tbuckley/cabot-search huggingface dataset:
Abstract 883: PRDX4 as a novel target for pancreatic cancer
Authors: Pallavi Jain, Azin Sayad, Erik Mollen, Michael Xie, Kevin Brown, Jason Moffat, David Hedley, Paul Boutros, Bradley Wouters, Marianne Koritzinsky
Journal: Cancer Research (2019)

Abstract Pancreatic cancer (PCa) is a fatal malignancy showing a 5% 5-year survival rate, creating an urgent need for new therapeutic targets. Many cancers have high production of reactive oxygen species (ROS), leaving them potentially vulnerable to targeting proteins involved in ROS metabolism. In line with this, we identified Peroxiredoxin 4 (PRDX4) as an essential gene in 26% of pancreatic cell lines by mining functional genomics datasets. PRDX4 is localized in the endoplasmic reticulum (ER) where it metabolizes H2O2. We validated in nine established PCa cell lines and patient derived primary cell lines that depletion of PRDX4 using siRNA or shRNA leads to inhibition of proliferation and cell death in a subset of pancreatic cancer cells. This was accompanied by increased levels of reactive oxygen species (ROS) as measured by flow cytometry. Dual-Depletion of NADPH oxidase 4 (NOX4) and PRDX4 could rescue the cell death phenotype thereby indicating that increase in ROS was a consequence of NOX4 activity. PRDX4 depletion led to focal accumulation of phosphorylated H2AX (γH2AX) in the cellular nuclei, consistent with DNA damage. Phosphorylation of H2AX was exclusively dependent upon activation of the upstream kinase DNA-PKcs. Cells depleted for PRDX4 were also more sensitive to ionizing radiation. Depleting PRDX4 with inducible shRNA in established xenografts inhibited tumor growth. Finally, using transcriptome data accompanying the functional genomics datasets, we identified a 2-gene expression signature that predicts sensitivity to PRDX4 targeting. This study indicates that depletion of PRDX4 causes increased ROS resulting in DNA damage leading to DNA-PKcs activation, inhibition of proliferation and cell death in a subset of pancreatic cancers. PRDX4 is a potential novel therapeutic target that may act synergistically with radiation therapy. Citation Format: Pallavi Jain, Azin Sayad, Erik Mollen, Michael Xie, Kevin Brown, Jason Moffat, David Hedley, Paul Boutros, Bradley Wouters, Marianne Koritzinsky. PRDX4 as a novel target for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 883.
Abstract 17133: High Respiratory Exchange Ratio at Submaximal Exercise Level Predicts Adverse Clinical Outcomes in Patients With Heart Failure
Authors: Naoya Kakutani, Arata Fukushima, Takashi Yokota, Takashi Katayama, Ryosuke Shirakawa, Satoshi Maekawa, Hideo Nambu, Takahiro Abe, Takaaki Furihata, Junichi Matsumoto, Masaya Tsuda, Takayuki Nakajima, Katsuma Yamanashi, Yoshikuni Obata, Shingo Takada, Akimichi Saito, Koichi Okita, Shintaro Kinugawa
Journal: Circulation (2017)

Introduction: Peak oxygen consumption (peak VO2) is an established indicator in patients with chronic heart failure (HF), though it is effort-dependent and highly influenced by patient motivation. ...
Are Adolescents and Young Adults (AYA) with Acute Lymphoblastic Leukemia (ALL) Receiving Pediatric or Adult ALL Regimens: A Population-Based Statewide Evaluation of the Approach to AYA ALL across Pediatric and Adult Cancer Centers
Authors: Lori S. Muffly, Elysia Alvarez, Daphne Lichtensztajn, Renata Abrahao, Theresa H.M. Keegan, Scarlett Gomez
Journal: Blood (2017)
A Phase 1-2 Dose-Escalation and Cohort- Expansion Study of eFT508, a Selective, Orally Bioavailable Inhibitor of MNK1 and MNK2, in Patients with Hematological Malignancies
Authors: Ajay K. Gopal, Rod Ramchandren, Nashat Y. Gabrail, Manish R Patel, Ding Wang, Langdon L Miller, Vikas Goel, Gary G Chiang, Kevin R Webster, Sam Sperry, Debra T Vallner, Cara Casseday, Jeremy Barton
Journal: Blood (2017)
Radiation-guided anti-P-selectin antibody for tumor targeted imaging and therapy
Authors: Ghazal Hariri, Ying Zhang, Zhaozhong Han, Martin Brechbiel, Todd Peterson, Ronald Baldwin, Dennis Hallahan
Journal: Cancer Research (2007)

