tbuckley/cabot-search huggingface dataset:
PTH-102 Association of gut microbiota with mucosal inflammation in ulcerative colitis
Authors: MN Quraishi, A Rossiter, B Chung, M Beaumont, E Liaskou, R Horniblow, A Beggs, D Withers, S Ghosh, C Tselepis, G Hirschfield, T Iqbal
Journal: Gut (2017)

Introduction  Disturbance in gut microbiota (dysbiosis) is a characteristic feature of ulcerative colitis (UC). It remains unclear whether this dysbiosis contributes to disease pathogenesis by driving immune dysregulation or is merely secondary to mucosal inflammation. We aimed to determine whether dysbiosis varied between areas of inflamed and non-inflamed colon in patients with UC and whether this was associated with a humoral immune response.  Method  We collected colonic biopsies from histologically confirmed areas of inflamed and non-inflamed colon from 15 patients with active UC. DNA was extracted and gut microbiota was characterised using 16s rRNA based analysis. Inferred metagenomic analysis for microbial function was performed by PICRUSt. As a marker of mucosal humoral immune responses, inflamed and non-inflamed colonic biopsy samples were cultured for 1 to 3 days prior to measurement of total immunoglobulin (Ig) production by ELISA.  Results  Consistent with previous observations patients with UC demonstrated reduced bacterial diversity with an increase in Proteobacteria, Bacteroides and Clostridiales species along with a decrease in Firmicutes to Bacteroides ratio. No differences were found in the microbial diversity nor phylae and genera in mucosally adherent gut microbiota between inflamed and non-inflamed colonic segments in patients with active UC. This observation was also seen when patients were subdivided based on disease activity as defined by Mayo scoring. PICRUSt analysis revealed genes associated with bacterial chemotaxis, motility and flagellar assembly were enriched in the inflamed tissue. Total Ig production did not differ between inflamed (n=6, mean 4966 +/- sd 3670 ng/ml) and non-inflamed tissue (n=11; mean 5756 +/- sd 8989 ng/ml; p>0.05) suggesting that equal numbers of antibody-producing B cells are present.  Conclusion  We have demonstrated that the dysbiosis observed in patients with UC is consistent and is not influenced by mucosal inflammation or disease activity. Genes associated with bacterial invasion and flagellin are enriched at sites of inflammation. Mucosal Ig production was not upregulated at sites of inflammation possibly suggestive of a uniform humoral response. These functional pathways in colitis associated inflammation provide insight into contribution of microbiota in its pathogenesis.  Disclosure of Interest  None Declared
The Bruton's Tyrosine Kinase (BTK) Inhibitor ARQ 531 Effectively Inhibits Wild Type and C481S Mutant BTK and Is Superior to Ibrutinib in a Mouse Model of Chronic Lymphocytic Leukemia
Authors: Sean D. Reiff, Rose Mantel, Lisa L. Smith, Samantha McWhorter, Virginia M. Goettl, Amy J. Johnson, Sudharsan Eathiraj, Giovanni Abbadessa, Brian Schwartz, John C. Byrd, Jennifer A. Woyach
Journal: Blood (2016)
Abstract 5785: Characterization of a novel microfluidic in vitro model of the blood-tumor and blood-brain barrier
Authors: Jessica Griffith, Tori Terrell-Hall, Amanda Ammer, Paul Lockman
Journal: Cancer Research (2017)

