tbuckley/cabot-search huggingface dataset:
Abstract 1331: Synthesis and evaluation of FPR1 inhibitors as a novel treatment for cancers
Authors: Amin Aghamohammadi, Di Lu, Anwar Salem, Patricia A. Cooper, Steven D. Shnyder, Victoria Vinader, Kamyar Afarinkia
Journal: Cancer Research (2021)

Abstract The formyl peptide receptor-1 (FPR1) is a member of 7TM GPCRs. It was first identified in phagocytic leukocytes and has been found to play a role in innate immune response to bacterial infection. Recently FPR1 has been shown to be overexpressed in many malignant cancers and particularly in glioblastoma. Our more recent investigation has shown that increased expression of FPR1 in cancer is most notably prominent in the periphery of the necrotic foci. We have hypothesised that FPR1 activation by molecules released from the hypoxic/necrotic core of tumours (including Annexin-A1 and short chain-N-formylated peptides such as fMLF) leads to increased proliferation, invasion, resistance, and angiogenesis. Therefore, antagonism of FPR1 should prevent these key drivers of malignancy in cancer. Here we present the synthesis and biological evaluation of a series of pyrazole compounds that potently inhibit FPR1. In addition, we provide a computational rationale for their relative potency based on docking of the molecules inside a homology model of FPR1. We will also show the efficacy of our lead compound, ICT12035 (IC50 =30nM in calcium mobilisation assay) in a number 2D and 3D proliferation and invasion assays in vitro, and in an in vivo animal model where it arrests tumour growth. Furthermore, we demonstrate the significance of FPR1 in tumour resistance by showing that ICT12035 increases the efficacy of cytotoxic agents TMZ and BCNU, as well as radiation in vitro. ICT12035 significantly abrogates the effects fMLF induced resistance to TMZ and BCNU in in U87 cell lines. A similar effect is also observed in a cell viability assay where in the addition of ICT12035 significantly increased cell death following radiation. Our findings suggest that inhibiting FPR1 in combination with chemotherapy and radiotherapy could be a new treatment strategy against cancers. Citation Format: Amin Aghamohammadi, Di Lu, Anwar Salem, Patricia A. Cooper, Steven D. Shnyder, Victoria Vinader, Kamyar Afarinkia. Synthesis and evaluation of FPR1 inhibitors as a novel treatment for cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1331.
Outcomes of serial multiparametric magnetic resonance imaging in patients managed with active surveillance for prostate cancer
Authors: S. Luzzago, M.L. Piccinelli, M. Fontana, F.M.G. Botticelli, G. Cozzi, F.A. Mistretta, M. Catellani, R. Bianchi, A. Cioffi, E. Di Trapani, P. Pricolo, S. Alessi, A. Brescia, M. Ferro, D.V. Matei, G. Petralia, G. Musi, O. De Cobelli
Journal: European Urology (2021)
Abstract 968: Focal adhesion kinase (FAK) inhibitor APG-2449 sensitizes ovarian tumors to chemotherapy via CD44 downregulation
Authors: Ran Tao, Douglas D. Fang, Yuanbao Li, Kaixiang Zhang, Chunhua Xu, Xu Fang, Qixin Wang, Dajun Yang, Yifan Zhai
Journal: Cancer Research (2021)

Abstract Ovarian cancer is one of the deadliest malignancies in women, and up to 70% of patients with epithelial ovarian cancer have FAK overexpression, amplification, or activation. FAK plays an important role in cellular migration, growth factor signaling, cell cycle progression, cellular survival and chemoresistance. This biomarker is also significantly associated with higher tumor stage, metastasis, and shorter overall survival in patients with ovarian cancer. Inhibition of FAK is therefore emerging as a promising treatment target. APG-2449 is a clinical stage FAK/ALK/ROS1 multi-kinase inhibitor. In this study we investigated antitumor activity of APG-2449 combined with standard-of-care chemotherapeutics in ovarian cancer in the preclinical setting. In a mouse xenograft tumor model derived from ovarian cancer cell line OVCAR-3, which was resistant to platinum-based therapies, APG-2449 combined with paclitaxel, and paclitaxel plus carboplatin, synergistically enhanced antitumor