4187    Purpose/Objective : Radiation induces translocation of P-selectin from storage reservoirs within the tumor endothelium to the luminal surface of microvasculature. This radiation-inducible expression of P-selectin on tumor-associated endothelial cells can be developed for tumor-targeted therapy and imaging. We developed specific antibodies against P-selectin, and tested the feasibility of imaging and therapy of irradiated lung tumors  in vivo  using targeted therapeutic radioisotopes.   Materials & Methods : Single chain variable fragments (ScFv) of murine and human antibodies were selected by screening phage-displayed ScFv libraries on purified P-selectin. The selected ScFvs were prioritized by affinity (ELISA and FMAT), specificity (cell and tissue staining), and stability. Prioritized antibodies were engineered for conjugating with different carriers, expressed in  E. coli  and purified on affinity columns. The ScFvs were conjugated with chelating agents (DTPA and DOTA) and radioisotopes for imaging and therapy. These radioimmunoconjugates were injected into mice with irradiated lung tumors. Biodistribution of the ScFv-conjugates  in vivo  was monitored with near-infrared (NIR) imaging, gamma camera imaging, and micro-PET.   Results:  It was found that ScFv antibodies against P-selectin specifically bind to irradiated HUVEC cells  in vitro , and target irradiated tumor xenografts  in vivo . DTPA-conjugated ScFv loaded with radioisotope specifically and efficiently targeted irradiated tumor within hours as revealed with gamma camera imaging and micro-PET. ScFv were labeled with In-111 for initial imaging studies and with Cu-64 for subsequent imaging and therapy studies. Biodistribution and pharmacokinetics of therapeutic radioisotopes targeted to P-selectin in irradiated  in vivo  lung tumor models will be presented.      Conclusions : P-Selectin is specifically induced by irradiation of tumor vascular endothelium. Screening of phage-displayed antibody fragments is an efficient means for selecting anti-P-selectin antibody with high affinity and specificity. Radiation-induced expression of P-selectin on tumor vascular endothelial cells can be utilized for imaging and therapy of tumors. Therapeutic radioimmunoconjugates targeting P-selectin can be used for imaging and therapy in irradiated  in vivo  lung tumor models.
Genomic Patterns of Local Adaptation under Gene Flow in Arabidopsis lyrata
Authors: Tuomas Hämälä, Outi Savolainen
Journal: Molecular Biology and Evolution (2019)

Short-scale local adaptation is a complex process involving selection, migration, and drift. The expected effects on the genome are well grounded in theory but examining these on an empirical level has proven difficult, as it requires information about local selection, demographic history, and recombination rate variation. Here, we use locally adapted and phenotypically differentiated Arabidopsis lyrata populations from two altitudinal gradients in Norway to test these expectations at the whole-genome level. Demography modeling indicates that populations within the gradients diverged <2 kya and that the sites are connected by gene flow. The gene flow estimates are, however, highly asymmetric with migration from high to low altitudes being several times more frequent than vice versa. To detect signatures of selection for local adaptation, we estimate patterns of lineage-specific differentiation among these populations. Theory predicts that gene flow leads to concentration of adaptive loci in areas of low recombination; a pattern we observe in both lowland-alpine comparisons. Although most selected loci display patterns of conditional neutrality, we found indications of genetic trade-offs, with one locus particularly showing high differentiation and signs of selection in both populations. Our results further suggest that resistance to solar radiation is an important adaptation to alpine environments, while vegetative growth and bacterial defense are indicated as selected traits in the lowland habitats. These results provide insights into genetic architectures and evolutionary processes driving local adaptation under gene flow. We also contribute to understanding of traits and biological processes underlying alpine adaptation in northern latitudes.
David Oliver: Radical pragmatism and medical leadership
Authors: David Oliver
Journal: BMJ (2019)

