tbuckley/cabot-search huggingface dataset:
Abstract 3077: ATRXLoss and IDH1R132H impair self-renewal of glioma stem cells after proton radiotherapy
Authors: Ángel Adrian Garcés, Lawrence Bronk, Krishna P. Bhat, David R. Grosshans
Journal: Cancer Research (2021)

Abstract Background: Glioblastoma Multiforme (GBM-Grade IV) is the most aggressive form of glioma in the USA carrying only a 15 month median survival time. IDH1R132H is an early onset mutation present in 70-80% of low grade gliomas (LGG-Grade I and II) and secondary GBM patients that causes intracellular oxidative stress and impairment of post-radiation DNA damage repair (DDR) via Homologous Recombination (HR). Although IDH1R132H is associated with improved patient survival and clinical response to chemotherapy, astrocytoma (LGG) patients specifically also harbor ATRXLoss, a genetic alteration that inactivates the ATRX chromatin remodeling protein and impairs DDR via non-homologous end joining (NHEJ). Importantly, the recent discovery of glioma stem cells (GSCs), a subpopulation of chemoradioresistant, self-renewable, tumor initiating cells known to promote tumor recurrence, presents a new target for therapeutic intervention. However, the mechanisms by which IDH1R132H and ATRXLoss contribute to GSC sensitivity to proton radiotherapy (PRT), a more tumor specific and cytotoxic form of radiation therapy than conventional X-rays (XRT), is not well understood. We hypothesize that both IDH1R132H and ATRXLoss contribute to the impairment of GSC self-renewal after PRT, but not after XRT. Methods: Isogenic MGG18-IDH1WT, MGG18-IDH1R132H, TS543-ATRXWT, and TS543-ATRXLoss patient derived glioma cells were cultured as neurospheres and treated with 3-6 Gy of XRT or PRT. GSC self-renewal, based on neurosphere formation frequency, was quantified using extreme limiting dilution analysis (ELDA). Results: TS543-ATRXLoss significantly inhibited GSC self-renewal over TS543-ATRXWT when subject to PRT (Pairwise Testing Pr(&amp;gt;χ2)&amp;lt;0.01). However, TS543-ATRXWT displayed lower GSC self-renewal compared to TS543-ATRXLoss when subject to XRT (Pr(&amp;gt;χ2)&amp;lt;0.0001). Interestingly, similar results were found in the isogenic MGG18 cell lines. MGG18-IDH1R132H displayed higher radiosensitivity to PRT (Pr(&amp;gt;χ2)&amp;lt;0.05) while MGG18-IDH1WT displayed higher radiosensitivity to XRT (Pr(&amp;gt;χ2)&amp;lt;0.01), as defined by GSC self-renewal. Conclusions: We conclude that ATRXLoss and IDH1R132H both substantially contribute to PRT sensitivity in GSCs, thereby supporting the benefits of PRT for astrocytoma patients. Our future experiments will further elucidate the biological mechanisms by which ATRXLoss and IDH1R132H confer PRT sensitivity, especially via dsDNA damage and apoptosis. Citation Format: Ángel Adrian Garcés, Lawrence Bronk, Krishna P. Bhat, David R. Grosshans. ATRXLoss and IDH1R132H impair self-renewal of glioma stem cells after proton radiotherapy [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 3077.
