tbuckley/cabot-search huggingface dataset:
Abstract 809: Neurotensin increases tyrosine phosphorylation of HER3
Authors: Terry W. Moody, Irene Ramosalvarez, Robert T. Jensen
Journal: Cancer Research (2021)

Abstract Neurotensin (NTS) is an autocrine growth factor for non-small cell lung cancer cells. NTS stimulates and the NTSR1 antagonist SR48692 inhibits NSCLC growth (Moody et al., Life Sci 2014; 100: 25). NSCLC patients, whose tumors have high NTSR1, have significantly lower relapse-free survival than those with low NTSR1 (Younes et al., Oncotarget 2014; 5: 8252). NTS addition to NSCLC cells increases the tyrosine phosphorylation of the EGFR and HER2 (Moody et al., Eur J Pharmacol 2019; 865:172735). Activation of HER3 in NSCLC mediates aggressive growth and drug resistance. Therefore the ability of NTSR1 to regulate transactivation of HER3 was investigated. By RT-PCR, HER3 and NTSR1 but not NTSR2 mRNA was present in NSCLC cells. NTS addition to NCI-H358 or H441 cells increased HER3 and ERK tyrosine phosphorylation by 210% and 240%, respectively and the increase caused by NTS was antagonized by SR48692 or mAb3481 (HER3 mAb). The increase is phosphorylation of Tyr1289-HER3 caused by NTS or neuregulin-1 addition to NSCLC cells was due to the formation of HER2-HER3 and EGFR-HER3 heterodimers. NTSR1 regulation of HER3 or Akt phosphorylation was impaired by PP2 (Src inhibitor) or GM6001 (MMP inhibitor). Because N-acetylcysteine (antioxidant) or Tiron (superoxide scavenger) inhibited the ability of NTS to increase HER3 phosphorylation, reactive oxygen species (ROS) are essential. Using a clonogenic assay, NTS increased NSCLC colony number whereas SR48692 or mAb3481 reduced colony number. The results indicate that NTS increased HER3 tyrosine phosphorylation in a ROS-/Src-/MMP-dependent manner. In summary, NTSR1 transactivates HER3 resulting in ERK and Akt phosphorylation increasing the proliferation and survival of NSCLC cells. Citation Format: Terry W. Moody, Irene Ramosalvarez, Robert T. Jensen. Neurotensin increases tyrosine phosphorylation of HER3 [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 809.
225Ac-DOTATOC–Targeted Somatostatin Receptor α-Therapy in a Patient With Metastatic Neuroendocrine Tumor of the Thymus, Refractory to β-Radiation
Authors: Jingjing Zhang, Harshad R. Kulkarni, Richard P. Baum
Journal: Clinical Nuclear Medicine (2021)

Somatostatin receptor-targeted α-therapy using α-emitter 225Ac-labeled somatostatin analogs has been suggested as a treatment option in advanced metastatic neuroendocrine tumors (NETs) failing treatment with β-emitters, such as 177Lu or 90Y. Thymus NETs are rare and usually more aggressive than other neuroendocrine tumor entities. We present here a case with β-radiation refractory metastatic thymus NET, who demonstrated an excellent therapy response (molecular and morphological remission, as well as significantly improved clinical symptoms) after 225Ac-DOTATOC-targeted α-therapy, without any adverse effects during the treatment or in the follow-up period.
Effect of tezepelumab on airway inflammatory cells, remodelling, and hyperresponsiveness in patients with moderate-to-severe uncontrolled asthma (CASCADE): a double-blind, randomised, placebo-controlled, phase 2 trial
Authors: Sarah Diver, Latifa Khalfaoui, Claire Emson, Sally E Wenzel, Andrew Menzies-Gow, Michael E Wechsler, James Johnston, Nestor Molfino, Jane R Parnes, Ayman Megally, Gene Colice, Christopher E Brightling
Journal: The Lancet Respiratory Medicine (2021)
Abstract 2235: A comprehensive map of genetic interactions in childhood cancer reveals multiple underlying biological mechanisms
Authors: Josephine Daub, Saman Amini, Xiaotu Ma, Natalie Jager, Jinghui Zhang, Stefan Pfister, Frank Holstege, Patrick Kemmeren
Journal: Cancer Research (2021)

