tbuckley/cabot-search huggingface dataset:
Abstract 1734: Modulation of immune responses to cancer by bi-specific IL-2/IL-13 superkines
Authors: Fahar Merchant, Minh To
Journal: Cancer Research (2021)

Abstract Introduction: The IL-2 pathway plays a vital role in stimulating a pro-inflammatory (Th1) response against cancer through expansion and activation of effector CD8 T and NK cells. In contrast, the IL-4/IL-13 pathway stimulates myeloid derived suppressor cells (MDSCs) and M2 skewing of tumor associated macrophage (TAM) to foster an anti-inflammatory (Th2) response that is often exploited by cancers as a means to dampen the effects of the Th1 pathway. Therefore, suppression of MDSC and M2 TAM through inhibition of the IL-4/IL-13 pathway together with stimulation of effector immune cells through activation of the IL-2 pathway have the potential to invigorate a pro-inflammatory response in an otherwise immune suppressive tumor microenvironment (TME). To achieve this goal, we leveraged the versatility of our IL-2 and IL-13 superkine platforms to engineer long-acting bi-specific constructs to co-target surface receptors of these respective pathways. Experimental Procedure: Studies included binding analyses by BLI/Octet and Biacore/SPR, signaling analyses using IL-2 and IL-4/IL-13 reporter assays, signaling analysis in human PBMC, and in vitro M1/M2 macrophage polarization assay. Summary of Data: sIL2M-Fc-sIL13M is a bi-specific superkine composed of an IL-2 super-agonist (sIL2M) and IL-13 super-antagonist (sIL13M) linked together by human IgG1 Fc. sIL2M binds CD122 with superior affinity over IL-2 but does not engage CD25, which is expressed on immune-suppressive Tregs. sIL13M has higher affinity than IL-13 for IL13Rα1, which together with IL-4Rα forms a functional receptor complex. In pSTAT5 assay using primary human PBMCs, sIL2M-Fc-sIL13M showed enhanced potency over IL-2 in the activation of CD8 T-cells and NK cells while exhibiting limited activity on Treg. In an IL-4/IL-13 dependent pSTAT6 reporter assay, sIL2M-Fc-sIL13M demonstrated dose-dependent antagonism against stimulatory activity of both IL-4 and IL-13. This antagonistic effect was further validated with inhibition of IL-13 induced M2 polarization of macrophages in vitro. Conclusion: sIL2M-Fc-sIL13M is a bi-specific superkine capable of concomitantly stimulating a Th1 response through activation of the IL-2 pathway and suppressing a Th2 response through inhibition of the IL-4/IL-13 pathway. Additional bi-specific superkine constructs are currently under testing, including those designed to enable accumulation in TME by engaging the decoy IL-13Rα2 that is overexpressed on a number of different tumor types. Citation Format: Fahar Merchant, Minh To. Modulation of immune responses to cancer by bi-specific IL-2/IL-13 superkines [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 1734.