BerkshireMy recent column on the paucity of doctors as NHS hospital chief executives brought an interesting postbag, sparking more reflection on my part. 1 Clinically active doctors can often assume management, educational, and leadership roles that stop short of full time organisational executive.Perhaps the lack of doctor chief executives isn't a big deal if we're influential in other ways.
Abstract 3184: Targeting multiple solid tumor types with anti-CD70 allogeneic CAR-T cells
Authors: Mary Lee Dequeant, Sushant Karnik, Zinkal Padalia, Minh Thu Tham, Tony Ho, Julie Carson, Jonathan A. Terrett
Journal: Cancer Research (2019)

Abstract CD70 (CD27 ligand) is highly expressed in multiple hematologic malignancies, such as non-Hodgkin lymphoma, multiple myeloma, and chronic lymphocytic leukemia, and is uniquely highly expressed in the solid tumor type clear cell renal cell carcinoma (ccRCC). Malignancies showing high CD70 expression have been the subject of multiple clinical trials evaluating anti-CD70 agents, such as antibodies with enhanced antibody-dependent cell-mediated cytotoxicity and antibody drug conjugates (ADCs). The focus on high expression indications seems to be a requirement, particularly for ADCs. We have shown previously that CTX130, a CRISPR/Cas9 gene-edited allogeneic anti-CD70 CAR-T, is potently cytotoxic against even the lowest expressing RCC cells (e.g. ACHN). With this in mind, we evaluated CD70 expression in other solid tumor indications, including pancreatic, lung, and ovarian cancers, and assessed the cytotoxic activity of CTX130 against cell lines derived from these tumor types. These studies show that high expression is not a requirement for potent activity for CAR-T cells as it appears to be for CD70-targeted ADCs. Further, these data highlight a translational medicine route for CTX130 in many solid tumor indications. Citation Format: Mary Lee Dequeant, Sushant Karnik, Zinkal Padalia, Minh Thu Tham, Tony Ho, Julie Carson, Jonathan A. Terrett. Targeting multiple solid tumor types with anti-CD70 allogeneic CAR-T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3184.
Abstract 968: Targeting intratumoral heterogeneity in TNBC with novel combinations of FDA-approved drugs
Authors: Nathan A. Truchan, Joseph P. Burnett, Duxin Sun
Journal: Cancer Research (2019)

Abstract Triple negative breast cancer, like so many other solid tumors, has intratumoral heterogeneity which makes it difficult to treat. It is paramount to understand the question, “where does the intratumoral heterogeneity come from?” To that end, we developed a dual color reporter cell line using CRISPR/Cas9 to precisely knock in fluorescent proteins, mCherry and EGFP, behind CSC marker ALDH1A3 and differentiation marker CD24 respectively, in the TNBC cell line SUM149. With fluorescent microscopy we are able to track individual cells over time, view symmetrical and asymmetrical self-renewal, differentiation, and lineage restriction. Through direct observation we determined that the intratumoral heterogeneity comes from CSCs. In short, CSCs give rise to all the different cell types found within TNBC. Once we established the reporter cell line we wanted to ensure that any response to therapeutics was the same as in the parental SUM149 cell line. In the past, we have treated parental SUM149 with docetaxel or sulforaphane. We therefore treated our reporter cells with either docetaxel or sulforaphane. The sulforaphane treatment resulted in a significant reduction of CSCs while the docetaxel resulted in significantly more CSCs, both results matched the results from parental SUM149. To our surprise the docetaxel treatment result was due to the significant de-differentiation of mCherrylow to mCherryhigh cells. The de-differentiation and incomplete elimination of the heterogeneous cell populations pose a significant problem for TNBC patients, one that must be addressed. In order to overcome this issue, we will use our reporter cells to test already approved FDA drugs to find and evaluate novel combinations for their ability to completely eliminate the heterogeneous cell populations found within TNBC. Citation Format: Nathan A. Truchan, Joseph P. Burnett, Duxin Sun. Targeting intratumoral heterogeneity in TNBC with novel combinations of FDA-approved drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 968.
A phase 3 study of durvalumab with or without bevacizumab as adjuvant therapy in patients with hepatocellular carcinoma (HCC) who are at high risk of recurrence after curative hepatic resection
Authors: J. Knox, A. Cheng, S. Cleary, P. Galle, N. Kokudo, R. Lencioni, J. Park, J. Zhou, H. Mann, S. Morgan, X. Liu, S. Chin, G. Vlahovic, J. Fan
Journal: Annals of Oncology (2019)
Abstract 4351: Single-cell RNA sequencing reveals transcriptomic heterogeneity in response to epigenetic inhibitors
Authors: Andrew R. Conery, Sungmi Park, Michael J. Steinbaugh, Barbara M. Bryant, Shruti Apte, Patricia J. Keller, C. C. Yuan, Bill Bradley, Archana Bommi-Reddy, Robert J. Sims
Journal: Cancer Research (2019)

