tbuckley/cabot-search huggingface dataset:
Abstract 624: Humanized mouse models for evaluation of cancer therapies
Authors: Olivier Duchamp, Francis Bichat, Caroline Mignard, François Ghiringhelli, Jean-François Mirjolet
Journal: Cancer Research (2016)

Abstract Mice with a humanized immune system, so called “humanized” mouse models, have been established to study the complex interaction of the human immune system during human disorders. In case of cancer research, the in vivo model ideally should recapitulate the biological characteristics of the human tumor and of the related tumor microenvironment in patient such as immune system. Human immune system is reconstituted in immunodeficient mice using either human PBMCs or hematopoietic stem cells (HSCs). Humanized mice bearing human target tumor cells constitute relevant models for evaluation of cancer therapeutics such as bispecific antibodies, immune cell targeting antibodies. In vivo proof of concept studies were performed with humanized mice xenografted with either human disseminated lymphoma or with human solid tumors (tumor cell line and Patient Derived Xenograft model, Her2 positive breast, colon, ovarian and lung cancers) and treated with therapeutic antibodies. Biomarkers of response to immune cell targeting therapies were evaluated by flow cytometry as well as immunohistochemistry analyses. In case of disseminated B-cell lymphoma grafted into mice reconstituted with human PBMC, efficacy of antibody was evidenced by an increased survival and a high decrease of human B cells in mouse bone marrow. Lung and ovarian PDX developed in HSC reconstituted BRGS mice induced an increase in Tregs and a change in T/B ratio in blood and spleen samples. Furthermore, we evidenced the presence of Tregs within human PDX tumor by immunohistochemistry. Citation Format: Olivier Duchamp, Francis Bichat, Caroline Mignard, François Ghiringhelli, Jean-François Mirjolet, IMODI Consortium. Humanized mouse models for evaluation of cancer therapies. [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 624.
Trends in Obesity Prevalence in Adults With a History of Cancer: Results From the US National Health Interview Survey, 1997 to 2014
Authors: Heather Greenlee, Zaixing Shi, Christine L. Sardo Molmenti, Andrew Rundle, Wei Yann Tsai
Journal: Journal of Clinical Oncology (2016)

Obesity after a diagnosis of specific cancers has been associated with worse prognosis. We examined the trend in obesity prevalence among cancer survivors in the United States in the past two decades and compared trends with those of adults without a history of cancer.
Glucocorticoids at the Olympic Games: state-of-the-art review
Authors: Ken Fitch
Journal: British Journal of Sports Medicine (2016)

In this state-of-the-art review, the author discusses the history of prohibiting glucocorticoids (GCs) and how this has occurred over nearly three decades at the Olympic Games. He relates how prohibiting systemic GCs in sport was a major factor in the development of therapeutic use exemptions and the fluctuating status of non-systemic GCs (banned, not banned). Concern is expressed that for 2017, the World Anti-Doping Agency (WADA) is proposing to prohibit injecting GCs shortly prior to competition. The author notes that in 1986, when GCs were first prohibited, analytical chemistry techniques could not distinguish the route of GC administration from its urinary concentration. Thirty years later, this remains the case. Importantly, this article discusses how the desired pharmacological effects of injecting GCs locally and intra-articularly can be achieved and why exercising vigorously immediately or shortly after a GC injection is therapeutically unsound. The review concludes by agreeing that injecting GCs shortly prior to strenuous training or competition is medically unwise but stresses that this is a clinical matter that sport—not WADA—needs to address. Cycling and rowing have managed this successfully for the past 5 years.
Highly bioavailable silibinin nanoparticles inhibit HCV infection
Authors: Ching-Hsuan Liu, Chun-Ching Lin, Wen-Chan Hsu, Chueh-Yao Chung, Chih-Chan Lin, Alagie Jassey, Shun-Pang Chang, Chen-Jei Tai, Cheng-Jeng Tai, Justin Shields, Christopher D Richardson, Ming-Hong Yen, D Lorne J Tyrrell, Liang-Tzung Lin
Journal: Gut (2016)