Abstract 2272: Interrogating RAS isoform and mutational specificity for effectors with bioluminescence resonance energy transfer (BRET)
Authors: Megan Rigby, John Columbus, Vanessa Wall, Dominic Esposito, Thomas Turbyville
Journal: Cancer Research (2021)

Abstract Mutations in the small GTPases HRAS, NRAS, and splice variants KRAS4a and KRAS4b occur in roughly 20% of all cancers1. Each of these four RAS isoforms share a high degree of homology, yet play distinct biological roles; mouse models devoid of KRAS die mid-gestation, whereas HRAS and NRAS null mice survive2. The occurrence of RAS isoform mutations and their specific oncogenic codon substitutions are non-uniform across cancer types, with KRAS mutations in the G12 position frequently driving colorectal cancer while NRAS Q61 mutations are commonly present in skin cancer1. Several explanations have been proposed for this, including differential regulation at the level of transcription, mRNA stability, translation, and protein stability, along with distinctions in post-translational modification, localization, and tissue-specific availability of effectors3. Subtle differences in the biochemical properties of amino acid substitutions may also influence the dominant mutational forms across cancer types. However, the question of whether RAS isoforms and their specific codon substitutions preferentially engage with certain effectors within a cellular context remains unclear, despite considerable efforts. Here, we utilize bioluminescence resonance energy transfer (BRET) between mVenus- and NanoLuc-tagged recombinant proteins to derive quantitative measurements of effector affinity across RAS isoforms and common mutants. By transiently expressing a fixed concentration of NanoLuc-tagged effectors while titrating increasing amounts of mVenus-tagged RAS in a cellular system, we generated saturation curves that reflect the nature of binding between the protein pair in vivo to help untangle this longstanding question. We further validated interactions by immunoprecipitation, and determined construct expression and colocalization via western blot and confocal microscopy. 1Prior IA, Hood FE, Hartley JL. The frequency of Ras mutations in cancer. Cancer Research 20202Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nature Reviews Cancer 2003;3:459-653Li S, Balmain A, Counter CM. A model for RAS mutation patterns in cancers: finding the sweet spot. Nature Reviews Cancer 2018;18:767-77 Citation Format: Megan Rigby, John Columbus, Vanessa Wall, Dominic Esposito, Thomas Turbyville. Interrogating RAS isoform and mutational specificity for effectors with bioluminescence resonance energy transfer (BRET) [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 2272.
Abstract 2302: The mechanism of activation of monomeric B-Raf V600E
Authors: Ryan C. Maloney, Mingzhen Zhang, Hyunbum Jang, Ruth Nussinov
Journal: Cancer Research (2021)

Abstract B-Raf V600E mutations are frequent in cancer, including over 50% of all melanoma. B-Raf, like many other kinases, undergoes structural changes as it transitions between the inactive and active conformations. Key among these changes are the movement of αC helix from an inactive “OUT” conformation to an active “IN” conformation, and the movement of the activation loop from a closed inactive conformation to an open active conformation. Yet even with the knowledge of what the inactive and active conformations are, questions remain concerning how the V600E mutation activates B-Raf. In particular, we seek to understand why B-Raf V600E is constitutively active in its monomeric state while wild type B-Raf requires dimerization. Here, we investigate the differences between the wild type and mutant B-Raf monomers using molecular dynamics (MD) simulations. We included ATP in the nucleotide binding pocket to more fully explore how it is positioned within B-Raf. Our results show that the 1 µs simulations are too short to capture large conformational changes, however some of the simulations show a transient formation and breaking of the key salt-bridge between Lys483 and Glu501, which gives insight into the movement of the αC helix between the OUT and IN conformations. In addition, the dihedral angles around the DFG motif move towards a more active configuration for B-Raf V600E, while those of the wild type adopt a more inactive orientation. These simulations aid in our understanding of the dynamics of activation in B-Raf V600E. Citation Format: Ryan C. Maloney, Mingzhen Zhang, Hyunbum Jang, Ruth Nussinov. The mechanism of activation of monomeric B-Raf V600E [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 2302.
Is the increase in the number of shock waves per session more effective than standard treatment in extracorporeal shockwave lithotripsy? A prospective and comparative study
Authors: J.D. López-Acón, J. Díaz-Carnicero, A. Budía Alba, D.G. Ordaz-Jurado, P. Bahilo-Mateu, M. Trassierra-Villa, D. Vivas-Consuelo, F. Boronat-Tormo
Journal: European Urology (2021)
Comparative Analysis of the Diagnostic Capabilities of a Computer Radiography System and a Portable Flat-Panel Detector for Mammography
Authors: O. O. Manyilova
Journal: Radiology - Practice (2021)

For screening and diagnostic examinations of the mammary glands, it is recommended to use both digital mammographic systems and a system for digitizing images. There are two modifications for digitalization of images, a computer radiography system for mammography and a portable flat-panel detector. The article provides a comparative analysis of the diagnostic capabilities of a computer radiography system and a portable flat-panel detector.
