tbuckley/cabot-search huggingface dataset:
Abstract 6697: DT095895, a selective EP4 receptor antagonist with monotherapy efficacy in syngeneic mouse model(s) and best-in-class properties
Authors: Anne-Laure Blayo, Laurène Deshons, Alexia Dumont, Christel Franchet, Célia Halter, Ludovic Herbin, Gaël Hommet, Stanislas Mayer, Alban Bessede, Imane Nafia, Marjorie Sidhoum, Xavier Leroy, Stephan Schann
Journal: Cancer Research (2020)

Abstract Elevated levels of Prostaglandin E2 (PGE2), an eicosanoid notably synthesized by the cyclooxygenase-2 (COX-2), exert strong immunosuppressive effects in the tumor microenvironment. COX-2-positive solid tumors have the ability to use this pathway as a resistance mechanism, especially to escape from the host immune system, thus limiting the anti-tumor effects of immune checkpoint inhibitors (ICI). These immunosuppressive effects are largely mediated by the EP4 receptor, expressed on multiple immune cells. A novel series of EP4 receptor antagonists has been developed, with improved pharmacokinetic properties when compared to the EP4 receptor antagonists currently being evaluated in clinical trials. An intensive lead optimization program led to the identification of DT095895, a small molecule development candidate with a “best-in class” potential. Its preclinical package will be presented in the poster. DT095895 was assessed in multiple syngeneic mouse tumor models selected for their COX-2 expression profile. Efficacy was seen both in a monotherapy setting, as well as in combination with ICI. Additionally, a specific biomarker program was implemented and validated in order to show target engagement. A phospho-flow murine whole blood assay was set up to assess the ability of DT095895 to inhibit CREB phosphorylation induced by a selective EP4 receptor agonist in CD3+ cells. This biomarker was further developed for human whole blood to support Phase 1 and clinical trials studies. In conclusion, DT095895 is a selective EP4 receptor antagonist and demonstrates strong anti-tumor effects in multiple syngeneic mouse tumor models, both as a monotherapy and in combination with ICI, through the inhibition of the PGE2-induced immunosuppression. DT095895 progresses in regulatory development. Citation Format: Anne-Laure Blayo, Laurène Deshons, Alexia Dumont, Christel Franchet, Célia Halter, Ludovic Herbin, Gaël Hommet, Stanislas Mayer, Alban Bessede, Imane Nafia, Marjorie Sidhoum, Xavier Leroy, Stephan Schann. DT095895, a selective EP4 receptor antagonist with monotherapy efficacy in syngeneic mouse model(s) and best-in-class properties [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6697.
Risk factors and timing of subsequent cutaneous squamous cell carcinoma in patients with cutaneous squamous cell carcinoma: A retrospective cohort study
Authors: Marla Rodriguez, Brandon T. Beal, Manisha Manmohan, Elanee Simmons, Vamsi Varra, David Xiong, Anna Eversman, Isaac N. Briskin, Thomas Knackstedt, Allison T. Vidimos
Journal: Journal of the American Academy of Dermatology (2020)
mRNA Delivery Using Bioreducible Lipidoid Nanoparticles Facilitates Neural Differentiation of Human Mesenchymal Stem Cells
Authors: Xuewei Zhao, Zachary Glass, Jinjin Chen, Liu Yang, David L. Kaplan, Qiaobing Xu
Journal: Advanced Healthcare Materials (2020)

Abstract Mesenchymal stem cells (MSCs) are widely used in regenerative medicine and tissue engineering and delivering biological molecules into MSCs has been used to control stem cell behavior. However, the efficient delivery of large biomolecules such as DNA, RNA, and proteins into MSCs using nonviral delivery strategies remains an ongoing challenge. Herein, nanoparticles composed of cationic bioreducible lipid‐like materials (lipidoids) are developed to intracellularly deliver mRNA into human mesenchymal stem cells (hMSCs). The delivery efficacy to hMSCs is improved by adding three excipients including cholesterol, 1,2‐dioleoyl‐sn‐glycero‐3‐phosphoethanolamine (DOPE), and 1,2‐distearoyl‐sn‐glycero‐3‐phosphoethanolamine‐polyethylene glycol (DSPE‐PEG) during lipidoid nanoparticle formulation. Using an optimized lipidoid formulation, Cas9 mRNA and single guide RNA (sgRNA) targeting neuron restrictive silencing factor (NRSF) are delivered to hMSCs, leading to successful neural‐like differentiation as demonstrated by the expression of synaptophysin (SYP), brain‐derived neurotrophic factor (BDNF), neuron‐specific enolase (NSE), and neuron‐specific growth‐associated protein (SCG10). Overall, a synthetic lipid formulation that can efficiently deliver mRNA to hMSCs is identified, leading to CRISPR‐based gene knockdown to facilitate hMSCs transdifferentiation into neural‐like lineage.
