Agent-based re-engineering of ErbB signaling: A modeling pipeline for integrative Systems Biology.

Bioinformatics. 2016 Dec 20;:

Authors: Das AA, Darsana TA, Jacob E

Abstract
MOTIVATION: Experiments in systems biology are generally supported by a computational model which quantitatively estimates the parameters of the system by finding the best fit to the experiment. Mathematical models have proved to be successful in reverse engineering the system. The data generated is interpreted to understand the dynamics of the underlying phenomena. The question we have sought to answer is that - is it possible to use an agent-based approach to re-engineer a biological process, making use of the available knowledge from experimental and modelling efforts? Can the bottom-up approach benefit from the top-down exercise so as to create an integrated modelling formalism for systems biology? We propose a modelling pipeline that learns from the data given by reverse engineering, and uses it for re-engineering the system, to carry out in-silico experiments.
RESULTS: A mathematical model that quantitatively predicts co-expression of EGFR-HER2 receptors in activation and trafficking has been taken for this study. The pipeline architecture takes cues from the population model that gives the rates of biochemical reactions, to formulate knowledge-based rules for the particle model. Agent-based simulations using these rules, support the existing facts on EGFR-HER2 dynamics. We conclude that, re-engineering models, built using the results of reverse engineering, opens up the possibility of harnessing the power pack of data which now lies scattered in literature. Virtual experiments could then become more realistic when empowered with the findings of empirical cell biology and modelling studies.
AVAILABILITY: Implemented on the Agent Modelling Framework developed in-house. C++code templates available in Supplementary material.
CONTACT: eliz@niist.res.in, liz.csir@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID: 27998938 [PubMed - as supplied by publisher]

The Development of Spasmolytic Polypeptide/TFF2-Expressing Metaplasia (SPEM) During Gastric Repair Is Absent in the Aged Stomach.

Cell Mol Gastroenterol Hepatol. 2016 Sep;2(5):605-624

Authors: Engevik AC, Feng R, Choi E, White S, Bertaux-Skeirik N, Li J, Mahe MM, Aihara E, Yang L, DiPasquale B, Oh S, Engevik KA, Giraud AS, Montrose MH, Medvedovic M, Helmrath MA, Goldenring JR, Zavros Y

Abstract
BACKGROUND & AIMS: During aging, physiological changes in the stomach result in more tenuous gastric tissue that is less capable of repairing injury, leading to increased susceptibility to chronic ulceration. Spasmolytic polypeptide/trefoil factor 2-expressing metaplasia (SPEM) is known to emerge after parietal cell loss and during Helicobacter pylori infection, however, its role in gastric ulcer repair is unknown. Therefore, we sought to investigate if SPEM plays a role in epithelial regeneration.
METHODS: Acetic acid ulcers were induced in young (2-3 mo) and aged (18-24 mo) C57BL/6 mice to determine the quality of ulcer repair with advancing age. Yellow chameleon 3.0 mice were used to generate yellow fluorescent protein-expressing organoids for transplantation. Yellow fluorescent protein-positive gastric organoids were transplanted into the submucosa and lumen of the stomach immediately after ulcer induction. Gastric tissue was collected and analyzed to determine the engraftment of organoid-derived cells within the regenerating epithelium.
RESULTS: Wound healing in young mice coincided with the emergence of SPEM within the ulcerated region, a response that was absent in the aged stomach. Although aged mice showed less metaplasia surrounding the ulcerated tissue, organoid-transplanted aged mice showed regenerated gastric glands containing organoid-derived cells. Organoid transplantation in the aged mice led to the emergence of SPEM and gastric regeneration.
CONCLUSIONS: These data show the development of SPEM during gastric repair in response to injury that is absent in the aged stomach. In addition, gastric organoids in an injury/transplantation mouse model promoted gastric regeneration.

PMID: 27990460 [PubMed - in process]

Classical Challenges in the Physical Chemistry of Polymer Networks and the Design of New Materials.