Abstract Despite increasing survival rates, childhood cancer is still the major cause of disease-related child death in developed countries. Genetic interactions between mutated genes play an important role in cancer development. They can be detected by searching for pairs of mutated genes that co-occur more (or less) often than expected. Co-occurrence suggests a cooperative role in cancer development, while mutual exclusivity points to synthetic lethality, a phenomenon of interest in cancer treatment research. Little is however known about genetic interactions in childhood cancer. Here, we apply a statistical pipeline to detect genetic interactions in a combined dataset comprising over 2,500 tumors from 23 cancer types. The resulting genetic interaction map of childhood cancers comprises 15 co-occurring and 27 mutually exclusive candidates. The biological mechanisms underlying most candidates are either tumor subtype, pathway epistasis or cooperation while synthetic lethality plays a much smaller role. Thus, other explanations beyond synthetic lethality should be considered when interpreting results of genetic interaction tests. Citation Format: Josephine Daub, Saman Amini, Xiaotu Ma, Natalie Jager, Jinghui Zhang, Stefan Pfister, Frank Holstege, Patrick Kemmeren. A comprehensive map of genetic interactions in childhood cancer reveals multiple underlying biological mechanisms [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 2235.
Abstract 2486: Pleiotropic anti-cancer effects of STING in estrogen receptor positive breast cancer cells
Authors: Chun-Yu Liu, Ji-Lin Chen, Chun-Teng Huang, Pei-Yi Chu, Mei-Fang Tseng, Yu-Hsuan Lee, Wan-Lun Wang, Ling-Ming Tseng
Journal: Cancer Research (2021)

Abstract Purpose: Stimulator of interferon genes (STING) is an upstream regulator of interferon and NF-κB, the key mediators of immune and inflammatory responses associated with cancer, triggered by cytosolic DNA. Downregulation of STING in breast tumor tissues has been reported. STING elicits caspase-8-dependent cell apoptosis via NF-κB in breast cancer cells. STING agonists are considered as potent anti-cancer agents. The current study aims to assess the biological functions of STING in breast cancer progression. Experimental design: Data of mRNA expression levels and recurrence-free survival in patients with breast cancer from The Cancer Genome Atlas and Kaplan Meier-plotter databases were analyzed. Transwell assays were used to evaluate cell migrated and invaded abilities. Sphere formation was performed in stem cell-selective medium and ultra-low attachment plates. Two STING agonists, ADU-S100 and diABZI STING agonist-1 trihydrochloride, were used for in vitro studies. The molecular events were examined by Western blot analysis. Results: Data from public database showed that lower transcripts levels of STING in Her2 and luminal B breast cancer tissues than normal breast tissues. Luminal-type breast cancer cell lines harbored low STING transcripts compared with other subtypes. Importantly, breast cancer patients with low expression levels of STING was associated with worse recurrence-free survival. Results of immunoblotting indicated that breast cancer cell lines have lower STING protein expressions than normal MCF10A cells. Knockdown of STING led to aggressive phenotypes of MCF10A and BT474 cells. In contrast, overexpression of STING suppressed the abilities of migration, invasion and sphere formation of MCF7 and BT474 cells. The markers of epithelial were increased while the markers of mesenchymal and stemness were decreased by STING overexpression. STING agonist slightly suppressed cell viability of breast cancer cells but not MCF10A cells. Treatment of STING agonists reduced cell migrated ability with upregulation of E-cadherin and γ-catenin. Conclusion: These findings suggest that STING serves tumor-suppressive effects in breast cancer. Citation Format: Chun-Yu Liu, Ji-Lin Chen, Chun-Teng Huang, Pei-Yi Chu, Mei-Fang Tseng, Yu-Hsuan Lee, Wan-Lun Wang, Ling-Ming Tseng. Pleiotropic anti-cancer effects of STING in estrogen receptor positive 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 2486.
Abstract 8303: Silica-Gold Nanoparticles and Mesenchymal Stem Cells versus Composite Ferro-Magnetic Approach for Management of Atherosclerotic Plaque and Artery Remodeling
Authors: Alexander Kharlamov, Alexander Perrish, Jan Gabinsky
Journal: Circulation (2011)

