tbuckley/cabot-search huggingface dataset:
Abstract 3585: HER3 and IGF1R are major mediators of both acquired and intrinsic cetuximab resistance in head and neck squamous cell carcinomas
Authors: Ida Kjaer, Trine Lindsted, Camilla Fröhlich, Ivan D. Horak, Michael Kragh, Jesper V. Olsen, Mikkel W. Pedersen
Journal: Cancer Research (2015)

Abstract Head and neck squamous cell carcinoma (HNSCC) is among the leading causes of death worldwide. HNSCC originates from the squamous epithelium of the upper aerodigestive tract, including the lip, oral cavity, pharynx, larynx and paranasal sinuses. The epidermal growth factor receptor (EGFR) has been found to play an essential role in driving the malignancy of HNSCC. The monoclonal antibody targeting EGFR, cetuximab, has been approved for clinical use in HNSCC patients, in combination with either radiation or chemotherapy. However, intrinsic and acquired cetuximab resistance is a major problem for effective therapy. Thus, a better understanding of the mechanisms responsible for cetuximab resistance is valuable for development of the next generation of antibody therapeutics. In order to investigate the molecular mechanisms behind cetuximab resistance in HNSCC, we screened a panel of cell lines for sensitivity to cetuximab. As expected, the cell lines exhibited a varied response to cetuximab. The most sensitive cell line, HN5, was used to establish a number of cetuximab-resistant clones. These resistant clones had lower EGFR levels but remained partially dependent on EGFR, as demonstrated by EGFR gene knockdown and treatment with a mixture of two anti-EGFR antibodies. HER3 and IGF1R are known to be major drivers of resistance to EGFR targeting therapies, and therefore we investigated the role of the two receptors in resistant clones with a mixture of antibodies against EGFR, HER3 and IGF1R. The antibody mixture, which simultaneously blocked EGFR, HER3 and IGF1R signaling, resulted in near total growth inhibition of cetuximab resistant clones. These results were extended to HNSCC cell lines with intrinsic resistance to cetuximab and also in these cell lines the three target mAb mixture led to effective growth inhibition. In conclusion, our results demonstrate that HNSCC cell lines have a heterogeneous response to cetuximab and that HER3 and IGF1R effectively compensate for EGFR inhibition in both the acquired and intrinsic cetuximab resistant setting. Our results thus provide a rationale for simultaneous targeting of EGFR, HER3, and IGF1R in HNSCC. Citation Format: Ida Kjaer, Trine Lindsted, Camilla Fröhlich, Ivan D. Horak, Michael Kragh, Jesper V. Olsen, Mikkel W. Pedersen. HER3 and IGF1R are major mediators of both acquired and intrinsic cetuximab resistance in head and neck squamous cell carcinomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3585. doi:10.1158/1538-7445.AM2015-3585
Abstract 4469: A novel class of inhibitors of the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1) with potential for the treatment of cancer
Authors: Lai-Ming Ching, Brian D. Palmer, Petr Tomek, Jack U. Flanagan, Kimiora Henare
Journal: Cancer Research (2015)

Abstract A broad range of cancers express the tryptophan catabolising enzyme indoleamine 2,3-dioxygenase 1 (IDO1) as a mechanism of suppressing the endogenous anti-tumour immunity. High IDO1 expression by their tumours is associated with poor patient prognosis and has prompted the discovery of small molecule inhibitors of the enzyme for development as anti-cancer agents. Towards this end, we carried out a high throughput screen of 42,000 small molecules in the Walter and Eliza Hall Institute for Medical Research compound library and retrieved over 30 good hits with diverse structures that inhibited recombinant human IDO1 with potencies in the low μM range. Initial structure activity relationship studies of the best hits led us to focus on one chemical class, which, although less potent than some of the other hits on the list, exhibited a number of features that make it more favourable for development as a therapeutic agent. SN35837, the non-optimised hit from the high throughput screen is highly cell permeable and displays improved potency in inhibiting cytoplasmic hIDO1 in cell-based assays, compared to that for enzymatic assays. Complete inhibition of IDO1 function is seen at concentrations that has no measurable effects on cell viability. The imidazole lead from New Links Genetics, NLG919 has decreased activity in cells, whilst Incyte's hydroxyamidine inhibitor INCB024360 has similar potency in cellular and enzymatic assays. The maximum tolerated dose SN35837 in C57Bl/6 mice given as a single intraperitoneal bolus dose was 500 mg/kg. Mice tolerated daily intraperitoneal or subcutaneous administrations of SN35837 at 150 mg/kg. Statistically significant inhibition of growth of subcutaneously implanted GL261 gliomas and Lewis Lung carcinomas in syngeneic hosts were achieved after daily administration of 75 mg/kg SN35837. Preliminary studies indicate that the non-optimised hit also synergises when given in combination with anti-PD1 and anti-CTLA-4 antibodies. We conclude that derivatives of SN35837 may provide effective and potent inhibitors of IDO1 suitable for development as anti-cancer agents. Citation Format: Lai-Ming Ching, Brian D. Palmer, Petr Tomek, Jack U. Flanagan, Kimiora Henare. A novel class of inhibitors of the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1) with potential for the treatment of cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4469. doi:10.1158/1538-7445.AM2015-4469
D-4F Restores eNOS-Dependent Vasodilation in Sickle Cell Disease by Decreasing Proinflammatory HDL.
Authors: Kirkwood A. Pritchard, Jingli Wang, Hao Xu, Deron W. Jones, Sandra L. Holzhauer, Thomas D. Foster, Keith T. Oldham, Cheryl A. Hillery
Journal: Blood (2005)
372. U1 snRNA-Mediated Correction of a Splicing Error of the Dopa Decarboxylase Gene
Authors: Ni-Chung Lee, Yu-May Lee, Yin-Hsiu Chien, Barry Byrne, Wuh-Liang Hwu
Journal: Molecular Therapy (2016)

