tbuckley/cabot-search huggingface dataset:
ADAR2 increases in exercised heart and protects against myocardial infarction and doxorubicin-induced cardiotoxicity
Authors: Xiaoting Wu, Lijun Wang, Kai Wang, Jin Li, Rui Chen, Xiaodong Wu, Gehui Ni, Chang Liu, Saumya Das, Joost P.G. Sluijter, Xinli Li, Junjie Xiao
Journal: Molecular Therapy (2021)

Exercise training benefits the heart. The knowledge of post-transcription regulation, especially RNA editing, in hearts remain rare. ADAR2 is an enzyme that edits adenosine to inosine nucleotides in double-stranded RNA, and RNA editing is associated with many human diseases. We found that ADAR2 was upregulated in hearts during exercise training. AAV9-mediated cardiac-specific ADAR2 overexpression attenuated acute myocardial infarction (AMI), MI remodeling, and doxorubicin (DOX)-induced cardiotoxicity. In vitro, overexpression of ADAR2 inhibited DOX-induced cardiomyocyte (CM) apoptosis. but it could also induce neonatal rat CM proliferation. Mechanistically, ADAR2 could regulate the abundance of mature miR-34a in CMs. Regulations of miR-34a or its target genes (Sirt1, Cyclin D1, and Bcl2) could affect the pro-proliferation and anti-apoptosis effects of ADAR2 on CMs. These data demonstrated that exercise-induced ADAR2 protects the heart from MI and DOX-induced cardiotoxicity. Our work suggests that ADAR2 overexpression or a post-transcriptional associated RNA editing via ADAR2 may be a promising therapeutic strategy for heart diseases.
Interventional Optical Imaging Permits Instant Visualization of Pathological Zones of Ablated Tumor Periphery and Residual Tumor Detection
Authors: Xuefeng Kan, Guanhui Zhou, Feng Zhang, Hongxiu Ji, Hui Zheng, Jeffrey Forris Beecham Chick, Karim Valji, Chuansheng Zheng, Xiaoming Yang
Journal: Cancer Research (2021)

Abstract Optical imaging (OI) provides real-time clinical imaging capability and simultaneous molecular, morphological, and functional information of disease processes. In this study, we present a new interventional OI technique, which enables in vivo visualization of three distinct pathologic zones of ablated tumor periphery for immediate detection of residual tumors during a radiofrequency ablation (RFA) session. Rabbits with orthotopic hepatic tumors were divided into two groups (n = 8/group): incomplete RFA and complete RFA. Indocyanine green-based interventional OI was used to differentiate three pathological zones: ablated tumor, transition margin, and residual tumor or surrounding normal liver—with quantitative comparison of signal-to-background ratios among the three zones and between incompletely and completely ablated tumors. Subsequent ex vivo OI and pathologic correlation were performed to confirm the findings of interventional OI. Interventional OI could differentiate incompletely or completely ablated tumor peripheries, thus permitting identification of residual tumor. This technique may open new avenues for immediate assessment of tumor eradication during a single interventional ablation session. Significance: Interventional optical imaging can instantly visualize pathologic zones of ablated tumor peripheries to detect residual tumors, which could revolutionize current image-guided interventional oncologic ablation techniques.
FBXO11 Is Recurrently Mutated in Burkitt Lymphoma and Its Inactivation Accelerates Lymphomagenesis in Eμ-Myc mice
Authors: Chiara Pighi, Mara Compagno, Taek-Chin Cheong, Teresa Poggio, Qi Wang, Fernanda Langellotto, Anoop Sendamarai, Kyriacos Markianos, Paola Francia Di Celle, Alberto Zamò, Roberto Chiarle
Journal: Blood (2017)
Abstract 1312: Anticancer activity of CA102N in breast cancer cells <i>in vitro</i> and <i>in vivo</i>
Authors: Eskouhie Tchaparian, Louis Lin, Ann Wang
Journal: Cancer Research (2021)