Silibinin is a flavonolignan that is well established for its robust antiviral activity against HCV infection and has undergone several clinical trials for the management of hepatitis C. Despite its potency, silibinin suffers from poor solubility and bioavailability, restricting its clinical use. To overcome this limitation, we developed highly bioavailable silibinin nanoparticles (SB-NPs) and evaluated their efficiency against HCV infection.SB-NPs were prepared using a nanoemulsification technique and were physicochemically characterised. Infectious HCV culture systems were used to evaluate the influence of SB-NP on the virus life cycle and examine their antioxidant activity against HCV-induced oxidative stress. The safety profiles of SB-NP, in vivo pharmacokinetic studies and antiviral activity against infection of primary human hepatocytes were also assessed.SB-NP consisted of nanoscale spherical particles (<200 nm) encapsulating amorphous silibinin at >97% efficiency and increasing the compound's solubility by >75%. Treatment with SB-NP efficiently restricted HCV cell-to-cell transmission, suggesting that they retained silibinin's robust anti-HCV activity. In addition, SB-NP exerted an antioxidant effect via their free radical scavenging function. Oral administration of SB-NP in rodents produced no apparent in vivo toxicity, and pharmacokinetic studies revealed an enhanced serum level and superior biodistribution to the liver compared with non-modified silibinin. Finally, SB-NP efficiently reduced HCV infection of primary human hepatocytes.Due to SB-NP's enhanced bioavailability, effective anti-HCV activity and an overall hepatoprotective effect, we suggest that SB-NP may be a cost-effective anti-HCV agent that merits further evaluation for the treatment of hepatitis C.
Phase I/II safety and antitumor activity of nivolumab (nivo) in patients (pts) with advanced hepatocellular carcinoma (HCC): Interim analysis of the CheckMate-040 dose escalation study.
Authors: Anthony B. El-Khoueiry, Bruno Sangro, Thomas Cheung Yau, Todd S. Crocenzi, Theodore Hobart Welling, Winnie Yeo, Akhil Chopra, Jeffrey Anderson, Christine Marie Dela Cruz, Lixin Lang, Jaclyn Neely, Ignacio Melero
Journal: Journal of Clinical Oncology (2016)

4012 Background: For pts with advanced HCC on sorafenib (sor), overall survival (OS) is 11 mo; median OS with best supportive care (BSC) post-sor failure is 7–8 mo.Safety and preliminary antitumor efficacy of nivo, a fully human IgG4 mAb PD-1 inhibitor, was evaluated in a multiple ascending-dose, phase 1/2 study in pts with advanced HCC with clinical follow-up to 3 yrs. Methods: Pts had histologically-confirmed, advanced HCC, Child-Pugh (CP) score ≤ 7, and previously failed, refused, or were intolerant of sor. Dose escalation occurred in 3 parallel cohorts by etiology: no active hepatitis virus infection, HBV-infection, or HCV-infection. Pts received nivo 0.1–10 mg/kg for up to 2 yrs. The primary endpoint was safety. Secondary endpoints included antitumor activity by RECIST 1.1 and DOR; exploratory endpoints included biomarker assessment. Results: 51 pts were enrolled and treated with nivo: baseline CP scores were 5 (n=44) or 6 (n=7), 76% had extrahepatic metastasis, 12% had vascular invasion, and 73% had prior sor. 10 pts remain on study; 41 discontinued, most (n=35) due to PD and 1 due to a treatment-related adverse event (TRAE) of ALT and AST increase. TRAEs occurred in 39 pts (77%); most common were rash and AST increase (20% each). Grade 3-4 TRAEs were seen in 10 pts (20%); most common were AST increase (10%), lipase and ALT increase (6% each). A maximum tolerated dose was not reached. Efficacy data are reported in the Table. 48 pts were evaluable for response. Responses were observed in pts with and without quantifiable PD-L1 as assessed by IHC. Antiviral responses in HCV-infected pts have been observed. Conclusions: Nivo was well tolerated with a manageable safety profile. Treatment produced durable responses and disease stabilization across all dose levels and cohorts. Reported OS rates were favorable relative to historical data for BSC. Clinical trial information: NCT01658878.Efficacy Total (N=48) ORR 7 (15) CR, n (%) 3 (6) PR, n (%) 4 (8) SD, n (%) 24 (50) PD, n (%) 15 (31) Not evaluable 2 (4) Median DOR, mo 23.7 Pts with decline in tumor burden from baseline, n (%) 17 (37) Median OS,a (95% CI), mo 15.1 (9.6, 28.6) OS Rate,a % 6 mo 67 9 mo 67 12 mo 59 18 mo 48 aBased on entire pt population.
Identification Of BCL6 As a Therapeutic Target In MLL-Rearranged ALL
Authors: Christian Hurtz, Huimin Geng, Erica Ballabio, Gang Xiao, Carina Ng, Behzad Kharabi Masouleh, Cheryl L. Willman, Scott A. Armstrong, Thomas Milne, Ari Melnick, Markus Muschen
Journal: Blood (2013)
Are BMI prosthetics uncontrollable Frankensteinian monsters?
Authors: Sara Weinberger, Dov Greenbaum
Journal: Brain-Computer Interfaces (2016)