Aromatic l-amino acid decarboxylase (AADC) deficiency is an inborn error of monoamine neurotransmitter synthesis that resulted in dopamine and serotonin deficiency. The DDC gene founder mutation IVS6+4A>T is highly prevalent in Chinese patients with AADC deficiency. In this study, we employed U1 snRNA to correct this splicing error. We first used a modified U1 snRNA sequence (IVS-AAA) that matched both the mutated nucleotide and exonic U1 binding sequences corrected the splicing error of both mutated human DDC minigene and mouse artificial splicing construct in vitro. We further injected an adeno-associated viral (AAV) vector to express IVS-AAA in the brain of a knock-in mouse model with either 1×1010 vg or 2×1010 vg per mouse. This treatment was well-tolerated and slightly improved the survival and brain dopamine levels of mice with AADC deficiency. Therefore, U1 snRNA-mediated gene therapy can be a promising method to treat genetic diseases caused by splicing errors, but the efficiency of such a treatment needs improvements.
Abstract 4543: Characterization of the liposomal formulation of eribulin mesylate (E7389) in mice
Authors: Makoto Asano, Kenji Hyodo, Yanke Yu, Edgar Schuck, Junji Matsui, Hiroshi Ishihara, Hiroshi Kikuchi, Kenichi Nomoto
Journal: Cancer Research (2015)

Abstract E7389 (eribulin mesylate, Halaven, Eisai) is a fully synthetic analog of the marine sponge natural product halichondrin B. It has been approved in US and more than 50 countries worldwide for treatment of advanced breast cancer. To improve the therapeutic index of E7389, a liposomal formulation of E7389, E7389-LF is under development. In this study, we characterized the pharmacokinetics of E7389-LF and E7389 (aqueous formulation) in mice and evaluated the anti-tumor activity of E7389-LF and E7389 in mouse xenograft model. In general the pharmacokinetics of E7389-LF was characterized by a small volume of distribution, slow clearance, and slow elimination in all liposomal formulations tested. Plasma AUC of E7389-LF was more than 600 fold larger than that of E7389 in tumor bearing mice. Tumor AUC of E7389-LF was also observed. Moreover, free E7389 (not liposome encapsulated and not protein bound) was measured in mouse plasma by ultracentrifugation method. The concentration ratio of E7389 in ultracentrifuged mouse plasma (UCM) vs E7389 in plasma after a 2 mg/kg i.v. of E7389 ranged from 54.19% to 65.41%, which was similar to the free fraction in the mouse plasma. The respective concentration ratio of E7389 in UCM vs E7389 in plasma after a 2 mg/kg i.v. of E7389-LF ranged from 0.07% to 0.59%, and the exposure, expressed as AUC, of UCM/plasma ratio was determined to be 0.2%. The free E7389 exposure, measured by UCM, after E7389-LF administration was about 1.5 fold of that after E7389 administration. Anti-tumor activity of E7389-LF and E7389 was evaluated in a human pharynx carcinoma, FaDu, xenograft model. E7389-LF showed dose-dependent anti-tumor effect with regression of tumors at 2.5 mg/kg dose, which was significantly better than that after E7389 administration in this model. These findings suggest that E7389-LF showed better anti-tumor activity than that of E7389 in human FaDu xenograft mouse model. Citation Format: Makoto Asano, Kenji Hyodo, Yanke Yu, Edgar Schuck, Junji Matsui, Hiroshi Ishihara, Hiroshi Kikuchi, Kenichi Nomoto. Characterization of the liposomal formulation of eribulin mesylate (E7389) in mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4543. doi:10.1158/1538-7445.AM2015-4543
Human splicing diversity and the extent of unannotated splice junctions across human RNA-seq samples on the Sequence Read Archive
Authors: Abhinav Nellore, Andrew E. Jaffe, Jean-Philippe Fortin, José Alquicira-Hernández, Leonardo Collado-Torres, Siruo Wang, Robert A. Phillips III, Nishika Karbhari, Kasper D. Hansen, Ben Langmead, Jeffrey T. Leek
Journal: Genome biology (2016)