シロリムス溶出ステント埋込後の晩期(1.5年以上)血管造影転帰のパターン:3つのパターンの分類
Authors: Nakano Yosuke, Ishikawa Tetsuya, Murakami Akimichi, Nakata Kotaro, Suzuki Teruhiko, Kubota Takeyuki, Miyamoto Takashi, Endoh Akira, Mutoh Makoto, Imai Kamon
Journal: Circulation (2010)
A multi-trial based external validation of the Halabi nomogram in predicting the overall survival of metastatic castration-resistant prostate cancer patients
Authors: D. Modonutti, J. Keeley, M. Paciotti, C. Hwang, M. Menon, Q-D. Trinh, C.G. Rogers, G. Novara, F. Abdollah
Journal: European Urology (2021)
Abstract 1746: Designing a dendritic cell-targeted immunotherapy for the treatment of pancreatic ductal adenocarcinoma
Authors: Ron Kleiner, Daniella Vaskovich, Sabina Pozzi, Anat Eldar-Boock, Dikla Ben-Shushan, Helena Florindo, Ronit Satchi-Fainaro
Journal: Cancer Research (2021)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death. Low response rate, acquired resistance, severe side effects, highly desmoplastic and immunosuppressive microenvironment have limited the clinical outcomes of immunotherapy in PDAC. To overcome these hurdles, we set to design a novel immunotherapy that would be safe, efficacious, and selective to PDAC. The failure of immunotherapies to yield clinical response in PDAC is partially attributed to the inefficient antigen presentation by dendritic cells (DC) which results in insufficient T cells stimulation despite their expression of tumor-associated antigens (TAA). DC have an important role in the initiation and regulation of the innate and adaptive arms of the immune system. By efficient presentation of antigens, DC elicit an antigen-specific immune response. Trp53R172H is among the most common TP53 mutations in human PDAC, and is known as one of PDAC TAA. Despite the poor clinical outcomes, longer survival time was observed in PDAC patients with tumors that express high number of TAA combined with an abundant presentation of CD8+ T cell. To that end, we designed a DC-targeted nanoparticle (NP) containing PDAC Trp53R172H TAA and immune potentiators, with the DC targeting moiety, mannose, that was covalently conjugated to the NP, to enhance TAA presentation on DC. This approach led to specific activation of T cells against PDAC's TAA. The therapeutic activity of the NP was evaluated in vitro by our newly established 3D PDAC spheroids model, which is composed of freshly isolated murine stromal cells, therefore, better imitates the complex microenvironment found in PDAC. Along with an in vivo PDAC model, we evaluated the safety profile and therapeutic efficacy of our NP. The NP proposed herein successfully activated splenocytes and induced a specific cytotoxic reaction against PDAC cells ex vivo, which may result in improved survival rate. Citation Format: Ron Kleiner, Daniella Vaskovich, Sabina Pozzi, Anat Eldar-Boock, Dikla Ben-Shushan, Helena Florindo, Ronit Satchi-Fainaro. Designing a dendritic cell-targeted immunotherapy for the treatment of pancreatic ductal adenocarcinoma [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 1746.
Abstract 2132: Ezh2-Y641F mutation interacts with Stat3 to regulate the melanoma tumor immune response via disruption of IFN signaling
Authors: Sarah M. Zimmerman, Samantha Nixon, George P. Souroullas
Journal: Cancer Research (2021)

Abstract Cancer genetic sequencing studies have identified systematic alterations of epigenetic and chromatin modifiers in most cancers, consistent with the fact that chromatin modifiers, such as the Polycomb Repressive Complex 2 (PRC2), regulate the expression of tumor suppressors. In melanoma, 10% of patients exhibit amplifications or point mutations in EZH2, the enzymatic subunit of PRC2; however, the oncogenic mechanisms of EZH2 mutations in melanoma remain elusive. Previously, we observed that expression of Ezh2-Y641F in melanoma cells resulted in upregulation of IFN-related genes. We thus sought to better understand this mutation and the consequences of IFN signaling changes on tumor growth and the tumor immune response. We discovered that Ezh2-Y641F directly interacts with and methylates Stat3, a known regulator of interferon signaling. To understand the effects of this interaction, we performed ChIP-seq for Ezh2 and Stat3 in melanoma cells and found that the binding profiles of Stat3 and Ezh2 are greatly changed in Ezh2-Y641F cells. Furthermore, Ezh2 and Stat3 binding sites co-localized at several genomic loci in Ezh2-Y641F cells, including a region that regulates Ezh2. Knockdown of Stat3 in melanoma cells decreased Ezh2 expression and partially reduced expression of the IFN-related genes that were initially upregulated by Ezh2-Y641F. Analysis of the tumor-infiltrating immune cells by flow cytometry revealed increased CD8+ T cells and decreased myeloid cells in Ezh2-Y641F melanomas, consistent with a more favorable immune response, although tumor growth was unchanged. Genetic inhibition of Stat3 expression via shRNA rescued this phenotype. Our data suggest a novel interaction between the PRC2 complex and Stat3 in melanoma, which has significant physiological consequences on the tumor immune response. Molecular and genomic analysis suggest that Ezh2 and Stat3 together regulate gene expression, including Ezh2 itself. Overall, these data highlight the significant role of chromatin regulators on the tumor immune response. Citation Format: Sarah M. Zimmerman, Samantha Nixon, George P. Souroullas. Ezh2-Y641F mutation interacts with Stat3 to regulate the melanoma tumor immune response via disruption of IFN signaling [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 2132.
