tbuckley/cabot-search huggingface dataset:
Abstract SY27-02: Targeting leukemia stem cells with small molecule inhibitors of PRC1
Authors: Tomasz Cierpicki
Journal: Cancer Research (2016)

Abstract Bmi1 is a stem cell gene, which determines the proliferative capacity and self-renewal potential of normal and leukemic stem cells. Multiple studies identified Bmi1 to be able to induce oncogenic transformation and promote tumor growth in a variety of in vitro and in vivo animal models. Bmi1 is a central component of the Polycomb Repressive Complex 1 (PRC1) and interacts with Ring1B protein to form an active E3 ligase, which ubiquitinates histone H2A on lysine K119. This epigenetic modification of H2A is required to maintain transcriptionally repressive state of many genes. Small molecule inhibitors of the Ring1B-Bmi1 E3 ligase activity have not been reported to date, but are highly desired as potential therapeutic agents targeting cancer stem cells. Employing fragment screening approach we identified small molecule inhibitors of Ring1B-Bmi1. Using medicinal chemistry, we developed potent compounds that bind to Ring1B-Bmi1 and inhibit its E3 ubiquitin ligase activity with low micromolar affinities. In cells, Ring1B-Bmi1 inhibitors revealed robust downregulation of H2A K119 ubiquitination. Treatment of model cell lines enriched in leukemia initiating cells show that the Ring1B-Bmi1 inhibitor blocks the self-renewal capacity and induces cellular differentiation. Our approach validates that RING ligases represent novel class of ‘druggable’ epigenetic targets. Citation Format: Tomasz Cierpicki. Targeting leukemia stem cells with small molecule inhibitors of PRC1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY27-02.
5-Methyl-tetrahydrofolic acid rapidly improves endothelial function and superoxide production in human atherosclerosis: Effects on tetrahyd robiopterin-dependent eNOS coupling
Authors: C A Antoniades, C Shirodaria, P Leeson, J Lee, N Warrick, J De Bono, D Taggart, C Ratnatunga, R Pillai, K M Channon
Journal: Journal of the American College of Cardiology (2006)
Exploratory analysis of clinical and translational factors associated with the inflamed phenotype in HNSCC.
Authors: Narendiran Rajasekaran, Holbrook Edwin Kohrt, Zhixiang Zuo, Michaela K. Keck, Arun Khattri, Mark W. Lingen, Justin Paul Kline, Thomas Gajewski, Everett E. Vokes, Tanguy Y. Seiwert
Journal: Journal of Clinical Oncology (2015)

3031 Background: Immunotherapy with PD-1/PD-L1 axis blockade shows encouraging activity in head and neck squamous cell carcinoma (HNSCC). T-cell inflammation and gamma interferon driven gene expression patterns delineate a group of tumors that are most likely to benefit from anti-PD-1 therapy (Seiwert ASCO 2015, Keck CCR 2015). We examined two large, genetically annotated cohorts (TCGA & CHGC) in order to identify putative clinical and translational biomarkers that may predict benefit from anti-PD-1/anti-PD-L1 therapy in patients with HNSCC. Methods: 424 HNSCC tumors from the TCGA cohort were used to calculate a continuous score for tumor inflammation/inflamed mesenchymal phenotype (Keck CCR 2015). Respective scores were then correlated with available clinical, and translational characteristics. We used a second cohort, the Chicago Head and Neck Cancer Genomics cohort (CHGC) N = 132 for validation. In particular we focused on HPV status, tobacco use, anatomic site, stage, gender, race, and mutational burden for discovery of novel biomarkers/associations for HNSCC immunotherapy. Results: HPV status was moderately associated with inflamed phenotype in both cohorts (58/55) of HPV-positive tumors showed a high degree of inflammation, which only 30%/34% of HPV-negative tumors showed this. Smoking status, race, gender, anatomic site (controlling for HPV status), and stage did not correlate with the inflamed phenotype. The highest mutational burdens were seen in inflamed tumors, however correlation was weak. Conclusions: ‘Inflamed phenotype’ is a candidate predictive biomarker of clinical benefit from anti-PD-1 treatment and HPV status correlates with inflamed phenotype. In this study none of other the examined clinical or pathologic features including mutational burden demonstrated predictive characteristics of a therapeutic biomarker to PD-1/PD-L1 blockade.
Abstract 331: Beta-catenin nuclear translocation in colorectal cancer cells is suppressed by PDE10A inhibition, cGMP elevation, and activation of PKG
Authors: Kevin J. Lee, Ashley S. Lindsey, Luciana Madeira da Silva, Alisa Trinh, Bernard Gary, Joel Andrews, Veronica Ramirez-Alcantara, Adam B. Keeton, Wen-Chi Chang, Margie Clapper, Gary A. Piazza
Journal: Cancer Research (2016)