Organic carbon monoxide prodrug, BW-CO-111, in protection against chemically-induced gastric mucosal damage
Authors: Dominik Bakalarz, Marcin Surmiak, Xiaoxiao Yang, Dagmara Wójcik, Edyta Korbut, Zbigniew Śliwowski, Grzegorz Ginter, Grzegorz Buszewicz, Tomasz Brzozowski, Jakub Cieszkowski, Urszula Głowacka, Katarzyna Magierowska, Zhixiang Pan, Binghe Wang, Marcin Magierowski
Journal: Acta Pharmaceutica Sinica B (2020)

Metal-based carbon monoxide (CO)-releasing molecules have been shown to exert anti-inflammatory and anti-oxidative properties maintaining gastric mucosal integrity. We are interested in further development of metal-free CO-based therapeutics for oral administration. Thus, we examine the protective effect of representative CO prodrug, BW-CO-111, in rat models of gastric damage induced by necrotic ethanol or aspirin, a representative non-steroidal anti-inflammatory drug. Treatment effectiveness was assessed by measuring the microscopic/macroscopic gastric damage area and gastric blood flow by laser flowmetry. Gastric mucosal mRNA and/or protein expressions of HMOX1, HMOX2, nuclear factor erythroid 2-related factor 2, COX1, COX2, iNos, Anxa1 and serum contents of TGFB1, TGFB2, IL1B, IL2, IL4, IL5, IL6, IL10, IL12, tumor necrosis factor α, interferon γ, and GM-CSF were determined. CO content in gastric mucosa was assessed by gas chromatography. Pretreatment with BW-CO-111 (0.1 mg/kg, i.g.) increased gastric mucosal content of CO and reduced gastric lesions area in both models followed by increased GBF. These protective effects of the CO prodrug were supported by changes in expressions of molecular biomarkers. However, because the pathomechanisms of gastric damage differ between topical administration of ethanol and aspirin, the possible protective and anti-inflammatory mechanisms of BW-CO-111 may be somewhat different in these models.
Thrombosis in <scp>COVID</scp>‐19
Authors: Thomas C. Hanff, Amir M. Mohareb, Jay Giri, Jordana B. Cohen, Julio A. Chirinos
Journal: American Journal of Hematology (2020)

Thrombotic complications are frequent in COVID-19 and contribute significantly to mortality and morbidity. We review several mechanisms of hypercoagulability in sepsis that may be upregulated in COVID-19. These include immune-mediated thrombotic mechanisms, complement activation, macrophage activation syndrome, antiphospholipid antibody syndrome, hyperferritinemia, and renin-angiotensin system dysregulation. We highlight biomarkers within each pathway with potential prognostic value in COVID-19. Lastly, recent observational studies have evaluated a role for the expanded use of therapeutic anticoagulation in COVID-19. We review strengths and weaknesses of these studies, and we also discuss the hypothetical benefit and anticipated challenges of fibrinolytic therapy in COVID-19.