activity, whereas the chemotherapeutics showed no activity. Synergistic antitumor activity was also observed in multiple patient-derived xenograft (PDX) models derived from women with chemoinsensitive ovarian cancer, which also frequently expresses high levels of FAK. By comparing gene expression profiles of PDX tumors obtained from responders and nonresponders to the combined therapy, we identified CD44 (a marker for cancer stem cells) as a potentially predictive biomarker. Western blot analysis confirmed higher protein levels of CD44 in pretreated tumors of responders. Interestingly, downregulation of CD44 levels was observed in combination-treated tumors, suggesting that these combinations reduced cancer stem cell populations in ovarian cancer. Accordingly, in ovarian cancer cells exposed to APG-2449 alone or combined with paclitaxel, numbers of cells positive for CD44 or aldehyde dehydrogenase 1 (ALDH1; another marker for cancer stem cells) decreased in a dose-dependent manner. In summary, our data suggest that FAK inhibition by APG-2449 sensitizes ovarian tumors to chemotherapeutics in preclinical tumor models of ovarian cancer. The synergistic antitumor activity was mediated by downregulation of CD44+ or ALDH1+ cancer stem cell populations. These findings encourage clinical development of APG-2449 in combination with chemotherapies for treatment of ovarian cancer. Citation Format: Ran Tao, Douglas D. Fang, Yuanbao Li, Kaixiang Zhang, Chunhua Xu, Xu Fang, Qixin Wang, Dajun Yang, Yifan Zhai. Focal adhesion kinase (FAK) inhibitor APG-2449 sensitizes ovarian tumors to chemotherapy via CD44 downregulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 968.
Abstract 2503: Crispr/cas-9-mediated genome editing reveals that RBPMS acts as a tumor suppressor in ovarian cancer
Authors: Rohit K. Sharma, Ginette S. Santiago-Sánchez, Robert J. Rabelo-Fernández, Blanca I. Quiñones-Díaz, Fatima Valiyeva, Pablo E. Vivas-Mejia
Journal: Cancer Research (2021)

Abstract RNA-Binding Protein with Multiple Splicing (RBPMS) is a member of a family of proteins that bind to the nascent RNA transcripts and regulate their processing, which includes pre-mRNA splicing and transport/localization/stability of the RNA molecule. Evidence indicates that RBPMS also binds to members of the AP-1 (c-Jun and c-Fos) transcription factor repressing his activity. Until now, little is known about the biological function of RBPMS in ovarian cancer. To understand the role of RBPMS in ovarian cancer we generated CRISPR (clustered regularly interspaced short palindromic repeats)-mediated RBPMS knock-out vectors that were stably transfected in the ovarian cancer cells OVCAR3. The Guide-it Genotype confirmation Kit was used to determine the type of mutations (monoallelic, biallelic, or unchanged) present in the developed clones. Additionally, resulting CRISPR-cleavage products were analyzed to establish the cleavage efficiency of the Cas9/sgRNA complex by densitometry analysis. We found that CRISPR clone cells grow faster and increase their invasiveness ability compared with control CRISPR cells. Furthermore, immunohistochemical (IHC) analysis in a tissue array showed that RBPMS staining was significantly lower in high-grade serous ovarian cancer (HGSOC) tissues as compared to normal ovarian tissues. RBPMS was also decreased in platinum-resistant ovarian cancer cells as compared to platinum-sensitive cancer cells. Senescence-associated β-galactosidase (β-Gal) levels were higher in CRISPR-clones as compared with empty vector and ovarian cancer cells, which suggest RBPMS knockdown induces senescence. These studies along with the data of proteomics and RNAseq suggest that RBPMS acts as a tumor suppressor gene and lower levels of RBPMS are associated with the cisplatin resistance of ovarian cancer cells. Citation Format: Rohit K. Sharma, Ginette S. Santiago-Sánchez, Robert J. Rabelo-Fernández, Blanca I. Quiñones-Díaz, Fatima Valiyeva, Pablo E. Vivas-Mejia. Crispr/cas-9-mediated genome editing reveals that RBPMS acts as a tumor suppressor in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2503.
