tbuckley/cabot-search huggingface dataset:
Abstract 2096: Bozitinib, a highly selective inhibitor of cMet, demonstrates robust activity in gastric, lung, hepatic and pancreatic in vivo models
Authors: Joe Shih, Boyu Zhong, Hepeng Shi, David Xue, Gavin S. Choy, Sanjeev Redkar
Journal: Cancer Research (2017)

Abstract Background: cMET is a receptor tyrosine kinase that is located on the cell surface and is activated by the binding of its ligand, hepatocyte growth factor (HGF). In cancer cells, MET can be aberrantly active and cause abnormal signaling, which leads to tumor growth, angiogenesis, and metastasis. In vitro studies have demonstrated that bozitinib (CBT-101, PLB-1001) is a highly selective and specific inhibitor (8 nM) of tumor cell proliferation. Methods: In-vivo PD studies of gastric (MKN45), lung (LUM858, LU1901, LU2503), hepatic (LIM0612, LIM0801), and pancreatic (KP4) were evaluated. These models covered both the HGF-dependent and HGF-independent mechanisms. Among these models, LUM858, LU1901, LU2503, LIM0612 and LIM0801 are PDX models. In particular, in the LU1901 model, bozitinib (BT) was compared to capmatinib (INC280). Groups included: BT at 1, 3 and 10 mg/kg QD×21 and INC280 at 1, 3, and 10 mg/kg QD×21 and 10 mg/kg BID×21 via IG, CDDP 5 mg/kg, Q7D×3 as a positive control via IP and the vehicle control (QD×21 via IG). Each group (n=8 mice) and the tumor volume was evaluated on D21. Results: In MKN45, LU2503, LIM0612 and LIM0801, the effect of BT seemed superior than that of crizotinib; in LUM858, its effect was higher than that of erlotinib; in LU1901, its effect was higher than that of crizotinib and INC280. In the LU1901 model, the strongest activity was observed at BT 10 mg/kg with a T/C ratio of 2%, compared to an equi-dose of INC280 (T/C of 22%). All doses of BT and INC280 were well tolerated; no mouse experienced weight loss. In MKN45 model, BT showed a PK/PD correlation and dose-dependence. BT inhibited the phosphorylation of c-Met protein; the rate of target inhibition exceeded 90% at &amp;gt;7 mg/kg. The plasma concentration for BT decreased over time with a significant decrease 16h after its administration, conferring at least 16h of phosphorylation inhibition of the c-Met protein. Conclusions: In conclusion, BT was well-tolerated, with no animal death nor major weight loss. The in vivo experiments demonstrated that BT is a viable candidate with effective anti-tumor activities. BT is currently under evaluation in cMet dysregulated NSCLC (NCT02896231) with additional trials planned. Citation Format: Joe Shih, Boyu Zhong, Hepeng Shi, David Xue, Gavin S. Choy, Sanjeev Redkar. Bozitinib, a highly selective inhibitor of cMet, demonstrates robust activity in gastric, lung, hepatic and pancreatic in vivo models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2096. doi:10.1158/1538-7445.AM2017-2096
Abstract 269: Cardiac Specific Disruption of Drp-1 Causes the Development of Cardiac Dysfunction via Inhibition of Autophagy and Induction of Apoptosis
Authors: Yoshiyuki Ikeda, Junichi Sadoshima
Journal: Circulation Research (2013)