Abstract Background: There is a need for a cost-effective and reliable in vitro model of the blood-tumor barrier (BBB) and blood-brain barrier (BTB) for primary and metastatic lesions in brain. Current models do not accurately recapitulate physiological conditions and are unreliable with up to a 100-fold variance in predicting drug permeability into brain tumors. Methods: Human umbilical vein endothelial cells (HUVECs) were cultured with either CTX-TRD2 rat astrocytes (BBB) or Met-1 murine breast cancer cells (BTB) in a microfluidic chip, which contained chambers separated by a porous wall. Shear stress was induced on HUVECs by perfusion of media through the apical chamber, and permeability was characterized by the diffusion of fluorescent tracers, one of which is subject to P-gp efflux. Data was compared to in-vivo work. Results: Permeability of free Texas Red was significantly higher (p&amp;lt;0.05) in BTB chips (kin= 13.1 ± 1.3 X 10-3) than in the BBB chips (Kin=2.5 ± 0.3 X 10-3). There was a similar trend observed in larger markers, but these were not significantly different. The movement of Rhodamine 123 was also restricted, indicating functional P-gp efflux in vitro, similar to data from published in vivo studies. In the BBB model, diffusion of Rho123 increased 14-fold in the presence of verapamil (kin=14.7 ± 7.5 X 10-3) and eight fold with the addition of Cyclosporine A (kin=8.8 ± 1.8 X 10-3). In the BTB model, this increase was also observed, but to a lesser extent, as only 3 and 2-fold increases in permeability were observed, respectively. The magntidue of permeability changes were not significantly different from in-vivo models in both passive diffusion and active efflux experiments. Conclusion: The novel microfluidic chip is a cost-effective in vitro model which recapitulates the BTB and BBB physiology and can predict permeability more reliably than current in-vitro models. Citation Format: Jessica Griffith, Tori Terrell-Hall, Amanda Ammer, Paul Lockman. Characterization of a novel microfluidic in vitro model of the blood-tumor and blood-brain barrier [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 5785. doi:10.1158/1538-7445.AM2017-5785
Abstract 3236: Delivering selective and cell-active inhibitors of V804M mutant RET kinase through structure-guided drug discovery
Authors: Allan M. Jordan, Rebecca Newton, Bohdan Waszkowycz, Richard Bayliss, Habiba Begum, Daniel Burschowsky, Aude Echalier, Samantha Hitchin, Colin Hutton, Shaun Johns, Stuart Jones, Li-Ying Lin, Mark Richards, Chitra Seewooruthun, Alex Stowell, Ian Waddell, Mandy Watson, Donald Ogilvie
Journal: Cancer Research (2017)

Abstract Activating gene fusions in the RET receptor tyrosine kinase have been found to drive 1-2% of lung adenocarcinomas and therefore offer an attractive target for targeted therapy. Whilst non-selective tyrosine kinase inhibitors with RET activity are efficacious in this setting, their use is generally limited by dose limiting toxicity associated with their more potent activity versus other targets, specifically KDR (VEGFR2) in the case of cabozantinib and vandetanib. Given this limitation, there is considerable interest in developing more selective inhibitors of RET kinase. Tyrosine kinase inhibitors are prone to early clinical failure due to mutations in the kinase ATPase binding domain, which render the kinase catalytically active but no longer sensitive to drug treatment. Such mutations often occur in the so-called “gatekeeper” region and in this specific case, resistance is predicted to arise from a Val-Met or Val-Leu mutation at residue 804. Through a combination of computational methods, structural biology and drug design, we have identified and further optimized a series of inhibitors of the V804M mutant RET kinase which show sub-micromolar cellular activity in cells driven by V804M RET. Moreover, these agents show excellent selectivity against the wtRET kinase and KDR. As such, these agents may offer valuable start-points for second-generation RET inhibitors for use in patents who relapse after treatment with first generation selective RET inhibitors. Citation Format: Allan M. Jordan, Rebecca Newton, Bohdan Waszkowycz, Richard Bayliss, Habiba Begum, Daniel Burschowsky, Aude Echalier, Samantha Hitchin, Colin Hutton, Shaun Johns, Stuart Jones, Li-Ying Lin, Mark Richards, Chitra Seewooruthun, Alex Stowell, Ian Waddell, Mandy Watson, Donald Ogilvie. Delivering selective and cell-active inhibitors of V804M mutant RET kinase through structure-guided drug discovery [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 3236. doi:10.1158/1538-7445.AM2017-3236
Intrabone Transplantation of a Single Cord Blood Unit Using Non-Irradiated Reduced-Intensity Conditioning
Authors: Makoto Murata, Yoshinobu Maeda, Masayoshi Masuko, Yasushi Onishi, Tomoyuki Endo, Seitaro Terakura, Yuichi Ishikawa, Chisako Iriyama, Yoko Ushijima, Tatsunori Goto, Nobuharu Fujii, Mitsune Tanimoto, Hironori Kobayashi, Yasuhiko Shibasaki, Noriko Fukuhara, Yoshihiro Inamoto, Ritsuro Suzuki, Tadashi Matsushita, Yoshihisa Kodera, Hitoshi Kiyoi, Tomoki Naoe, Tetsuya Nishida
Journal: Blood (2016)
Abstract 1783: Early detection of thymidylate synthase resistance in non-small cell lung cancer with FLT-PET imaging
Authors: Xiao Chen, Yizeng Yang, Sharyn Katz
Journal: Cancer Research (2017)