The growing use of brain-machine interfaces (BMI) raises a number of legal and ethical concerns, in particular, when the BMI controls a prosthetic or other robotic device. For example, mediating a BMI via artificially intelligent (AI) software – particularly predictive AI software that may even take over control of the device in the event of too much noise – can confound issues of cause and effect. Significantly, the determination of cause is necessary for ascertaining and assigning criminal guilt. Further, recent research has shown that BMIs interfacing particularly via the brain’s posterior parietal cortex (PPC) can result in smoother motions by the prosthetic, in part given the PPC’s role in broadly planning limb movements. However, in tapping directly into this area of the brain, a prosthetic arguably will move as a result of preconscious thought rather than conscious thought, an important consideration when applied to criminal law that sees automatism as a potential defense. This distinction between conscious and preconscious control over a prosthetic becomes even more relevant as such an interface may also circumvent important command and control elements downstream of the BMI’s collected neural impulses, those command and control elements being particularly relevant for our (at least colloquial) conception of free will.
Clinical Criteria to Identify Patients With Sepsis
Authors: Anil N. Makam, Oanh Kieu Nguyen
Journal: JAMA (2016)

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Abstract 97: A novel PTPRK-FILIP1 fusion gene in invasive mucinous adenocarcinoma of lung without known driver mutations
Authors: Sung-Hye Hong, Geon Kook Lee, Sang Hoon Song, Seung Youn Lee, Jin Young Kim, Ji-Youn Han
Journal: Cancer Research (2016)

Abstract Invasive mucinous adenocarcinoma (IMA) accounts for 2 to 10% of all adenocarcinoma cases of the lung and has a poor prognosis. The KRAS mutation is the most commonly detected genetic alteration in IMAs. Recent progress has permitted the identification of novel fusions such as NRG1. In an effort to further discovery of new driver oncogenes, we have carried out whole-transcriptome sequencing of IMA. To exclude IMA cases with known driver oncogenes, we performed targeted sequencing using the Ion AmpliSeq Cancer Hotspot Panel. We also tested other currently known fusion genes in lung cancer including CD74-NRG1, TPM3-ROS1, SDC4-ROS1, SLC34A2-ROS1, CD74-ROS1, EZR-ROS1, LRIG-ROS1, KIF5B-RET, CCDC6-RET1, EZR-ERBB4, TRIM24-BRAF, KIAA1468-RET, EML4-ALK, and KIF5B-ALK using RT-PCR. Finally we found 10 IMA cases without known driver oncogenes and performed transcriptome paired-end sequencing (the Illumina HiSeq platform). We utilized and compared 3 bioinformatic pipelines, FusionMap, deFuse, and ChimeraScan to identify fusion events. Of 10 IMA cases tested, we found 2 novel fusions, PTPRK-FILIP1 and CEP85L-RNGTT, from a never-smoking female patient. They were shared across all three fusion-finder and never reported in TCGA fusion gene data portal. Only PTPRK-FILIP1 was showed an in-frame fusion between exon 2 of PTPRK and 5’ UTR of FILIP1. It was confirmed by RT-PCR analysis and Sanger sequencing. This precise fusion was not present in the matched normal tissue. The reading frame is preserved that both the start codon of PTPRK and FILIP1. However, PTPRK mRNA expression is increased until exon 2 because of the fusion includes only two exons of PTPRK. Otherwise, expression analysis showed significant increase of FILIP1 mRNA expression in the affected tumor pair sample. The protein product from FILIP1 is closely associated with the protein filamin A, which is associated with tumor proliferation, cell migration, and metastasis. Many studies have reported that filamin A as a poor prognostic factor. Considering its implication in tumor proliferation, cell migration, and metastasis, PTPRK-FILIP1 could be a novel target for IMA. This is the first report of PTPRK-FILIP1 fusion gene in IMA without known driver mutations. Further functional validation of FILIP1 fusion is planned. Citation Format: Sung-Hye Hong, Geon Kook Lee, Sang Hoon Song, Seung Youn Lee, Jin Young Kim, Ji-Youn Han. A novel PTPRK-FILIP1 fusion gene in invasive mucinous adenocarcinoma of lung without known driver mutations. [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 97.
Abstract 1302: A comprehensive approach to delineate FGFR2 targeted therapy response in diffuse gastric cancer
Authors: Jiamin Chen, Hojoon Lee, Hanlee Ji
Journal: Cancer Research (2016)