Abstract 1618: Inhibition of lung tumorigenesis by a novel small molecule CA170 targeting the immune checkpoint protein VISTA
Authors: Jing Pan, Yao Chen, Qi Zhang, Achia Khatun, Katie Palen, Li Wang, Chuanjia Yang, Bryon D. Johnson, Charles R. Myers, Shizuko Sei, Robert H. Shoemaker, Ronald A. Lubet, Yian Wang, Weiguo Cui, Ming You
Journal: Cancer Research (2021)

Abstract Immunotherapy using monoclonal antibodies to block immune checkpoints is becoming a mainstream therapy for multiple late-stage cancers owing to their efficacy in improving clinical outcomes. However, relatively low response rates and persistent clinical side effects indicate the need for additional strategies to block immune-suppressive pathways. VISTA (V-domain Ig Suppressor of T cell Activation), which is expressed on cells of the myeloid and lymphoid lineages, is an emerging target for cancer immunotherapy. Blocking VISTA activates both innate and adaptive immunity to eradicate tumors in mice. We found that CA170, a novel orally bioavailable tripeptide small molecule antagonist of VISTA and PD-L1/PD-L2, has potent anticancer efficacy on carcinogen-induced mouse lung tumorigenesis. Remarkably, lung tumor development was almost completely suppressed when CA170 was combined with an MHC-II-directed KRAS peptide vaccine. Flow cytometry and single cell RNA sequencing (scRNA-seq) revealed that CA170 increases CD8+ T cell infiltration and effector functions by decreasing the tumor infiltration of myeloid derived suppressor cells (MDSCs) and regulatory T cells (Tregs), while the KRAS vaccine primarily induces expansion of CD4+ effector T cells. Inhibition of VISTA by CA170 has strong efficacy against lung tumorigenesis with broad immunoregulatory functions that influence effector, memory and regulatory T cells, and promotes an adaptive T cell tumor-specific immune response that enhances efficacy of the KRAS vaccine. Citation Format: Jing Pan, Yao Chen, Qi Zhang, Achia Khatun, Katie Palen, Li Wang, Chuanjia Yang, Bryon D. Johnson, Charles R. Myers, Shizuko Sei, Robert H. Shoemaker, Ronald A. Lubet, Yian Wang, Weiguo Cui, Ming You. Inhibition of lung tumorigenesis by a novel small molecule CA170 targeting the immune checkpoint protein VISTA [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 1618.
Central role of c-Src in NOX5- mediated redox signalling in vascular smooth muscle cells in human hypertension
Authors: Livia L Camargo, Augusto C Montezano, Misbah Hussain, Yu Wang, Zhiguo Zou, Francisco J Rios, Karla B Neves, Rheure Alves-Lopes, Fazli R Awan, Tomasz J Guzik, Thomas Jensen, Richard C Hartley, Rhian M Touyz
Journal: Cardiovascular Research (2021)

Abstract Aims NOX-derived reactive oxygen species (ROS) are mediators of signalling pathways implicated in vascular smooth muscle cell (VSMC) dysfunction in hypertension. Among the numerous redox-sensitive kinases important in VSMC regulation is c-Src. However, mechanisms linking NOX/ROS to c-Src are unclear, especially in the context of oxidative stress in hypertension. Here, we investigated the role of NOX-induced oxidative stress in VSMCs in human hypertension focusing on NOX5, and explored c-Src, as a putative intermediate connecting NOX5-ROS to downstream effector targets underlying VSMC dysfunction. Methods and results VSMC from arteries from normotensive (NT) and hypertensive (HT) subjects were studied. NOX1,2,4,5 expression, ROS generation, oxidation/phosphorylation of signalling molecules, and actin polymerization