Abstract 1461: PHI-101, a potent and novel inhibitor of CHK2 in ovarian and breast cancer cells
Authors: June H-J Han, Kyu-Tae Kim, Jeejin Im, Sojung Park, Min Kyung Choi, Inki Kim, Ky-Youb Nam, JeongHyeok Yoon
Journal: Cancer Research (2021)

Abstract Purpose: Development of the potent and selective checkpoint kinase 2 (CHK2) inhibitor to overcome limiting clinical utility of poly(ADP-ribose) polymerase 1 (PARP1) inhibitors. Experimental Procedure: Preclinical evaluation of PHI-101 for cellular and molecular potency in ovarian and breast cancer cell lines and patient derived primary cells; it includes biochemical binding assay, cellular assays, animal efficacy studies, combination study, signaling pathway effect examination, and cell cycle analysis. Summary: CHK2 is a serine/threonine kinase and a cell cycle checkpoint regulator involved in the ATM-mediated DNA repair upon replication blocks and DNA damage. It has been proposed that Chk2 functions as a barrier to tumorigenesis by maintaining genomic stability, and this DNA damage induction is thought to prevent or delay genetic instability and tumorigenesis. The inhibition of CHK2 is a promising approach to achieve synthetic lethality of cancer cells when combined with PARP1 inhibitors. Solid cancer indications of PHI-101 was identified by the Chemiverse Network module which is an AI and Big data-based in-house drug discovery platform. Biochemical kinase assays for PHI-101 showed stronger affinity to CHK2 over CHK1 more than 5-fold. PHI-101 treatment of ovarian and breast cancer cells for 72 hrs elicit a synergistic lethal response in combination with PARP1 inhibitor Olaparib regardless of functional BRCA and P53 in the cells. PHI-101 also potentiates a countermeasure to dose-limiting toxicity triggered by genotoxic agents such as cisplatin and topotecan. The present results from in vivo and in vitro preclinical testing do demonstrate that PHI-101 is a highly potent inhibitor of CHK2 and may exert mono- and combinational therapeutic activity in ovarian and breast cancer model. Conclusion: The preclinical evaluation of PHI-101, a novel CHK2 inhibitor, showed clear evidence of anticancer activity for refractory ovarian and breast cancer cells and improved efficacy in both in vitro and in vivo models. Consequently, PHI-101 is currently under investigation in Phase 1 clinical trials for relapsed or refractory ovarian cancer patients. Citation Format: June H-J Han, Kyu-Tae Kim, Jeejin Im, Sojung Park, Min Kyung Choi, Inki Kim, Ky-Youb Nam, JeongHyeok Yoon. PHI-101, a potent and novel inhibitor of CHK2 in ovarian and breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1461.
Defining the ideal urology training programme from the trainee’s and professor’s perspective: Is there a concordance in their idea of good training?
Authors: G. Mantica, D.M. Carrion, K.H. Pang, T. Ucar, S. Parodi, S. Tappero, L. Lazarou, I. Glykas, C. Zambaftis, M. Lourenco, D.A. Gonzalez Padilla, L.E. Ortega Polledo, J. Gomez Rivas, F. Esperto
Journal: European Urology (2021)
Cyclic GMP modulating drugs in cardiovascular diseases: mechanism-based network pharmacology
Authors: Alexandra Petraina, Cristian Nogales, Thomas Krahn, Hermann Mucke, Thomas F Lüscher, Rodolphe Fischmeister, David A Kass, John C Burnett, Adrian J Hobbs, Harald H H W Schmidt
Journal: Cardiovascular Research (2021)

Mechanism-based therapy centred on the molecular understanding of disease-causing pathways in a given patient is still the exception rather than the rule in medicine, even in cardiology. However, recent successful drug developments centred around the second messenger cyclic guanosine-3'-5'-monophosphate (cGMP), which is regulating a number of cardiovascular disease modulating pathways, are about to provide novel targets for such a personalized cardiovascular therapy. Whether cGMP breakdown is inhibited or cGMP synthesis is stimulated via guanylyl cyclases or their upstream regulators in different cardiovascular disease phenotypes, the outcomes seem to be so far uniformly protective. Thus, a network of cGMP-modulating drugs has evolved that act in a mechanism-based, possibly causal manner in a number of cardiac conditions. What remains a challenge is the detection of cGMPopathy endotypes amongst cardiovascular disease phenotypes. Here, we review the growing clinical relevance of cGMP and provide a glimpse into the future on how drugs interfering with this pathway may change how we treat and diagnose cardiovascular diseases altogether.
