tbuckley/cabot-search huggingface dataset:
Sensitivity to<i>BUB1B</i>Inhibition Defines an Alternative Classification of Glioblastoma
Authors: Eunjee Lee, Margaret Pain, Huaien Wang, Jacob A. Herman, Chad M. Toledo, Jennifer G. DeLuca, Raymund L. Yong, Patrick Paddison, Jun Zhu
Journal: Cancer Research (2017)

Glioblastoma multiforme (GBM) remains a mainly incurable disease in desperate need of more effective treatments. In this study, we develop evidence that the mitotic spindle checkpoint molecule BUB1B may offer a predictive marker for aggressiveness and effective drug response. A subset of GBM tumor isolates requires BUB1B to suppress lethal kinetochore-microtubule attachment defects. Using gene expression data from GBM stem-like cells, astrocytes, and neural progenitor cells that are sensitive or resistant to BUB1B inhibition, we created a computational framework to predict sensitivity to BUB1B inhibition. Applying this framework to tumor expression data from patients, we stratified tumors into BUB1B-sensitive (BUB1BS) or BUB1B-resistant (BUB1BR) subtypes. Through this effort, we found that BUB1BS patients have a significantly worse prognosis regardless of tumor development subtype (i.e., classical, mesenchymal, neural, proneural). Functional genomic profiling of BUB1BR versus BUB1BS isolates revealed a differential reliance of genes enriched in the BUB1BS classifier, including those involved in mitotic cell cycle, microtubule organization, and chromosome segregation. By comparing drug sensitivity profiles, we predicted BUB1BS cells to be more sensitive to type I and II topoisomerase inhibitors, Raf inhibitors, and other drugs, and experimentally validated some of these predictions. Taken together, the results show that our BUB1BR/S classification of GBM tumors can predict clinical course and sensitivity to drug treatment. Cancer Res; 77(20); 5518-29. ©2017 AACR.
コアセルベート被覆ポリ(lactic-co-グリコール酸)ナノファイバーによる成長因子の二重送達はマウス皮膚弁モデルにおける血管新生を改善する【Powered by NICT】
Authors: Lee Min Suk, Ahmad Taufiq, Lee Jinkyu, K Awada Hassan, Wang Yadong, Kim Kyobum, Shin Heungsoo, Yang Hee Seok
Journal: Biomaterials (2017)
Radiologic progression of glioblastoma under therapy—an exploratory analysis of AVAglio
Authors: Martha Nowosielski, Benjamin M Ellingson, Olivier L Chinot, Josep Garcia, Cedric Revil, Alexander Radbruch, Ryo Nishikawa, Warren P Mason, Roger Henriksson, Frank Saran, Philipp Kickingereder, Michael Platten, Thomas Sandmann, Lauren E Abrey, Timothy F Cloughesy, Martin Bendszus, Wolfgang Wick
Journal: Neuro-Oncology (2017)

In this exploratory analysis of AVAglio, a randomized phase III clinical study that investigated the addition of bevacizumab (Bev) to radiotherapy/temozolomide in newly diagnosed glioblastoma, we aim to radiologically characterize glioblastoma on therapy until progression and investigate whether the type of radiologic progression differs between treatment arms and is related to survival and molecular data.Five progression types (PTs) were categorized using an adapted algorithm according to MRI contrast enhancement behavior in T1- and T2-weighted images in 621 patients (Bev, n = 299; placebo, n = 322). Frequencies of PTs (designated as classic T1, cT1 relapse, T2 diffuse, T2 circumscribed, and primary nonresponder), time to progression (PFS), and overall survival (OS) were assessed within each treatment arm and compared with molecular subtypes and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status.PT frequencies differed between the Bev and placebo arms, except for "T2 diffuse" (12.4% and 7.1%, respectively). PTs showed differences in PFS and OS; with "T2 diffuse" being associated with longest survival. Complete disappearance of contrast enhancement during treatment ("cT1 relapse") showed longer survival than only partial contrast enhancement decrease ("classic T1"). "T2 diffuse" was more commonly MGMT hypermethylated. Only weak correlations to molecular subtypes from primary tissue were detected.Progression of glioblastoma under therapy can be characterized radiologically. These radiologic phenotypes are influenced by treatment and develop differently over time with differential outcomes. Complete resolution of contrast enhancement during treatment is a favorable factor for outcome.
