tbuckley/cabot-search huggingface dataset:
Abstract #1991: Validation of novel colorectal cancer genes as potential therapeutic targets using functional genomics approaches
Authors: Marian Grade, Amanda Hummon, Jordi Camps, Georg Emons, Melanie Spitzner, Jochen Gaedcke, Michael Difilippantonio, Heinz Becker, Tim Beissbarth, Michael Ghadimi, Natasha Caplen, Thomas Ried
Journal: Cancer Research (2009)

Background: Despite the implementation of sophisticated therapeutic strategies into clinical practice, colorectal cancer is still a major cause of cancer death in the Western world. Thus, establishing novel therapeutic options remains of considerable clinical interest. Materials and Methods: Since amplified and/or over-expressed genes represent promising targets for therapeutic intervention, we profiled a series of 90 primary colorectal cancers and 50 matched normal mucosa biopsies using gene expression microarrays. Towards functional validation, mRNA expression levels of 28 genes, identified as showing significant levels of over-expression in the primary tumors, were established in 25 colorectal cancers cell lines by real-time PCR. We then systematically silenced a subset of these genes using synthetic siRNAs, and screened for siRNA duplexes that reduced cellular viability. Results: We could first confirm that the majority of genes were similarly deregulated comparing primary colorectal cancers and cell lines. Using RNAi analysis, we could subsequently show that silencing nine out of 14 highly up-regulated genes reduced the cellular viability of SW480 cells, with a maximum reduction of 73%. Among these hits we identified RRM2, TACSTD2, and HMGA1. This effect was independently confirmed for up to four different siRNA duplexes, and in HT-29 and DLD-1 cells. In order to identify the signaling pathways involved in reduction of viability, we subsequently analyzed the global transcriptomic changes following RNAi using whole-genome microarrays, and identified the disruption of a variety of cancer-relevant pathways. Discussion: Our experimental strategy of combining extensive gene expression profiling and RNAi-based gene silencing led to the independent identification of RRM2 and TACSTD2, two genes that were very recently discovered as therapeutic targets, and HMGA1, and we subsequently unveiled the deregulation of the underlying signaling pathways. In addition, we identified novel promising molecular targets.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1991.
Hidden genetic variation shapes the structure of functional elements in Drosophila
Authors: Mahul Chakraborty, Nicholas W. VanKuren, Roy Zhao, Xinwen Zhang, Shannon Kalsow, J. J. Emerson
Journal: Nature Genetics (2017)

Abstract Mutations that add, subtract, rearrange, or otherwise refashion genome structure often affect phenotypes, although the fragmented nature of most contemporary assemblies obscures them. To discover such mutations, we assembled the first new reference-quality genome of Drosophila melanogaster since its initial sequencing. By comparing this new genome to the existing D. melanogaster assembly, we created a structural variant map of unprecedented resolution and identified extensive genetic variation that has remained hidden until now. Many of these variants constitute candidates underlying phenotypic variation, including tandem duplications and a transposable element insertion that amplifies the expression of detoxification-related genes associated with nicotine resistance. The abundance of important genetic variation that still evades discovery highlights how crucial high-quality reference genomes are to deciphering phenotypes.
Patient characteristics after completion of recruitment from the phase 3 IMPALA study with lefitolimod in metastatic colorectal carcinoma
Authors: D. Cunningham, E. Van Cutsem, R. Salazar, M. Ducreux, W. Scheithauer, F. Sclafani, E. Wiegert, M. Schmidt, C. Tournigand, A. Sobrero, D. Arnold
Journal: Annals of Oncology (2017)
Novel <i>In Vitro</i> Cancer Models for Optimizing Anti-EGFR Therapies
Authors: Stefania Napolitano, Fortunato Ciardiello
Journal: Clinical Cancer Research (2017)