Abstract Histone modification is a fundamental regulatory mechanism of gene transcription and is associated with multiple diseases including cancer and inflammatory diseases. The factors that place and read these modifications can be co-opted in pathological conditions to give rise to disease-promoting transcriptional states, and thus represent promising targets for therapeutic small molecule inhibition. A central challenge in the development of epigenetic cancer therapy is the identification of transcriptionally sensitive cells within a heterogeneous population as a way to maximize therapeutic efficacy. To explore this challenge, we used single cell RNA-sequencing to characterize the transcriptional response of intrinsically heterogeneous human cancer and primary cell populations to small molecule inhibitors of epigenetic factors including the BET bromodomains, EZH2 methyltransferase, and CBP/EP300 acetyltransferase. Through clustering and differential expression analysis, we show that bulk transcriptional response in a mixed population of primary or tumor cells can be driven by a profound response in a hypersensitive subpopulation. Further, through the use of trajectory analysis, we show that epigenetic inhibitors can skew cell fate or differentiation status depending on the heterogeneity of the starting population. Overall, our results demonstrate the value of single cell transcriptomics for understanding the response of cell populations to epigenetic small molecule inhibitors and for enhancing the therapeutic potential of targeting pathogenic transcriptional programs. Citation Format: Andrew R. Conery, Sungmi Park, Michael J. Steinbaugh, Barbara M. Bryant, Shruti Apte, Patricia J. Keller, C. C. Yuan, Bill Bradley, Archana Bommi-Reddy, Robert J. Sims. Single-cell RNA sequencing reveals transcriptomic heterogeneity in response to epigenetic inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4351.
Abstract 1250: Radotinib induces cell death of multiple myeloma cells
Authors: Jae-Cheol Jo, Sook-Kyoung Heo, Eui-Kyu Noh, Jeong Yi Kim, Jun Young Sung, Ho-Min Yu, Yoo Kyung Jeong, Lan Jeong Ju, Yunsuk Choi
Journal: Cancer Research (2019)