Acc Chem Res. 2016 Dec 20;49(12):2786-2795

Authors: Wang R, Sing MK, Avery RK, Souza BS, Kim M, Olsen BD

Abstract
Polymer networks are widely used from commodity to biomedical materials. The space-spanning, net-like structure gives polymer networks their advantageous mechanical and dynamic properties, the most essential factor that governs their responses to external electrical, thermal, and chemical stimuli. Despite the ubiquity of applications and a century of active research on these materials, the way that chemistry and processing interact to yield the final structure and the material properties of polymer networks is not fully understood, which leads to a number of classical challenges in the physical chemistry of gels. Fundamentally, it is not yet possible to quantitatively predict the mechanical response of a polymer network based on its chemical design, limiting our ability to understand and characterize the nanostructure of gels and rationally design new materials. In this Account, we summarize our recent theoretical and experimental approaches to study the physical chemistry of polymer networks. First, our understanding of the impact of molecular defects on topology and elasticity of polymer networks is discussed. By systematically incorporating the effects of different orders of loop structure, we develop a kinetic graph theory and real elastic network theory that bridge the chemical design, the network topology, and the mechanical properties of the gel. These theories show good agreement with the recent experimental data without any fitting parameters. Next, associative polymer gel dynamics is discussed, focusing on our evolving understanding of the effect of transient bonds on the mechanical response. Using forced Rayleigh scattering (FRS), we are able to probe diffusivity across a wide range of length and time scales in gels. A superdiffusive region is observed in different associative network systems, which can be captured by a two-state kinetic model. Further, the effects of the architecture and chemistry of polymer chains on gel nanostructure are studied. By incorporating shear-thinning coiled-coil protein motifs into the midblock of a micelle-forming block copolymer, we are able to responsively adjust the gel toughness through controlling the nanostructure. Finally, we review the development of novel application-oriented materials that emerge from our enhanced understanding of gel physical chemistry, including injectable gel hemostats designed to treat internal wounds and engineered nucleoporin-like polypeptide (NLP) hydrogels that act as biologically selective filters. We believe that the fundamental physical chemistry questions articulated in this Account will provide inspiration to fully understand the design of polymer networks, a group of mysterious yet critically important materials.

PMID: 27993006 [PubMed - in process]

Comparison of Presentation and Outcome in 100 Pediatric Hodgkin Lymphoma Patients Treated at Children Hospital, Lahore, Pakistan and Royal Marsden Hospital, UK.

J Coll Physicians Surg Pak. 2016 Nov;26(11):904-907

Authors: Faizan M, Taj MM, Anwar S, Asghar N, Ahmad A, Lancaster D, Atra A, Ali AS

Abstract
OBJECTIVE: To compare differences in demographics and outcomes in childhood Hodgkin lymphoma (HL) presenting at the Children's Hospital Lahore (CHL), and Royal Marsden Hospital (RMH), UK.
STUDY DESIGN: An observational comparative study.
PLACE AND DURATION OF STUDY: From January 2011 to February 2012 at CH, Lahore and from October 2008 to February 2012 at RMH, UK.
METHODOLOGY: Consecutive HL patients (50 from each hospital) were inducted. Data regarding age, gender, staging, histopathology and outcome were analysed. Clinical and pathological staging done according to Ann-Arbor and World Health Organization classification. Treatment duration was 6-8 months. They were followed for 6 months post-treatment. Frequencies of variables were noted and compared. Chi-square test was used for determining significance.
RESULTS: Patients from Children's Hospital, Lahore were younger (mean 7.9 years) with male predominance (n=42, 84%). Histopathology showed Mixed Cellularity (MC) in 32 (64%), Nodular Sclerosis (NS) in 5 (10%), Lymphocyte Rich in 4 (8%) and lymphocyte depleted in 1 (2%), nodular lymphocyte predominant (NLP) in 1 (2%) each. Majority presented in stage IV (n=25,50%), or stage III (n=20,40%). Constitutional B symptoms were present in 37 (74%). Bone marrow involvement observed in 23 (46%). Remission was achieved in 42 (84%) patients; 2 (4%) relapsed, 4 (8%) expired and 2 (4%) left against medical advice. In contrast, RMH patients were older (mean 11.8 years.) and 30 (60%) were males. NS (n=40,80%) and NLP (n=6,12%) types were predominant. Two (4%) patients were in stage I, 27 (54%) in stage II, 12 (24%) in stage III and 9 (18%) presented in stage IV. Fourteen (28%) had B-symptoms. None had bone marrow disease. Event free survival was 46 (92%). Four (8%) patients relapsed. Three responded to second line therapy and one relapsed postautologous transplant.
CONCLUSION: Significant differences were observed in age at presentation, stage, histopathology and extent of bone marrow involvement between the groups. Of interest is the bone marrow involvement in stage IV patients in Pakistan. Delayed diagnosis account for advanced stage but difference in pathological subtype needs further study.