Preclinical models, which are able to recapitulate the biology and pathology of the original individual cancer, are needed to better investigate mechanisms of response and resistance to anticancer therapies. In this respect, novel in vitro models for metastatic colorectal cancer could be of high value. Clin Cancer Res; 24(4); 727-9. ©2017 AACRSee related article by Luraghi et al., p. 807.
Abstract 15060: Low Transvalvular Flow Rate, Not Low Stroke Volume Index, Predicts Mortality in Patients With Low-Gradient, Low-Valve Area Aortic Stenosis Undergoing Aortic Valve Intervention
Authors: Anastasia Vamvakidou, Wenying Jin, Oleksandr Danylenko, Navtej Chahal, George Papsozomenos, David Whiteside, Ann Banfield, Catherine West, Rajdeep Khattar, Roxy Senior
Journal: Circulation (2017)

Introduction:  Transvalvular flow rate (FR) 2  in patients with low aortic valve area (AVA) 2  and low mean gradient   Hypothesis:  We hypothesised that low FR is a superior predictor of mortality versus low SVi in patients with low-gradient low-AVA AS undergoing AVI.   Methods:  We retrospectively followed up consecutive patients with low-AVA low-gradient AS who underwent AVI between 2010-2014 for all-cause mortality.   Results:  Of the 274 patients with mean age 74.8±12 years, 130 (47.4%) had low SVi, 118 (43.1%) low FR and 74 (27%) low left ventricular ejection fraction (LVEF)    Conclusions:  In patients with low-gradient low-AVA AS undergoing AVI, low FR not low SVi was an independent predictor of mortality. 2
Ultrasensitive NIR‐SERRS Probes with Multiplexed Ratiometric Quantification for In Vivo Antibody Leads Validation
Authors: Homan Kang, Sinyoung Jeong, Ahla Jo, Hyejin Chang, Jin‐Kyoung Yang, Cheolhwan Jeong, San Kyeong, Youn Woo Lee, Animesh Samanta, Kaustabh Kumar Maiti, Myeong Geun Cha, Taek‐Keun Kim, Sukmook Lee, Bong‐Hyun Jun, Young‐Tae Chang, Junho Chung, Ho‐Young Lee, Dae Hong Jeong, Yoon‐Sik Lee
Journal: Advanced Healthcare Materials (2017)

Abstract Immunotargeting ability of antibodies may show significant difference between in vitro and in vivo. To select antibody leads with high affinity and specificity, it is necessary to perform in vivo validation of antibody candidates following in vitro antibody screening. Herein, a robust in vivo validation of anti‐tetraspanin‐8 antibody candidates against human colon cancer using ratiometric quantification method is reported. The validation is performed on a single mouse and analyzed by multiplexed surface‐enhanced Raman scattering using ultrasensitive and near infrared (NIR)‐active surface‐enhanced resonance Raman scattering nanoprobes (NIR‐SERRS dots). The NIR‐SERRS dots are composed of NIR‐active labels and Au/Ag hollow‐shell assembled silica nanospheres. A 93% of NIR‐SERRS dots is detectable at a single‐particle level and signal intensity is 100‐fold stronger than that from nonresonant molecule‐labeled spherical Au NPs (80 nm). The result of SERRS‐based antibody validation is comparable to that of the conventional method using single‐photon‐emission computed tomography. The NIR‐SERRS‐based strategy is an alternate validation method which provides cost‐effective and accurate multiplexing measurements for antibody‐based drug development.
Philosopher's disease and its antidote: Perspectives from prenatal behavior and contagious yawning and laughing
Authors: Robert R Provine
Journal: Behavioral and Brain Sciences (2017)