Identification of subtypes in colorectal cancer and their prognostic values
Authors: R. D. Kennedy, V. Proutski, A. Tanney, A. Winter, J. M. Black, P. Kerr, P. G. Johnston, D. P. Harkin
Journal: Journal of Clinical Oncology (2009)

4041 Background: The discovery and widespread acceptance of molecular subtypes in breast cancer has changed the way that this disease is viewed. Similarly, we have focussed on stage II colorectal cancer where 20–25% of patients are at risk of recurrent disease following surgery. There are currently several types of colorectal cancer recognised by histopathological methods, however, little has been published regarding disease classification at a molecular level. Methods: We have taken an unbiased approach to the molecular classification of colorectal cancer. Using a colorectal cancer disease specific microarray platform we have performed expression profiling and bioinformatic analysis of 500 formalin fixed and paraffin embedded (FFPE) stage II colorectal cancer samples, in order to identify and characterise molecular subtypes. Results: We have identified molecular subtypes for colorectal cancer. One of these subtypes is enriched with tumours with microsatellite instability (MSI) that are predominantly proximal, mucinous and poorly differentiated. It is notable that while MSI is generally accepted to be associated with a good prognosis, we have found both good and poor prognosis patients within this subtype. A second subtype contains tumors with a low CpG island methylator phenotype. Another subtype is defined by an expression pattern consistent with activation of tumor suppressors. The remaining subtypes are newly identified. Conclusions: We have identified molecular subtypes in colorectal cancer. We will present how knowledge about these subtypes may affect patient management and may be used to guide the development of novel therapeutic strategies. [Table: see text]
Changes in Peripheral and Local Tumor Immunity after Neoadjuvant Chemotherapy Reshape Clinical Outcomes in Patients with Breast Cancer
Authors: Margaret L. Axelrod, Mellissa J. Nixon, Paula I. Gonzalez-Ericsson, Riley E. Bergman, Mark A. Pilkinton, Wyatt J. McDonnell, Violeta Sanchez, Susan R. Opalenik, Sherene Loi, Jing Zhou, Sean Mackay, Brent N. Rexer, Vandana G. Abramson, Valerie M. Jansen, Simon Mallal, Joshua Donaldson, Sara M. Tolaney, Ian E. Krop, Ana C. Garrido-Castro, Jonathan D. Marotti, Kevin Shee, Todd W. Miller, Melinda E. Sanders, Ingrid A. Mayer, Roberto Salgado, Justin M. Balko
Journal: Clinical Cancer Research (2020)

Abstract Purpose: The recent approval of anti-programmed death-ligand 1 immunotherapy in combination with nab-paclitaxel for metastatic triple-negative breast cancer (TNBC) highlights the need to understand the role of chemotherapy in modulating the tumor immune microenvironment (TIME). Experimental Design: We examined immune-related gene expression patterns before and after neoadjuvant chemotherapy (NAC) in a series of 83 breast tumors, including 44 TNBCs, from patients with residual disease (RD). Changes in gene expression patterns in the TIME were tested for association with recurrence-free (RFS) and overall survival (OS). In addition, we sought to characterize the systemic effects of NAC through single-cell analysis (RNAseq and cytokine secretion) of programmed death-1–high (PD-1HI) CD8+ peripheral T cells and examination of a cytolytic gene signature in whole blood. Results: In non-TNBC, no change in expression of any single gene was associated with RFS or OS, while in TNBC upregulation of multiple immune-related genes and gene sets were associated with improved long-term outcome. High cytotoxic T-cell signatures present in the peripheral blood of patients with breast cancer at surgery were associated with persistent disease and recurrence, suggesting active antitumor immunity that may indicate ongoing disease burden. Conclusions: We have characterized the effects of NAC on the TIME, finding that TNBC is uniquely sensitive to the immunologic effects of NAC, and local increases in immune genes/sets are associated with improved outcomes. However, expression of cytotoxic genes in the peripheral blood, as opposed to the TIME, may be a minimally invasive biomarker of persistent micrometastatic disease ultimately leading to recurrence.