Dynamic molecular analysis and clinical correlates of tumor evolution within a phase II trial of panitumumab-based therapy in metastatic colorectal cancer
Authors: S. Siena, A. Sartore-Bianchi, R. Garcia-Carbonero, M. Karthaus, D. Smith, J. Tabernero, E. Van Cutsem, X. Guan, M. Boedigheimer, A. Ang, B. Twomey, B.A. Bach, A.S. Jung, A. Bardelli
Journal: Annals of Oncology (2017)

BackgroundMutations in rat sarcoma (RAS) genes may be a mechanism of secondary resistance in epidermal growth factor receptor inhibitor-treated patients. Tumor-tissue biopsy testing has been the standard for evaluating mutational status; however, plasma testing of cell-free DNA has been shown to be a more sensitive method for detecting clonal evolution.Materials and methodsArchival pre- and post-treatment tumor biopsy samples from a phase II study of panitumumab in combination with irinotecan in patients with metastatic colorectal cancer (mCRC) that also collected plasma samples before, during, and after treatment were analyzed for emergence of mutations during/post-treatment by next-generation sequencing and BEAMing.ResultsThe rate of emergence of tumor tissue RAS mutations was 9.5% by next-generation sequencing (n= 21) and 6.3% by BEAMing (n = 16). Plasma testing of cell-free DNA by BEAMing revealed a mutant RAS emergence rate of 36.7% (n = 39). Exploratory outcomes analysis of plasma samples indicated that patients who had emergent RAS mutations at progression had similar median progression-free survival to those patients who remained wild-type at progression. Serial analysis of plasma samples showed that the first detected emergence of RAS mutations preceded progression by a median of 3.6 months (range, -0.3 to 7.5 months) and that there did not appear to be a mutant RAS allele frequency threshold that could predict near-term outcomes.ConclusionsThis first prospective analysis in mCRC showed that serial plasma biopsies are more inclusive than tissue biopsies for evaluating global tumor heterogeneity; however, the clinical utility of plasma testing in mCRC remains to be further explored.ClinicalTrials.gov IdentifierNCT00891930
in vitroおよびin vivoでHER2受容体を標的とするB型肝炎ウイルスコア粒子のエンジニアリング【Powered by NICT】
Authors: Mohamed Suffian Izzat Fahimuddin Bin, Wang Julie Tzu-Wen, O Hodgins Naomi, Klippstein Rebecca, Garcia-Maya Mitla, Brown Paul, Nishimura Yuya, Heidari Hamed, Bals Sara, K Sosabowski Jane, Ogino Chiaki, Kondo Akihiko, T Al-Jamal Khuloud
Journal: Biomaterials (2017)
Characteristics and Outcome in Patients with High Ankle-Brachial-Index; From IMPACT-ABI Registry
Authors: Shimizu Kunihiko, Miura Takashi, Abe Naoyuki, Nishimura Hitoshi, Hashizume Naoto, Oguchi Yasutaka, Minamisawa Masatoshi, Yoshie Koji, Mochidome Tomoaki, Shoin Wataru, Ebisawa Souichiro
Journal: Circulation (2016)
抗接着抗菌ペプチド被覆はマウス尿路感染症モデルにおけるカテーテル関連感染を予防する【Powered by NICT】