Abstract Phosphodiesterase 10A (PDE10A) is a cGMP and cAMP degrading PDE isozyme that is highly expressed in the brain striatum where it appears to play an important role in cognition and psychomotor activity. PDE10 inhibitors are being developed for the treatment of schizophrenia and Huntington's disease and are generally well tolerated, possibly because of low expression levels in most peripheral tissues. We recently reported high levels of PDE10 in colon tumors and that genetic silencing of PDE10 by siRNA or inhibition with small molecule inhibitors can suppress colon tumor cell growth with a high degree of selectivity over normal colonocytes (Li et al., Oncogene 2015). These observations suggest PDE10 may have an unrecognized role in tumorigenesis. Here we report that the concentration range by which the highly specific PDE10 inhibitor, Pf-2545920 (MP-10), inhibited colon tumor cell growth parallels the concentration range required to increase cGMP and cAMP levels, and activate PKG and PKA, respectively. Moreover, PDE10 knockdown by shRNA reduced the sensitivity of colon tumor cells to the growth inhibitory activity of Pf-2545920. Pf-2545920 also inhibited the translocation of β-catenin to the nucleus, thereby reducing β-catenin mediated transcription of survivin, which resulted in caspase activation and apoptosis. This was determined to be through a PKG mediated pathway through the use of small molecule inhibitors of PKG and PKA. PDE10 mRNA was also found to be elevated in colon tumors compared with normal tissues in a cDNA array. We also report the increase in PDE10 mRNA in 50% of a small collection of human clinical specimens collected at the Mitchell Cancer Institute (n = 13). In addition, novel PDE10 inhibitor, MCI-030, reduced tumor size and activated PDE10 signaling mechanisms in vivo. These findings suggest that PDE10 can be targeted for cancer therapy or prevention whereby inhibition results in cGMP elevation and PKG activation to reduce β-catenin-mediated transcription of survival proteins leading to the selective apoptosis of cancer cells. Citation Format: Kevin J. Lee, Ashley S. Lindsey, Luciana Madeira da Silva, Alisa Trinh, Bernard Gary, Joel Andrews, Veronica Ramirez-Alcantara, Adam B. Keeton, Wen-Chi Chang, Margie Clapper, Gary A. Piazza. Beta-catenin nuclear translocation in colorectal cancer cells is suppressed by PDE10A inhibition, cGMP elevation, and activation of PKG. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 331.
The Utility Of Minimal Residual Disease (MRD) Assessment At First Relapse: Results From The BSBMT/Ukmf Myeloma X (Intensive) Trial
Authors: John Ashcroft, Ruth M de Tute, David A Cairns, Marie Fletcher, Roger G Owen, Andy Rawstron, Sheila J.M. O'Connor, Cathy D. Williams, John A Snowden, J. D. Cavenagh, Christopher Parrish, Treen Morris, Julia MB Brown, Gordon Cook
Journal: Blood (2013)
Abstract 59: Regulation of SIRT3 signal related metabolic reprogramming in gastric cancer
Authors: doyeon lee, SungSook Yu, Dawoon E.Jung1 Jung, YeoSong Lee, Beom Ku Choi, Yong Chan Lee
Journal: Cancer Research (2016)