Abstract CA102N is a novel anticancer product designed to deliver its payload (Nim) to cells via the CD44 receptor. CA102N is currently in Phase 1 clinical trial for the treatment of metastatic colorectal cancer (mCRC). The major target of CA102N is the PI3K/Akt/mTOR cell signaling pathway, one of the most significantly deregulated pathway in several human cancers, including breast cancer. In the present study, the anticancer activity of CA102N was assessed on cell signaling, cell proliferation, and apoptosis in vitro in MDA-MB-231 human breast cancer cells. The antitumor efficacy was also tested in vivo in xenograft mice. We demonstrated that CA102N selectively inhibited MDA-MB-231 breast cancer cell growth and proliferation in vitro Administration of CA102N at 4.6mg/kg in xenograft mice resulted in effective tumor growth inhibition (TGI, 80%) with no apparent treatment-related toxicity. Suppression of PI3K/Akt downstream signaling was also detected in vitro. These results suggest that CA102N may represent a new potential treatment option for breast cancer. Combinations therapies and schedules are currently being explored in mice. to maximize the basis for its advancement therapy into the clinic. Citation Format: Eskouhie Tchaparian, Louis Lin, Ann Wang. Anticancer activity of CA102N in breast cancer cells in vitro and in vivo [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 1312.
<i>Helicobacter pylori</i> infection has a detrimental impact on the efficacy of cancer immunotherapies
Authors: Paul Oster, Laurie Vaillant, Erika Riva, Brynn McMillan, Christina Begka, Caroline Truntzer, Corentin Richard, Marine M Leblond, Meriem Messaoudene, Elisavet Machremi, Emeric Limagne, Francois Ghiringhelli, Bertrand Routy, Gregory Verdeil, Dominique Velin
Journal: Gut (2021)

In this study, we determined whether Helicobacter pylori (H. pylori) infection dampens the efficacy of cancer immunotherapies.Using mouse models, we evaluated whether immune checkpoint inhibitors or vaccine-based immunotherapies are effective in reducing tumour volumes of H. pylori-infected mice. In humans, we evaluated the correlation between H. pylori seropositivity and the efficacy of the programmed cell death protein 1 (PD-1) blockade therapy in patients with non-small-cell lung cancer (NSCLC).In mice engrafted with MC38 colon adenocarcinoma or B16-OVA melanoma cells, the tumour volumes of non-infected mice undergoing anticytotoxic T-lymphocyte-associated protein 4 and/or programmed death ligand 1 or anti-cancer vaccine treatments were significantly smaller than those of infected mice. We observed a decreased number and activation status of tumour-specific CD8+ T cells in the tumours of infected mice treated with cancer immunotherapies independent of the gut microbiome composition. Additionally, by performing an in vitro co-culture assay, we observed that dendritic cells of infected mice promote lower tumour-specific CD8+ T cell proliferation. We performed retrospective human clinical studies in two independent cohorts. In the Dijon cohort, H. pylori seropositivity was found to be associated with a decreased NSCLC patient survival on anti-PD-1 therapy. The survival median for H. pylori seropositive patients was 6.7 months compared with 15.4 months for seronegative patients (p=0.001). Additionally, in the Montreal cohort, H. pylori seropositivity was found to be associated with an apparent decrease of NSCLC patient progression-free survival on anti-PD-1 therapy.Our study unveils for the first time that the stomach microbiota affects the response to cancer immunotherapies and that H. pylori serology would be a powerful tool to personalize cancer immunotherapy treatment.
Abstract 1879: CIT-801: a bifunctional anti-PD1xIL15 agent demonstrated synergy and enhanced in vivo anti-tumor efficacy
Authors: Yiwen Li, Yuxiang Hu, Welson Wang, Wei Wu
Journal: Cancer Research (2021)

