cas9 structural complex with sgRNA and DNA
Authors: Anita Wary
Journal: Cancer Research (2018)

Abstract The ability of genome editing tool to correct genetic disease, or edit the tumor causing gene, will not only benefit human race, but also plants and animal kingdom. The CRISPR/Cas9 system can be used to target specific genomic loci by single guide RNAs (sgRNAs). Using publicly available literature, we have modeled the structure of Streptococcus pyogenes Cas9 molecule in complex with sgRNA and its target DNA at 2.5 A° resolution. The crystal structure determination revealed a two-lobed architecture made of: (a) target recognition and (b) nuclease lobes, positioning the sgRNA:DNA hetero-duplex in a positively charged groove at their interface. While the recognition lobe interacts with the sgRNA and DNA, the nuclease lobe contains the HNH and RuvC nuclease domains that are responsible for cleavage of the complementary and non-complementary target DNA strands, respectively. The nuclease lobe also harbors a carboxyl-terminal domain to provide additional specificity for interaction with the protospacer adjacent motif (PAM) DNA sequence. This structural analyses show the molecular mechanism of RNA-guided DNA targeting by Cas9, thus providing the CRIPSR/Cas9 genetic machinery its ability to edit specific DNA sequence. (Key Ref: Nishimasu H et al., Cell. 2014;156:935-49) Citation Format: Anita Wary. Modeling the CRISPR/Cas9 structural complex with sgRNA and DNA [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 1374.
Young patients with breast cancer (&lt; 35 years): Single-institution study of 194 patients from India.
Authors: B. K Mohanti, Vinod Raina, Ajay Gogia, S. V. S Deo, N. K Shukla
Journal: Journal of Clinical Oncology (2012)

e11013 Background: Breast cancer in young women ( &lt; 35 years) is uncommon and accounts for 1-2 % of all breast cancer in the West .There is paucity of data on young breast cancer from India. The aim of our study was to assess clinical and pathological parameters and outcome in young breast cancer patients. Methods: Annually we register approximately 350 new cases of breast cancer of whom young patients constitute a small fraction. This analysis was carried out in 194 patients with aged 35 years or less, who were registered in our clinic between 2000-2009, this constituted about 5.5 % of all new cases. Patients records were analysed from computer database using ICD code (C-50) Results: The median age was 31 years (range 21-35). The median duration of symptoms was 11.8 months (range 0.5-40). Breast lump was the commonest (93%) presenting symptom (left &gt;right side). Ninety percent of patients were married and median age at first child birth was 23 years. Positive family history was elicited in 8 patients, and 3 patients presented with synchronous malignancy. The TNM (7 th edition) stage distribution was stage I was 3 %, stage II- 20%, stage III- 55%, and stage IV- 22%. The median clinical tumour size was 5.9 cm. Modified Radical mastectomy was the commonest surgical procedure and this was done in 81 % of cases. The histopathological analysis showed 94% had infiltrating ductal carcinoma. Sixty percent of tumours were high grade and 56% had pathological node positive disease. ER/PR status and Her2 Neu status was available in 65% and 50% respectively. Out of these patients ER and her2neu positivity was 40% and 37% respectively. Triple negative breast cancer (TNBC) constituted 31%. A combination of anthracyclines and taxanes were used in the vast majority of patients and herceptin was used only in 5 %. With a median follow up of 30 months, three years event free (EFS) and overall survival (OS) was 50% and 60%. Higher Nodal stage, tumour size (&gt;5 c.m ), negative ER/PR status and visceral metastasis at baseline predicted poor outcome. Conclusions: Young women constituted 5.5% cases with higher proportion of triple negativity, this is higher than the western population reflecting younger age of our population of breast cancer in general with a resultant poorer outcome.
Informed, uncorrupted clinical decision making should be the measure of marketing
Authors: Alastair Matheson
Journal: BMJ (2018)

Parker and colleagues discuss ethical drug marketing.1 One simple, potent yardstick for distinguishing acceptable from bad drug marketing derives from the perspective of the prescribing doctor.

When treatment decisions are made, the clinician’s reasoning should be free from interference, evidence based, cost aware, and appropriate to the needs and wishes of the patient. This basic principle of medicine leads to two fundamental marketing requirements.