Cyclin D1 Driven CDK4 Activity Is Responsible for Hypersensitivity to NOXA Inducing Combination Treatment in Mantle Cell Lymphoma (MCL) Cells
Authors: Simon Heine, Elisabeth Silkenstedt, Michael A Dengler, Kleih Markus, German Ott, Neus Giménez Carabaza, Colomer Dolors, Heiko van der Kuip, Walter E. Aulitzky
Journal: Blood (2017)
Frontline Azacitidine As a Bridge to Allogeneic Transplantation in Acute Myeloid Leukemia
Authors: Michael Richard Grunwald, Michael Keith Allister Zimmerman, Danielle Boselli, Lauren M. Bohannon, Myra M Robinson, Daniel T. Peters, Jing Ai, Thomas G. Knight, Jigar Trivedi, Dragos Plesca, James T Symanowski, Edward A Copelan, Jonathan M. Gerber
Journal: Blood (2017)
Predictors of Response and Survival in 206 AML Patients Treated with Guadecitabine in a Phase 2 Study
Authors: Hagop M. Kantarjian, Gail J. Roboz, Patricia L Kropf, Elias J. Jabbour, Karen W.L. Yee, Casey L. O'Connell, Guillermo Garcia-Manero, Elizabeth A. Griffiths, Katherine J. Walsh, Wendy Stock, Raoul Tibes, Nikolai A. Podoltsev, Yong Hao, Valerie Ahanonu, Mohammad Azab, Jean-Pierre Issa
Journal: Blood (2017)
Phase I clinical trial with VEGFR2-epitope peptide and gemcitabine for patients with advanced pancreatic cancer
Authors: H. Yamaue, M. Miyazawa, R. Ohsawa, M. Tani, M. Kawai, S. Hirono, S. Ina, T. Tsunoda, Y. Nakamura
Journal: Journal of Clinical Oncology (2009)

2567 Background: The prognosis of pancreatic cancer patients is one of the most dismal of all cancers. Gemcitabine is a potent anticancer drug for pancreatic cancer, however, one should consider that the clinical benefit of anticancer drugs is limited and other potent therapeutic tool is eagerly awaited. Vascular endothelial growth factor (VEGF) is a glycoprotein which is predominantly related to the neoplastic angiogenesis. VEGF-receptor 2 (VEGFR2; Flk-1 and KDR) is an essential target for tumor angiogenesis. We first identify the epitope peptides of vascular endothelial growth factor receptor 2 (VEGFR2) and confirmed that stimulation using these peptides induces CTLs with potent cytotoxicity in HLA class I-restricted fashion. Methods: We proceeded to Phase I clinical trial using gemcitabine and one of these peptides. Patients were sequentially allocated to cohorts of 6 patients per group receiving 0.5, 1.0, 2.0mg of peptides/body. No intra-patient dose escalation was permitted. The eligibility criteria are: being aged between 20- and 80- year old, expecting the survival more than 3 months after the initiation of this treatment, adequate organ function including bone marrow function, and having HLA-A*2402 (A24) genotype. The enrolled patients received 4 cycles of VEGFR2 peptide sc. and 3 cycles of 1,000 mg/m2 gemcitabine weekly. Results: No patients had grade 3 and 4 toxicity, and dose escalation was succeeded without any DLT. CTL response was observed in 50%, 67%, and 67% of 0.5mg, 1.0mg, and 2.0mg cohort, respectively. The delayed type hypersensitivity of the peptide-injection site was recognized in 83%, 67%, and 100% of 0.5mg, 1.0mg, and 2.0mg cohort, respectively. Therefore, we concluded that MTD should be 2.0mg of peptide. Disease control rate (&gt;SD) was 67% (12/18 patients), and one patient had PR. The median survival time was 8.72 months. Conclusions: These results are promising to proceed the pivotal clinical trial, and the randomized phase II/III trial will start in 2009. No significant financial relationships to disclose.