Challenging cases in high-risk prostate cancer patients treated with Retzius-sparing robot-assisted radical prostatectomy
Authors: P. Dell’Oglio, S. Tappero, M. Longoni, C. Buratto, P. Scilipoti, S. Secco, A. Olivero, A.M. Bocciardi, A. Galfano
Journal: European Urology (2021)
Smoking and Incidence of Colorectal Cancer Subclassified by Tumor-Associated Macrophage Infiltrates
Authors: Tomotaka Ugai, Juha P Väyrynen, Koichiro Haruki, Naohiko Akimoto, Mai Chan Lau, Rong Zhong, Junko Kishikawa, Sara A Väyrynen, Melissa Zhao, Kenji Fujiyoshi, Andressa Dias Costa, Jennifer Borowsky, Kota Arima, Jennifer L Guerriero, Charles S Fuchs, Xuehong Zhang, Mingyang Song, Molin Wang, Marios Giannakis, Jeffrey A Meyerhardt, Jonathan A Nowak, Shuji Ogino
Journal: JNCI Journal of the National Cancer Institute (2021)

Abstract Background Biological evidence indicates that smoking can influence macrophage functions and polarization, thereby promoting tumor evolution. We hypothesized that the association of smoking with colorectal cancer incidence might differ by macrophage infiltrates. Methods Using the Nurses’ Health Study and the Health Professionals Follow-up Study, we examined the association of smoking with incidence of colorectal cancer subclassified by macrophage counts. Multiplexed immunofluorescence (for CD68, CD86, IRF5, MAF, and MRC1 [CD206]) combined with digital image analysis and machine learning was used to identify overall, M1-polarized, and M2-polarized macrophages in tumor. We used inverse-probability–weighted multivariable Cox proportional hazards regression models to control for potential confounders and selection bias because of tissue data availability. All statistical tests were 2-sided. Results During follow-up of 131 144 participants (3 648 370 person-years), we documented 3092 incident colorectal cancer cases, including 871 cases with available macrophage data. The association of pack-years smoked with colorectal cancer incidence differed by stromal macrophage densities (Pheterogeneity = .003). Compared with never smoking, multivariable-adjusted hazard ratios (95% confidence interval) for tumors with low macrophage densities were 1.32 (0.97 to 1.79) for 1-19 pack-years, 1.31 (0.92 to 1.85) for 20-39 pack-years, and 1.74 (1.26 to 2.41) for 40 or more pack-years (Ptrend = .004). In contrast, pack-years smoked was not statistically significantly associated with the incidence of tumors having intermediate or high macrophage densities (Ptrend &amp;gt; .009, with an α level of .005). No statistically significant differential association was found for colorectal cancer subclassified by M1-like or M2-like macrophages. Conclusions The association of smoking with colorectal cancer incidence is stronger for tumors with lower stromal macrophage counts. Our findings suggest an interplay of smoking and macrophages in colorectal carcinogenesis.
Abstract CT210: Trial in Process: Phase 1 studies of BI 1701963, a SOS1::KRAS Inhibitor, in combination with MEK inhibitors, irreversible KRASG12C inhibitors or irinotecan.
Authors: Marco H. Hofmann, Hengyu Lu, Ulrich Duenzinger, Daniel Gerlach, Francesca Trapani, Annette A. Machado, Joseph R. Daniele, Irene Waizenegger, Michael Gmachl, Dorothea Rudolph, Christopher P. Vellano, Marcelo Marotti, Vitomir Vucenovic, Timothy P. Heffernan, Joseph R. Marszalek, Mark P. Petronczki, Norbert Kraut
Journal: Cancer Research (2021)

Abstract The SOS1i::KRAS inhibitor BI 1701963 is the first direct RAS signaling modifier to enter phase I clinical trials both as a monotherapy as well as in combination. SOS1::KRAS inhibitors exhibit activity against a broad spectrum of KRAS alleles, including the major G12D/V/C and G13D oncoproteins, while sparing the interaction of KRAS with SOS2. Here, we present pre-clinical data showing enhanced pathway modulation and synergistic anti-tumor effects following vertical pathway inhibition of BI 1701963 in combination with mitogen-activated protein kinase inhibitors (MEKi; trametinib and BI 3011441) or KRAS G12C inhibitors (MRTX849 and BI 1823911). Furthermore, SOS1::KRAS inhibitor treatment sensitizes tumor cells to increased DNA damage in combination with irinotecan. Our results highlight the suitability of SOS1::KRAS inhibitors as a backbone in combination therapies targeting KRAS-dependent tumors. Pre-clinical combination data supported the start of multiple phase I trials investigating the safety, tolerability, recommended dose and preliminary efficacy of BI 1701963 alone and in combination with other anti-cancer agents. Combination trials of BI 1701963 with MEKi include cohorts of patients with KRAS mutant solid tumors, such as non-small cell lung cancer (NSCLC), colorectal cancer (CRC), cholangiocarcinoma and pancreatic adenocarcinoma. Trials exploring the combination of BI 1701963 with irreversible KRAS G12C inhibitors (MRTX849 and BI 1823911) will include cohorts of patients with KRAS G12C mutant NSCLC and CRC. In a further study, the combination of BI 1701963 with irinotecan is being evaluated in patients with KRAS mutant CRC. Primary endpoints include dose-limiting toxicities, treatment-emergent or -related adverse events. Secondary endpoints include pharmacokinetic and pharmacodynamic properties of combination regimens and preliminary efficacy. Citation Format: Marco H. Hofmann, Hengyu Lu, Ulrich Duenzinger, Daniel Gerlach, Francesca Trapani, Annette A. Machado, Joseph R. Daniele, Irene Waizenegger, Michael Gmachl, Dorothea Rudolph, Christopher P. Vellano, Marcelo Marotti, Vitomir Vucenovic, Timothy P. Heffernan, Joseph R. Marszalek, Mark P. Petronczki, Norbert Kraut. Trial in Process: Phase 1 studies of BI 1701963, a SOS1::KRAS Inhibitor, in combination with MEK inhibitors, irreversible KRASG12C inhibitors or irinotecan. [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 CT210.
