tbuckley/cabot-search huggingface dataset:
P08.66 Concomitant treatment with metformin plus temolomide increases the anti-tumor effects on glioblastoma in vitro and in vivo
Authors: S. Yang, S. Lee
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) is one of the most aggressive cancers and the most common primary brain tumor. Although the concomitant chemoradiotherapy using temozolomide (TMZ) has been established as the standard therapy, the median survival is approximately 14 months. Metformin is an oral biguanide introduced in the 1950s for the treatment of type 2 diabetes. A recent epidemiologic survey found that metformin also had significant effects on tumorigenesis. The purpose of the study is to investigate the efficacy of combined therapy with TMZ and metformin for the treatment of GBM in vitro and in vivo. Metformin and TMZ inhibit survival of U87MG cells in a dose- and time-dependent manner, respectively. The combination of metformin and temzolomide enhances the antitumor effect. Flow cytometry analysis showed that combination of metformin and temzolomide induces an increase in the percentage of apoptotic cells. Notably, the combination of metformin and TMZ enhances AMPK phosphorylation and inhibit mTOR, when compared with vehicle-treated cells and single-agent therapy. In xenograft models, the survival of mice treated with combined therapy with clinically relevant dosage of TMZ and metformin is similar with that of mice treated with single-agent therapy (67 vs. 56 days). Increased dosage of metformin combined with TMZ prolongs the survival in vivo injected with U87 or TMZ-resistance U87 cells. Our results show that metformin enhances the anti-tumor effect of TMZ via AMPK-mTOR signaling pathway. The presented data reinforce that metformin might be a good candidate for combined regimen with TMZ in clinical settings.
Identification of cancer-related genes that are alternatively spliced at high frequency in lung adenocarcinoma using whole genome exon arrays
Authors: Liqiang Xi, Andrew Feber, Vanita Gupta, Maoxin Wu, Rodney Landreneau, Virginia Litle, James Luketich, Tony Godfrey
Journal: Cancer Research (2007)

LB-217   Genomic analysis has demonstrated that alternative splicing occurs in up to 60% of human genes with the majority reported to be associated with tissue-type or with normal development. Some individual gene studies have found that alternative splice variants are associated with cancer and play important roles in apoptosis, transformation, motility, and metastasis of tumors. We present an exploratory genome-wide study using Affymetrix Human Exon arrays to identify splice variant expression differences between normal lung and lung adenocarcinoma.  40 paired tumor-normal specimens from 20 patients (14 female and 6 male) with lung adenocarcinoma were used for the study. RNA from each sample was labeled and hybridized on GeneChip Human Exon 1.0 ST Arrays according to Affymetrix protocols. Analysis was focused initially on the 19,076 RefSeq genes for which there are ~285,000 probe sets on the arrays. Probe-level analysis with RMA and alternative splicing analysis with ANOVA were performed using the Partek Genomics Suite. Putative alternately spliced genes were entered into the Ingenuity Pathway Analysis software and genes reported to be associated with cancer were chosen for more detailed examination.  >2051 genes were identified as alternately spliced between tumor and normal with p We have demonstrated that alternative splicing in a high frequency occurs in lung adenocarcinomas. Two genes may also have gender-specific alternate splicing in tumors; an interesting finding given the epidemiologic and survival differences between men and women with lung adenocarcinoma. If these findings can be verified, alternate splice events could prove useful for lung cancer diagnosis and as novel targets for therapeutic development.
Overexpressed Fatty Acid Synthase in Gastrointestinal Stromal Tumors: Targeting a Progression-Associated Metabolic Driver Enhances the Antitumor Effect of Imatinib
Authors: Chien-Feng Li, Fu-Min Fang, Yen-Yang Chen, Ting-Ting Liu, Ti-Chun Chan, Shih-Chen Yu, Li-Tzong Chen, Hsuan-Ying Huang
Journal: Clinical Cancer Research (2017)