Gene annotations, such as those in GENCODE, are derived primarily from alignments of spliced cDNA sequences and protein sequences. The impact of RNA-seq data on annotation has been confined to major projects like ENCODE and Illumina Body Map 2.0.We aligned 21,504 Illumina-sequenced human RNA-seq samples from the Sequence Read Archive (SRA) to the human genome and compared detected exon-exon junctions with junctions in several recent gene annotations. We found 56,861 junctions (18.6%) in at least 1000 samples that were not annotated, and their expression associated with tissue type. Junctions well expressed in individual samples tended to be annotated. Newer samples contributed few novel well-supported junctions, with the vast majority of detected junctions present in samples before 2013. We compiled junction data into a resource called intropolis available at http://intropolis.rail.bio . We used this resource to search for a recently validated isoform of the ALK gene and characterized the potential functional implications of unannotated junctions with publicly available TRAP-seq data.Considering only the variation contained in annotation may suffice if an investigator is interested only in well-expressed transcript isoforms. However, genes that are not generally well expressed and nonetheless present in a small but significant number of samples in the SRA are likelier to be incompletely annotated. The rate at which evidence for novel junctions has been added to the SRA has tapered dramatically, even to the point of an asymptote. Now is perhaps an appropriate time to update incomplete annotations to include splicing present in the now-stable snapshot provided by the SRA.
Abstract 5011: generation of rejuvenated murine antigen-specific T cells by reprogramming to pluripotency and redifferentiation
Authors: Fumito Ito, Noemi Fusaki, Hidehito Saito
Journal: Cancer Research (2015)

Abstract Background: Adoptive cell therapy with autologous antigen-specific T cells is a promising approach for treating patients with chronic viral infections and various cancers. A major limitation of this approach is the difficulty of obtaining sufficient numbers of T cells with the characteristics necessary for in vivo effectiveness. Less-differentiated T cells with long telomeres would be an ideal T-cell subset for adoptive T cell therapy; however, generating large numbers of these “young” T cells is problematic. This limitation of adoptive T cell therapy can be overcome by using induced pluripotent stem cells (iPSCs) that self-renew, maintain pluripotency, and provide an unlimited source of autologous T cells for immunotherapy. However, in vivo antitumor reactivity of iPSC-rejuvenated T cells remains unknown due to the lack of animal model. Methods: To establish preclinical model of evaluating iPSC-rejuvenated antigen-specific T cells, we reprogrammed OT-1 T cell receptor (TCR) transgenic CD8 T cells using Sendai virus vectors encoding Oct3/4, Sox2, Klf4 and c-Myc transcription factors. Pluripotency and differentiation capacity of generated iPSCs were evaluated. Results: Twenty days after infection with Sendai virus vectors, we obtained murine embryonic stem cell-like colonies from OT-1 CD8 T cells. Immunofluorescence staining and RT-PCR analyses revealed pluripotency of established colonies. The iPSCs formed embryoid bodies in vitro, and upregulation of marker genes for all three germ layers was detected. The iPSCs differentiated into teratomas in vivo comprising all three embryonic germ layers in immune-deficient NOD/SCID mice. The iPSCs retained the same rearranged configuration of TCR chain genes as the original OT-1 T cells. Furthermore, OT-1 T cell-derived iPSCs differentiated into T cells on delta-like ligand 1 expressing OP9 (OP9/DL1) murine bone marrow stromal cells. Conclusions: Generation of rejuvenated T cells by reprogramming to pluripotency and redifferentiation is feasible. This type of approach may be useful for adoptive T cell therapy. We acknowledge DNAVEC Corporation for kindly providing Sendai virus vectors. This study was supported by the University of Michigan Start-up fund. Citation Format: Fumito Ito, Noemi Fusaki, Hidehito Saito. generation of rejuvenated murine antigen-specific T cells by reprogramming to pluripotency and redifferentiation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5011. doi:10.1158/1538-7445.AM2015-5011
336. Targeted Genome Modifications for Improved Adoptive Immunotherapy
Authors: Philippe Duchateau, Alexandre Juillerat, Julien Valton, Laurent Poirot
Journal: Molecular Therapy (2015)