Authors: Yu Kai, C Y Lo Joey, Yan Mei, Yang Xiaoqiang, E Brooks Donald, E W Hancock Robert, Lange Dirk, N Kizhakkedathu Jayachandran
Journal: Biomaterials (2017)
Interferon Regulatory Factor 4 Inhibits Neointima Formation by Engaging Krüppel-Like Factor 4 Signaling
Authors: Wen-Lin Cheng, Zhi-Gang She, Juan-Juan Qin, Jun-Hong Guo, Fu-Han Gong, Peng Zhang, Chun Fang, Song Tian, Xue-Yong Zhu, Jun Gong, Zhi-Hua Wang, Zan Huang, Hongliang Li
Journal: Circulation (2017)

The mechanisms underlying neointima formation remain unclear. Interferon regulatory factors (IRFs), which are key innate immune regulators, play important roles in cardiometabolic diseases. However, the function of IRF4 in arterial restenosis is unknown.IRF4 expression was first detected in human and mouse restenotic arteries. Then, the effects of IRF4 on neointima formation were evaluated with universal IRF4-deficient mouse and rat carotid artery injury models. We performed immunostaining to identify IRF4-expressing cells in the lesions. Smooth muscle cell (SMC)-specific IRF4-knockout (KO) and -transgenic (TG) mice were generated to evaluate the effects of SMC-IRF4 on neointima formation. We used microarray, bioinformatics analysis, and chromatin immunoprecipitation assay to identify the downstream signals of IRF4 and to verify the targets in vitro. We compared SMC-IRF4-KO/Krüppel-like factor 4 (KLF4)-TG mice with SMC-IRF4-KO mice and SMC-specific IRF4-TG/KLF4-KO mice with SMC-specific IRF4-TG mice to investigate whether the effect of IRF4 on neointima formation is KLF4-dependent. The effect of IRF4 on SMC phenotype switching was also evaluated.IRF4 expression in both the human and mouse restenotic arteries is eventually downregulated. Universal IRF4 ablation potentiates neointima formation in both mice and rats. Immunostaining indicated that IRF4 was expressed primarily in SMCs in restenotic arteries. After injury, SMC-IRF4-KO mice developed a thicker neointima than control mice. This change was accompanied by increased SMC proliferation and migration. However, SMC-specific IRF4-TG mice exhibited the opposite phenotype, demonstrating that IRF4 exerts protective effects against neointima formation. The mechanistic study indicated that IRF4 promotes KLF4 expression by directly binding to its promoter. Genetic overexpression of KLF4 in SMCs largely reversed the neointima-promoting effect of IRF4 ablation, whereas ablation of KLF4 abolished the protective function of IRF4, indicating that the protective effects of IRF4 against neointima formation are KLF4-dependent. In addition, IRF4 promoted SMC dedifferentiation.IRF4 protects arteries against neointima formation by promoting the expression of KLF4 by directly binding to its promoter. Our findings suggest that this previously undiscovered IRF4-KLF4 axis plays a key role in vasculoproliferative pathology and may be a promising therapeutic target for the treatment of arterial restenosis.