Abstract Accounts of behavior, including imitation, often suffer from philosopher's disease : the unnecessary, inappropriate, theoretically driven explanation of behavior in terms of cognition, rationality, and consciousness. Embryos are perversely unphilosophical and unpsychological, starting to move before they receive sensory input. Postnatal contagious yawning and laughing indicate that pseudo-imitative behavior can occur without conscious intent or other higher-order cognitive process.
Coronary Plaque Microstructure and Composition Modify Optical Polarization
Authors: Martin Villiger, Kenichiro Otsuka, Antonios Karanasos, Pallavi Doradla, Jian Ren, Norman Lippok, Milen Shishkov, Joost Daemen, Roberto Diletti, Robert-Jan van Geuns, Felix Zijlstra, Gijs van Soest, Peter Libby, Evelyn Regar, Seemantini K. Nadkarni, Brett E. Bouma
Journal: JACC. Cardiovascular imaging (2017)

This study aimed to evaluate whether polarimetry, performed using a modified optical frequency domain imaging (OFDI) system, can improve the assessment of histological features relevant to characterizing human coronary atherosclerosis. The microscopic structure and organization of the arterial wall influence the polarization of the infrared light used by OFDI. Modification of the OFDI apparatus, along with recently developed image reconstruction methods, permits polarimetric measurements simultaneously with conventional OFDI cross-sectional imaging through standard intravascular imaging catheters. The main coronary arteries of 5 cadaveric human hearts were imaged with an OFDI system capable of providing polarimetric assessment. Cross-sectional views of tissue birefringence, measured in refractive index units, and depolarization, expressed as the ratio of depolarized signal to total intensity, were reconstructed, together with conventional OFDI images. Following imaging, the vessels underwent histological evaluation to enable interpretation of the observed polarization features of individual tissue components. Birefringence in fibrous tissue was significantly higher than in intimal tissue with minimal abnormality (0.44 × 10−3 vs. 0.33 × 10−3; p < 0.0001). Birefringence was highest in the tunica media (p < 0.0001), consistent with its high smooth muscle cell content, cells known to associate with birefringence. In fibrous areas, birefringence showed fine spatial features and close correspondence with the histological appearance of collagen. In contrast, necrotic cores and regions rich in lipid elicited significant depolarization (p < 0.0001). Depolarization was also evident in locations of cholesterol crystals and macrophages. Intravascular measurements of birefringence and depolarization can be obtained using conventional OFDI catheters in conjunction with a modified console and signal processing algorithms. Polarimetric measurements enhance conventional OFDI by providing additional information related to the tissue composition and offer quantitative metrics enabling characterization of plaque features.
Abstract 18108: Hospitalized Heart Failure Patients of Native American, Pacific Islander, Asian, Hispanic, and African American Background Have Significantly Different Baseline Characteristics and Outcomes Compared With White Patients
Authors: Eric T Wang, David P Kao
Journal: Circulation (2016)

Introduction:  Racial differences in heart failure (HF) hospitalization characteristics and outcomes between white and African American (AA) populations have been described previously. However there remains a paucity of information regarding other major race groups, particularly Native American (NA), Asian, and Pacific Islanders (PI). We analyzed HF hospitalization within these race groups with the objective to identify differences in baseline characteristics and outcomes.   Methods:  Over 134.5 million administrative hospital records between 1994-2013 were screened for a primary diagnosis of HF using ICD-9 code 428. Outcomes included death, discharge home (including with home health), and skilled nursing facility (SNF). Risk factor associations with death and disposition home vs SNF/intermediate care were identified using multivariable logistic regression adjusted for age, gender, and several common comorbid conditions.   Results:  A total of 4,628,725 HF hospitalizations were identified. Of these 3,031,810 identified as white, 770,339 as AA, 83,627 as Asian, 12,024 as Native American, and 2,862 as Pacific Islander. Similar to white patients (med. age 79 years), Asians were older (med. 77 years) whereas NAs (med. 67 years), PIs (med. 72 years), and AAs (med. 64 years) were younger (p   Conclusion:  There are notable differences in patient characteristics and outcomes among hospitalized NA, Asian, PI and Hispanic patients compared with white and AAs.
<i>BRCA 1/2</i> mutations by next-generation sequencing testing in 200 Romanian high-risk patients with breast cancer.
Authors: Alexandru E. Eniu, Nicoleta Zenovia Antone, Andrei Stoian, Eleonora Dronca, Ramona DOINA Matei, Marjolijn Ligtenberg, Hicham Ouchene, Rares Eniu, Laura Pop
Journal: Journal of Clinical Oncology (2017)