Purpose: In gastrointestinal stromal tumors (GIST), lipid-metabolizing enzymes remain underexplored, including fatty acid synthase (FASN).Experimental Design: Forty GISTs were quantitated for FASN mRNA abundance. FASN immunoexpression was informative in 350 GISTs, including 213 with known KIT/PDGFRA/BRAF genotypes. In imatinib-resistant FASN-overexpressing GIST cells, the roles of overexpressed FASN and FASN-targeting C75 in tumor phenotypes, apoptosis and autophagy, KIT transcription, PI3K/AKT/mTOR activation, and imatinib resistance were analyzed by RNAi or myristoylated-AKT transfection. The therapeutic relevance of dual blockade of FASN and KIT was evaluated in vivoResults:FASN mRNA abundance significantly increased from very low/low-risk to high-risk levels of NCCN guidelines (P < 0.0001). FASN overexpression was associated with a nongastric location (P = 0.05), unfavorable genotype (P = 0.005), and increased risk level (P < 0.001) and independently predicted shorter disease-free survival (P < 0.001). In vitro, FASN knockdown inhibited cell growth and migration, inactivated the PI3K/AKT/mTOR pathway, and resensitized resistant GIST cells to imatinib. C75 transcriptionally repressed the KIT promoter, downregulated KIT expression and phosphorylation, induced LC3-II and myristoylated AKT-suppressible activity of caspases 3 and 7, attenuated the PI3K/AKT/mTOR/RPS6/4E-BP1 pathway activation, and exhibited dose-dependent therapeutic additivism with imatinib. Compared with both monotherapies, the C75/imatinib combination more effectively suppressed the growth of xenografts, exhibiting decreased KIT phosphorylation, Ki-67, and phosphorylated PI3K/AKT/mTOR levels and increased TUNEL labeling.Conclusions: We have characterized the prognostic, biological, and therapeutic implications of overexpressed FASN in GISTs. C75 represses KIT transactivation, abrogates PI3K/AKT/mTOR activation, and provides a rationale for dual blockade of KIT and FASN in treating imatinib-resistant GISTs. Clin Cancer Res; 23(16); 4908-18. ©2017 AACR.
Adenoma surveillance and colorectal cancer incidence: a retrospective, multicentre, cohort study
Authors: Wendy Atkin, Kate Wooldrage, Amy Brenner, Jessica Martin, Urvi Shah, Sajith Perera, Fiona Lucas, Jeremy P Brown, Ines Kralj-Hans, Paul Greliak, Kevin Pack, Jill Wood, Ann Thomson, Andrew Veitch, Stephen W Duffy, Amanda J Cross
Journal: The Lancet Oncology (2017)

BackgroundRemoval of adenomas reduces colorectal cancer incidence and mortality; however, the benefit of surveillance colonoscopy on colorectal cancer risk remains unclear. We examined heterogeneity in colorectal cancer incidence in intermediate-risk patients and the effect of surveillance on colorectal cancer incidence.MethodsWe did this retrospective, multicentre, cohort study using routine lower gastrointestinal endoscopy and pathology data from patients who, after baseline colonoscopy and polypectomy, were diagnosed with intermediate-risk adenomas mostly (>99%) between Jan 1, 1990, and Dec 31, 2010, at 17 hospitals in the UK. These patients are currently offered surveillance colonoscopy at intervals of 3 years. Patients were followed up through to Dec 31, 2014.We assessed the effect of surveillance on colorectal cancer incidence using Cox regression with adjustment for patient, procedural, and polyp characteristics. We defined lower-risk and higher-risk subgroups on the basis of polyp and procedural characteristics identified as colorectal cancer risk factors. We estimated colorectal cancer incidence and standardised incidence ratios (SIRs) using as standard the general population of England in 2007. This trial is registered, number ISRCTN15213649.Findings253 798 patients who underwent colonic endoscopy were identified, of whom 11 944 with intermediate-risk adenomas were included in this analysis. After a median follow-up of 7·9 years (IQR 5·6–11·1), 210 colorectal cancers were diagnosed. 5019 (42%) patients did not attend surveillance and 6925 (58%) attended one or more surveillance visits. Compared to no surveillance, one or two surveillance visits were associated with a significant reduction in colorectal cancer incidence rate (adjusted hazard ratio 0·57, 95% CI 0·40–0·80 for one visit; 0·51, 0·31–0·84 for two visits). Without surveillance, colorectal cancer incidence in patients with a suboptimal quality colonoscopy, proximal polyps, or a high-grade or large adenoma (≥20 mm) at baseline (8865 [74%] patients) was significantly higher than in the general population (SIR 1·30, 95% CI 1·06–1·57). By contrast, in patients without these features, colorectal cancer incidence was lower than that of the general population (SIR 0·51, 95% CI 0·29–0·84).InterpretationColonoscopy surveillance benefits most patients with intermediate-risk adenomas. However, some patients are already at low risk after baseline colonoscopy and the value of surveillance for them is unclear.FundingNational Institute for Health Research Health Technology Assessment, Cancer Research UK.
Basal CD34+ Cell Count Predicts Peripheral Blood Hematopoietic Progenitor Cells Mobilization in Healthy Donors after Administration of G-CSF
Authors: Massimo Martino, Mercedes Gori, Annalisa Pitino, Antonella Dattola, Roberta Fedele, Giuseppe Alberto Gallo, Santina Barillà, Antonella Pontari, Giuseppe Irrera, Giuseppe Messina, Tiziana Moscato, Giuseppe Console, Fortunato Morabito, Giovanni Tripepi
Journal: Blood (2016)
Authors’reply: Concern regarding the alleged spread of hypervirulent lymphogranuloma venereum Chlamydia trachomatis strain in Europe
Authors: Fruzsina Petrovay, Eszter Balla, Timea Erdősi
Journal: Eurosurveillance (2017)