Fission and fusion affect mitochondrial turnover in part by modulating mitophagy. This study aimed to clarify the role of mitochondrial fission in regulating cardiac function and autophagy in the heart. Dynamin-related protein 1 (Drp-1) plays an essential role in mediating mitochondrial fission. Therefore, we generated cardiac specific Drp-1 KO mice and utilized cultured cardiomyocytes transduced with adenovirus harboring short hairpin Drp-1 (Ad-shDrp-1) to test the effect of Drp-1 disruption both in vivo and in vitro. In Drp-1 KO hearts we observed a significantly greater mitochondrial mass ratio compared to control, as assessed by electron microscopy (Drp-1 KO: 3.57 ± 1.38, control: 1.18 ± 0.31, P&lt;0.05). Mitochondrial ATP content was significantly lower (0.70 ± 0.07 vs 1.03 ± 0.10, P&lt;0.05), while mitochondrial swelling was significantly greater (% decrease in absorbance; 8.01 ± 1.99 vs 2.01 ± 0.58, P&lt;0.05) in Drp-1 KO hearts versus control. Mitochondrial membrane potential, assessed by JC-1 staining, was significantly reduced in myocytes with knockdown of Drp-1. Taken together, these results suggest that inhibition of fission causes mitochondrial dysfunction. We also examined the effect of Drp-1 depletion on autophagy. We found that the amount of LC-3 II was significantly less (0.47 ± 0.16 vs 1.32 ±0.34, P&lt;0.05), whereas p62 expression was significantly greater (1.14 ± 0.16 vs 0.16 ± 0.06, P&lt;0.01) in Drp-1 KO hearts compared to control. The number of LC3 dots in Ad-shDrp-1 transduced myocytes was lower than that of sh-scramble treatment. We investigated apoptosis and found that the amount of cleaved caspase-3 (0.62 ± 0.24 vs 0.18 ± 0.04, P&lt;0.05) and the number of TUNEL positive cells (0.22 ± 0.12 vs 0.03 ± 0.06%, P&lt;0.01) were higher in Drp-1 KO versus control hearts. Cardiac systolic function was reduced (ejection fraction; 44.5 ± 6.3 vs 85.4 ± 5.7%, P&lt;0.01) and LVW/tibia length was greater (4.48 ± 0.38 vs 3.84 ± 0.58, P&lt;0.05) in Drp-1 KO mice compared to control. Finally, we observed that the survival rate of Drp-1 KO mice was significantly reduced compared to control mice. Our results demonstrate that inhibition of mitochondrial fission via disruption of Drp-1 inhibits autophagy and causes mitochondrial dysfunction, thereby promoting cardiomyopathy.
Abstract 827: Statistical analyses of stable housekeeping gene expression in cancer post-irradiation
Authors: Albert R. Wang, Gopal Iyer, Sean Brennan, Shay Bourgeois, Eric Armstrong, Pari Shah, Paul M. Harari
Journal: Cancer Research (2017)

Abstract Ionizing radiation (IR) can induce DNA damage in human cells and result in changes in gene expression. The changes could also include some of the commonly used housekeeping genes (HKG), and thus making them unstable over the time period after being exposed to radiation. Normalization of housekeeping genes is critical for understanding gene expression post-irradiation. Toward the validation of stable HKGs, cancer cell lines from head and neck, non-small cell lung and pancreas were irradiated to 2, 4 and 6 Gy IR doses. Statistical analysis of RNA expression of fourteen HKGs measured at 5 min to 48hrs post-irradiation reveal tradition HKGs such as beta-actin (ACTB) and glucose-6-phosphate-dehydrogenase (G6PD) to be unstable, while TATA-Box Binding Protein (TBP) and Importin 8 (IPO8) was identified as stable HKGs in non-small lung and pancreas cell across all IR doses and time. Interestingly in head and neck cancer, TBP is also found stable across all IR doses and time. The statistical framework used for identification and validation of HKGs can serve as a reliable metric for quantifying gene expression post-irradiation. Citation Format: Albert R. Wang, Gopal Iyer, Sean Brennan, Shay Bourgeois, Eric Armstrong, Pari Shah, Paul M. Harari. Statistical analyses of stable housekeeping gene expression in cancer post-irradiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 827. doi:10.1158/1538-7445.AM2017-827
Abstract 407: Whole-genome pooled CRISPR/Cas library screens to identify new hepatocellular carcinoma drivers and drug targets in combination with sorafenib
Authors: Takahiro Kodama, Justin Y. Newberg, Nancy A. Jenkins, Tetsuo Takehara, Neal G. Copeland
Journal: Cancer Research (2017)