Chimeric antigen receptor (CAR)-redirected T-cells have given rise to long-term durable remissions and remarkable objective response rates in patients with refractory leukemia, raising hopes that a wider application of CAR technology may lead to a new paradigm in cancer treatment. Similarly, transcription activator-like effector nuclease (TALEN™)-mediated gene editing has emerged as powerful strategy to introduce targeted mutations and holds great promise in therapeutics and offers multiple opportunities to improve CAR T-cell therapies. The knockout of the TCR alpha gene eliminates TCR expression and abrogates the donor T-cell's potential for graft-versus-host disease (GvHD) while maintaining a potent anti-tumoral activity. Thus it is possible to manufacture T-cells from third-party healthy donors to generate allogeneic "off-the-shelf" engineered CAR T-cells. Disruption of CD52 or deoxycytidine kinase genes may be a useful approach to makes T-cells compatible with concurrent oncology treatments such as alemtuzumab or Fludarabine while the bypass of key immune checkpoint regulators such PD1/PDL1 by inactivation of T-cells receptors would potentiate the antitumor T-cell response by impairing the interaction of the inhibitory receptor PD-1 on T cells with PD-L1 expressed on tumor cells. Here, we will present in vitro and in vivo proof of concepts demonstrating the potential of TALEN™-mediated gene editing for adoptive T-cell therapy.
Review: In adults with asthma, vitamin D<sub>3</sub> reduces rate of severe exacerbation but does not improve symptoms
Authors: Daniel I. Steinberg
Journal: Annals of Internal Medicine (2016)

ACP Journal Club20 December 2016Review: In adults with asthma, vitamin D3 reduces rate of severe exacerbation but does not improve symptomsDaniel I. Steinberg, MDDaniel I. Steinberg, MDIcahn School of Medicine at Mount Sinai, New York, New York, USA (D.I.S.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJC-2016-165-12-066 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationMartineau AR, Cates CJ, Urashima M, et al. Vitamin D for the management of asthma. Cochrane Database Syst Rev. 2016;9:CD011511. https://pubmed.ncbi.nlm.nih.gov/27595415Clinical Impact RatingsGIM/FP/GP: Pulmonology: Reference1 Beard JA, Bearden A, Striker R. Vitamin D and the anti-viral state. J Clin Virol. 2011;50:194-200. [PMID: 21242105] Google Scholar Author, Article, and Disclosure InformationAffiliations: Icahn School of Medicine at Mount Sinai, New York, New York, USA (D.I.S.)This article was published at Annals.org on 6 December 2016. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 20 December 2016Volume 165, Issue 12Page: JC66KeywordsAsthmaChildrenClinical trial reportingDatabasesEmergency departmentForced expiratory volume in the first second of expirationHospitalizationsSerious adverse eventsUpper respiratory tract infectionsVitamin D ePublished: 20 December 2016 Issue Published: 20 December 2016 Copyright & PermissionsCopyright © 2016 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Abstract SY43-01: Stereochemistry matters: L-2HG as a tumor response to hypoxia
Authors: Craig B. Thompson, Andrew M. Intlekofer, Raymond G. Dematteo, Sriram Venneti, Lydia W. S. Finley, Chao Lu, Ariën S. Rustenburg, Patrick B. Grinaway, John D. Chodera, Justin R. Cross, Alexander R. Judkins
Journal: Cancer Research (2015)