DNA nanotechnology-based composite-type gold nanoparticle-immunostimulatory DNA hydrogel for tumor photothermal immunotherapy
Authors: Tomoya Yata, Yuki Takahashi, Mengmeng Tan, Hirotaka Nakatsuji, Shozo Ohtsuki, Tatsuya Murakami, Hiroshi Imahori, Yuka Umeki, Tomoki Shiomi, Yoshinobu Takakura, Makiya Nishikawa
Journal: Biomaterials (2017)
Multifunctional superparamagnetic nanoparticles conjugated with fluorescein-labeled designed ankyrin repeat protein as an efficient HER2-targeted probe in breast cancer
Authors: Dong-Li Li, Jian-Er Tan, Ying Tian, Shun Huang, Peng-Hui Sun, Meng Wang, Yan-Jiang Han, Hong-Sheng Li, Hu-Bing Wu, Xing-Mei Zhang, Yi-Kai Xu, Quan-Shi Wang
Journal: Biomaterials (2017)

Based on the discordance of human epidermal growth factor receptor-2 (HER2) expression between primary and metastatic/recurrent breast cancer, HER2 molecular imaging, which had potential to systemically assess and dynamically monitor HER2 expression, might improve the selection of patients for anti-HER2 therapy. In this study, designed ankyrin repeat protein (DARPin) G3, a novel binding protein with picomolar affinity for HER2, was used and multifunctional superparamagnetic nanoparticles modified with fluorescein-5-maleimide-labeled DARPin G3 (SPIO-G3-5MF) were developed for HER2 imaging. Our results showed that SPIO-G3-5MF nanoparticles, which possessed uniform size of about 100 nm, favorable dispersity and low cytotoxicity, could selectively bind to HER2-positive breast cancer cells even in the presence of trastuzumab. Biodistribution assay demonstrated that abundant accumulation and long retention of SPIO-G3-5MF were observed in HER2-positive transplantation breast tumors although a portion of SPIO-G3-5MF nanoparticles were unavoidably captured by liver and spleen. Further MR imaging revealed that SPIO-G3-5MF could selectively image HER2-positive transplantation breast tumors, yielding remarkable T2 signal reduction (50.33 ± 2.90% at 6 h and 47.29 ± 9.36% at 24 h). Our study suggested that SPIO-G3-5MF might be a promising MR molecular probe for diagnosing and monitoring HER2 expression state of breast cancer in the future.
Breakthroughs in modern cancer therapy and elusive cardiotoxicity: Critical research‐practice gaps, challenges, and insights
Authors: Ping‐Pin Zheng, Jin Li, Johan M Kros
Journal: Medicinal Research Reviews (2017)

Abstract To date, five cancer treatment modalities have been defined. The three traditional modalities of cancer treatment are surgery, radiotherapy, and conventional chemotherapy, and the two modern modalities include molecularly targeted therapy (the fourth modality) and immunotherapy (the fifth modality). The cardiotoxicity associated with conventional chemotherapy and radiotherapy is well known. Similar adverse cardiac events are resurging with the fourth modality. Aside from the conventional and newer targeted agents, even the most newly developed, immune‐based therapeutic modalities of anticancer treatment (the fifth modality), e.g., immune checkpoint inhibitors and chimeric antigen receptor (CAR) T‐cell therapy, have unfortunately led to potentially lethal cardiotoxicity in patients. Cardiac complications represent unresolved and potentially life‐threatening conditions in cancer survivors, while effective clinical management remains quite challenging. As a consequence, morbidity and mortality related to cardiac complications now threaten to offset some favorable benefits of modern cancer treatments in cancer‐related survival, regardless of the oncologic prognosis. This review focuses on identifying critical research‐practice gaps, addressing real‐world challenges and pinpointing real‐time insights in general terms under the context of clinical cardiotoxicity induced by the fourth and fifth modalities of cancer treatment. The information ranges from basic science to clinical management in the field of cardio‐oncology and crosses the interface between oncology and onco‐pharmacology. The complexity of the ongoing clinical problem is addressed at different levels. A better understanding of these research‐practice gaps may advance research initiatives on the development of mechanism‐based diagnoses and treatments for the effective clinical management of cardiotoxicity.