Pilot Use of a Novel DNA Methytransferase -1 (DNMT1) Flow Cytometric Pharmacodynamic Assay to Evaluate Response to Low-Dose Azacitidine Therapy for Acute Myeloid Leukemia or Myelodysplastic Syndrome Relapse after Allogeneic Hematopoietic Cell Transplantation
Authors: Najla H El Jurdi, Masumi Ueda, Philip Woost, Hillard M Lazarus, Paolo Caimi, Brenda W. Cooper, Richard Creger, Jane A. Little, Linda Baer, Lauren Brister, Ehsan Malek, Leland Metheny, Folashade Otegbeye, Ben K. Tomlinson, Basem M. William, James Jacobberger, Marcos De Lima
Journal: Blood (2017)
Abstract 1147: RNA-targeting approaches to modulate alternative RNA splicing in cancer
Authors: Nathan K. Leclair, Laura Urbanski, Mattia Brugiolo, Marina Yurieva, Brenton R. Graveley, Albert Cheng, Olga Anczukow
Journal: Cancer Research (2021)

Abstract Alternative RNA splicing (AS) is a critical step in gene expression regulation. This differential inclusion of sequences in the mRNA is a source of functional transcriptomic diversity that allows multiple RNA isoforms to be expressed from the same gene. Dysregulation of AS is hallmark of cancer and leads to the expression of RNA isoforms that promote tumor initiation and maintenance. Understanding how tumor-associated RNA isoforms impact cancer biology is needed for the development of cancer therapies targeting AS. Here, we describe two approaches to modulate AS in cancer cells. First, we utilize CRISPR-Artificial Splicing Factors (CASFx), splicing factor domains fused to catalytically inactive Cas13 proteins, to direct splicing activity to a specific site using a guide RNA (gRNA). We demonstrate that this approach can be used to promote either exon inclusion or skipping in mRNA from several cancer-associated genes (e.g., HRAS, EP400, TRA2β, SRSF3) depending on the gRNA binding location and the splicing-factor domain fusion. Second, we develop antisense oligonucleotides (ASOs) that target a non-coding poison exon in the oncogenic splicing factor TRA2β. This exon functions as a regulatory “poison exon”, which induces RNA degradation when included, and is differentially spliced in multiple tumor types compared to their corresponding adjacent normal tissue. TRA2β-targeting ASOs promoting poison exon inclusion cause decreased TRA2β protein expression, increased cell death, and decreased proliferation across multiple cancer cell lines. Additionally, compared to cancer cells, normal cell lines were less affected by TRA2β-targeting ASO toxicity, demonstrating a therapeutic window for using this technology to specifically target cancer cells. Citation Format: Nathan K. Leclair, Laura Urbanski, Mattia Brugiolo, Marina Yurieva, Brenton R. Graveley, Albert Cheng, Olga Anczukow. RNA-targeting approaches to modulate alternative RNA splicing in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1147.