Firstly, the only acceptable form of marketing should be the provision of information …
Abstract 3537: FBXW7-mediated extracellular signal-regulated kinase 3 stability in cancer development
Authors: Seung-Min Kim, Cheol-Jung Lee, Sun-Mi Yoo, Seon-Yeon Cho, Juhee Park, Yong-Yeon Cho
Journal: Cancer Research (2018)

Abstract Extracellular signal-regulated kinase (ERK) is an atypical member of the mitogen-activated protein kinase (MAPK) family. Initial studies have demonstrated that ERK3 was highly expressed in the central nervous system, skeletal muscle, lung, thymus, and testis. Interestingly, unlikely with classical MAPKs including ERK1/2, JNKs and p38s, ERK3 is known to have narrow substrate specificity. Although the function of ERK3 has studied for last three decades, some information for the role of ERK3 is currently available. Recent studies indicate that ERK3 is upregulated in diverse cancer tissues including lung cancer and colon cancer and ERK2 promotes cancer cell migration and invasion in triple-negative breast cancer. Interestingly, ERK3 showed short protein half-life about 30-60 min and ubiquitin-specific protease 20, a deubiquitinase, induced the ERK3 protein level. Thus, identification of E3 ubiquitin ligase is important to understand ERK3 function in cell transformation and cancer development. In this study, we identified that FBXW7, a member of F-box protein complex, bind with ERK3. Moreover, we found that ectopic expression of FBXW7 decreased ERK3 protein level in a dose dependent manner. By proteome analysis, we found that ERK3 contained FBXW7 specific degron motif in C-terminal variable region. Importantly, FBXW7 depletion in HCT-116 restored ERK3 protein level. Taken together, we concluded that FBXW7 is a specific binding partner of ERK3 and may regulate ERK3 protein stability. Key words: MAPK, ERK3, FBXW7, ubiquitination, protein stability Citation Format: Seung-Min Kim, Cheol-Jung Lee, Sun-Mi Yoo, Seon-Yeon Cho, Juhee Park, Yong-Yeon Cho. FBXW7-mediated extracellular signal-regulated kinase 3 stability in cancer development [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 3537.
Abstract 15339: Molecular Analysis of Epigenetic Modification Process in Distressed Cardiomyocytes May Explor Indication of Mitral Valve Surgery for Advanced Heart Failure Associated With Non-ischemic Dilated Cardiomyopath
Authors: Noriyuki Kashiyama, Shigeru Miyagawa, Koichi Toda, Teruya Nakamura, Yasushi Yoshikawa, Satsuki Fukushima, Shunsuke Saito, Daisuke Yoshioka, Emiko Ito, Akima Harada, Maki Takeda, Takayoshi Ueno, Toru Kuratani, Yoshiki Sawa
Journal: Circulation (2015)

Introduction: Mitral valve (MV) surgery for functional mitral regurgitation (MR) associated with advanced heart failure (HF) is a surgical challenge with surgical indication not clearly established. It was recently reported that the epigenetic modification, such as methylation or acetylation of histone H3, is closely related to functional reversibility of cardiomyocytes in advanced HF. Hypothesis: We herein hypothesized that epigenetic profiles in the left ventricle (LV) may be associated with clinical outcome of MV surgery for non-ischemic dilated cardiomyopathy (NIDCM)-causing advanced HF. Methods: Thirteen patients diagnosed as having NIDCM underwent chordal sparing MV replacement for severe MR associated with low ejection fraction (EF) (&lt;35%) between 2012 and 2015. Intraoperatively biopsied LV tissue was immunohistologically labeled by histone H3 lysine 9 tri-methylation (H3K9me3) and acetylation (H3K9ac), and then the scores ranging from 0 to 12 were assigned as intensity and percentage of positive staining cardiac cell nuclei. Results: Four patients (31%) necessitated left ventricular assist device (LVAD) implantation for persistent low output syndrome post-MV replacement, and one patient died of cardiac failure on day 260. Preoperative factors assessed by routine echocardiogram or right heart catheter study, such as LVEF (26±3 vs 24±6%, p=0.49), LV end-systolic dimension index (159±49 vs 188±58 ml/m2, p=0.42), or mean pulmonary arterial pressure (27±11 vs 22±9mmHg, p=0.42), were not a predictive factor of LVAD implantation post-MV surgery. In contrast, preoperative LV stroke work index (LVSWI) was significantly lower in the patients who had LVAD implantation (13±2 vs 22±7 g·m/m2/beat, p=0.02). In addition, the scores of H3K9me3 and H3K9ac were significantly lower in the patients with LVAD implantation (3.0±0.7 vs 6.5±1.9, p&lt;0.01 and 4.1±0.7 vs 8.9±1.9, p&lt;0.01, respectively) and closely correlated with preoperative LVSWI. Conclusions: Reduced H3K9 methylation and acetylation in cardiomyocytes was closely related to preoperative poor LV performance and represented poor clinical outcome after MV replacement in advanced NIDCM, suggesting that these parameters may be useful factors in determining the surgical indication.
Transient Mitochondrial Permeability Transition Pore Opening Mediates Preconditioning-Induced Protection
Authors: DerekHausenloy, AbigailWynne, MichaelDuchen, DerekYellon
Journal: Circulation (2004)