e13116 Background: To determine types and frequencies of BRCA 1 (B1) or BRCA2 (B2) mutations in high-risk Romanian breast cancer patients, as there is no data published in this population. Methods: This prospective study evaluates the germline BRCA1/BRCA2 mutations in 200 Romanian high-risk breast cancer patients tested between February 2015-January 2017 at IOCN. Inclusion criteria selected patients diagnosed with breast cancer before 40 years, triple negative breast cancer under the age of 50, or having conventional family history criteria. All patients signed an informed consent. BRCA1/BRCA2 testing was performed using an AmpliSeq-based sequencing analysis, on the Ion Torrent Personal Genome Machine (Life Technologies) at RCFG. The pathogenic mutations were validated using Sanger technology. MLPA was performed for all 200 patients. Results: We analyzed 200 high-risk breast cancer patients and found 32 (16%) patients with pathogenic mutations, 23 (11.5%) patients with B1 and 9 (4.5%) patients with B2 mutations. The majority of patients (99.5%) presented normal MLPA results; only one sample (0.5%) presented a deletion at CHEK2-9(10). The frequency of class 5 mutations identified in B1 gene were c.1687C &gt; T (1%), c.181T &gt; G (2%), c.3607C &gt; T (3.5%), c.4218delG (0.5%), c.5329_5330insC (c.5266dupC) (4.5%) and for the B2 gene c.1528G &gt; T (0.5%), c.4022C &gt; G (0.5%), c.7007G &gt; A (0.5%), c.8695C &gt; T (0.5%), c.9253 delA (0.5%), c.9371A &gt; T (2%). Conclusions: Frequency of deleterious BRCA mutations in our cohort was 11.5% for BRCA1 and 4.5% for BRCA2. This prospective study presents the first extensive results on frequency and types of germline BRCA1/2 mutations in Romanian high-risk breast cancer patients. Clinical trial information: NCT02317120. [Table: see text]
High prevalence of Taenia solium taeniasis and cysticercosis in Tibetan schoolchildren in western Sichuan, China: a cross-sectional study
Authors: Tiaoying Li, John J Openshaw, Xingwang Chen, Alexis C Medina, Stephen A Felt, Huan Zhou, Scott D Rozelle, Stephen P Luby
Journal: The Lancet (2017)
Blood Pressure Trajectories in the 20 Years Before Death
Authors: João Delgado, Kirsty Bowman, Alessandro Ble, Jane Masoli, Yang Han, William Henley, Scott Welsh, George A. Kuchel, Luigi Ferrucci, David Melzer
Journal: JAMA Internal Medicine (2017)