Abstract Helicobacter pylori (H.pylori) infection of the gastric mucosa is strongly associated with chronic gastritis, peptic ulcer disease and gastric cancer. Individuals infected with H.pylori possessing CagA protein produce more reactive oxygen species (ROS) and increase the risk of developing gastric cancer. Sirtuins are NAD+ dependent deacetylases that regulate cellular metabolism in response to stress. Recently, mitochondrial sirtuin, SIRT3, is known to be a tumor suppressor via its ability to suppress ROS and regulate hypoxia inducible factor 1α (HIF-1α). However, it has not been investigated whether increased ROS production by H.pylori is regulated by SIRT3 via HIF-1α regulation and is mediated through intracellular CagA. We aimed to investigate the correlation between SIRT3, ROS and HIF-1α in H.pylori infected gastric epithelial cells. In this study, we showed that SIRT3 deficient AGS cells exhibited augmented HIF-1α protein stabilization and transcriptional activity in hypoxic condition. We also found that H.pylori CagA downregulated SIRT3 activity and induced ROS production through HIF-1α stabilization, similar to hypoxic condition in gastric epithelial cells. Overexpression of SIRT3 inhibited the stabilization of HIF-1α protein and attenuated the increase in HIF-1α transcriptional activity in hypoxia. Moreover, H.pylori CagA attenuated HIF-1α stability and transcriptional activity in SIRT3 overexpressed gastric epithelial cells. Taken together, these findings provide a valuable insight into the potential role of SIRT3 in the development of gastric cancer by regulating the HIF-1α protein. Citation Format: doyeon lee, SungSook Yu, Dawoon E.Jung1 Jung, YeoSong Lee, Beom Ku Choi, Yong Chan Lee. Regulation of SIRT3 signal related metabolic reprogramming in gastric cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 59.
Abstract 3417: Peripheral CD8+CD28-suppressive T lymphocytes act as a prognosticator among breast cancer patients with adoptive T-cell immunotherapy
Authors: Qingkun Song, Jun Ren, Jing Yu, Xiaoli Wang, Xinna Zhou, Herbert Kim Lyerly
Journal: Cancer Research (2016)

Abstract Introduction: This study aimed to assess the prognostic value of CD8+CD28− T lymphocyte in peripheral blood among breast cancer patients treated with adoptive T lymphocytes immunotherapy. Methods: 217 patients participated in the follow-up study. CD8+CD28− proportion was measured by flow cytometry in peripheral T cells. The median survival was estimated by Kaplan-Meier curve, Log-rank test and Cox hazard proportion regression model, between groups of CD8+CD28− proportion more than 24.2% and less than or equal to 24.2% in peripheral T cells. Results The median follow-up period was 15 months. Median time to progression was 11.8 months among patients with CD8+CD28− proportion less than or equal to 24.2% and 7.1 months among patients with CD8+CD28− proportion more than 24.2% (p&amp;lt;0.05). With further adjustments, CD8+CD28− proportion of more than 24.2% produced a HR being 2.13 (95%CI 1.45, 3.12) for progression. Patients with CD8+CD28− proportion of less than or equal to 24.2% had median overall survival of 36.2 months, 10.6-month longer than patients with higher CD8+CD28− proportion (p&amp;lt;0.05). With further adjustments, CD8+CD28− proportion of more than 24.2% produced a 86% higher risk for death (HR = 1.86, 95%CI 1.07, 3.24). Conclusion Peripheral CD8+CD28− proportion had a negative association with progression-free and overall survival among breast cancer patients receiving adoptive T cell immunotherapy. CD8+CD28− suppressive T cell was a potential biomarker for breast cancer patients’ prognosis. Citation Format: Qingkun Song, Jun Ren, Jing Yu, Xiaoli Wang, Xinna Zhou, Herbert Kim Lyerly. Peripheral CD8+CD28-suppressive T lymphocytes act as a prognosticator among breast cancer patients with adoptive T-cell immunotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3417.
Enlarged Right Atrium
Authors: Bijan Jahangiri, O Christopher Raffel
Journal: New England Journal of Medicine (2016)

A 57-year-old man presented to the ED with peripheral edema. Physical findings were consistent with atrial fibrillation, tricuspid regurgitation, and heart failure on the right side. A radiograph of the chest showed a high cardiothoracic ratio and a very large right atrium.
Abstract SY44-02: ECM remodeling at the pre-metastatic niche
Authors: Janine T. Erler
Journal: Cancer Research (2016)

Abstract The extracellular matrix (ECM) is one of the most important regulators of cellular and tissue function in the body. The ECM is known to play a critical role in driving cancer progression, and yet we lack knowledge of how ECM is altered during tumour progression to promote cancer metastasis. We have found that an enzyme secreted by tumor and stromal cells called lysyl oxidase (LOX) is responsible for altering the ECM at primary and metastatic sites to greatly enhance metastasis. LOX is an amine oxidase that catalyses the crosslinking of collagens and elastin in the ECM. LOX activity alters the structural and biochemical properties of the ECM, to drive cell proliferation, invasion and angiogenesis. Importantly, LOX modifies pre-metastatic tissue microenvironments prior to tumor cell arrival, enhancing metastatic colonisation and outgrowth. We are expanding our studies to further investigate how ECM is remodeled during cancer progression and how this impacts on cell behavior to drive metastasis. Citation Format: Janine T. Erler. ECM remodeling at the pre-metastatic niche. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY44-02.
NEET: India’s single exam for admission to medical school promises transparency and quality
Authors: Avinash Supe
Journal: BMJ (2016)