Background— Transient (low-conductance) opening of the mitochondrial permeability transition pore (mPTP) may limit mitochondrial calcium load and mediate mitochondrial reactive oxygen species (ROS) signaling. We hypothesize that transient mPTP opening and ROS mediate the protection associated with myocardial preconditioning and mitochondrial uncoupling. Methods and Results— Isolated perfused rat hearts were subjected to 35 minutes of ischemia/120 minutes of reperfusion, and the infarct-risk-volume ratio was determined by tetrazolium staining. Inhibiting mPTP opening during the preconditioning phase with cyclosporine-A (CsA, 0.2 μmol/L) or sanglifehrin-A (SfA, 1.0 μmol/L) abolished the protection associated with ischemic preconditioning (IPC) (20.2±3.6% versus 45.9±2.5% with CsA, 49.0±7.1% with SfA; P<0.001); and pharmacological preconditioning with diazoxide (Dzx, 30 μmol/L) (22.1±2.7% versus 46.3±3.0% with CsA, 48.4±5.5% with SfA; P<0.001), CCPA (the adenosine A1-receptor agonist, 200 nmol/L) (24.9±4.5% ...
Abstract 5754: Hypoxia-induced tumor plasticity and immune resistance involves an alteration of target recognition by a mechanism involving TGF-beta signaling
Authors: Stephane Terry, Stephanie Buart, Jean-Paul Thiery, Fathia Mami-Chouaib, Salem Chouaib
Journal: Cancer Research (2018)

Abstract Backgound: Hypoxia is known to shape the tumor microenvironment of developing tumors and contributes to both tumor progression and escape to immune surveillance. Previous work using non-small cell lung carcinoma cells (NSCLC) showed that hypoxia promotes epithelial-mesenchymal transition (EMT) in a fraction of carcinoma cells and that acquisition of a more mesenchymal (Mes) phenotype by certain cancer subclones correlates with an increased propensity to resist cytotoxic T lymphocytes (CTL) attacks as compared to more Epithelial (Epi) cancer subclones. Moreover, numerous studies identified alterations or loss of major histocompatibility complex (MHC) class I as a potential mechanism of tumor escape in cancer. Here, we asked whether hypoxia-induced EMT could regulate MHC class I expression and whether that could impact on resistance to CTL-mediated killing. Methods and Results : By comparing CMH class I in various NSCLC cancer subclones that have experienced hypoxic stress, we found that cancer clones with enhanced Mes features have a reduced expression of CMH class I molecules, as compared to those with a more Epi phenotype. Transient siRNA knockdown of hypoxia effectors HIF-1α or HIF-2α did not affect the expression of CMH class I molecules suggesting that EMT effectors, rather that HIFs, directly regulate CMH class I expression. Among EMT effectors, TGF-β expression was found to be highly upregulated in Mes cancer clones. Moreover, treatment of these cells with TGF-βR inhibitors markedly upregulated CMH class I expression. and as target cells, increases their susceptibility to CTL-mediated killing. However, blocking of TGF-β using Ab to TGF-β during the coculture time had no significant effects on CTL-mediated killing. This suggests that the observed changes in target cell susceptibility occurs through TGF-β-mediated repression of MHC class I rather than by cancer cell production of TGF-β affecting CTL effector functions. Conclusions: These results suggest that the increase in TGF-β signaling, especially found in EMTed Mes carcinoma cells in response to hypoxic stress, contributes to downregulate CMH class I expression in these cells while coinciding with a reduced susceptibilty to CTL attacks. The development of agents targeting hypoxia or EMT components should provide new therapeutic opportunities in combination with current approaches. Citation Format: Stephane Terry, Stephanie Buart, Jean-Paul Thiery, Fathia Mami-Chouaib, Salem Chouaib. Hypoxia-induced tumor plasticity and immune resistance involves an alteration of target recognition by a mechanism involving TGF-beta signaling [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 5754.