Liver-fibrosis-activated transcriptional networks govern hepatocyte reprogramming and intra-hepatic communication
Authors: Anne Loft, Ana Jimena Alfaro, Søren Fisker Schmidt, Felix Boel Pedersen, Mike Krogh Terkelsen, Michele Puglia, Kan Kau Chow, Annette Feuchtinger, Maria Troullinaki, Adriano Maida, Gretchen Wolff, Minako Sakurai, Riccardo Berutti, Bilgen Ekim Üstünel, Peter Nawroth, Kim Ravnskjaer, Mauricio Berriel Diaz, Blagoy Blagoev, Stephan Herzig
Journal: Cell Metabolism (2021)
Use of ureteric stent related mobile phone application UROSTENTZ App (free of cost) in COVID-19 for improving patient communication and safety: A prospective pilot study from a university hospital
Authors: B.M. Zeeshan Hameed, B. Somani, P. Hegde, S. Jayadeva, M. Shah, N. Naik, S. Kankaria, V. Hiremath
Journal: European Urology (2021)
Injectable catalyst-free “click” organic-inorganic nanohybrid (click-ON) cement for minimally invasive in vivo bone repair
Authors: Xifeng Liu, Emily T. Camilleri, Linli Li, Bipin Gaihre, Asghar Rezaei, Sungjo Park, A. Lee Miller II, Maryam Tilton, Brian E. Waletzki, Andre Terzic, Benjamin D. Elder, Michael J. Yaszemski, Lichun Lu
Journal: Biomaterials (2021)
Abstract 1917: Immunomodulatory effects of a novel, enhanced potency gibbon ape leukaemia virus (GALV) fusogenic membrane glycoprotein-expressing herpes simplex virus platform with increased efficacy combined with anti PD-1 therapy
Authors: Victoria Roulstone, Joan Kyula, Suzanne Thomas, Linta Kuncheria, Praveen K. Bommareddy, Henry Smith, Harriet Whittock, Robert S. Coffin, Kevin Harrington
Journal: Cancer Research (2021)

Abstract Oncolytic viral immunotherapies are attractive because they are self-amplifying, can kill tumors through multiple, immunologically visible mechanisms and have the ability to promote anti-tumor immune responses. RP1 is a novel, enhanced potency oncolytic HSV that has been genetically engineered to express human GM-CSF and the gibbon ape leukemia virus fusogenic membrane glycoprotein with the R sequence deleted (GALV-GP R-), providing constitutive fusion activity. GALV-GP R- binds pit-1 receptors on human and rat, but not mouse, cells to mediate cell-cell fusion. RP1 potently kills human tumor-derived cells, including a panel of melanoma and head and neck cell lines, as demonstrated here. In vivo, using a human melanoma model in nude mice, higher titres (2-3 log) of virus were retrieved from tumors treated with the virus expressing GALV-GP R- (i.e. RP1) versus an equivalent non-GALV-GP R- expressing virus. No virus was retrieved from uninjected tumors. In addition to enhanced direct effects on injected tumors, contralateral uninjected tumors were significantly smaller in groups treated with RP1 versus the GALV-GP R- non-expressing virus despite restriction of virus replication to the injected tumor. This effect was seen in nude mice, i.e. without an adaptive immune system, suggesting contribution of innate (e.g. NK cell-mediated) immunity to the contralateral effects observed. In the immunocompetent mouse 4434 melanoma model, RP1 also reduced tumor burden in both injected and uninjected tumors, again with absolute restriction of virus replication to injected tumors. Animals treated with RP1 had splenomegaly and a population of tumor-infiltrating PD-L1+ cells within injected tumors at one week post-treatment, albeit without a contribution of fusion mediated by GALV-GP R- in this model. FACS-based analysis identified these PD-L1+ cells as predominantly CD45+/CD11b(med/low)/LY6G+ neutrophils. Co-treatment with RP1 and an anti-mouse PD-1 antibody increased anti-tumor effects and the levels of CD3+ cells in uninjected tumors. Data from detailed RNAseq transcriptional analyses from injected and uninjected tumors will also be presented. Citation Format: Victoria Roulstone, Joan Kyula, Suzanne Thomas, Linta Kuncheria, Praveen K. Bommareddy, Henry Smith, Harriet Whittock, Robert S. Coffin, Kevin Harrington. Immunomodulatory effects of a novel, enhanced potency gibbon ape leukaemia virus (GALV) fusogenic membrane glycoprotein-expressing herpes simplex virus platform with increased efficacy combined with anti PD-1 therapy [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 1917.