Abstract PD1/PD-L1 antibody has revolutionized cancer therapy. However, only a subset of cancer patients are responsive to anti-PD1 antibody treatment. Lack of immune effector cells in the tumor microenvironment (cold tumor) is considered a major reason for such a resistance. Interleukin 15 (IL15) is a cytokine critical for the survival and proliferation of T-cells and NK cells. We hypothesized that a combination of IL15 with anti-PD1 antibody might turn a cold tumor into a hot tumor and overcome tumor resistance to PD1 therapy, and therefore benefit a larger cancer patient population. We have constructed a homodimeric bifunctional agent (CIT-801) that is composed of an anti-PD1 antibody (CIT-100) and IL15 plus the sushi domain of IL15Rα. In vitro, this bifunctional anti-PD1xIL15 agent retained the ability of its anti-PD1 component to enhance T-cell activation in both mixed leukocyte reaction (MLR) and PD1 luciferase reporter assays. It also retained the ability of its IL15 component to stimulate the proliferation of T-cells. Moreover, the bifunctional agent was able to enhance the activation, proliferation and cytotoxicity of NK cells in vitro. In a syngeneic MC38 tumor model with human-PD1 knock-in mice, the bifunctional anti-PD1xIL15 agent strongly inhibited tumor growth, superior to anti-PD1 antibody treatment alone. In summary, anti-PD1xIL15 bifunctional compound CIT-801 has shown a great therapeutic potential and is worth further development. Citation Format: Yiwen Li, Yuxiang Hu, Welson Wang, Wei Wu. CIT-801: a bifunctional anti-PD1xIL15 agent demonstrated synergy and enhanced in vivo anti-tumor efficacy [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 1879.
OAS1/RNase L executes RIG-I ligand–dependent tumor cell apoptosis
Authors: Daniel F. R. Boehmer, Simone Formisano, Carina C. de Oliveira Mann, Stephan A. Mueller, Michael Kluge, Philipp Metzger, Meino Rohlfs, Christine Hörth, Lorenz Kocheise, Stefan F. Lichtenthaler, Karl-Peter Hopfner, Stefan Endres, Simon Rothenfusser, Caroline C. Friedel, Peter Duewell, Max Schnurr, Lars M. Koenig
Journal: Science Immunology (2021)

5′-Triphosphate RNA–induced apoptosis consists of a RIG-I–dependent priming and an OAS1/RNase L–dependent effector phase.
Abstract 1440: Novel imipridone ONC206 suppresses ovarian cancer progression through modulating immune cell response
Authors: Chi Lam Au Yeung, Wen Hu, Sammy Ferri-Borgogno, Rohinton S. Tarapore, Joshua E. Allen, Karen H. Lu, Samuel C. Mok
Journal: Cancer Research (2021)

Abstract Advanced ovarian cancer (stages III and IV) is the most lethal gynecologic malignancy in the United States. Survival of this cancer has not improved to a major extent over the past decade. High-grade serous ovarian cancer (HGSC), in particular, is notable for its initial sensitivity to chemotherapy using platinum and taxane combination following debulking surgery. However, the vast majority of these cancers (&amp;gt;75-80%) recur within 12-24 months after diagnosis, and patients die of progressively chemotherapy-resistant disease. The identification of prognostic or predictive markers, for ovarian cancer is crucial to the development of therapeutic targets and thus improvement of survival. ONC201 is the first clinical bitopic antagonist of dopamine receptor D2 (DRD2), that is well tolerated and currently being investigated in several clinical trials for oncology. ONC206 is a chemical derivative of ONC201 with the same impridone core structure, which is also a DRD2 antagonist that exhibits distinct receptor pharmacology and nanomolar potency in various preclinical cancer models. However, the effects of ONC206 on HGSC progression and the mechanism of action have not been thoroughly explored. Preliminary data demonstrated that overexpression of DRD2 is associated with poor overall survival rates in patients with advanced stage HGSC. ONC206-treated HGSC cells demonstrated significantly lower growth rates and higher percentage of apoptotic cells than ONC201-treated cells did in vitro. Besides, intraperitoneal injection of ONC206 (100 mg/kg) twice a week into HGSC-bearing immunocompetent mice demonstrated decreased tumor volume in vivo. In addition, by using suspension mass cytometry with a panel of 28 antibodies, fresh tumor tissues from ONC206-treated mice showed markedly increase in intratumoral NK cells and activated CD8+ T cells densities. These data suggest that ONC206 is more potent than ONC201 in suppressing HGSC growth directly. In addition, ONC206 may also suppresses HGSC growth through activating immune cell response in tumor tissues. Further studies that define the molecular mechanism by which DRD2 modulates the tumor suppressive effect of ONC206 on HGSC cells by suppressing HGSC directly or enhancing anti-tumor immune cell activity will be perform to establish ONC206 as a novel therapeutic agent in treatment of HGSC patients. Citation Format: Chi Lam Au Yeung, Wen Hu, Sammy Ferri-Borgogno, Rohinton S. Tarapore, Joshua E. Allen, Karen H. Lu, Samuel C. Mok. Novel imipridone ONC206 suppresses ovarian cancer progression through modulating immune cell response [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 1440.
Down-regulation of A20 promotes immune escape of lung adenocarcinomas
Authors: Kristina Breitenecker, Monika Homolya, Andreea C. Luca, Veronika Lang, Christoph Trenk, Georg Petroczi, Julian Mohrherr, Jaqueline Horvath, Stefan Moritsch, Lisa Haas, Margarita Kurnaeva, Robert Eferl, Dagmar Stoiber, Richard Moriggl, Martin Bilban, Anna C. Obenauf, Christiane Ferran, Balazs Dome, Viktoria Laszlo, Balázs Győrffy, Katalin Dezso, Judit Moldvay, Emilio Casanova, Herwig P. Moll
Journal: Science Translational Medicine (2021)