and migration were assessed in the absence and presence of NOX5 (melittin) and Src (PP2) inhibitors. NOX5 and p22phox-dependent NOXs (NOX1–4) were down-regulated using NOX5 siRNA and p22phox-siRNA approaches. As proof of concept in intact vessels, vascular function was assessed by myography in transgenic mice expressing human NOX5 in a VSMC-specific manner. In HT VSMCs, NOX5 was up-regulated, with associated oxidative stress, hyperoxidation (c-Src, peroxiredoxin, DJ-1), and hyperphosphorylation (c-Src, PKC, ERK1/2, MLC20) of signalling molecules. NOX5 siRNA reduced ROS generation in NT and HT subjects. NOX5 siRNA, but not p22phox-siRNA, blunted c-Src phosphorylation in HT VSMCs. NOX5 siRNA reduced phosphorylation of MLC20 and FAK in NT and HT. In p22phox- silenced HT VSMCs, Ang II-induced phosphorylation of MLC20 was increased, effects blocked by melittin and PP2. NOX5 and c-Src inhibition attenuated actin polymerization and migration in HT VSMCs. In NOX5 transgenic mice, vascular hypercontractilty was decreased by melittin and PP2. Conclusion We define NOX5/ROS/c-Src as a novel feedforward signalling network in human VSMCs. Amplification of this system in hypertension contributes to VSMC dysfunction. Dampening the NOX5/ROS/c-Src pathway may ameliorate hypertension-associated vascular injury.
Abstract 1877: IOA-237 - A potent anti-CD73 mAb demonstrates monotherapeutic and combination efficacy in solid tumor models
Authors: Marcel A. Deken, Alan M. Carruthers, Karolina Niewola-Staszkowska, Gráinne Gernon, Hilary Sandig, Pritom Shah, Michael M. Lahn, Zoë Johnson
Journal: Cancer Research (2021)

Abstract CD73, an ecto-5'-nucleotidase, is frequently overexpressed in the tumor microenvironment and can be found on tumor, stromal cells and immune cells. Its function is to catalyze the conversion of adenosine monophosphate (AMP) to adenosine and phosphate, both at the cell surface and as a soluble factor. CD73 has gained interest as a therapeutic target in cancer due to the immunosuppressive role of adenosine in the tumor microenvironment. IOA-237 is a fully human, phage derived monoclonal antibody fully cross-reactive to mouse and human and with high potency against soluble and cell surface CD73. This novel antibody demonstrates in vitro and in vivo characteristics that suggest a best-in-class potential. We demonstrate that IOA-237 is able to significantly reduce tumor outgrowth in multiple mouse models of solid tumors. In the low CD73 expressing CT26 mouse colorectal cancer model, monotherapeutic application of IOA-237 showed tumor outgrowth reduction compared with isotype control. Best-in-class potential was confirmed with head-to-head comparison against a clinical stage anti-CD73 mAb, MEDI9447. Furthermore, inhibition of CD73 by IOA-237 was combined with inhibitors of novel immuno-oncology targets to study complementary modes of action in mouse models of solid tumors. These data indicate the potential of IOA-237 in monotherapeutic and combination therapeutic approaches and warrants further development. Additional in vitro and in vivo efficacy studies are ongoing and non-clinical safety studies are being planned. Citation Format: Marcel A. Deken, Alan M. Carruthers, Karolina Niewola-Staszkowska, Gráinne Gernon, Hilary Sandig, Pritom Shah, Michael M. Lahn, Zoë Johnson. IOA-237 - A potent anti-CD73 mAb demonstrates monotherapeutic and combination efficacy in solid tumor models [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 1877.