Background. Some modern angioplasty techniques generally just manipulate the form of the plaque and have some clinical and technical restrictions, relatively high complication rate and restenosis risk. Methods. A total of 180 patients with stable angina were randomly assigned to the three groups (60 patients into nanogroup with the use of 60/15-70/40 nm silica-gold nanoparticles (NPs) transplanted by endoscopic cardiac surgery in the composition of bioengineered on-artery patch grown on the basis of biopolymeric scaffold and host circulating CD45-CD34-CD73+CD105+ progenitor cells, 60 - into ferro-magnetic group with 60/15-70/40 nm silica-gold iron-bearing NPs with delivery in hand of magnetic navigation system, and 60 - in sirolimus-eluting stenting control). NPs were detonated with near-infrared laser irradiation on day 3 under the drug antithrombotic protection. We have used a modified method for the preparation of NPs as described by Lee (2008) and Deng H (2005). Studied proximal left anterior descending arteries were observed by 30 MHz intravascular ultrasound (IVUS). Results. A change of the plaque volume (PV, mm3) as-intervened/ in 9 months in groups were −24.3/ −66.8%, −29.5/ −42.3% and −11.4/ +4.3% (p&lt;0.01) respectively. An impact over the non-organic part of the plaque (mineral deposits, calcium necrotic core) was predominated in nanogroup (−43.4% vs −12.1% and +3.7% respectively, p&lt;0.005). While first 4 weeks, 3/60 (5%), 2/60 (3.3%), 7/60 (11.7%) cases of acute atherothrombosis were revealed in groups respectively (p&lt;0.01). Restenosis confirmed in 3 (5%) patients of stenting group only. Event free survival (cardiac death, recurrent symptoms, MI) in 9 mns was 95, 91.7 and 85% in groups respectively (p&lt;0.01). Coronary flow-mediated vasodilation was observed after hyperemia and injection of nitroglycerine (+10.2 and +16.6%, +8.2 and +9.6%, +8.1 and +9.8% in groups respectively, p&lt;0.05). Conclusion. Nanoburning is the novel promising technique to demolish and melt the plaque especially in combination with stem cell technologies challenging functional restoration of the vessel. Plasmonics is the high-effective and safe alternative to stenting for angioplasty.
Prognostic factors in metastatic rhabdomyosarcoma (RMS): The results of a pooled analyze from U.S. and European cooperative groups
Authors: O. Oberlin, A. Rey, E. Lyden, G. Bisogno, M. C. Stevens, W. H. Meyer, C. Bergeron, C. Ellershaw, H. McDowell, M. Carli
Journal: Journal of Clinical Oncology (2007)

9542 Background: Prognosis factors on outcome for metastatic RMS are still matter of discussion. The analysis of a large cohort of patients can give arguments for development of risk-based therapy. Methods: We studied data from SIOP 84, SIOP 98, European Intergroup MMT89–91, Italian RMS4.99, IRS-III, -IV Pilot, -IV, -V, -D9501 to look at the influence of age, histology, sites of primary and metastatic disease, and number of sites of metastatic disease at the 3 year event-free survival. Results: 788 patients were included in the analyze and 776 in the multivariate analyse. The 3 year overall survival and EFS were 34% (se 1.7) and 27 % (se 1.6) respectively. By univariate analysis, 3-year EFS was significantly influenced by age 10 years or more (15% vs 36%), alveolar histology (28% vs 40%), location of primary tumor in unfavorable site -parameningeal, extremity and “other” sites- (31% vs 48%) the presence of three or more metastatic (17% vs 38%), the presence of bone or bone marrow involvement (24% vs 45%). By multivariate analysis, histology had no more impact on EFS. The EFS was strongly correlated to the number of the 4 other unfavorable prognostic factors: age, site of the primary, number of metastis sites, bone/bone marrow involvement relative risks were 1.6 for age (p&lt;0.0001), 1.4 for site of primary tumor (p=0.002), 1.3 for bone/bone marrow involvement (p=0.005), 1.4 for number of metastatic sites (p=0.002). EFS was 58% for the 46 patients without any factors and was respectively 40%, 22%, 14% and 4% in patients with 1 factor (250 patients), 2 factors (233 patients), 3 factors (177 patients) or 4 factors (70 patients) (p&lt;0.01). Conclusions: This analysis identified subsets of patients with very different outcomes. Patients with EFS less than 50% might be appropriate candidates for experimental approaches. No significant financial relationships to disclose.
Perioperative safety and postoperative health-related quality of life in patients receiving salvage cystectomy and urinary diversion as a last-line option for benign diseases
Authors: Y. Volz, L. Eismann, P. Pfitzinger, J-F. Jokisch, G. Schulz, A. Buchner, B. Schlenker, C. Stief, A. Kretschmer
Journal: European Urology (2021)
Abstract 376: Prognostic significance of Glasgow prognostic score in NSCLC patients treated with immunotherapy after platinum-based cytotoxic chemotherapy
Authors: Hye Seon Kang, In Kyoung Kim, Jin Woo Kim
Journal: Cancer Research (2021)