PMID: 27981925 [PubMed - in process]

Comparison of Three Information Sources for Smoking Information in Electronic Health Records.

Cancer Inform. 2016;15:237-242

Authors: Wang L, Ruan X, Yang P, Liu H

Abstract
OBJECTIVE: The primary aim was to compare independent and joint performance of retrieving smoking status through different sources, including narrative text processed by natural language processing (NLP), patient-provided information (PPI), and diagnosis codes (ie, International Classification of Diseases, Ninth Revision [ICD-9]). We also compared the performance of retrieving smoking strength information (ie, heavy/light smoker) from narrative text and PPI.
MATERIALS AND METHODS: Our study leveraged an existing lung cancer cohort for smoking status, amount, and strength information, which was manually chart-reviewed. On the NLP side, smoking-related electronic medical record (EMR) data were retrieved first. A pattern-based smoking information extraction module was then implemented to extract smoking-related information. After that, heuristic rules were used to obtain smoking status-related information. Smoking information was also obtained from structured data sources based on diagnosis codes and PPI. Sensitivity, specificity, and accuracy were measured using patients with coverage (ie, the proportion of patients whose smoking status/strength can be effectively determined).
RESULTS: NLP alone has the best overall performance for smoking status extraction (patient coverage: 0.88; sensitivity: 0.97; specificity: 0.70; accuracy: 0.88); combining PPI with NLP further improved patient coverage to 0.96. ICD-9 does not provide additional improvement to NLP and its combination with PPI. For smoking strength, combining NLP with PPI has slight improvement over NLP alone.
CONCLUSION: These findings suggest that narrative text could serve as a more reliable and comprehensive source for obtaining smoking-related information than structured data sources. PPI, the readily available structured data, could be used as a complementary source for more comprehensive patient coverage.

PMID: 27980387 [PubMed]

Elementary, My Dear Watson - the era of natural language processing in transplantation.

Am J Transplant. 2016 Dec 15;:

Authors: Ho B, Skaro A, Montag S, Zhao L

Abstract
The use of modern data acquisition and analytics commonly in use in the technology sector by Google, IBM, and others have long been the envy of the health services researcher. In this issue, Srinivas et al. have demonstrated feasibility in the use of data mining and natural language processing (NLP) in data abstraction.(1) In their study they developed predictive models for graft loss and patient survival in kidney transplantation using single-center retrospective data. This article is protected by copyright. All rights reserved.

PMID: 27977903 [PubMed - as supplied by publisher]

The Outcome of Endoscopic Transethmosphenoid Optic Canal Decompression for Indirect Traumatic Optic Neuropathy with No-Light-Perception.

J Ophthalmol. 2016;2016:6492858

Authors: Yu B, Ma Y, Tu Y, Wu W

Abstract
Purpose. To present the safety and effect of endoscopic transethmosphenoid optic canal decompression (ETOCD) for indirect traumatic optic neuropathy (ITON) patients with no-light-perception (NLP). Methods. A retrospective study performed on 96 patients (96 eyes) with NLP after ITON between June 1, 2010, and June 1, 2015, who underwent ETOCD, was reviewed. Visual outcome before and after treatment was taken into comparison. Results. The overall visual acuity improvement rate after surgery was 46.9%. The improvement rates of visual acuity of patients who received treatment within 3 days of injury, 3-7 days after injury, and later than 7 days were 63.6%, 42.9%, and 35.7%, respectively. Statistically significant difference was detected between the effective rates of within-3-day group and later-than-7-day group (χ(2) = 5.772, P = 0.016). The effective rate of atrophy group and nonatrophy group was 25.0% and 51.3%, respectively. The effective rate was significantly higher in nonatrophy group (χ(2) = 4.417, P = 0.036). Conclusion. For patients suffering from ITON with NLP, time to medical treatment within 3 days is an influential factor for visual prognosis. Optic nerve atrophy is an important predictor for visual prognosis. Treatment should still be recommended even for cases of delayed presentation to hospital.