A20 represents an immune checkpoint in lung adenocarcinomas, and its loss may be compensated by targeting the TBK1–STAT1–PD-L1 axis.
Avoiding renorraphy at the end of off-clamp robotic partial nephrectomy does not jeopardize surgical and functional outcomes: A multicenter analysis
Authors: A. Brassetti, A. Bove, U. Anceschi, M.C. Ferriero, R. Mastroianni, L. Misuraca, F. Proietti, S. Guaglianone, G. Tuderti, M. Gallucci, G. Simone
Journal: European Urology (2021)
Abstract ND08: Anti-CD25 Mab: Selective depletion of T-regulatory cells
Authors: Theresa Kolben
Journal: Cancer Research (2021)

Abstract Tregs can suppress anti-tumour immune responses allowing for tumour growth. The negative prognostic impact of Tregs has been shown in several tumor settings. So far, Treg depletion has not been successful in patients, either because relevant Treg depletion was not achieved or because Teff cells have either been impacted or depleted as well. RG6292 has been optimised for ADCC selective depletion of cells with high CD25 density (Treg) and spares effector T cells by preserving IL-2-STAT5 signaling. RG6292 is currently tested in a Ph1 dose escalation study, and is given as monotherapy i.v. Q3W in adult patients with advanced solid tumors. 29 pts have been treated thus far at dose levels ranging from 0.3 mg to 35 mg. A dose dependent peripheral Treg depletion was observed as expected from RG6292 design and a significant flux of activated CD8+T cells as well as increase of PDL1 expression and intensity were observed in 3/3 patients in on-treatment biopsies taken 28 days after initiation of treatment. RG6292 at the doses tested was well tolerated in patients with advanced metastatic solid tumors and yielded encouraging PD effects consistent with its mechanism of action. Citation Format: Theresa Kolben. Anti-CD25 Mab: Selective depletion of T-regulatory 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 ND08.
Abstract 2960: A novel mouse model of pancreatic cancer reveals new insights into cell cycle deregulation
Authors: Christina Adams, Lynn Wang, Tim S. Wang, Nichol Miller, Elizabeth McMillan, Monica Ramstetter, John Chionis, Koleen Eisele, Jonathan Almaden, Timothy Affolter, Smitha Pillai, Todd VanArsdale, Chris Dillon, Stephen G. Dann
Journal: Cancer Research (2021)