Autologous EBV-Specific T Cells (CMD-003): Early Results from a Multicenter, Multinational Phase 2 Trial for Treatment of EBV-Associated NK/T-Cell Lymphoma
Authors: Won Seog Kim, Kirit M. Ardeshna, Yi Lin, Yasuhiro Oki, Jia Ruan, Eric D. Jacobsen, Dok Hyun Yoon, Cheolwon Suh, Felipe Suarez, Pierluigi Porcu, Jonathan E Brammer, John Radford, Lihua E. Budde, Jin Seok Kim, Gilles Salles, Catherine M. Bollard, Arnaud Jaccard, Hye Jin Kang, Shannon Inman, Maryann Murray, Kurt C. Gunter, Daniel Y. Lee, Cliona M. Rooney, Helen E. Heslop
Journal: Blood (2017)
Association of the level of HER2/neu (HER2) gene amplification in breast cancer and the magnitude of antigen specific T-cell immunity achieved after HER2 vaccination
Authors: D. Wallace, M. Disis, A. Coveler, D. Higgins, J. Childs, N. Bates, L. Salazar, M. Slota, Y. Dang, J. Waisman
Journal: Journal of Clinical Oncology (2009)

3059 Background: Studies have demonstrated that the level of HER2 gene amplification in breast cancer, assessed by fluorescence in situ hybridization (FISH), correlates with favorable clinical response after treatment with trastuzumab. We questioned whether HER2 gene amplification impacted the development of HER2-specific T-cell immunity following immunization with a HER2 vaccine. Methods: Patients with HER2+ stage III or IV breast cancer, treated to complete remission or stable bone only disease, were enrolled in one of two concurrent clinical trials of HER2-specific vaccines. Eligibility criteria between the two studies were similar. Patients received either a plasmid DNA-based vaccine encoding the HER2 intracellular domain or a peptide-based vaccine composed of 3 HER2 class II epitopes. Peripheral blood was assessed for HER2-specific T-cell responses by interferon gamma (IFN-g) ELISPOT prior to, immediately after, and 6 months to 1 year after the end of vaccinations. Both immune response and FISH data were available on 31 patients. Results: Correlation of FISH levels to IFN-g spots/well in evaluable patients revealed the level of HER2 gene amplification was not related to the presence of pre-existent HER2-specific T-cell immunity prior to vaccination (p=0.43), the generation of a HER2-specific immune response after vaccination (p=0.35), or the persistence of the HER2-specific T-cell response (p=0.33). However, the magnitude of the T-cell response achieved was less as HER2 gene amplification increased (p=0.05). Conclusions: The level of HER2 gene amplification in the primary tumor can adversely impact the magnitude of HER2-specific T-cell immunity achieved after vaccination. No significant financial relationships to disclose.
FRI0033 Erythropoietin-receptor-expression in fibroblast-like synoviocytes
Authors: U Kessler, S Woelfer, N Kukoc-Zivojnov, JP Kaltwasser, B Moeller
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> The anaemia of chronic disease in patients with rheumatoid arthritis (RA) can be corrected by treatment with recombinant human erythropoietin (rHu-Epo). In addition to an increase of haemoglobin concentration during therapy with rHu-Epo, a significant reduction of disease activity was observed in different RA-studies. Especially the decrease of the number of swollen and tender joints during rhu-Epo treatment suggests a direct anti-inflammatory effect of rHu-Epo. <h3>Objectives</h3> As the expression of the erythropoietin-receptor (Epo-R) was recently shown for different non-erythroid cells – as for example endothelial and neuronal cells, we investigated the expression of Epo-R in fibroblast-like synoviocytes to gain a first experimental approach for the observed anti-inflammatory effect of rHu-Epo in RA. <h3>Methods</h3> We cultivated fibroblast-like synoviocytes derived from synovial membranes (n = 17) or synovial fluid (n = 13) that were gained from patients with RA (n = 22), osteoarthritis (n = 3) or spondylarthropathy (n = 5). Biopsy material has been minced and digested with collagenase, fluid derived cells have been directly cultured. Cells were passaged two to five times and characterised by FACS analysis. Expression of Epo-R was determined by nested RT-PCR. The chosen primers annealed at Exon III (forward primer 1 and 2), Exon VIII (backward primer 1) and Exon VII (backward primer 2). The obtained PCR-product was sequenced by automated fluorescent DNA sequencing. <h3>Results</h3> The cultured cells morphologically represented fibroblast-like cells. It was shown by FACS analysis that they were CD14 and CD86 negative and CD54 and CD90-Thy-1 positive. RT-PCR products representing the human Epo-R could be demonstrated in fibroblast-like synoviocytes from biopsy and arthrocentesis from patients with RA, OA and SpA. The specifity of the PCR products could be proven by sequencing of the product of three different cell-lines. The obtained sequence was completely identical with that of the DNA data base for more than 350 bases (Exon IV to Exon VI). <h3>Conclusion</h3> We could demonstrate for the first time the expression of Epo-R in fibroblast-like synoviocytes. This observation gives evidence that rHu-Epo directly afflicts fibroblast-like synoviocytes (via Epo-R) and therefore provides a possible explanation for the anti-inflammatory effect of rHu-Epo in patients with RA.