Preview this article: Authors'reply: Concern regarding the alleged spread of hypervirulent lymphogranuloma venereum Chlamydia trachomatis strain in Europe, Page 1 of 1 < Previous page | Next page > /docserver/preview/fulltext/eurosurveillance/22/15/eurosurv-22-30512-5-1.gif
P01.07 The Dystroglycan Complex Promotes Mesenchymal-Like Glioblastoma through Interaction with EphA Receptor Tyrosine Kinases
Authors: B. W. Day, F. Al-Ejeh, Z. C. Bruce, K. S. Ensbey, T. Robertson, B. W. Stringer, J. N. Rich, J. D. Lathia, K. P. Campbell, A. W. Boyd
Journal: Neuro-Oncology (2017)

Glioblastomas (GBMs) are the most common and malignant CNS neoplasms with a very poor prognosis. They display cellular hierarchies containing self-renewing tumorigenic glioma stem cells (GSCs) in a highly vascular complex microenvironment. One proposed niche for GSCs is the perivascular environment or vascular bed of the tumor, where these cells have the potential to undergo mesenchymal differentiation. Extracellular matrix (ECM) proteins and basement membrane formation are key structural components of this niche and regulate normal stem cell and tumor proliferation. Dystroglycan (DG) is a receptor that mediates laminin binding and is highly glycosylated. DG is comprised of a transmembrane β-subunit (βDG) and a cell-surface α-subunit (αDG), a G-like domain on laminin binds to a glycan structure on αDG and this interaction plays a critical role in assembling ECM proteins in many epithelial tissues, including the brain. Eph receptor tyrosine kinases are implicated in tissue boundary formation during development and mediate cell migration through regulation of repulsive and adhesive guidance cues. More recently the Eph family have been shown to be functionally over expressed in a wide variety of human cancers. Our previous findings found that EphA3 is highly expressed on GSCs particularly around blood vessels and act in a kinase independent manner to maintain a mesenchymal phenotype promoting glioma tumorigenesis. Moreover, EphA3 has been shown to be over expressed and functional on mesenchymal stromal cells in a number of human cancers, and EphA3 antibody targeting inhibited tumor growth by disrupting newly formed tumor microvasculature. We have generated compelling data showing that αDG is one of the central mediators regulating attachment to ECM proteins within the GBM vascular niche and is responsible for driving a mesenchymal phenotype by direct interaction with EphA3. αDG is co-expressed with EphA3 and integrin α6. Knockdown of DG induces differentiation and reduces intracranial tumor formation increasing overall survival in mesenchymal subtype GBM animal models. Furthermore, we show that an αDG antibody, which specifically binds to αDG glycosylation sites preventing laminin binding, induces a potent anti-proliferative and differentiation response irrespective of GBM molecular subtype. These data identify αDG as a driver of mesenchymal GBM and validate αDG a potential GSC therapeutic target.
Evolocumab Added to Statins to Reduce Progression of Coronary Atherosclerosis—Reply
Authors: Stephen J. Nicholls, Ransi Somaratne, Steven E. Nissen
Journal: JAMA (2017)