Abstract Introduction: The Glasgow prognostic score (GPS) reflects the host systemic inflammatory response and is validated prognostic factor in lung cancer. However, little is known about the prognostic role in non-small cell lung cancer (NSCLC) patients treated with immunotherapy after platinum-based cytotoxic chemotherapy. Patient and Methods: This study used a lung cancer cohort of the Catholic Medical Center of Korea between January 2018 and June 2020. We included the patients who were diagnosed with unresectable advanced stage NSCLC or recurrent disease after pulmonary resection and had received at least one regimen of platinum-based chemotherapy before being administered immunotherapy. The patients with NSCLC treated with anti-PD1 or anti-PD-L1 (pembrolizumab, nivolumab, or atezolizumab) and assessed the prognostic value of the GPS. The GPS was calculated using C-reactive protein and albumin concentrations within 1 week before starting anti-PD1 or anti-PD-L1 treatment. Results: A total of 78 patients with NSCLC treated with immunotherapy as 2nd or 3rd line therapy after platinum-based chemotherapy. Kaplan-Meier analyses revealed that higher GPS was significant predictors of shorter progression free survival (PFS) (Log rank &amp;lt; 0.001) and overall survival (OS) (Log rank &amp;lt; 0.001). In cox-regression multivariate analysis, the hazard ratios for disease progression were 2.146 (95% CI: 0.814-5.656; P = 0.123) for a GPS of 1 and 9.73 (95% CI: 2.931-32.298, P &amp;lt; 0.001) for a GPS of 2 relative to a GPS of 0. Older age (P = 0.033), lower PD-L1 expression (P = 0.036) and higher GPS (P = 0.007) were independently associated with shorter OS. Conclusion: Higher GPS were identified as one of poor prognostic factor for OS and PFS in NSCLC patients received immunotherapy as 2nd or 3rd line therapy after platinum-based chemotherapy. Citation Format: Hye Seon Kang, In Kyoung Kim, Jin Woo Kim. Prognostic significance of Glasgow prognostic score in NSCLC patients treated with immunotherapy after platinum-based cytotoxic chemotherapy [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 376.
Abstract 3193: Development and functional characterization of NC762, a novel therapeutic antibody targeting B7-H4, for the treatment of malignancies
Authors: Kristina Archer, Justine Ceradoy, Tiffany Coupet, Jason Bosiacki, Chang Song, Ido Weiss, Sue Niu, Tete Obot, Jinglin Xu, Tom O'Neill, Alison Ferrell, Hasan Abukharma, Zac Cusumano, Dallas Flies, Sol Langermann, Linda N. Liu
Journal: Cancer Research (2021)

Abstract Human B7 homolog 4 (B7-H4) is a transmembrane protein in the B7 family of molecules that is expressed on tumor cells in the tumor microenvironment (TME). High protein expression on tumors and low expression on healthy tissue makes B7-H4 an attractive molecule for direct targeting with low off-target toxicity. NC762 is a humanized immunoglobulin gamma 1, kappa (IgG1κ) monoclonal antibody specific for human B7-H4 that is being developed for the treatment of cancer and demonstrates an excellent safety profile in IND-enabling studies. The IgG1κ region of NC762 contains three-point mutations (S239D/A330L/I332E a.k.a. DLE) which enhances binding to CD16a (FcγRIIIa) in order to increase antibody-dependent cellular cytotoxicity (ADCC) activity. NC762 binds to human B7-H4 on SKBR3 cells, a breast cancer cell line that endogenously expresses B7-H4 and induces in vitro ADCC activity. Despite the high homology, NC762 does not cross-react with rodent B7-H4, therefore, in vivo testing was performed in a humanized xenograft murine model in NSG mice, where NC762 restricted tumor growth in a dose-dependent manner. Depleting human natural killer (NK) cells prior to tumor inoculation reduced anti-B7-H4 parent antibody activity, supporting a role for NK-cell mediated ADCC in tumor growth retardation. However, in the absence of human PBMCs, NC762 also achieved significant anti-tumor activity. Furthermore, a mutant of NC762 with a low FcγR binding IgG1 domain showed similar activity as the DLE IgG1, demonstrating an ADCC-independent mechanism of tumor growth restriction mediated by B7-H4 mAb treatment. Together, these results indicate that even with the ADCC-enhanced IgG1κ region, NC762 is able to mediate ADCC-independent anti-tumor activity for the eradication of B7-H4 expressing tumors; and is expected to provide benefit in multiple oncology indications. Citation Format: Kristina Archer, Justine Ceradoy, Tiffany Coupet, Jason Bosiacki, Chang Song, Ido Weiss, Sue Niu, Tete Obot, Jinglin Xu, Tom O'Neill, Alison Ferrell, Hasan Abukharma, Zac Cusumano, Dallas Flies, Sol Langermann, Linda N. Liu. Development and functional characterization of NC762, a novel therapeutic antibody targeting B7-H4, for the treatment of malignancies [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 3193.
Abstract 1482: M4645 is a potent and highly selective inhibitor of disease relevant cKIT mutations for the treatment of metastatic or recurrent GIST
Authors: Nina Linde, Andreas Blum, Dieter Dorsch, Ulrich Graedler, Michael Busch, Nina Glaser, Carl Petersson, Aaron Ruff, Eva Sherbetjian, Christina Esdar
Journal: Cancer Research (2021)