CaMKIIδC Drives Early Adaptive Ca <sup>2+</sup> Change and Late Eccentric Cardiac Hypertrophy
Authors: Senka Ljubojevic-Holzer, Anthony W. Herren, Natasa Djalinac, Julia Voglhuber, Stefano Morotti, Michael Holzer, Brent M. Wood, Mahmoud Abdellatif, Ingrid Matzer, Michael Sacherer, Snjezana Radulovic, Markus Wallner, Milan Ivanov, Stefan Wagner, Samuel Sossalla, Dirk von Lewinski, Burkert Pieske, Joan Heller Brown, Simon Sedej, Julie Bossuyt, Donald M. Bers
Journal: Circulation Research (2020)

Rationale: CaMKII (Ca 2+ -Calmodulin dependent protein kinase) δC activation is implicated in pathological progression of heart failure (HF) and CaMKIIδC transgenic mice rapidly develop HF and arrhythmias. However, little is known about early spatio-temporal Ca 2+ handling and CaMKII activation in hypertrophy and HF. Objective: To measure time- and location-dependent activation of CaMKIIδC signaling in adult ventricular cardiomyocytes, during transaortic constriction (TAC) and in CaMKIIδC transgenic mice. Methods and Results: We used human tissue from nonfailing and HF hearts, 4 mouse lines: wild-type, KO (CaMKIIδ-knockout), CaMKIIδC transgenic in wild-type (TG), or KO background, and wild-type mice exposed to TAC. Confocal imaging and biochemistry revealed disproportional CaMKIIδC activation and accumulation in nuclear and perinuclear versus cytosolic regions at 5 days post-TAC. This CaMKIIδ activation caused a compensatory increase in sarcoplasmic reticulum Ca 2+ content, Ca 2+ transient amplitude, and [Ca 2+ ] decline rates, with reduced phospholamban expression, all of which were most prominent near and in the nucleus. These early adaptive effects in TAC were entirely mimicked in young CaMKIIδ TG mice (6–8 weeks) where no overt cardiac dysfunction was present. The (peri)nuclear CaMKII accumulation also correlated with enhanced HDAC4 (histone deacetylase) nuclear export, creating a microdomain for transcriptional regulation. At longer times both TAC and TG mice progressed to overt HF (at 45 days and 11–13 weeks, respectively), during which time the compensatory Ca 2+ transient effects reversed, but further increases in nuclear and time-averaged [Ca 2+ ] and CaMKII activation occurred. CaMKIIδ TG mice lacking δB exhibited more severe HF, eccentric myocyte growth, and nuclear changes. Patient HF samples also showed greatly increased CaMKIIδ expression, especially for CaMKIIδC in nuclear fractions. Conclusions: We conclude that in early TAC perinuclear CaMKIIδC activation promotes adaptive increases in myocyte Ca 2+ transients and nuclear transcriptional responses but that chronic progression of this nuclear Ca 2+ -CaMKIIδC axis contributes to eccentric hypertrophy and HF.