PMID: 27965891 [PubMed - in process]

Simplifying EHR Overview of Critically Ill Patients Through Vital Signs Monitoring.

IEEE J Biomed Health Inform. 2016 Dec 09;

Authors: Vilic A, Hoppe K, Petersen J, Kjaer T, Sorensen H

Abstract
This paper presents a novel data-driven approach to graphical presentation of text-based electronic health records (EHR) while maintaining all textual information. We have developed the Patient Condition Timeline (PCT) tool, which creates a timeline representation of a patients' physiological condition during admission. PCT is based on electronical monitoring of vital signs and then combining these into Early Warning Scores (EWS). Hereafter, techniques from Natural Language Processing (NLP) are applied on existing EHR to extract all entries. Finally, the two methods are combined into an interactive timeline featuring the ability to see drastic changes in the patients' health, and thereby enabling staff to see where in the EHR critical events have taken place.

PMID: 27959834 [PubMed - as supplied by publisher]

E-Cigarette Social Media Messages: A Text Mining Analysis of Marketing and Consumer Conversations on Twitter.

JMIR Public Health Surveill. 2016 Dec 12;2(2):e171

Authors: Lazard AJ, Saffer AJ, Wilcox GB, Chung AD, Mackert MS, Bernhardt JM

Abstract
BACKGROUND: As the use of electronic cigarettes (e-cigarettes) rises, social media likely influences public awareness and perception of this emerging tobacco product.
OBJECTIVE: This study examined the public conversation on Twitter to determine overarching themes and insights for trending topics from commercial and consumer users.
METHODS: Text mining uncovered key patterns and important topics for e-cigarettes on Twitter. SAS Text Miner 12.1 software (SAS Institute Inc) was used for descriptive text mining to reveal the primary topics from tweets collected from March 24, 2015, to July 3, 2015, using a Python script in conjunction with Twitter's streaming application programming interface. A total of 18 keywords related to e-cigarettes were used and resulted in a total of 872,544 tweets that were sorted into overarching themes through a text topic node for tweets (126,127) and retweets (114,451) that represented more than 1% of the conversation.
RESULTS: While some of the final themes were marketing-focused, many topics represented diverse proponent and user conversations that included discussion of policies, personal experiences, and the differentiation of e-cigarettes from traditional tobacco, often by pointing to the lack of evidence for the harm or risks of e-cigarettes or taking the position that e-cigarettes should be promoted as smoking cessation devices.
CONCLUSIONS: These findings reveal that unique, large-scale public conversations are occurring on Twitter alongside e-cigarette advertising and promotion. Proponents and users are turning to social media to share knowledge, experience, and questions about e-cigarette use. Future research should focus on these unique conversations to understand how they influence attitudes towards and use of e-cigarettes.

PMID: 27956376 [PubMed - in process]

Thematic issue of the Second combined Bio-ontologies and Phenotypes Workshop.

J Biomed Semantics. 2016 Dec 12;7(1):66

Authors: Verspoor K, Oellrich A, Collier N, Groza T, Rocca-Serra P, Soldatova L, Dumontier M, Shah N

Abstract
This special issue covers selected papers from the 18th Bio-Ontologies Special Interest Group meeting and Phenotype Day, which took place at the Intelligent Systems for Molecular Biology (ISMB) conference in Dublin in 2015. The papers presented in this collection range from descriptions of software tools supporting ontology development and annotation of objects with ontology terms, to applications of text mining for structured relation extraction involving diseases and phenotypes, to detailed proposals for new ontologies and mapping of existing ontologies. Together, the papers consider a range of representational issues in bio-ontology development, and demonstrate the applicability of bio-ontologies to support biological and clinical knowledge-based decision making and analysis.The full set of papers in the Thematic Issue is available at http://www.biomedcentral.com/collections/sig .