Prostate Specific Membrane Antigen (PSMA) PET/CT compared to standard of care imaging in the assessment of renal cancers: A multi-institutional series
Authors: A. Tariq, A. Pearce, H. Rhee, P. Thomas, D. Pattison, S. Kyle, A. Navaratnam, N. Dunglison, R. Esler, J. Yaxley, M. Roberts
Journal: European Urology (2021)
Abstract 1472: Novel EGFR WT sparing, HER2 selective inhibitors for the treatment of HER2 exon 20 insertion driven tumors address a clear unmet medical need
Authors: Ralph A. Neumüller, Birgit Wilding, Dirk Scharn, Dietrich Böse, Valeria Santoro, Daniel Gerlach, Peter Ettmayer, Thomas Gerstberger, Julian Fuchs, Matthias Treu, Stephan Zahn, Anke Baum, Paolo Chetta, Mark Pearson, Darryl B. McConnell, Norbert Kraut, Flavio Solca
Journal: Cancer Research (2021)

Abstract Activating mutations in ERBB2 receptors are tractable oncogenes in 2-3% of NSCLC patients for whom no approved targeted therapies are available. In this indication, oncogenic mutations in HER2 predominantly affect the tyrosine kinase domain and cluster in exon 20 of the ERBB2 gene. We initiated a drug discovery program aiming at discovering novel HER2 selective inhibitors sparing EGFR WT activity. Focus was set on the most frequent HER2 mutation (ERBB2 A775 insYVMA), which is least sensitive to current compounds tested in clinical trials. Here, we report the identification and pharmacological characterization of novel selective HER2 exon 20 mutation TKIs that differ from currently tested TKIs such as poziotinib, TAK-788 or BDTX-189. We could demonstrate that selective inhibition of oncogenic HER2 signaling abrogates oncogenic signaling in in vitro models. Cell survival and proliferation was reduced, which translated into tumor regressions in preclinical CRISPR engineered xenotransplantation models of HER2 exon 20 mutants. The in vivo efficacy was confirmed in patient-derived tumor models. Our results suggest that HER2 exon 20 insertions can be effectively treated by a potent and highly selective HER2 inhibitor that spares EGFR wild type. These findings warrant the upcoming clinical testing in HER2 mutant NSCLC patients in order to effectively treat this aggressive type of cancer. Citation Format: Ralph A. Neumüller, Birgit Wilding, Dirk Scharn, Dietrich Böse, Valeria Santoro, Daniel Gerlach, Peter Ettmayer, Thomas Gerstberger, Julian Fuchs, Matthias Treu, Stephan Zahn, Anke Baum, Paolo Chetta, Mark Pearson, Darryl B. McConnell, Norbert Kraut, Flavio Solca. Novel EGFR WT sparing, HER2 selective inhibitors for the treatment of HER2 exon 20 insertion driven tumors address a clear unmet medical need [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 1472.
The three-dimensional reconstructed virtual images improve the reliability, accuracy, and efficiency of the R.E.N.A.L. nephrometry score for preoperative assessment
Authors: K. Yoshitomi, Y. Komai, T. Yamamoto, E. Fukagawa, K. Hamada, Y. Yoneoka, M. Fujiwara, R. Fujiwara, T. Oguchi, N. Numao, T. Yuasa, S. Yamamoto, I. Fukui, J. Yonese
Journal: European Urology (2021)