Abstract Backgrounds and Aims: Hepatocellular carcinoma (HCC) is a deadly cancer and its mortality rate ranks third among all cancer types worldwide. To comprehensively understand its genetic drivers, over 500 HCC genomes have been sequenced but they reveal the existence of thousands of infrequently mutated genes. This intra- and inter-tumor heterogeneity, combined with large number of passenger mutations, has made it difficult to identify the true drivers of HCC. In addition, sorafenib is the currently only FDA-approved molecular target drug in HCC but its anti-tumor effect is very limited. To overcome these problems, we performed two forward genetic screens using recently innovated whole-genome pooled CRISPR/Cas library. Methods: Two human liver cancer cell lines, Huh-7 and SNU-398, were lentivirally transduced with Geckov2 library and transduced cells were selected with puromycin. First, transduced cells were orthotopically injected into the liver of the Nude mice and monitored for tumor formation. To identify potential tumor suppressor genes (TSGs) in the liver, gRNAs enriched in the orthotopic liver tumors were determined by sequencing of gDNA in these tumors. Next, transduced cells were treated with vehicle or sorafenib in vitro for 14 days. To identify potential targets which inhibition show synergistic anti-tumor effect with sorafenib, we determined gRNAs depleted in cells with sorafenib treatment compared to cells with vehicle treatment. Results: In the first in vivo screening, we identified 62 genes targeted by 2 or more highly enriched gRNAs in Huh-7 cells-derived tumors and 47 genes in SNU-398 cells-derived tumors. Twenty-nine genes were common including 4 miRNAs. TCGA analysis revealed that HCC patients with mutation or copy number alteration in any of these genes showed worse overall survival and disease free survival compared to HCC patients without them. In addition, gene expression levels of 3 candidate TSGs, BPHL, CTSZ and PLCG2 were significantly negatively correlated with poor survival of HCC patients. In the second in vitro screening, CYP7B1, HS3ST5, NLRC4, and Mir-1237 were identified as potential drug targets in combination with sorafenib in HCC. Conclusion: Whole-genome pooled CRISPR/Cas library screens discovered potential new hepatocellular carcinoma drivers and drug targets in combination with sorafenib. Citation Format: Takahiro Kodama, Justin Y. Newberg, Nancy A. Jenkins, Tetsuo Takehara, Neal G. Copeland. Whole-genome pooled CRISPR/Cas library screens to identify new hepatocellular carcinoma drivers and drug targets in combination with sorafenib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 407. doi:10.1158/1538-7445.AM2017-407
Secukinumab-Induced Psoriasiform Eruption
Authors: Michael J. Sladden, Christopher S. Sladden, Wayne P. F. Gulliver
Journal: JAMA Dermatology (2017)

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Poly(2-ethyl-2-oxazoline) conjugate of doxorubicin bound via pH-sensitive hydrazone linker: comparison with poly[N-(2-hydroxypropyl)methacrylamide] peer
Authors: Ondrej Sedlacek, Bryn D. Monnery, Jana Mattova, Olga Janouskova, Jan Kucka, Anita Hocherl, Jiri Panek, Richard Hoogenboom, Martin Hruby
Journal: Journal of Controlled Release (2017)
Abstract 4203: Kinase inhibitor demonstrates efficacy in patient derived xenograft model of fibrolamellar hepatocellular carcinoma featuring DNAJB1-PRKACA gene fusion
Authors: Jayant Thatte, Elvira C. Talaoc, Colleen Scott, Ken Ren, Thomas Broudy
Journal: Cancer Research (2017)

Abstract Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare and distinct primary hepatic malignancy that has conventionally been considered to be a histologic variant of hepatocellular carcinoma. However, it has more recently been recognized as a distinct clinical entity with respect to its epidemiology and prognosis. The etiology of FL-HCC is unclear and there is no clinical or histological evidence for association with chronic liver disease. Recent genetic studies have identified the fusion gene DNAJB1-PRKACA as a recurrent genetic lesion in the disease. Molecular pathogenesis of FL-HCC; however, is not well understood and has been reported to occur in association with focal nodular hyperplasia. Overexpression of genes in PIK3, MAPK and RAS pathways is observed in FL-HCC and in contrast to viral-associated HCC, epigenetic instability is rare in FL-HCC. Here we describe development of a novel FL-HCC Patient Derived Xenograft (PDX) model LI5132. RNASeq analysis revealed presence of DNAJB1-PRKACA gene fusion on chromosome 19, a molecular signature of FL-HCC. Clinical diagnosis as HCC of fibrolamellar type was confirmed by H&amp;E staining in the PDX tumor. The PDX tumor had a distinctive intratumoral fibrosis with a lamellar pattern. PDX model was established by inoculating patient tumor cells subcutaneously in NOD-SCID mice. Robust tumor growth was observed with a 100% take rate in NOD-SCID mice. To evaluate the translational relevance of this model toward therapeutic development, the efficacy of a novel multi-target Aurora kinase A and angiokinase inhibitor, ENMD-2076, was evaluated in a therapeutic mode in this model. ENMD-2076 showed significant efficacy in suppressing tumor growth in NOD-SCID mice, at the 200 mg/kg dose evaluated in this study. Weight loss observed during the treatment period could not be attributed to ENMD-2076 as it was similar to weight loss observed with vehicle treatment. ENMD-2076 has now progressed in to phase II trials in the clinic for treatment of FL-HCC. This demonstrates the translational utility of this FL-HCC model in development of anti-cancer therapeutic agents. Citation Format: Jayant Thatte, Elvira C. Talaoc, Colleen Scott, Ken Ren, Thomas Broudy. Kinase inhibitor demonstrates efficacy in patient derived xenograft model of fibrolamellar hepatocellular carcinoma featuring DNAJB1-PRKACA gene fusion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4203. doi:10.1158/1538-7445.AM2017-4203
Abstract 649: Emigrant pre-REP tumor infiltrating lymphocytes profoundly differ from remnant T-cells
Authors: Michelle R. Simpson-Abelson, Christopher Mosychuk, Maria Fardis, Michael T. Lotze
Journal: Cancer Research (2017)