Outdoor Light at Night and Breast Cancer Incidence in the Nurses’ Health Study II
Authors: Peter James, Kimberly A. Bertrand, Jaime E. Hart, Eva S. Schernhammer, Rulla M. Tamimi, Francine Laden
Journal: Environmental Health Perspectives (2017)

Background: Animal and epidemiologic studies suggest that exposure to light at night (LAN) may disrupt circadian patterns and decrease nocturnal secretion of melatonin, which may disturb estrogen regulation, leading to increased breast cancer risk. Objectives: We examined the association between residential outdoor LAN and breast cancer incidence using data from the nationwide U.S.-based Nurses' Health Study II cohort. Methods: We followed 109,672 women from 1989 through 2013. Cumulative LAN exposure was estimated using time-varying satellite data for a composite of persistent nighttime illumination at ∼1 km2 scale for each residence during follow-up. Incident invasive breast cancer cases were confirmed by medical record review. We used Cox proportional hazard models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for anthropometric, reproductive, lifestyle, and socioeconomic risk factors. Results: Over 2,187,425 person-years, we identified 3,549 incident breast cancer cases. Based on a fully adjusted model, the estimated HR for incident breast cancer with an interquartile range (IQR) (31.6 nW/cm2/sr) increase in cumulative average outdoor LAN was 1.05 (95% CI: 1.00, 1.11). An association between LAN and breast cancer appeared to be limited to women who were premenopausal at the time of a case [HR=1.07 (95% CI: 1.01, 1.14) based on 1,973 cases vs. HR=1.00 (95% CI: 0.91, 1.09) based on 1,172 cases in postmenopausal women; p-interaction=0.08]. The LAN–breast cancer association was observed only in past and current smokers at the end of follow-up [HR=1.00 (95% CI: 0.94, 1.07) based on 2,215 cases in never smokers; HR=1.10 (95% CI: 1.01, 1.19) based on 1,034 cases in past smokers vs. HR=1.21 (95% CI: 1.07, 1.37) for 300 cases in current smokers; p-interaction=0.08]. Conclusions: Although further work is required to confirm our results and to clarify potential mechanisms, our findings suggest that exposure to residential outdoor light at night may contribute to invasive breast cancer risk. https://doi.org/10.1289/EHP935
Prognostic Impact of Subclonal TP53 Aberrations in Chronic Lymphocytic Leukemia Validated By a Robust Targeted Next Generation Sequencing Assay
Authors: Christian Brieghel, Christina Westmose Yde, Caspar da Cunha-Bang, Savvas Kinalis, Lone Bredo Pedersen, Lars Jønson, Finn Cilius Nielsen, Carsten Utoft Niemann
Journal: Blood (2016)
Age and Outcomes of Primary Prevention Implantable Cardioverter-Defibrillators in Patients With Nonischemic Systolic Heart Failure
Authors: Marie Bayer Elming, Jens C. Nielsen, Jens Haarbo, Lars Videbæk, Eva Korup, James Signorovitch, Line Lisbeth Olesen, Per Hildebrandt, Flemming H. Steffensen, Niels E. Bruun, Hans Eiskjær, Axel Brandes, Anna M. Thøgersen, Finn Gustafsson, Kenneth Egstrup, Regitze Videbæk, Christian Hassager, Jesper Hastrup Svendsen, Dan E. Høfsten, Christian Torp-Pedersen, Steen Pehrson, Lars Køber, Jens Jakob Thune
Journal: Circulation (2017)

Background: The DANISH study (Danish Study to Assess the Efficacy of ICDs [Implantable Cardioverter Defibrillators] in Patients With Non-Ischemic Systolic Heart Failure on Mortality) did not demonstrate an overall effect on all-cause mortality with ICD implantation. However, the prespecified subgroup analysis suggested a possible age-dependent association between ICD implantation and mortality with survival benefit seen only in the youngest patients. The nature of this relationship between age and outcome of a primary prevention ICD in patients with nonischemic systolic heart failure warrants further investigation. Methods: All 1116 patients from the DANISH study were included in this prespecified subgroup analysis. We assessed the relationship between ICD implantation and mortality by age, and an optimal age cutoff was estimated nonparametrically with selection impact curves. Modes of death were divided into sudden cardiac death and nonsudden death and compared between patients younger and older than this age cutoff with the use of χ 2 analysis. Results: Median age of the study population was 63 years (range, 21–84 years). There was a linearly decreasing relationship between ICD and mortality with age (hazard ratio [HR], 1.03; 95% confidence interval [CI], 1.003–1.06; P =0.03). An optimal age cutoff for ICD implantation was present at ≤70 years. There was an association between reduced all-cause mortality and ICD in patients ≤70 years of age (HR, 0.70; 95% CI, 0.51–0.96; P =0.03) but not in patients &gt;70 years of age (HR, 1.05; 95% CI, 0.68–1.62; P =0.84). For patients ≤70 years old, the sudden cardiac death rate was 1.8 (95% CI, 1.3–2.5) and nonsudden death rate was 2.7 (95% CI, 2.1–3.5) events per 100 patient-years, whereas for patients &gt;70 years old, the sudden cardiac death rate was 1.6 (95% CI, 0.8–3.2) and nonsudden death rate was 5.4 (95% CI, 3.7–7.8) events per 100 patient-years. This difference in modes of death between the 2 age groups was statistically significant ( P =0.01). Conclusions: In patients with systolic heart failure not caused by ischemic heart disease, the association between the ICD and survival decreased linearly with increasing age. In this study population, an age cutoff for ICD implantation at ≤70 years yielded the highest survival for the population as a whole. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00542945.