Abstract Dysregulation of fibroblast growth factor receptors (FGFRs) signaling has been associated with tumorigenesis and progression in various cancers. Preclinical models have shown that FGFR2 signaling activation due to FGFR2 amplification is essential driver for specific gastric cancers. Cancer cell lines or patient-derived gastric cancer xenograft models with FGFR2 amplification are highly sensitive to AZD4547, which is a small-molecule tyrosine kinase (TRK) inhibitor that selectively targets FGFR1-3. However, recent clinical trial studies failed to demonstrate the therapeutic potential of AZD4547 in patients with FGFR2 amplification. For this study, we identified critical genetic and molecular features that determine the response to FGFR2 inhibitors in gastric cancer. To systematically delineate the pathways that modulate response to FGFR2 inhibitors, we identified CRISPR-library-based gene knockouts that result in resistance to AZD4547 in Kato III cells, a gastric cancer cell line with high sensitivity to this drug. Although majority of transduced Kato III cells undergo cell senescence upon AZD4547 treatment, a small population of resistant cells rendered by CRISPR knockout is enriched. Subsequent sequencing and pathway analysis reveal the alternative activated pathways that contribute to the cell growth in lieu of FGFR2 inhibition. Furthermore, we applied the elastic-net regression analysis to identify genetic features associated with the drug sensitivity to FGFR2 inhibition in cancer cell lines. The cell line drug response data are derived from the Cancer Therapeutic Response Portal (CTRP v2) and the Cancer Cell Line Encyclopedia (CCLE). Notably, few cancer cell lines have high FGFR2 copy numbers (CN&amp;gt;4). The elastic-net algorithm simultaneously integrates mutation, copy number, gene expression data, and forms multiple linear regression to learn the coefficient weights associated with FGFR2 inhibitor sensitivity. Using the method, we identify the whole spectrum of genetic and molecular features that are potential drug response markers. In summary, our study provides new insight into genetic and molecular features that implicate in the cellular response to FGFR2 inhibitors, which can facilitate the development of more effective strategies to treat patients with FGFR2 amplification. Citation Format: Jiamin Chen, Hojoon Lee, Hanlee Ji. A comprehensive approach to delineate FGFR2 targeted therapy response in diffuse 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 1302.
Abstract 4527: Cellular stress response 1 down-regulates the expression of epidermal growth factor receptor and platelet-derived growth factor receptor through inactivation of splicing factor 3A3
Authors: Jian-Hua Luo, Ze-Hua Zuo, Yan P. Yu
Journal: Cancer Research (2016)