Abstract Background: Inhibition of thymidylate synthase (TS) results in a transient compensatory “flare” in thymidine salvage pathway activity which is measureable with 18F-thymidine (FLT) positron emission tomography (PET) at 2 hrs of exposure to therapy. Here we examine the predictive value of the FLT-PET measured “flare” for NSCLC sensitivity to pemetrexed, a commonly used TS inhibitor, in a preclinical model. Experimental Design: Resistance to pemetrexed therapy was induced in two sensitive human NSCLC cell lines, H460 and H1299, by overexpressing TS. TS overexpression was confirmed with RT-PCR and Western blotting and pemetrexed-resistance confirmed with IC50 assays. The presence of a pemetrexed-induced DNA salvage pathway “flare” was then measured using 3H-thymidine in both pemetrexed-sensitive (H460 and H1299) and resistant (H460R and H1299R) lines in vitro, as well as inherently resistant NSCLC cell lines CALU6, H522, H650, H661, H820, H1838, and validated with FLT-PET in vivo using H460 and H460R xenografts. Results: Overexpression of TS induced resistance to pemetrexed in the H460 and H1299 with IC50 for H460, H1299, H460R and H1299R measured as 0.141 μM, 0.656 μM, 22.842 μM, 213.120 μM, respectively. Significant increases in DNA salvage pathway activity (“flare”) was observed at 2hrs of therapy in the pemetrexed-sensitive H460 and H1299 lines but not the resistant H460R and H1299R, CALU6, H522, H650, H661, H820, H1838 cell lines in vitro using 3H-thymidine assays. Similarly, FLT “flare” was observed in the pemetrexed-sensitive H460 xenograft tumors but not the pemetrexed-resistant H460R xenograft tumors with post-therapy increases in measured FLTmax of 58% (STD 12.1) and 10.8% (STD 7.3) respectively. Conclusions: FLT-PET imaging of TS inhibition may provide an early indicator of NSCLC sensitivity to pemetrexed. Citation Format: Xiao Chen, Yizeng Yang, Sharyn Katz. Early detection of thymidylate synthase resistance in non-small cell lung cancer with FLT-PET imaging [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 1783. doi:10.1158/1538-7445.AM2017-1783
Abstract 2226: Sildenafil suppresses tumorigenesis in <i>Apc</i>Min<i>/+</i> mouse model
Authors: Sarah K. Sharman, Bianca N. Islam, Yali Hou, Allison Bridges, Nagendra Singh, Subbaramiah Sridhar, Frankin G. Berger, Darren D. Browning
Journal: Cancer Research (2017)

Abstract The cGMP signaling pathway regulates homeostasis in the colon epithelium and has been implicated in the suppression of colorectal cancer. Exisulind is a weak phosphodiesterase-5 (PDE5) inhibitor that was previously shown to reduce polyp formation in familial adenomatous polyposis (FAP) patients. Despite this validation of PDE5 as a therapeutic target, the failure of Exisulind due to toxicity halted further trials of cGMP elevating agents. The present study tested the effect of the PDE5 inhibitor sildenafil, and the receptor guanylyl-cyclase C (GCC) agonist linaclotide on tumorigenesis in the ApcMin/+ mouse model of colon cancer. Administration of either sildenafil or linaclotide to both wild type and ApcMin/+ mice caused dramatic effects on homeostasis that included reduced proliferation and increased goblet cell differentiation. With treatment beginning at 4 weeks, sildenafil and linaclotide caused a 50% and 67% (respectively) reduction in the number of polyps per mouse. Furthermore, the polyps in sildenafil and linaclotide treated animals exhibited a reduced proliferative index and increased mucus density compared to polyps from untreated mice. The mean polyp size was not changed by treatment with either drug. In support of a tumor-suppressive role for cGMP signaling in the intestine, the ApcMin/+ mice showed reduced levels of endogenous GCC agonists in the intestinal mucosa compared to wild type animals. This suggests that part of the tumor preventative effects observed here could be due to compensation for this deficit by augmenting cGMP signaling with PDE5 inhibitors or GCC agonists. While the tumor suppressive mechanism is not fully understood, the results presented here demonstrate in a preclinical model, that increasing intestinal cGMP levels by targeting PDE5 or GCC may be a viable chemoprevention strategy for human FAP patients. Citation Format: Sarah K. Sharman, Bianca N. Islam, Yali Hou, Allison Bridges, Nagendra Singh, Subbaramiah Sridhar, Frankin G. Berger, Darren D. Browning. Sildenafil suppresses tumorigenesis in ApcMin/+ mouse model [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 2226. doi:10.1158/1538-7445.AM2017-2226
Abstract 5431: Androgen receptor regulates the mitochondrial pyruvate carrier to fuel oncometabolism in prostate cancer
Authors: David A. Bader, Nagireddy Putluri, Sean M. Hartig, Sean E. McGuire
Journal: Cancer Research (2017)