It will improve the relevance of entrance tests and reduce financial malpractice

India’s medical education system is one of the largest in the world. Many of its graduates emigrate, and the quality of the education of these doctors has global impact. The number of medical schools in India has increased in the past 35 years, especially in the private sector. Presently, 200 government (27 180 seats) and 212 private (25 535 seats) medical schools admit 52 715 undergraduate students every year, and numbers are likely to increase.1

Currently, government and private medical schools have different admission criteria. Government schools select candidates based on their performance in an entrance examination. Private schools conduct independent entrance examinations and have a “management quota” that is filled by students who pay huge fees in effect to purchase a seat. Commonly called capitation fees, these are typically not reported or accounted for. …
P60 Acute lowering of portal pressure in cirrhotic rats by Anti-TNF therapy is associated with reduced NFkB-driven inflammation and improved eNOS function through the asymmetric dimethylarginine-dimethylarginine-diaminohydrolase axis
Authors: V Sharma, V Balasubramaniyan, G Metha, A Habtesion, C Turner, R N Dalton, N Davies, R Jalan, R P Mookerjee
Journal: Gut (2010)

Introduction  Anti-TNF (Infliximab) monotherapy has been shown to reduce hepatic inflammation and lower portal pressure in alcoholic hepatitis patients. Although the side effect profile of Infliximab limits its clinical use in these patients, ongoing study of the mechanism of this profound beneficial effect remains important to determine novel pathways and future therapeutic targets.  Aim  This study aimed to determine whether reduction of NFkB and its target gene TNFα by Infliximab has favourable effects upon the asymmetric dimethylarginine-dimethylarginine-diaminohydrolase (ADMA-DDAH) axis, increasing NO availability whilst lowering portal pressure in bile duct ligated (BDL) cirrhotic rats.  Method  Sham (n=6) and BDL (n=15) rats were compared 4 weeks after BDL surgery (treated with vehicle), and in an additional BDL group (n=6) 72 h after 10 mg/kg daily intraperitoneal Infliximab. Rats underwent direct portal pressure assessment under terminal anaesthesia.  Measurements  Plasma ALT (Cobas-Integra analyser); hepatic ADMA (LC/MS/MS); eNOS activity (radiometric assay). Hepatic protein expression for NFkB, TNF-α, inducible NOS (iNOS), 4-hydroxy nonenol (HNE) and DDAH-1 were measured by western blot.  Results  ALT was significantly (p  Conclusion  This study confirms significant lowering of portal pressure following Infliximab therapy in the BDL model of cirrhosis. This beneficial effect is associated with reduced hepatic inflammation and restoration of the abnormal ADMA-DDAH-eNOS axis providing potential new targets for portal hypertension therapy.
Cardiac resynchronization therapy guided by multimodality cardiac imaging
Authors: Matteo Bertini, Donato Mele, Michele Malagù, Andrea Fiorencis, Tiziano Toselli, Francesca Casadei, Teresa Cannizzaro, Cristina Fragale, Alessandro Fucili, Elena Campagnolo, Giorgio Benea, Roberto Ferrari
Journal: European Journal of Heart Failure (2016)
Phase I/II study of E7080 (lenvatinib), a multitargeted tyrosine kinase inhibitor, in patients (pts) with advanced hepatocellular carcinoma (HCC): Initial assessment of response rate.
Authors: Kiwamu Okita, Hiromitsu Kumada, Kenji Ikeda, Masatoshi Kudo, Seiji Kawazoe, Yukio Osaki, Masafumi Ikeda, Toshiyuki Tamai, Takuya Suzuki
Journal: Journal of Clinical Oncology (2012)