There is mixed evidence that blood pressure (BP) stabilizes or decreases in later life. It is also unclear whether BP trajectories reflect advancing age, proximity to end of life, or selective survival of persons free from hypertension.To estimate individual patient BP for each of the 20 years before death and identify potential mechanisms that may explain trajectories.We analyzed population-based Clinical Practice Research Datalink primary care and linked hospitalization electronic medical records from the United Kingdom, using retrospective cohort approaches with generalized linear mixed-effects modeling. Participants were all available individuals with BP measures over 20 years, yielding 46 634 participants dying aged at least 60 years, from 2010 to 2014. We also compared BP slopes from 10 to 3 years before death for 20 207 participants who died, plus 20 207 birth-year and sex-matched participants surviving longer than 9 years.Clinically recorded individual patient repeated systolic BP (SBP) and diastolic BP (DBP).In 46 634 participants (51.7% female; mean [SD] age at death, 82.4 [9.0] years), SBPs and DBPs peaked 18 to 14 years before death and then decreased progressively. Mean changes in SBP from peak values ranged from -8.5 mm Hg (95% CI, -9.4 to -7.7) for those dying aged 60 to 69 years to -22.0 mm Hg (95% CI, -22.6 to -21.4) for those dying at 90 years or older; overall, 64.0% of individuals had SBP changes of greater than -10 mm Hg. Decreases in BP appeared linear from 10 to 3 years before death, with steeper decreases in the last 2 years of life. Decreases in SBP from 10 to 3 years before death were present in individuals not treated with antihypertensive medications, but mean yearly changes were steepest in patients with hypertension (-1.58; 95% CI, -1.56 to -1.60 mm Hg vs -0.70; 95% CI, -0.65 to -0.76 mm Hg), dementia (-1.81; 95% CI, -1.77 to -1.87 mm Hg vs -1.41; 95% CI, -1.38 to -1.43 mm Hg), heart failure (-1.66; 95% CI, -1.62 to -1.69 mm Hg vs -1.37; 95% CI, -1.34 to -1.39 mm Hg), and late-life weight loss.Mean SBP and DBP decreased for more than a decade before death in patients dying at 60 years and older. These BP decreases are not simply attributable to age, treatment of hypertension, or better survival without hypertension. Late-life BP decreases may have implications for risk estimation, treatment monitoring, and trial design.
Abstract IA11: Oxidized 5-methylcytosine: At the interface of epigenetics and DNA repair
Authors: Gerd Peter Pfeifer
Journal: Cancer Research (2017)

Abstract 5-methylcytosine (5mC) is an epigenetic DNA modification that represses transcription when placed into CpG-rich promoter sequences. The removal of 5mC from DNA occurs through stepwise oxidation of the methyl group by 5mC oxidases, the so-called Ten-Eleven-Translocation (TET) enzymes. These oxidases sequentially produce 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Whereas 5hmC occurs at substantial levels in several mammalian cell and tissue types, the other two oxidation products are often described as intermediates in the DNA demethylation pathway, which is completed by base excision repair following excision of 5fC and 5caC by thymine DNA glycosylase (TDG). 5caC is a block to polymerases and may elicit a DNA damage response. Mammalian genomes encode three TET enzymes, TET1, TET2, and TET3. TET3 exists as three major isoforms including an oocyte-specific form, likely responsible for the preferential oxidation of 5mC in the paternal genome of fertilized oocytes, as well as two somatic isoform that differ with regards to presence or absence of an N-terminal zinc finger-type CXXC domain. We recently characterized the full-length TET3 isoform containing the CXXC domain (TET3FL). This CXXC domain binds to unmethylated CpG sequences but, unexpectedly, its highest affinity is towards 5-carboxylcytosine (5caC). We determined the crystal structure of the CXXC domain - 5caC-DNA complex revealing the structural basis of the binding specificity of this domain as a reader of 5CcaCG sequences. We propose that binding of TET3 to its reaction product 5caC through its CXXC domain enforces the genomic specificity of this protein. Mapping of TET3FL in neuronal cell populations showed that Tet3FL is localized at the transcription start sites (TSS) of genes involved in lysosome function, mRNA processing and key genes of the base excision repair pathway. Thus, Tet3FL may function as a regulator of 5caC removal by base excision repair. TET3FL peaks coincided with binding sites for the master regulator of the lysosome and autophagy pathways, TFEB. Active removal of accumulating 5mC from the TSS of genes coding for essential proteins by TET3FL may be important for preventing age-associated diseases including neurodegeneration and cancer. Citation Format: Gerd Peter Pfeifer. Oxidized 5-methylcytosine: At the interface of epigenetics and DNA repair [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA11.
Neddylation Blockade Diminishes Hepatic Metastasis by Dampening Cancer Stem-Like Cells and Angiogenesis in Uveal Melanoma
Authors: Yanli Jin, Ping Zhang, Yun Wang, Bei Jin, Jingfeng Zhou, Jing Zhang, Jingxuan Pan
Journal: Clinical Cancer Research (2017)