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Abstract 14712: The Risk of Congestive Heart Failure in Children and Young Adults With Congenital Heart Disease in Sweden
Authors: Zacharias Mandalenakis, Thomas Gilljam, Annika Rosengren, Georgios Lappas, Peter Eriksson, Maria Fedchenko, Kristofer Skoglund, Mikael Dellborg
Journal: Circulation (2016)

Introduction: Patients with congenital heart disease (CHD) have an increased life expectancy during the last decades because of the improvement in pediatric care. However, increased admission to the hospitals due to congestive heart failure (CHF) in patients with CHD has been reported recently.

Hypothesis: The aim of the present study was to estimate the risk of developing CHF in children and young adults with CHD compared to matched controls.

Methods: We used data from the Swedish Patient and Cause of Death Registers to include all patients with a CHD diagnosis who were born between 1970 and 1993. Diagnoses were coded according to the International Classification of Diseases (ICD 8th, 9th, and 10th editions). Follow-up and comorbidity data were collected until 2011. Each patient with CHD was matched by age, sex, and county with 10 controls from the Total Population Register in Sweden.

Results: Among 26,906 patients (51.3 % men) with CHD and 269,053 matched controls, 675 and 449, respectively, were hospitalized with CHF; the mean follow-up was 18.5 years. The risk to develop CHF among CHD patients was 91.1 times greater (95% [CI] 53.4-155.6, p<0.001) compared to controls. CHD patients born in 1970s had a hazard ratio (HR) of 25.1 (95% [CI] 9.5-66.0, p<0.001) to develop CHF, in 1980s the HR was 102.6 (95% [CI] 47.1-223.4, p<0.001) and for those born in the beginning of 1990s was 246.7 (95% [CI] 60.0-1015.0, p<0.001).

Conclusions: The absolute risk to develop CHF in children and young adults with CHD was low; however, the relative risk was almost 90 times higher compared to matched controls. The risk increased exponentially with subsequent birth decade, probably due to the increased chances for survival. Further studies are indicated in order to determine the underlying mechanisms of CHF and in that case possible prevention or early treatment.
OS09.2 Enhancing immunity while neutralizing T cell-induced immunosuppression through combinatorial immunotherapy of glioblastoma
Authors: L. Zhai
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) is a common malignant brain tumor with a median overall survival of 14.6 months. Utilizing Hi-Seq. Illumina data from the cancer genome atlas, we recently discovered the presence of immunosuppressive indoleamine 2,3 dioxygenase 1 (IDO1) mRNA in ≥95% of patient-resected glioblastoma. This was in contrast to the presence of IDO1 in only 49% and 69% of patient-resected grade II (n=225) and grade III glioma (n=248), respectively. Multivariate statistical analysis demonstrate that, a high IDO1 mRNA level is prognostic for GBM patient survival (n=148; P=0.0076). Coincidently, the presence of mIDH1/2 is associated with a decrease in IDO1 mRNA, regardless of glioma grade (P<0.01). However, while increased methylation of IDO1-specific CpG motifs correlate with decreased IDO1 levels in grade II and III glioma (P<0.005), there is no correlation in GBM. Also puzzling, the canonical IDO1-inducing cytokine, interferon-gamma (IFNγ), fails to correlate with IDO1 expression in GBM. In contrast, high expression for markers of tumor-infiltrating T cells, CD3ε and CD8α, strongly correlate both with high IDO1 levels and decreased GBM patient survival (P<0.0001). To further explore the interaction of T cells, IDO1 and GBM, humanized mice reconstituted with a human immune system (ie. NSG-SGM3-BLT) and intracranially-engrafted human GBM, were treated with control IgG, or anti-human T cell depleting mAb. Our data show for the first time that, tumor-infiltrating human T cells directly increase IDO1 mRNA expression in human glioblastoma (n=3–8/group; P<0.001) through an IFNγ-independent mechanism. To understand the therapeutic implications of these findings, C57BL/6 mice with well-established (14 day post-intracranial) syngeneic GL261 were treated with control IgG, 10Gy whole brain radiation (WBR), PD-1 mAb and/or a pharmaceutical-grade, potent, blood brain barrier-penetrating IDO1 inhibitor; BGB-5777. While neither monotherapeutic nor dual therapeutic combinations affected survival, the triple treatment of WBR, with PD-1 and IDO1 blockade, led to a delay in mortality and durable survival advantage in ~40% of mice (n=9–10/group; P<0.0001) that was abrogated by T cell-depleting mAb (n=9–10/group; P<0.01). These data suggest that, future approaches aimed at eliciting immune-mediated GBM destruction should consider the simultaneous addition of immunosuppressive pathway inhibitors to achieve durable survival in patients with incurable brain cancer.
Mantle Cell Lymphoma Is Associated with a Variable Number of PD-1-Positive Tumor Infiltrating T-Cells
Authors: Naoto Tomita, Naoya Nakamura, Haruka Ikoma, Masahiro Hoshikawa, Akiko Uchida, Yu Uemura, Kazuyuki Sato, Yuka Tsuruoka, Yuji Nishio, Manabu Matsunawa, Yoshinori Suzuki, Yasushi Isobe, Hirotaka Sakai, Masayuki Kato, Yasuyuki Inoue, Ikuo Miura
Journal: Blood (2016)
Abstract 320: Activation of Protein Kinase G Enhances Proteasome-Mediated Degradation of Misfolded Proteins
Authors: Mark J Ranek, Douglas A Martin, Curtis Kost, Xuejun Wang
Journal: Circulation Research (2012)