PMID: 27955708 [PubMed - in process]

A Computational Chemistry Data Management Platform Based on the Semantic Web.

J Phys Chem A. 2016 Dec 12;

Authors: Wang B, Dobosh PA, Chalk SJ, Sopek M, Ostlund NS

Abstract
This paper presents a formal data publishing platform for computational chemistry using semantic web technologies. This platform encapsulates computational chemistry data from a variety of packages in an Extensible Markup Language (XML) file called CSX (Common Standard for eXchange). Based on a Gainesville Core (GC) ontology for computational chemistry, the CSX XML file is converted into the JavaScript Object Notation for Linked Data (JSON-LD) format using an XML Stylesheet Language Transformation (XSLT) file. Ultimately the JSON-LD file is converted to subject-predicate-object triples in a Turtle (TTL) file and published on the web portal. By leveraging semantic web technologies, we are able to place computational chemistry data onto web portals as a component of a Giant Global Graph (GGG) such that computer agents, as well as individual chemists, can access the data.

PMID: 27936706 [PubMed - as supplied by publisher]

LifeWatch Greece data-services: Discovering Biodiversity Data using Semantic Web Technologies.

Biodivers Data J. 2016;(4):e8443

Authors: Minadakis N, Marketakis Y, Doerr M, Bekiari C, Papadakos P, Gougousis A, Bailly N, Arvanitidis C

Abstract
BACKGROUND: Biodiversity data is characterized by its cross-disciplinary character, the extremely broad range of data types and structures, and the variety of semantic concepts that it encompasses. Furthermore there is a plethora of different data sources providing resources for the same piece of information in a heterogeneous way. Even if we restrict our attention to Greek biodiversity domain, it is easy to see that biodiversity data remains unconnected and widely distributed among different sources.
NEW INFORMATION: To cope with these issues, in the context of the LifeWatch Greece project, i) we supported cataloguing and publishing of all the relevant metadata information of the Greek biodiversity domain, ii) we integrated data from heterogeneous sources by supporting the definitions of appropriate models, iii) we provided means for efficiently discovering biodiversity data of interest and iv) we enabled the answering of complex queries that could not be answered from the individual sources. This work has been exploited, evaluated and scientificaly confirmed by the biodiversity community through the services provided by the LifeWatch Greece portal.

PMID: 27932908 [PubMed]

Publication of nuclear magnetic resonance experimental data with semantic web technology and the application thereof to biomedical research of proteins.

J Biomed Semantics. 2016 May 05;7(1):16

Authors: Yokochi M, Kobayashi N, Ulrich EL, Kinjo AR, Iwata T, Ioannidis YE, Livny M, Markley JL, Nakamura H, Kojima C, Fujiwara T

Abstract
BACKGROUND: The nuclear magnetic resonance (NMR) spectroscopic data for biological macromolecules archived at the BioMagResBank (BMRB) provide a rich resource of biophysical information at atomic resolution. The NMR data archived in NMR-STAR ASCII format have been implemented in a relational database. However, it is still fairly difficult for users to retrieve data from the NMR-STAR files or the relational database in association with data from other biological databases.
FINDINGS: To enhance the interoperability of the BMRB database, we present a full conversion of BMRB entries to two standard structured data formats, XML and RDF, as common open representations of the NMR-STAR data. Moreover, a SPARQL endpoint has been deployed. The described case study demonstrates that a simple query of the SPARQL endpoints of the BMRB, UniProt, and Online Mendelian Inheritance in Man (OMIM), can be used in NMR and structure-based analysis of proteins combined with information of single nucleotide polymorphisms (SNPs) and their phenotypes.
CONCLUSIONS: We have developed BMRB/XML and BMRB/RDF and demonstrate their use in performing a federated SPARQL query linking the BMRB to other databases through standard semantic web technologies. This will facilitate data exchange across diverse information resources.

PMID: 27927232 [PubMed - in process]

DNA Data Bank of Japan.