Annals Graphic Medicine - Dear Doctor I
Authors: K.C. Councilor
Journal: Annals of Internal Medicine (2017)

Web Exclusives5 September 2017Annals Graphic Medicine - Dear Doctor IFREEK.C. CouncilorK.C. CouncilorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G17-0005 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Disclosures: The author has disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G17-0005.Author/Illustrator Information: KC Councilor is a cartoonist, teacher, and doctoral candidate in communication arts (rhetoric, politics, and culture) at the University of Wisconsin-Madison. He draws comics about the experience of being transgender and about being human. You can see more of his work at www.kccouncilor.com.Author Contributions: Conception and design: KC Councilor.Analysis and interpretation of the data: KC Councilor.Drafting of the article: KC Councilor.Final approval of the article: KC Councilor.Collection and assembly of data: KC Councilor.Written and illustrated by KC Councilor. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 5 September 2017Volume 167, Issue 5Page: W36-W40KeywordsConflicts of interestDisclosureHealth care ePublished: 5 September 2017 Issue Published: 5 September 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
CXorf48 is a potential therapeutic target for achieving treatment-free remission in CML patients
Authors: M Matsushita, K Ozawa, T Suzuki, M Nakamura, N Nakano, S Kanchi, D Ichikawa, E Matsuki, M Sakurai, D Karigane, H Kasahara, N Tsukamoto, T Shimizu, T Mori, H Nakajima, S Okamoto, Y Kawakami, Y Hattori
Journal: Blood Cancer Journal (2017)

Abstract Although the introduction of tyrosine kinase inhibitors (TKIs) has improved overall survival of patients with chronic myeloid leukemia (CML), about half of the patients eventually relapse after cessation of TKIs. In contrast, the remainder of the patients maintain molecular remission without TKIs, indicating that the patients’ immune system could control proliferation of TKI-resistant leukemic stem cells (LSCs). However, the precise mechanism of immunity against CML-LSCs is not fully understood. We have identified a novel immune target, CXorf48, expressed in LSCs of CML patients. Cytotoxic T cells (CTLs) induced by the epitope peptide derived from CXorf48 recognized CD34 + CD38 − cells obtained from the bone marrow of CML patients. We detected CXorf48-specific CTLs in the peripheral blood mononuclear cells from CML patients who have discontinued imatinib after maintaining complete molecular remission for more than 2 years. Significantly, the relapse rate of CXorf48-specific CTL-negative patients was 63.6%, compared to 0% in CXorf48-specific CTL-positive patients. These results indicate that CXorf48 could be a promising therapeutic target of LSCs for immunotherapy to obtain durable treatment-free remission in CML patients.
Left ventricular ejection time is an independent predictor of incident heart failure in a community‐based cohort
Authors: Tor Biering‐Sørensen, Gabriela Querejeta Roca, Sheila M. Hegde, Amil M. Shah, Brian Claggett, Thomas H. Mosley, Kenneth R. Butler, Scott D. Solomon
Journal: European Journal of Heart Failure (2017)