Abstract Somatic mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2) contribute to the pathogenesis of cancer via production of the ‘oncometabolite’ D-2-hydroxyglutarate (D-2HG). Elevated D-2HG can block differentiation of malignant cells by functioning as a competitive inhibitor of alpha-ketoglutarate (alpha-KG) dependent enzymes, including Jumonji family histone lysine demethylases. 2HG is a chiral molecule that can exist in either the D- or L- enantiomer. Although cancer-associated IDH1/2 mutations exclusively produce D-2HG, biochemical studies have demonstrated that L-2HG functions as a more potent inhibitor of alpha-KG-dependent enzymes. Here we report that under conditions of oxygen limitation, mammalian cells selectively produce L-2HG via enzymatic reduction of alpha-KG. Hypoxia-induced L-2HG is not mediated by IDH1 or IDH2, but instead results from promiscuous substrate usage by lactate dehydrogenase A (LDHA). During hypoxia, the resulting increase in L-2HG is necessary and sufficient for the induction of increased methylation of histone repressive marks, including histone 3 lysine 9 (H3K9me3). Thus, L-2HG appears to function as a metabolic signaling intermediate, translating information about oxygen availability into epigenetic modifications that can influence gene expression and cellular differentiation. Citation Format: Craig B. Thompson, Andrew M. Intlekofer, Raymond G. Dematteo, Sriram Venneti, Lydia W. S. Finley, Chao Lu, Ariën S. Rustenburg, Patrick B. Grinaway, John D. Chodera, Justin R. Cross, Alexander R. Judkins. Stereochemistry matters: L-2HG as a tumor response to hypoxia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY43-01. doi:10.1158/1538-7445.AM2015-SY43-01
The Addition Of Interleukin-6 Inhibition To Standard Gvhd Prophylaxis Prevents Acute Gvhd: Interim Results Of a Phase I/II Clinical Study
Authors: Glen A Kennedy, Antiopi Varelias, Slavica Vuckovic, Ping Zhang, Kelli PA MacDonald, Justine Leach, Elise Sturgeon, Judy Avery, Stuart D Olver, Mary Lor, Cheryl J Hutchins, James A Morton, Simon TS Durrant, Ashish Misra, Elango Subramoniapillai, Jason P Butler, Cameron Curley, Siok K Tey, Geoffrey R Hill
Journal: Blood (2013)
Abstract 1693: ASN004, a novel 5T4-targeted Dolaflexin™ antibody drug conjugate, causes complete regression in multiple solid tumor models
Authors: Roger A. Smith, Nitin K. Damle, Sanjeeva P. Reddy, Alex Yurkovetskiy, Natalya Bodyak, Mao Yin, Dmitry Gumerov, Elena Ter-Ovanesyan, Liu Qin, Peter U. Park, Timothy B. Lowinger, Sandeep Gupta
Journal: Cancer Research (2015)

Abstract ASN004 is an Antibody Drug Conjugate (ADC) that targets the 5T4 oncofetal antigen (trophoblast glycoprotein), which is highly expressed in a wide range of malignant tumors, while having very limited expression in normal tissues. ASN004 incorporates a novel single-chain homo-dimer antibody, Fleximer® linker technology (Mersana Therapeutics), and several cytotoxic dolastatin (auristatin) analog warheads per ADC molecule (drug/antibody ratio ∼15). ASN004 shows high affinity for the 5T4 antigen and for 5T4-expressing tumor cells. As well, ASN004 shows potent cytotoxicity that is selective for 5T4-expressing tumor cells. ASN004 provides strong tumor regression and tumor-free survivors in multiple tumor xenograft models, at well-tolerated doses as low as 0.3 mg/kg iv. Furthermore, ASN004 causes tumor regression when administered to xenografts bearing more advanced (500 mm3) tumors. Robust, potent efficacy for ASN004 has also been demonstrated in head-to-head comparison studies with relevant reference ADCs. A favorable pharmacokinetics profile was observed in rodents and primates. Dose-range finding exploratory toxicology studies have been completed in both pharmacological and non-pharmacological non-clinical species. Efforts toward IND-enabling safety studies with this promising new agent are in progress. Citation Format: Roger A. Smith, Nitin K. Damle, Sanjeeva P. Reddy, Alex Yurkovetskiy, Natalya Bodyak, Mao Yin, Dmitry Gumerov, Elena Ter-Ovanesyan, Liu Qin, Peter U. Park, Timothy B. Lowinger, Sandeep Gupta. ASN004, a novel 5T4-targeted Dolaflexin™ antibody drug conjugate, causes complete regression in multiple solid tumor models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1693. doi:10.1158/1538-7445.AM2015-1693
Pre-Transplant CSF-1 Therapy Expands the Recipient Macrophage Pool and Modulates Graft Versus Host Disease After Allogeneic Hematopoietic Cell Transplantation
Authors: Daigo Hashimoto, Andrew Chow, Melanie Greter, Marylene Leboeuf, Florent Ginhoux, Takanori Teshima, Miriam Merad
Journal: Blood (2010)