320 Background: Lenvatinib is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFRβ. Maximum tolerated dose (MTD) of lenvatinib for solid tumor pts was determined to be 25 mg once daily dosing (qd), and MTD for HCC pts with Child-Pugh A was determined to be 12 mg qd. A preliminary assessment of response rate is presented in this report. Methods: Between July 9, 2010 and June 22, 2011, 46 pts with advanced HCC with Child-Pugh A were enrolled in Japan (n=43) and Korea (n=3). Pts may have received up to one prior treatment regimen including sorafenib. Pts were treated with a starting dose of lenvatinib 12 mg once daily in 28 day cycles until disease progression or development of unmanageable toxicities. Response rate was assessed by RECIST 1.1 (modified to evaluate viable lesions). Results: The first 42 consecutively enrolled pts (med age: 67; M: 76%, F: 24%) were evaluable for response and form the basis of this report. 45% had extra hepatic spread, 24% received prior chemotherapy and 91% had prior locoregional therapy. 19% were withdrawn from therapy due to adverse event. The most common toxicities were hypertension 71% (Gr 3: 48%), anorexia 50% (Gr 3: 2.4%), proteinuria 45% (Gr 3: 14%), palmar-plantar erythrodysaesthesia syndrome 43% (Gr 3: 4.8%), fatigue 43% (Gr 3: 0%), and thrombocytopenia 33% (Gr 3: 19%). No pts experienced Gr 4 toxicity. Confirmed Partial Responses (PRs) were observed in 14 pts (RR: 33%, 95% CI: 20-50) based on investigator assessment. Updated efficacy including median Time to Progression and survival data will be reported. Conclusions: Lenvatinib 12 mg qd when administered to advanced HCC pts with Child-Pugh A is associated with manageable toxicity. The preliminary assessment of efficacy on the basis of overall response rate suggests that lenvatinib may represent a new potential therapeutic agent for advanced HCC pts. Further assessment of safety and efficacy is ongoing.
Abstract 3914: Repurposing disulfiram for use as an anticancer drug: a story about metabolism and metal binding
Authors: Moe Wehbe, Malathi Anantha, Ian Backstrom, Ada Leung, Kent Chen, Minghan Shi, Armaan Malhotra, Katarina Edwards, Léon Sanche, Marcel B. Bally
Journal: Cancer Research (2016)

Abstract Disulfiram (DSF) is an FDA approved agent for the treatment of alcoholism with over 60 years of clinical use. It was identified in several high-throughput screen to be effective against glioma tumor initiating cells; this activity is amplified more than 100-fold in the presence of copper (Cu2+). DSF is metabolized to diethyldithiocarbamate (DDC), an established copper chelating agent. One mechanism attributed to the copper DDC (Cu(DDC)2) complex is proteosome inhibition. Cu(DDC)2 is very poorly soluble in aqueous solution; making it difficult to purse development for any cancer indication. A novel liposomal formulation of Cu(DDC)2 is described here; which represents the first iv injectable Cu(DDC)2. 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and cholesterol (CHOL) (55:45 molar ratio) liposomes were prepared by extrusion methods in the presence of 300 mM unbuffered CuSO4 to ∼100 nm in size. DDC was added to these pre-formed liposomes at room temperature, unentrapped drug was removed using column chromatography. The therapeutic activity of this formulation was determined in vitro against a variety of cancer cell lines. The toxicity and pharmacokinetic (PK) behaviour of this formulation was determined in CD-1 mice. DDC was tested in the presence and absence of Cu2+ in vitro with U251, U87, MDA231-BR and A549 cell lines giving IC50 values greater than &amp;gt;10 μM in the absence and from 300- 900 nM in the presence of Cu2+. The liposomal Cu(DDC)2 formulation was as active as unencapsulated Cu(DDC)2 when tested in vitro. The maximum tolerated dose of liposomal Cu(DDC)2 was determined to be 8mg/kg given iv using a Q2D schedule for two weeks. The PK studies suggested that Cu(DDC)2 was rapidly released from circulating liposomes. Initial efficacy studies were completed using convection enhanced delivery of liposomal Cu(DDC)2 in the F98 rat glioma model. Treatment resulted in a statistically significant delay in tumour growth upon injection of 10 μL of 0.5 mg Cu(DDC)2 /mL solution. Further anti-tumor efficacy studies are being conducted in a subcutaneous leukemia xenograft model (MV-4-11). This work describes a novel formulation of Cu(DDC)2, the active agent generated when administering DSF and Cu to treat cancer. Citation Format: Moe Wehbe, Malathi Anantha, Ian Backstrom, Ada Leung, Kent Chen, Minghan Shi, Armaan Malhotra, Katarina Edwards, Léon Sanche, Marcel B. Bally. Repurposing disulfiram for use as an anticancer drug: a story about metabolism and metal binding. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3914.