Abstract The metabolic underpinnings of androgen receptor (AR)-driven growth in prostate cancer (PCa) are underexplored, hindering the development of strategies to leverage the metabolic properties differentiating PCa from normal tissue. To this end, we discovered a subunit of the mitochondrial pyruvate carrier (MPC), MPC2, is a direct AR target gene that is increased in PCa specimens and associated with clinical outcomes. Our observation suggests a targetable link between AR signaling and carbon trafficking in PCa. Indeed, MPC inhibition delays proliferation and alters metabolic properties in hormone sensitive and castrate resistant AR-driven PCa models. Next, using 13C metabolic flux analysis coupled with a reverse phase protein array, we determined MPC inhibition results in activation of the eIF2α/ATF4 integrated stress response pathway to partially compensate for MPC inhibition by coordinating increased glutamine incorporation into the citric acid cycle. Therefore, to amplify the effect of MPC inhibition, we restricted glutamine availability during MPC inhibition and found this combination resulted in proliferative arrest. Last, we extended our efforts in-vivo and demonstrated combinatorial MPC/glutaminase inhibition resulted in a significant reduction in castrate-resistant prostate tumor xenograft growth in mice with no overt host toxicity. We anticipate our findings will accelerate the development of clinical strategies to therapeutically manipulate carbon flux to starve clinically lethal castrate-resistant PCa. Citation Format: David A. Bader, Nagireddy Putluri, Sean M. Hartig, Sean E. McGuire. Androgen receptor regulates the mitochondrial pyruvate carrier to fuel oncometabolism in prostate cancer [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 5431. doi:10.1158/1538-7445.AM2017-5431
Abstract CT102: Rates and impact of combination immunotherapy with tumor treating fields in a glioma cohort
Authors: Yazmin Odia, Jessica Schulte, Fabio Iwamoto
Journal: Cancer Research (2017)

Abstract Tumor-treating fields (TTF) are approved for use in patients with glioblastomas at recurrence (2011) or adjuvant setting (2016) due to survival benefit in various trials. Since 12/2012, 46 patients were treated with TTF for de novo or recurrent gliomas at Columbia University. Rates and outcomes of combination with immunotherapy were analyzed, given the recent preclinical data of synergism between TTF and PD1 targeted therapy. The impact of compliance was also analyzed in multivariable analyses in this retrospective cohort. Of 44 treated patients, 18 (41%) were women and 2 (5%), 4 (9%) and 36 (86%) had WHO grade II, III and IV gliomas. Median age at diagnosis was 56 (23-84) years. TTF was used at recurrence in 38 (86%), with a median of 2 (0-4) prior recurrences. Prior therapies included bevacizumab (22, 50%), surgery [25/44 (57%) gross total], radiation and temozolomide. Median TTF therapy duration was 1.8 (0.1-20.3) months. Only 2 (5%) experienced skin toxicity requiring interruptions. Compliance goal of 75% was met by 11/44 (25%) glioma patients. Concurrent systemic therapy was used in 35 (80%), including temozolomide (12, 27%), nitrosourea (2, 5%), bevacizumab (17, 39%), immunotherapy (26, 59%) or other (5, 11%). Objective response rate (ORR) based on RANO was noted in 25/42 (60%) of all gliomas and 21/38 (55%) of glioblastomas, At interim follow-up, progression free (PFS) and overall (OS) survival were 2.7 and 6.9 months, respectively. PFS was significantly increased among glioblastoma patients treated with concurrent immunotherapy (PFS: 3.3 vs. 1.95, p=0.0364). Long-term follow-up PFS and OS will be re-analyzed, along with the potential confounding impact of compliance rates. TTF improves survival for patients with glioblastomas. Immunotherapy shows promise for various tumor histologies. The possible synergism between these modalities in preclinical studies and this retrospective glioma series warrants further study in randomized controlled gliomas trials. We propose a single-arm phase II trial of concurrent PD1 inhibitor and TTF for patients with bevacizumab-naïve glioblastoma at second or third recurrence. OS is the primary endpoint; secondary endpoints include PFS, ORR, predictive value of PDL1 expression, and impact of compliance. Results from the EF-14 trial will serve as a historical control. Citation Format: Yazmin Odia, Jessica Schulte, Fabio Iwamoto. Rates and impact of combination immunotherapy with tumor treating fields in a glioma cohort [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 CT102. doi:10.1158/1538-7445.AM2017-CT102
The eukaryotic gut virome in hematopoietic stem cell transplantation: new clues in enteric graft-versus-host disease
Authors: Jérôme Legoff, Matthieu Resche-Rigon, Jerome Bouquet, Marie Robin, Samia N Naccache, Séverine Mercier-Delarue, Scot Federman, Erik Samayoa, Clotilde Rousseau, Prescillia Piron, Nathalie Kapel, François Simon, Gérard Socié, Charles Y Chiu
Journal: Nature Medicine (2017)
Supercritical Fluid Technology: An Emphasis on Drug Delivery and Related Biomedical Applications
Authors: Ranjith Kumar Kankala, Yu Shrike Zhang, Shi‐Bin Wang, Chia‐Hung Lee, Ai‐Zheng Chen
Journal: Advanced Healthcare Materials (2017)