The Ubiquitin Proteasome System (UPS) plays a pivotal role in the intracellular protein homeostasis, thereby regulating a variety of cellular processes including protein quality control (PQC). Inadequate PQC and proteasome functional insufficiency are associated with and may play an important role in adverse cardiac remodeling and cardiac failure (CHF). This is best reflected by the increased presence of misfolded proteins and protein aggregates in failing human hearts. While the regulatory mechanisms of these processes remain poorly understood they carry significant clinical implications. Reduced protein kinase G (PKG) activity is well documented in CHF. Increasing the activity PKG, during various cardiovascular diseases improves patient prognosis. We hypothesize that PKG plays a role in regulating UPS function. Using both genetic and/or pharmacological manipulation of PKG activity in cultured cardiomyocytes and intact mice and taking advantage of a previously validated surrogate misfolded protein (GFPu or GFPdgn) as well as a bona fide misfolded protein (R120G-CryAB) that is known to cause proteinopathy in human and mice, our studies have revealed a significant role for PKG in UPS regulation. In cultured cardiomyocytes, PKG inhibition was achieved by PKG-specific siRNA transfection or administration of PKG pharmacological inhibitor while PKG activity was induced by adenoviral delivery of a constitutively active PKG or by the treatment of phosphodiesterase 5A inhibitor Sildenafil. PKG activation significantly stimulated UPS activity in cultured cardiomyocytes as indicated by a reduced protein level of GFPu and increased proteasome activities; while PKG inhibition reduced UPS proteolytic activity. Furthermore PKG activation resulted in enhanced removal of R120G-CryAB. These findings from cell culture studies were further corroborated by in vivo findings from manipulating the muscarinic (M) receptor in GFPdgn transgenic mice. The M receptor signals through PKG. Activating the M receptor deceased, while antagonizing the M receptor increased, the steady protein level of GFPdgn in the heart. Hence, we conclude that PKG positively regulates the UPS thereby supporting cardiomyocyte PQC.
Effect of the cooling sensation induced by olfactory stimulation by L-menthol on dyspnoea: a pilot study
Authors: Masashi Kanezaki, Satoru Ebihara
Journal: European Respiratory Journal (2017)

It is common for us to encounter patients suffering from dyspnoea who can occasionally obtain subjective relief when they sit near an open window or in front of a fan. In fact, a recent randomised controlled study showed the effectiveness of a handheld fan blowing air across the nose and mouth in reducing the sensation of breathlessness in patients with advanced disease [1]. It has also been reported that, in patients with chronic obstructive pulmonary disease, breathing cold air reduces the sensation of dyspnoea and improves exercise performance [2]. However, the mechanism behind this effect remains unclear. Olfactory stimulation by L-menthol and dyspnoea <http://ow.ly/tL77308wKSS>