Abstract Cellular stress response 1 (CSR1) is a tumor suppressor gene that plays an important role in regulating cell death. In this report, we showed that the N-terminus of CSR1 interacts with splicing factor 3A, subunit 3 (SF3A3). The SF3A3 binding motif was identified in the region of amino acids 62-91 of CSR1 through cell-free binding analyses. The interaction between CSR1 and SF3A3 led to migration of SF3A3 from nucleus to cytoplasm. The cytoplasmic redistribution of SF3A3 significantly reduced the splicing efficiency of epidermal growth factor receptor and platelet-derived growth factor receptor. Induction of CSR1 or down-regulation of SF3A3 also significantly reduced the splicing activity of oxytocin reporter gene both in vivo and in vitro. Mutant CSR1 that lacks the SF3A3 binding motif contained no RNA splicing regulatory activity, while the peptide corresponding to the SF3A3 binding motif in CSR1 interfered with the wild type CSR1 mediated inhibition of RNA splicing. Interaction of CSR1 and SF3A3 is essential for CSR1 mediated cell death. To our knowledge, this is the first report demonstrating that RNA splicing is negatively regulated by redistribution of a splicing factor. Citation Format: Jian-Hua Luo, Ze-Hua Zuo, Yan P. Yu. Cellular stress response 1 down-regulates the expression of epidermal growth factor receptor and platelet-derived growth factor receptor through inactivation of splicing factor 3A3. [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 4527.
Abstract 1455: IL-4 derived from T follicular helper cells in tumor draining lymph nodes regulate myeloid cell properties and anti-tumor immunity
Authors: Hidekazu Shirota, Dennis M. Klinman, Shuku-ei A. Ito, Chikashi Ishioka
Journal: Cancer Research (2016)

Abstract Recent findings show that immune cells constitute a large fraction of the tumor microenvironment and modulate tumor progression. Clinical data indicate that chronic inflammation is present at tumor sites and that IL-4 in particular is up-regulated. Current results demonstrate that T follicular helper (Tfh) cells arise in tumor draining lymph nodes where they produce an abundance of IL-4. Deletion of IL-4 expressing Tfh cells improves anti-tumor immunity, delays tumor growth and reduces the immunosuppressive activity of myeloid-derived suppressor cells (MDSC) and M2 macrophages. These findings suggest that IL-4 from Tfh cells impact anti-tumor immunity and constitute an attractive therapeutic target to reduce immune suppression in the tumor microenvironment and thus enhance the efficacy of cancer immunotherapy. Citation Format: Hidekazu Shirota, Dennis M. Klinman, Shuku-ei A. Ito, Chikashi Ishioka. IL-4 derived from T follicular helper cells in tumor draining lymph nodes regulate myeloid cell properties and anti-tumor immunity. [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 1455.
Abstract 992: Long noncoding RNA UPAT promotes colon tumorigenesis by inhibiting degradation of UHRF1
Authors: Kenzui Taniue, Yasuko Takeda, Tetsu Akiyama
Journal: Cancer Research (2016)

Abstract Increasing evidence suggests that lncRNAs play critical roles in a diverse set of biological processes, including proliferation, differentiation, embryogenesis, neurogenesis and stem cell pluripotency. It has been reported that many lncRNAs regulate gene expression and various post-transcriptional processes, including splicing, transport, translation and degradation of mRNA. Furthermore, recent studies have shown that Many lncRNAs play critical roles in tumor development and progression. We attempted to identify lncRNAs critical for the tumorigenicity of colon tumor cells. We have found that a lncRNA termed UPAT is required for the survival and tumorigenicity of colorectal cancer cells. We also show that UPAT interacts with and stabilizes the epigenetic factor UHRF1 by interfering with its β-TrCP-mediated ubiquitination. UHRF1 plays key roles in multiple biological processes, including proliferation and development. Moreover, UHRF1 is overexpressed in various tumors, including colon cancer, and plays a critical role in the proliferation and survival of tumor cells. Furthermore, we demonstrate that UHRF1-UPAT complex upregulate SCD1 and SPRY4, which play critical roles in the survival and proliferation of colon cancer cells. Our findings suggest that UPAT-mediated stabilization of UHRF1 is critical for the proliferation and tumorigenicity of colon tumor cells. Our results suggest that UHRF1-UPAT axis may be a promising molecular target for colon cancer therapies. Citation Format: Kenzui Taniue, Yasuko Takeda, Tetsu Akiyama. Long noncoding RNA UPAT promotes colon tumorigenesis by inhibiting degradation of UHRF1. [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 992.