During the past few decades, supercritical fluid (SCF) has emerged as an effective alternative for many traditional pharmaceutical manufacturing processes. Operating active pharmaceutical ingredients (APIs) alone or in combination with various biodegradable polymeric carriers in high-pressure conditions provides enhanced features with respect to their physical properties such as bioavailability enhancement, is of relevance to the application of SCF in the pharmaceutical industry. Herein, recent advances in drug delivery systems manufactured using the SCF technology are reviewed. We provide a brief description of the history, principle, and various preparation methods involved in the SCF technology. Next, we aim to give a brief overview, which provides an emphasis and discussion of recent reports using supercritical carbon dioxide (SC-CO2 ) for fabrication of polymeric carriers, for applications in areas related to drug delivery, tissue engineering, bio-imaging, and other biomedical applications. We finally summarize with perspectives.
Abstract 2554: PRR14, a novel regulator of Ras signaling pathway
Authors: Mei Yang, Meijun Long, Xiaoliu Shi, Zhi-Min Yuan, Hang Su
Journal: Cancer Research (2017)

Abstract PRR14, a component of nuclear lamina, has recently been identified as a novel oncogene in lung cancer. Frequently upregulated in lung cancers, PRR14 promotes tumorigenesis through activating the PI3-kinase/Akt/mTOR signal pathway. The regulatory effect is mediated by direct interaction with GRB2, a docking protein upstream of both PI3K and Ras. Indeed, PRR14 is commonly elevated in many cancer types including lung cancer and breast cancer, but our understanding of the underlying molecular mechanism is still very elusive. Given the complicated interplay between PI3K and Ras signal pathways and their importance in carcinogenesis and optimal treatment, we further explored the effect of PRR14 on Ras activation. We used MCF10A human mammary epithelial cells and its K-RasV12-induced cancerous counterparts to establish isogenic cell lines that express different levels of PRR14. Colony formation and growth curves were monitored simultaneously. Western blot and Ras pull-down activation assay were employed to examine protein level and Ras activity. Cell fractionation was performed to detect protein location. We found that the expression level of PRR14 positively correlated with both Ras protein level and its activity, resulting in consequent changes in cell proliferation and colony formation. Remarkably, elevated PRR14 promoted translocation of Ras from cytoplasm into the cell nucleus and its stabilization. In conclusion, PRR14 sequesters, stabilizes and activates Ras in cell nuclei. When upregulated, PRR14 promotes tumorigenesis, and Ras signaling pathway presents one of the complex underlying mechanisms. Citation Format: Mei Yang, Meijun Long, Xiaoliu Shi, Zhi-Min Yuan, Hang Su. PRR14, a novel regulator of Ras signaling pathway [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 2554. doi:10.1158/1538-7445.AM2017-2554
Health-related quality of life for immediate versus delayed androgen-deprivation therapy in patients with asymptomatic, non-curable prostate cancer (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial
Authors: Gillian M Duchesne, Henry H Woo, Madeleine King, Steven J Bowe, Martin R Stockler, Alice Ames, Catherine D'Este, Mark Frydenberg, Andrew Loblaw, Shawn Malone, Jeremy Millar, Keen Hun Tai, Sandra Turner
Journal: The Lancet Oncology (2017)