Nucleic Acids Res. 2016 Oct 24;:

Authors: Mashima J, Kodama Y, Fujisawa T, Katayama T, Okuda Y, Kaminuma E, Ogasawara O, Okubo K, Nakamura Y, Takagi T

Abstract
The DNA Data Bank of Japan (DDBJ) (http://www.ddbj.nig.ac.jp) has been providing public data services for thirty years (since 1987). We are collecting nucleotide sequence data from researchers as a member of the International Nucleotide Sequence Database Collaboration (INSDC, http://www.insdc.org), in collaboration with the US National Center for Biotechnology Information (NCBI) and European Bioinformatics Institute (EBI). The DDBJ Center also services Japanese Genotype-phenotype Archive (JGA), with the National Bioscience Database Center to collect human-subjected data from Japanese researchers. Here, we report our database activities for INSDC and JGA over the past year, and introduce retrieval and analytical services running on our supercomputer system and their recent modifications. Furthermore, with the Database Center for Life Science, the DDBJ Center improves semantic web technologies to integrate and to share biological data, for providing the RDF version of the sequence data.

PMID: 27924010 [PubMed - as supplied by publisher]

[Genomics of lung adenocarcinoma: pathogenetic significance and clinical applications.]

Recenti Prog Med. 2016 Dec;107(12):652-672

Authors: Palmirotta R, Acquafredda S, Argentiero A, Carella C, Lanotte L, Pappagallo N, Quaresmini D, Silvestris F

Abstract
Diagnostic and therapeutic approaches to non small cell lung cancer (NSCLC), especially adenocarcinoma, have recently undergone dramatic evolution according to the tremendous amount of molecular data collected on this cancer. In fact, the application of oncogenomics has identified novel molecular subtypes of NSCLC and led the way to diagnostic criteria based on the expression of specific genetic alterations that can provide prognostic and specific indications to the molecular targeted therapies. In NSCLC, several genes show "driver" molecular alterations that confer oncogenic potential to progenitor cells through the enrollment of metabolic pathways critical for cell proliferation and tumor development. On the other hand, clinical management of NSCLC with small molecules has undoubtedly provided optimistic results with both a significant increase in overall survival and reduction in therapy-related toxicity including relative complications. Thus, pharmacogenomics, as the newest tool for using the targeted therapy represents the most innovative approach for treatment of this cancer once the molecular aberrations are identified. In particular, the relative mutational status of several driver genes including EGFR, ALK, ROS1 and others, is directly correlated to a better response to thyrosin-kinase inhibitors. Furthermore, other therapeutic strategies with inhibitors of angiogenic receptors, PARP, histone-deacetylase, PI3K and HSP90, are intensively studied in pre-clinical models as well as in clinical trials for a potential adoption in clinical practice. The introduction of more advanced techniques for molecular profiling also allows to identify pathogenic variants of many other genes involved in the progression of lung adenocarcinoma with the aim to develop novel molecular targets for pharmacological research. In this review, we will revisit the current applications of oncogenomics in the diagnosis and treatment of this tumor.

PMID: 27997009 [PubMed - in process]

Pharmacogenetic variants associated with outcome in patients with advanced gastric cancer treated with fluoropyrimidine and platinum-based triplet combinations: a pooled analysis of three prospective studies.

Pharmacogenomics J. 2016 Dec 20;:

Authors: Meulendijks D, Rozeman EA, Cats A, Sikorska K, Joerger M, Deenen MJ, Beijnen JH, Schellens JH