Abstract Oncogenic mutations in cKIT in exons 9 and 11 are the main driver of gastrointestinal stromal tumors (GIST). Imatinib is standard of care in 1L in unresectable metastatic or recurrent GIST, yet secondary resistance mutations in exons 13/14 and 17/18 of the cKIT kinase domain frequently arise limiting efficacy. Currently approved 2L and 3L therapies sunitinib and regorafenib target these mutations only to some extent and show limited clinical benefit. Even with the recent approval of ripretinib as 4L treatment, a high unmet medical need remains for patients with imatinib resistance mutations in exon13/14. M4645 was designed to particularly inhibit the frequent V654A resistance mutation in exon 13 of cKIT. Based on cKIT inhibitor scaffolds identified within the Merck compound collection, a 3,5,6-substituted indazole-lead was discovered. Substituent optimization in the 5- and 6-positions of the core scaffold resulted in highly selective kinase inhibitors. Through variation at the 3-position, potency and physicochemical properties were optimized, resulting in the candidate molecule M4645 which combined potency, kinase selectivity, and solubility with a good safety profile. The excellent kinase selectivity could be rationalized by the crystal structure of cKIT V654A mutant kinase domain in complex with M4645. M4645 showed potent inhibition of cKIT autophosphorylation and of downstream P-ERK1/2 and P-AKT signaling in cell lines bearing activating and resistance mutations of cKIT. Dose-dependent inhibition of cKIT activation was demonstrated in a GIST xenograft model expressing the cKIT resistance mutation V654A in exon 13. Strong antitumor activity was observed in cell line and patient-derived GIST xenograft models with this imatinib resistance mutation. Compared to imatinib, M4645 induced prolonged anti-tumor response in a GIST model with a primary activating mutation of cKIT. In summary, the favorable profile and strong antitumor activity, particularly in GIST models expressing the V654A resistance mutation, suggests superiority of M4645 compared to currently available &amp;gt; 2L treatment options for unresectable metastatic or recurrent GIST patients. Citation Format: Nina Linde, Andreas Blum, Dieter Dorsch, Ulrich Graedler, Michael Busch, Nina Glaser, Carl Petersson, Aaron Ruff, Eva Sherbetjian, Christina Esdar. M4645 is a potent and highly selective inhibitor of disease relevant cKIT mutations for the treatment of metastatic or recurrent GIST [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 1482.
Abstract 2281: Impact of DNA contaminants on next-generation sequencing data quality
Authors: Amy Dubinsky, Lauren Saunders
Journal: Cancer Research (2021)

Abstract Nucleic acid purification and clean-up are critical steps for genomics applications, including next-generation sequencing (NGS). Variability in the quality of sample extraction methods can result in differential removal of inhibitors, or reaction contaminants, that diminish NGS experimental data quality. To maximize sample recovery and create more consistent results, efficient removal of inhibitors or contaminants is critical during nucleic acid isolation and purification. In this study, we examine the effect of three common tissue-specific nucleic acid contaminants: (1) collagen, (2) myoglobin, and (3) melanin, on NGS library prep and sequencing metrics. These contaminants are present in skin and muscle tissue and are known to cause inhibition of PCR reactions. In addition, we will extract DNA from both of these samples types and evaluate the performance of two commonly used DNA extraction technologies: (1) magnetic bead-based clean-up; and (2) silica-based columns, for their ability to remove contaminants from DNA extractions and the differential effect of these extraction methods on downstream NGS metrics. These findings demonstrate the importance of the choice of extraction chemistry on NGS metrics and read quality. We also demonstrate that magnetic bead-based- protocols offer a superior reliable, rapid, automatable method to produce high quality DNA and remove contaminants. Citation Format: Amy Dubinsky, Lauren Saunders. Impact of DNA contaminants on next-generation sequencing data quality [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 2281.
Diagnostic Accuracy of Cardiovascular Magnetic Resonance for Cardiac Transplant Rejection
Authors: Donghee Han, Robert J.H. Miller, Yuka Otaki, Heidi Gransar, Evan Kransdorf, Michelle Hamilton, Michele Kittelson, Jignesh Patel, Jon A. Kobashigawa, Louise Thomson, Daniel Berman, Balaji Tamarappoo
Journal: JACC. Cardiovascular imaging (2021)