Abstract Background: Radotinib is a medicine for the treatment of some types of cancer. It is approved in South Korea for use as a second-line treatment of chronic myeloid leukemia (CML). Its mechanism of action involves inhibition of the tyrosine kinase Bcr-Abl and of platelet-derived growth factor receptor (PDGFR). It has been little known the effects of radotinib on multiple myeloma (MM) cells. Methods: First, we examined cytotoxicity of radotinib on MM cell lines, RPMI-8226 and MM.1S. Annexin V positive cell, caspas-3 and -9 activities, cell cycle distribution and mitochondrial membrane potential (MMP, ΔΨm) were observed by analyzed with flow cytometric analysis. And diverse signaling pathways were investigated by Western blotting in MM cells. Results: Interestingly, radotinib caused cell death of MM cells. Radotinib induced Annexin V positive cells, and caspase pathway activation including caspase-3, -7 and -9. And its treatment remarkably decreased MMP in MM cells. As well as we observed that cytochrome c accumulated dose dependently in the cytosol of radotinib-treated RPMI-8226 and MM.1S cells. Moreover, radotinib decreased the expression of Bcl-xL and Bcl-2, and increased the expression of Bax and Bak in MM cells. Moreover, radotinib significantly suppressed MM cell growth in a xenograft animal model using RPMI-8226 cells. Conclusion: Radotinib may play an important role as a candidate or chemosensitizer for treatment agent in MM. These data indicate that radotinib has a potential for anti-cancer therapy in MM. Figure 1. Radotinib significantly suppressed MM cell growth in a xenograft animal model using RPMI-8226 cells. Citation Format: Jae-Cheol Jo, Sook-Kyoung Heo, Eui-Kyu Noh, Jeong Yi Kim, Jun Young Sung, Ho-Min Yu, Yoo Kyung Jeong, Lan Jeong Ju, Yunsuk Choi. Radotinib induces cell death of multiple myeloma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1250.
Abstract 3486: Combined inhibition of tumor suppressors PTEN and PP2A drives anoikis resistance and is associated with therapy relapse in prostate cancer
Authors: Christian Rupp, Aleksi Isomursu, Anna Aakula, Andrew Erickson, Song-Ping Li, Amanpreet Kaur, Pragya Shah, Yuba R. Pokharel, Lloyd Trottman, Jan Lammerding, Antti Rannikko, Pekka Taimen, Tuomas Mirtti, Ilkka Paatero, Johanna Ivaska, Jukka K. Westermarck
Journal: Cancer Research (2019)

Abstract Reactivation of tumor suppressor phosphatases may provide entirely novel opportunities for cancer therapy. Here, we discover clinically relevant functional co-operation between loss of activities of two human tumor suppressor phosphatases, PTEN, and PP2A. Analysis of prostate cancer tissue microarray material consisting of 358 patients treated primarily with radical prostatectomy revealed that overexpression of PP2A inhibitor protein PME-1 associates with significantly shorter time to therapy relapse in patients with PTEN-deficient PrCa. Further, PP2A inhibition by PME-1 overexpression in PTEN-deficient cell models inhibits apoptosis induction in anchorage-independent conditions (anoikis). PP2A reactivation by small molecules (SMAPs) was also found to inhibit viability of PTEN-deficient PrCa cells. Importantly, rather than regulating the well-known PP2A target pathways, PME-1 was found to physically associate with, and to regulate deformability of the nuclear lamina in PrCa cells. Mass spectrometry phosphoproteomics analysis identified several PME-1-regulated nuclear lamina constituents, and PME-1 deficient cells with compromised nuclear lamina were particularly vulnerable to apoptosis induction by mechanical stress. As a direct molecular target, Lamin A/C phosphorylation was found to be protected by PME-1-mediated PP2A inhibition under anoikis-inducing conditions. PME-1 inhibition in PrCa cells resulted in increased apoptosis in an in ovo tumor model, and PME-1-depleted cells had compromised long-term survival in zebrafish circulation. In summary we discover that PP2A reactivation by PME-1 targeting sensitizes PTEN-deficient PrCa cells to anoikis. Clinically, the results identify PME-1 as a novel candidate biomarker for increased relapse risk in PTEN-deficient PrCa, and indicate pharmacological PP2A activation as a novel potential therapeutic approach against circulating prostate cancer cells. At the general level, the results clearly emphasize the need for better understanding of phosphatases as key modulators of cancer progression. Citation Format: Christian Rupp, Aleksi Isomursu, Anna Aakula, Andrew Erickson, Song-Ping Li, Amanpreet Kaur, Pragya Shah, Yuba R. Pokharel, Lloyd Trottman, Jan Lammerding, Antti Rannikko, Pekka Taimen, Tuomas Mirtti, Ilkka Paatero, Johanna Ivaska, Jukka K. Westermarck. Combined inhibition of tumor suppressors PTEN and PP2A drives anoikis resistance and is associated with therapy relapse in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3486.