Abstract
The main treatment for advanced gastric cancer is fluoropyrimidine and platinum-based chemotherapy. We investigated the clinical validitiy of 19 candidate pharmacogenetic variants in ENOSF1 (enolase superfamily member 1), TYMS, CDA, MTHFR, TYMP, DPYD, ERCC1, ERCC2, GSTP1, GSTT1, GSTM1, CYP3A4 and CYP3A5 in relation to overall survival (OS), progression-free survival, objective response rate (ORR) and toxicity in 185 patients receiving triplet chemotherapy. The formal significance threshold was P<0.0026. TYMS VNTR (variable number of 28-bp tandem repeats) 3 R/3 R genotype was formally associated with inferior ORR (odds ratio (OR) 0.3, P=0.0025), whereas ENOSF1 rs2612091 G/G was nominally associated with OS after adjustment for TYMS 3 R/3 R (hazard ratio (HR) 1.5, P=0.041). In a subgroup analysis of patients with locally advanced disease (n=33), ENOSF1 rs2612091 was strongly associated with OS (HR 6.5, P=0.001). CYP3A4*22/CYP3A5*3 genotype was nominally associated with grade 3/4 toxicity in patients receiving docetaxel-containing chemotherapy (P=0.0175). This is the first study suggesting that ENOSF1 rs2612091 is prognostic or predictive of OS in gastric cancer. This finding requires prospective validation.The Pharmacogenomics Journal advance online publication, 20 December 2016; doi:10.1038/tpj.2016.81.

PMID: 27995989 [PubMed - as supplied by publisher]

Network-guided modelling allows tumor-type independent prediction of sensitivity to all-trans retinoic acid.

Ann Oncol. 2016 Dec 19;:

Authors: Bolis M, Garattini E, Paroni G, Zanetti A, Kurosaki M, Castrignano' T, Garattini SK, Biancardi F, Barzago MM, Gianni' M, Terao M, Pattini L, Fratelli M

Abstract
BACKGROUND: All-trans retinoic acid (ATRA) is a differentiating agent used in the treatment of acute-promyelocytic-leukemia and it is under-exploited in other malignancies despite its low systemic toxicity. A rational/personalized use of ATRA requires development of predictive tools allowing identification of sensitive cancer types and responsive individuals.
MATERIALS AND METHODS: RNA-Sequencing data for 10080 patients and 33 different tumor-types were derived from the TCGA and Leucegene datasets and completely re-processed. The study was performed using machine learning methods and network analysis.
RESULTS: We profiled a large panel of breast-cancer cell-lines for in vitro sensitivity to ATRA and exploited the associated basal gene-expression data to initially generate a model predicting ATRA-sensitivity in this disease. Starting from these results and using a network-guided approach, we developed a generalized model (ATRA-21) whose validity extends to tumor-types other than breast cancer. ATRA-21 predictions correlate with experimentally determined sensitivity in a large panel of cell-lines representative of numerous tumor-types. In patients, ATRA-21 correctly identifies APL as the most sensitive acute-myelogenous-leukemia subtype and indicates that uveal-melanoma and low-grade glioma are top-ranking diseases as for average predicted responsiveness to ATRA. There is a consistent number of tumor-types for which higher ATRA-21 predictions are associated with better outcomes.
CONCLUSIONS: In summary, we generated a tumor-type independent ATRA-sensitivity predictor which consists of a restricted number of genes and has the potential to be applied in the clinics. Identification of the tumor-types which are likely to be generally sensitive to the action of ATRA paves the way to the design of clinical studies in the context of these diseases. In addition, ATRA-21 may represent an important diagnostic tool for the selection of individual patients who may benefit from ATRA-based therapeutic strategies also in tumors characterized by lower average sensitivity.

PMID: 27993792 [PubMed - as supplied by publisher]

Interview with Dr Ghassan K Abou-Alfa.

Immunotherapy. 2016 Nov;8(11):1277-1279

Authors: Abou-Alfa GK

Abstract
Ghassan K Abou-Alfa joined the Gastrointestinal Oncology Service at Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College in New York back in 2001. Dr Abou-Alfa specializes in the treatment of gastrointestinal malignancies. Dr Abou-Alfa received his medical degree from the American University of Beirut, Lebanon, and completed his post-doctoral training at Yale University School of Medicine. His research is dedicated to finding novel therapies and improving the effectiveness of the current therapies for hepatocellular carcinoma, cholangiocarcinoma and gallbladder cancer, while continuing to understand the basic mechanisms of the diseases and its therapy. Dr Abou-Alfa has invested several years in helping develop multi-tyrosine kinases and more immune-modulator therapies. Dr Abou-Alfa has many publications in the field. He led on many occasions international teams of investigators. Dr Abou-Alfa serves as the chair of the National Cancer Institute (NCI) Task Force for Hepatobiliary Cancers and the chair of the AIDS Malignancy Consortium (AMC) Non-AIDS Defining Malignancies (NADC) Liver/GI Task Force. Dr Abou-Alfa also co-chairs the hepatobiliary cancers subgroup of the Alliance cooperative group, and is a cadre member of both the gastrointestinal cancers and pharmacogenomics and population pharmacology committees. Dr Abou-Alfa who has lectured worldwide on the subject on gastrointestinal malignancies, is also a strong advocate for raising awareness and support for improving the outcome of patients with this disease, and enhancing oncologic education worldwide.