Abstract 2253: Comparison of genomic alterations in neuroendocrine tumors originated from different primary sites
Authors: Qiyun Tang, Ye Tian, Xiaolin Li, Jian'an Bai, Min Liu, Ping Hu, Shanshan Zhang, Zanmei Xu, Yueting Qu, Aodi Wang
Journal: Cancer Research (2021)

Abstract Background: Neuroendocrine tumors (NETs) are heterogeneous, relatively rare tumors derive from neuroendocrine system. Currently, limited therapeutic strategies are available for NETs. Next-generation sequencing (NGS) and target gene-based precision therapy have shown promising efficacy in many tumors, but fare in NETs. Several reports illustrated that the primary sites of NETs were significantly bound up with the clinical response and prognosis. However, characteristics of their genomic alterations are insufficiency nowadays. Methods: A cohort of 94 Chinese NET patients were recruited, and the FFPE tumor tissues and matching blood samples from different primary sites were collected. Targeted next generation sequencing (NGS) of 450 genes was performed in OrigiMed (Shanghai, China) with a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Results: In all patients, the top 5 most-frequently aberrant genes were TP53 (46.8%, 44/94), RB1 (23.4% 22/94), MEN1 (20.2%, 19/94), KRAS (11.7%, 11/94) and ATRX (9.6%, 9/94). The enrolled NETs contain 7 different primary sites, namely, 37 pancreatic NETs (PNETs), 16 hepatic NETs (HNETs), 11 gastric NETs (GNETs), 10 gallbladder NETs (GB-NETs), 8 esophageal NETs (ENETs), 7 colorectal NETs (CNETs), and 5 small intestine NETs (SI-NETs). Based on origin sites, TP53 is the most widely distributed mutant gene in all sites except for PNETs (Ranked 3rd), while RB1 mutations were significantly higher in ENETs (75.0%, 6/8), GB-NETs (60.0%, 6/10) and GNETs (36.4%, 4/11). Other higher -frequency mutated genes among different sites showed greatly dissimilarity (MEN1, ATRX and DAXX in PNETs; FAT3, MAX, MUC16, GATA4 and OBSCN in HNETs; APC, KRAS and PTEN in GNETs; TERT, ERBB2 and YES1 in GB-NETs; LRP1B and FBXW7 in ENETs; APC, ADGRA2 and FGFR1 in CNETs; NF1 in SI-NETs). Furthermore, signaling pathways involved in potential drug-target genes were analyzed. Results revealed 16.0% (15/94) patients with aberrations in PI3K/AKT/mTOR pathway, 11.7% (11/94) in Cell-Cycle pathway, 9.6% (9/94) in HRD pathway, 9.6% (9/94) in FGF pathway and 16.0% (15/94) in other cancer-related genes (ERBB2, VHL, MET etc.). Conclusions: This study reveals the genomic alteration characteristics of NETs from different primary sites. The profiles obtained in our study may provide evidences for further targeted therapy to improve outcomes of Chinese NETs. Citation Format: Qiyun Tang, Ye Tian, Xiaolin Li, Jian'an Bai, Min Liu, Ping Hu, Shanshan Zhang, Zanmei Xu, Yueting Qu, Aodi Wang. Comparison of genomic alterations in neuroendocrine tumors originated from different primary sites [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 2253.