Post-operative infections, a silver lining from the COVID-19 pandemic. A retrospective cohort study from urology departments
Authors: B.L. Teixeira, J.F. Cabral, G. Mendes, M. Madanelo, M.A. Rcoha, S. Mesquita, J.R. Correia, C. Tavares, A. Marques-Pinto, F. Vila, J. Lindoro, A. Fraga
Journal: European Urology (2021)
Covid-19: Vaccines journal retracts controversial paper after editorial board members quit
Authors: Jacqui Wise
Journal: BMJ (2021)

The dynamic regulation of DNA methylation in postmitotic neurons is necessary for memory formation and other adaptive behaviors. Ten-eleven translocation 1 (TET1) plays a part in these processes by oxidizing 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), thereby initiating active DNA demethylation. However, attempts to pinpoint its exact role in the nervous system have been hindered by contradictory findings, perhaps due in part, to a recent discovery that two isoforms of the <i>Tet1</i> gene are differentially expressed from early development into adulthood. Here, we demonstrate that both the shorter transcript (<i>Tet1<sup>S</sup></i>) encoding an N-terminally truncated TET1 protein and a full-length <i>Tet1</i> (<i>Tet1<sup>FL</sup></i>) transcript encoding canonical TET1 are co-expressed in the adult mouse brain. We show that <i>Tet1<sup>S</sup></i> is the predominantly expressed isoform and is highly enriched in neurons, whereas <i>Tet1<sup>FL</sup></i> is generally expressed at lower levels and more abundant in glia, suggesting their roles are at least partially cell type-specific. Using viral-mediated, isoform and neuron-specific molecular tools, we find that the individual repression of each transcript leads to the dysregulation of unique gene ensembles and contrasting changes in basal synaptic transmission. In addition, <i>Tet1<sup>S</sup></i> repression enhances, while <i>Tet1<sup>FL</sup></i> impairs, hippocampal-dependent memory in male mice. Together, our findings demonstrate that each <i>Tet1</i> isoform serves a distinct role in the mammalian brain. <b>SIGNIFICANCE STATEMENT</b> In the brain, activity-dependent changes in gene expression are required for the formation of long-term memories. DNA methylation plays an essential role in orchestrating these learning-induced transcriptional programs by influencing chromatin accessibility and transcription factor binding. Once thought of as a stable epigenetic mark, DNA methylation is now known to be impermanent and dynamically regulated, driving neuroplasticity in the brain. We found that <i>Tet1</i>, a member of the ten-eleven translocation (TET) family of enzymes that mediates removal of DNA methyl marks, is expressed as two separate isoforms in the adult mouse brain and that each differentially regulates gene expression, synaptic transmission and memory formation. Together, our findings demonstrate that each <i>Tet1</i> isoform serves a distinct role in the CNS.
Abstract 274: Comparison of proteomics identification pipelines for lymphocyte characterization
Authors: Michaela A. McCown, Carolyn Allen, Daniel D. Machado, Samuel H. Payne
Journal: Cancer Research (2021)

Abstract Proteomics analyses can be adapted to samples as small as a single cell, however such sample reduction severely limits the number proteins identified and quantified. Multiple software pipelines exist for processing the raw data to quantitative protein tables. For very small sample amounts, the sensitivity of software algorithms can have a significant impact on the final results. We collected whole blood samples for two subjects by venous blood draws. Using antibody guided flow cytometry cell sorting, we separated B and T cell lymphocytes. For two subjects and two different blood collections, five replicates of 145 B cells or T cells were prepared for mass spectrometry for proteomics using the AutoPOTS workflow. Using the raw files from these forty runs, we perform protein quantification with a selection of common tools such as MaxQuant, ProteomeDiscoverer, and FragPipe and compare the number of identified and quantified proteins. In small sample proteomics, the primary objective is obtaining the most quantified proteins. Although each tool has advantages in terms of usability, speed, and sensitivity, our primary concern is sensitivity. At such a low sample input, we observe that the number of quantified proteins increases by 30% using the most sensitive algorithm. For identifying and quantifying proteins from small samples, the sensitivity of the software is the most important factor to consider. In addition to the identification sensitivity of each algorithm, we are exploring optimal parameters for increased protein quantification. Differences between samples appear regardless of the processing tool, showing that using a less sensitive tool will still characterize the trends but with a significant cost to the number of proteins. Using the most sensitive algorithm for small sample proteomics will greatly improve the number of proteins identified and quantified. Citation Format: Michaela A. McCown, Carolyn Allen, Daniel D. Machado, Samuel H. Payne. Comparison of proteomics identification pipelines for lymphocyte characterization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 274.
Nicotine inhibits the VTA-to-amygdala dopamine pathway to promote anxiety
Authors: Claire Nguyen, Sarah Mondoloni, Tinaïg Le Borgne, Ines Centeno, Maxime Come, Joachim Jehl, Clément Solié, Lauren M. Reynolds, Romain Durand-de Cuttoli, Stefania Tolu, Sébastien Valverde, Steve Didienne, Bernadette Hannesse, Jean-François Fiancette, Stéphanie Pons, Uwe Maskos, Véronique Deroche-Gamonet, Deniz Dalkara, Jean-Pierre Hardelin, Alexandre Mourot, Fabio Marti, Philippe Faure
Journal: Neuron (2021)