Abstract Adoptive T cell therapy with autologous tumor infiltrating lymphocytes (TIL) provides up to 56% objective response rates and a complete response in 24% of patients with metastatic melanoma. The process of generating TIL from resected tumor involves morcellating the tumor into 1-3 mm3 fragments and expanding TIL in the presence of Interleukin 2 (IL-2) in a pre-Rapid Expansion Protocol (pre-REP). During the ‘pre-REP’, tumor-resident immune cells emigrate (eTIL) and proliferate. The length of the pre-REP varies between 11-21 days, depending on cell growth. Residual tumor fragments (remnants) are discarded and the expanded eTIL are subjected to a Rapid Expansion Protocol (REP) with irradiated PBMC feeders, anti-CD3 and IL-2. Viable cells remaining in the tumor remnants (rTIL) following the pre-REP were investigated to assess their function and phenotype. We evaluated and compared the rTIL and eTIL in melanoma, breast, renal, pancreatic, lung and colorectal tumors (n=9). Tumor rTIL are consistently phenotypically distinct from eTIL, as determined by differential expression of various markers (Table 1). The fundamental differences in rTIL were: Increased CD69+ (7 fold MFI in CD4+) (p&amp;lt;.001); diminished LAG3 (2 fold MFI in CD8) (p&amp;lt;.05); TIM3 (3 and 2 fold MFI in CD8 and CD4 respectively) (p&amp;lt;.05/.01); CD154 (3 fold MFI in CD4) (p&amp;lt;.01); and CD56 (5%) (p&amp;lt;.05). Surprisingly, a REP of rTIL and eTIL resulted in comparable expansion. The phenotypic signature of TIL was sustained post-REP with fidelity of the individual expression of LAG3, Tim3, and CD28. These studies have identified significant differences in the biology of cell populations in terms of tissue-resident T cells and the signals associated with emigration and retention. These data provide additional insights on the individual TIL populations that could be utilized for adoptive T-cell therapy in patients and raise important questions about the nature of tissue-resident T cells in sites of chronic inflammation such as tumor. Table 1:Tumor resident remnant T cells are phenotypically distinct from emigrating T cells (N=9)Marker ExpressionLAG3 (CD8/ CD4) MFITim3 (CD8/ CD4) MFIPD-1 (CD8/ CD4) %CD69 (CD8/ CD4) MFICD154 (CD8/ CD4) MFICD28 (CD8/ CD4) MFICD57 (CD8/ CD4) %CD56%eTIL507/ 1442832/ 175636.95/ 471320/ 15431498/ 37511163/ 503618.76/ 19.65.615rTIL209/ 106877/ 74242.8/ 483437/ 223.41034/ 1167458.3/ 27959.16/8.51.027*P-values(CD8/ CD4) 0.05/ 0.210.05/ 0.010.38/ 0.890.11/ 0.0010.55/ 0.010.05/ 0.110.05/ 0.060.05 _______ Citation Format: Michelle R. Simpson-Abelson, Christopher Mosychuk, Maria Fardis, Michael T. Lotze. Emigrant pre-REP tumor infiltrating lymphocytes profoundly differ from remnant T-cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 649. doi:10.1158/1538-7445.AM2017-649
Ongoing hepatitis A among men who have sex with men (MSM) linked to outbreaks in Europe in Tel Aviv area, Israel, December 2016 – June 2017
Authors: Yael Gozlan, Itay Bar-Or, Aviya Rakovsky, Michal Savion, Ziva Amitai, Rivka Sheffer, Noa Ceder, Emilia Anis, Itamar Grotto, Ella Mendelson, Orna Mor
Journal: Eurosurveillance (2017)