Abstract 336: Gut microbiome predicts response to CDK4/6 inhibitor and immune check point inhibitor combination in patients with hormone receptor positive metastatic breast cancer
Authors: Chi Wah Wong, Susan E. Yost, Jin Sun Lee, Sarah K. Highlander, Yuan Yuan
Journal: Cancer Research (2021)

Abstract Background: CDK4/6 inhibitors (CDK4/6i) have been shown to modulate immune responses in the preclinical setting. Palbociclib is a front-line therapy for hormone receptor positive (HR+) metastatic breast cancer (MBC), and the combination with immune check point inhibitors (ICI) is increasingly being studied. An ongoing phase I trial was designed to test the safety and efficacy of palbociclib, pembrolizumab, and letrozole in postmenopausal women with HR+ HER2- MBC (NCT02778685). Stool microbiome was collected and analyzed. The aim of this study is to determine the association of gut microbiota and response using metagenome sequencing data through a machine learning model. Methods: Postmenopausal women with histologically proven stage IV HR+ HER2- MBC were enrolled. Stool samples were collected at baseline and during treatment for analysis using metagenome sequencing. Response per RECIST 1.1 were grouped into: responders (complete response or partial response) and non-responders (stable disease or progressive disease). Using metagenomic relative abundance data, a gradient-boosted tree model was developed with leave-one-patient-out cross validations to predict patient response at baseline. Kruskal-Wallis tests were used to assess the differences of the most important microbiota relative abundance (generated from the machine learning model) between responders and non-responders. Results: Forty-seven stool samples from 11 patients were collected at baseline and during treatment, and metagenome sequencing was performed. For predictive modeling, the validation Area Under the Receiver Operating Characteristic Curve (AUROC) and Area Under the Precision Recall Curve (AUPRC) were 0.71 and 0.83, respectively. Among the top 5 features from the model, patients with a larger relative abundance of Gemmiger formicillis have increased probability of responding to therapy (p&amp;lt;0.05 uncorrected), whereas an increase of Bacteroides vulgatus have reduced probability of responding to therapy (p&amp;lt;0.05 uncorrected). The relative abundance of Gemmiger formicillis at baseline has been reported in recent studies to be higher in patients with long term benefit (Aarnoutse et al. 2017). Thus, there is increasing evidence that gut microbiota plays a role in the pathogenesis of breast cancer and response of MBC patients to systemic cancer therapy. Citation Format: Chi Wah Wong, Susan E. Yost, Jin Sun Lee, Sarah K. Highlander, Yuan Yuan. Gut microbiome predicts response to CDK4/6 inhibitor and immune check point inhibitor combination in patients with hormone receptor positive metastatic breast 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 336.
Abstract 15159: Differential Recovery Between Regional Cerebral Oxygen Saturation and Physiological Parameters in Cardiopulmonary Arrest Patients After Return of Spontaneous Circulation
Authors: Goro Tajima, Tadahiko Shiozaki, Yoshihito Ogawa, Tomoya Hirose, Nobuto Mori, Tomohiro Ueki, Hiroo Izumino, Shuhei Yamano, Tomohito Hirao, Takamitsu Inokuma, Kazunori Yamashita, Osamu Tasaki
Journal: Circulation (2015)

Objective: We aimed to clarify the change in rSO2, blood pressure (BP) and arterial oxygen saturation (SpO2) in CPA patients who got return of spontaneous circulation (ROSC). Method: We measured rSO2 in CPA patients who were transferred to two tertiary emergency medical centers. On arrival, rSO2 sensor was attached to the forehead of patients, and monitored continuously during cardiopulmonary resuscitation. In the patients who got ROSC, we compared change in rSO2 and BP, SpO2, and evaluated the correlation between rSO2 and physiological parameters. Result: There were 79 CPA patients transferred to the tertiary emergency medical centers, and 38 patients got ROSC(Mean Age 74.8,M:F=25:13). rSO2 increased after ROSC, and showed the significance after 10 minutes after ROSC. Median rSO2 just after ROSC (ROSC 0) was 54.4% (47.2-59.5), and 66.0% (61.8-70.0) in 10 minutes after ROSC (ROSC 10) (Figure, p&lt;0.01 ROSC 0 vs ROSC 10). However, in BP and SpO2, there were no significant difference between in ROSC 0 and ROSC 10. BP rather showed lower tendency in ROSC 10 compared to ROSC 0. BP; 97mmHg (82.0-127) vs 82.0mmHg (67.0-120), SpO2; 86.0% (70.8-95.0) vs 93.0% (76.0-98.3) Conclusion: We clarified that there is a delay in rSO2 recovery compared to BP, SpO2 recovery after ROSC in CPA patients. It might be a therapeutic point to correct the delay in rSO2 recovery.