Purpose: Liver metastasis is the major and direct cause of death in patients with uveal melanoma (UM). There is no effective therapy for patients with metastatic UM. Improved treatments of hepatic metastatic patients with UM were urgently needed. Inspired by readily detectable key components in the neddylation pathway in UM cells, we aimed at exploring whether neddylation pathway was a therapeutic target for liver metastatic UM.Experimental Design: Expression of key proteins in the neddylation pathway in UM was detected by Western blotting, real-time quantitative RT-PCR (qRT-PCR), and immunohistochemical staining. Cellular proliferation, apoptosis, cell cycle, migration, and cancer stem-like cells (CSCs) properties were examined upon treatment with MLN4924, a potent and selective NAE inhibitor. Antitumor activity and frequency of CSCs were determined by using a NOD-SCID mouse xenograft model. Liver metastasis was evaluated by use of a NOD-scid-IL2Rg-/- mouse model.Results: NAE1 expression was readily detectable in UM. Inhibition of the neddylation pathway by MLN4924 repressed the CSCs properties in UM (capacities of tumorsphere formation and serially replating, aldehyde dehydrogenase-positive cells, and frequency of CSC) through Slug protein degradation. MLN4924 treatment disturbed the paracrine secretion of NF-κB-mediated VEGF-C and its dependent angiogenesis. The inhibitory effect of neddylation blockade on proliferation, which was confirmed by xenografted UM tumor in NOD-SCID mice, was involved in activation of ATM-Chk1-Cdc25C DNA damage response, and G2-M phase arrest. Neddylation inhibition profoundly inhibited hepatic metastasis in UM.Conclusions: Our studies validate the neddylation pathway as a promising therapeutic target for the treatment of patients with hepatic metastasis of UM. Clin Cancer Res; 24(15); 3741-54. ©2017 AACRSee related commentary by Yang et al., p. 3477.
Duvelisib, a novel oral dual inhibitor of PI3K-δ,γ, is clinically active in advanced hematologic malignancies
Authors: Ian W. Flinn, Susan O’Brien, Brad Kahl, Manish Patel, Yasuhiro Oki, Francine F. Foss, Pierluigi Porcu, Jeffrey Jones, Jan A. Burger, Nitin Jain, Virginia M. Kelly, Kerstin Allen, Mark Douglas, Jennifer Sweeney, Patrick Kelly, Steven Horwitz
Journal: Blood (2017)
Comparison of peri‐implant and periodontal marginal soft tissues in health and disease
Authors: Saso Ivanovski, Ryan Lee
Journal: Periodontology 2000 (2017)

Abstract The integrity of the peri‐implant soft‐tissue seal is crucial for maintaining peri‐implant tissue health. Whilst the transmucosal component of the restored implant shares some common features with teeth, namely the presence of a junctional epithelium and a connective tissue component, there are some important differences. A key difference is the nature of the relationship of the connective tissue with the implant surface, whereby there is ‘adaptation’ of collagen fibers in a parallel orientation in relation to the implant, but insertion of fiber attachment perpendicularly into cementum in the case of teeth. This, combined with reduced cellularity and vascularity in the peri‐implant connective tissue, may make implants more susceptible to disease initiation and progression. Furthermore, the presence of a subgingival connection between the implant and the abutment/restoration poses some specific challenges, and maintaining the integrity of this connection is important in preserving peri‐implant tissue health. Implant design features, such as the nature of the connection between the implant and the abutment, as well as the surface characteristics of the abutment and implants, may influence the maintenance of the integrity of soft tissue around implants. Iatrogenic factors, such as incorrect seating of the abutment and/or the restoration, and the presence of residual subgingival cement, will lead to loss of soft‐tissue integrity and hence predispose to peri‐implant disease.