PMID: 27993088 [PubMed - in process]

LIN28 phosphorylation by MAPK/ERK couples signalling to the post-transcriptional control of pluripotency.

Nat Cell Biol. 2016 Dec 19;:

Authors: Tsanov KM, Pearson DS, Wu Z, Han A, Triboulet R, Seligson MT, Powers JT, Osborne JK, Kane S, Gygi SP, Gregory RI, Daley GQ

Abstract
Signalling and post-transcriptional gene control are both critical for the regulation of pluripotency, yet how they are integrated to influence cell identity remains poorly understood. LIN28 (also known as LIN28A), a highly conserved RNA-binding protein, has emerged as a central post-transcriptional regulator of cell fate through blockade of let-7 microRNA biogenesis and direct modulation of mRNA translation. Here we show that LIN28 is phosphorylated by MAPK/ERK in pluripotent stem cells, which increases its levels via post-translational stabilization. LIN28 phosphorylation had little impact on let-7 but enhanced the effect of LIN28 on its direct mRNA targets, revealing a mechanism that uncouples LIN28's let-7-dependent and -independent activities. We have linked this mechanism to the induction of pluripotency by somatic cell reprogramming and the transition from naive to primed pluripotency. Collectively, our findings indicate that MAPK/ERK directly impacts LIN28, defining an axis that connects signalling, post-transcriptional gene control, and cell fate regulation.

PMID: 27992407 [PubMed - as supplied by publisher]

Budget impact of everolimus for the treatment of progressive, well-differentiated, non-functional neuroendocrine tumors of gastrointestinal or lung origin that are advanced or metastatic.

J Med Econ. 2016 Dec 16;:1-19

Authors: Rose DB, Nellesen D, Neary MP, Cai B

Abstract
BACKGROUND: Advanced neuroendocrine tumors (NETs) are a rare malignancy with considerable need for effective therapies. Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2016 for treatment of adults with progressive, well-differentiated, non-functional NETs of gastrointestinal (GI) or lung origin that are unresectable, locally advanced, or metastatic.
OBJECTIVE: To assess the 3-year budget impact for a typical US health plan following availability of everolimus for treatment of GI and lung NETs.
METHODS: An economic model was developed that considered two perspectives: an entire health plan and a pharmacy budget. The total budget impact included costs of drug therapies, administration, hospitalizations, physician visits, monitoring, and adverse events (AEs). The pharmacy model only considered drug costs.
RESULTS: In a US health plan with 1 million members, the model estimated 66 patients with well-differentiated, non-functional, and advanced or metastatic GI NETs and 20 with lung NETs undergoing treatment each year. Total budget impact in the first through third year after FDA approval ranged from $0.0568-$0.1443 per member per month (PMPM) for GI NETs and from $0.0181-$0.0355 PMPM for lung NETs. The total budget impact was lower than the pharmacy budget impact because it included cost offsets from administration and AE management for everolimus compared with alternative therapies (e.g., chemotherapies).
LIMITATIONS: Because GI and lung NETs are rare diseases with limited published data, several assumptions were made that may influence interpretation of results.
CONCLUSIONS: The budget impact for everolimus was minimal in this rare disease area with a high unmet need, largely due to low disease prevalence. These results should be considered in the context of significant clinical benefits potentially provided by everolimus, including significantly longer progression-free survival (PFS) for advanced GI and lung NET patients.

PMID: 27981858 [PubMed - as supplied by publisher]