Between December 2016 and June 2017, 19 Hepatitis A virus (HAV)-positive cases, 17 of which were among men who have sex with men (MSM) were identified in the Tel Aviv area. Seven of the 15 sewage samples collected between January and June 2017 were also HAV-positive. All sequences clustered with two of the three strains identified in the current European HAV outbreak. We demonstrate that despite an efficient vaccination programme, HAV can still be transmitted to an unvaccinated high-risk population.
Abstract 927: Cancer stem cell proliferation in human prostate cancer cells utilizing a new defined 3D spheroid culture system
Authors: Nick Asbrock, Vi Chu, Kan Saito
Journal: Cancer Research (2017)

Abstract Solid tumors grow in a three-dimensional (3D) spatial conformation, resulting in a heterogeneous exposure to oxygen and nutrients as well as to other physical and chemical stresses. To mimic the 3D spatial conformation, 3D in vitro culture models have been used in cancer research since the diffusion-limited distribution of oxygen (hypoxia), nutrients, metabolites, and signaling molecules is not mimicked in conventional two-dimensional (2D) monolayer cultures. One of the 3D in vitro culture models, the tumorsphere culture is an emerging model for studying and expanding the cancer stem cell (CSC) population. E006AA cell line is a spontaneously immortalized cell line derived from a Gleason 6 localized prostate cancer in a hormone-naive prostate cancer patient of African American descent. This cell line expresses androgen receptor and was repeatedly reported to be non-tumorigenic in nude mice. However this cell line forms continuously growing tumor in NOG-SCID triple-deficient mice (i.e., NOG-SCID mice not having NK, B, and T-cells) and an establishment of highly tumorgenic subline E006AA-hT was reported suggesting this cell line has a potential for CSC proliferation by 3D sphere cultures. Here we report tumorsphere cultures of E006AA cells by a new 3D spheroid culture media system. The cells showed continuous proliferation supported during serial passage of 3D tumorsphere cultures. In addition to the stable proliferation, increases of Aldehyde Dehydrogenase (ALDH) expressing CSC population were observed with the increase of passages of 3D tumorsphere cultures. Citation Format: Nick Asbrock, Vi Chu, Kan Saito. Cancer stem cell proliferation in human prostate cancer cells utilizing a new defined 3D spheroid culture system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 927. doi:10.1158/1538-7445.AM2017-927
Using Multifunctional Peptide Conjugated Au Nanorods for Monitoring β-amyloid Aggregation and Chemo-Photothermal Treatment of Alzheimer's Disease
Authors: Meng Li, Yijia Guan, Andong Zhao, Jinsong Ren, Xiaogang Qu
Journal: Theranostics (2017)

Development of sensitive detectors of Aβ aggregates and effective inhibitors of Aβ aggregation are of diagnostic importance and therapeutic implications for Alzheimer's disease (AD) treatment. Herein, a novel strategy has been presented by self-assembly of peptide conjugated Au nanorods (AuP) as multifunctional Aβ fibrillization detectors and inhibitors. Our design combines the unique high NIR absorption property of AuNRs with two known Aβ inhibitors, Aβ15-20 and polyoxometalates (POMs). The synthesized AuP can effectively inhibit Aβ aggregation and dissociate amyloid deposits with NIR irradiation both in buffer and in mice cerebrospinal fluid (CSF), and protect cells from Aβ-related toxicity upon NIR irradiation. In addition, with the shape and size-dependent optical properties, the nanorods can also act as effective diagnostic probes to sensitively detect the Aβ aggregates. This is the first report to integrate 3 segments, an Aβ-targeting element, a reporter and inhibitors, in one drug delivery system for AD treatment.