Abstract Overcoming checkpoints to cell cycle control is the basis for tumorigenesis and malignant growth. Therefore, models that recapitulate clinically relevant cell cycle deregulation enhance our understanding of defined tumors subsets. Specifically, pancreatic ductal adenocarcinomas (PDAs) frequently delete the 9p21 locus which contains the cyclin dependent kinase (CDK) inhibitors CDKN2A (p16, p14) and CDKN2B (p15), as well as methylthioadenosine phosphorylase (MTAP), a metabolic gene required for methionine salvage from methylthioadenosine. No model currently exists that accurately represents loss of the entire locus in a relevant disease context. Moreover, the contribution of MTAP to tumor progression remains largely unknown. Therefore, we have developed a novel genetically engineered mouse model (GEMM) of PDA which combines loss of the orthologous murine 9p21 region (4qC4) with activated KRAS [Pdx-Cre; LSL-KrasG12D; 9p21L/L (K9C)], which results in rapid adenocarcinoma formation and subsequent mortality in mice homozygous for 9p21 deletion. Single-cell RNA sequencing revealed a remarkable level of inter- and intra-tumoral heterogeneity, including a significant immune and stromal component that contribute to tumor growth and progression. Additionally, K9C derived cell lines are responsive to Pfizer's first-in class CDK2/4/6 selective inhibitor while displaying de novo resistance to CDK4/6 inhibitor Palbociclib. Allograft and single-cell RNA sequencing experiments corroborated these findings and implicate Myc in contributing to CDK2/4/6i sensitivity. Furthermore, phenotypic-based screens revealed synthetic-lethal hits with 9p21 loss, indicating ample opportunities for combination strategies in this select patient population. Thus, we show that the K9C model recapitulates salient aspects of PDA and is amenable to novel therapeutic intervention strategies that may aid in improving the outcomes of patients with this precise genetic background. *All procedures performed on animals were in accordance with regulations and established guidelines and were reviewed and approved by an Institutional Animal Care and use committee Citation Format: Christina Adams, Lynn Wang, Tim S. Wang, Nichol Miller, Elizabeth McMillan, Monica Ramstetter, John Chionis, Koleen Eisele, Jonathan Almaden, Timothy Affolter, Smitha Pillai, Todd VanArsdale, Chris Dillon, Stephen G. Dann. A novel mouse model of pancreatic cancer reveals new insights into cell cycle deregulation [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 2960.
Abstract 3060: Assessment of Coronary Red and White Thrombus by Optical Coherence Tomography
Authors: Takashi Kubo, Takashi Yamano, Takashi Masyo, Shigeho Takarada, Toshio Imanishi, Yoshiaki Tomobuchi, Takashi Akasaka
Journal: Circulation (2006)

[BACKGROUND] Recently, OCT has been proposed as a high-resolution imaging modality. However, the OCT appearance of thrombi in vivo has not been well described. We sought to analyze the optical cohe...
Abstract 1822: Novel DNA encoded tumor attacking bridges (dTABs) targeting IL13Rα2 display potent tumor control in an animal model of glioblastoma multiforme
Authors: Pratik Sanjivkumar Bhojnagarwala, Ryan O'Connell, Daniel Park, Ebony Gary, Xizhou Zhu, David Weiner
Journal: Cancer Research (2021)

Abstract Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with poor clinical prognosis and there is significant need for new, improved therapies. Immunotherapy is a growing therapeutic research area for patients with advanced brain cancers. DNA encoded Tumor Attacking Bridges (dTABs) are bispecific antibodies that redirect T cell activity against Tumor Associated Antigens (TAAs) of interest. Here, we describe the design and development of in vivo generated dTABs targeting IL13Rα2, which is expressed in tumors of approximately 75% of GBM patients. Four dTABs targeting 2 different epitopes of IL13Rα2 were designed to compare alternate orientations of heavy and light chains in the dTABs. All dTABs bound to U87 cells expressing target as well as CD3 on T cells. The dTABs induced T cell activation, cytokine production, and tumor killing in the presence of target expressing tumor cells in a dose dependent manner. An important issue in the field of antibody guided therapies is on target - off tumor T cell activity which can cause serious side effects in patients. In order to minimize such toxicities, we identified one arrangement of dTAB which induced high T cell activation with potent tumor killing in the presence of target expressing tumor cells, but not when co-cultured with tumors that do not express IL13Rα2. We were able to detect expression of this lead dTAB for up to 19 days in the serum of NSG mice after a single DNA injection followed by electroporation. Serum from mice injected with this dTAB activated T cells which potently killed target expressing U87 GBM cells. In a subcutaneous xenograft mouse model of human GBM, this in vivo produced dTAB demonstrated significant tumor control and improved survival of mice. This study illustrates the potential of dTABs targeting IL13Rα2 as a novel approach for immunotherapy of this difficult to treat brain cancer. Citation Format: Pratik Sanjivkumar Bhojnagarwala, Ryan O'Connell, Daniel Park, Ebony Gary, Xizhou Zhu, David Weiner. Novel DNA encoded tumor attacking bridges (dTABs) targeting IL13Rα2 display potent tumor control in an animal model of glioblastoma multiforme [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 1822.
Evaluation of Messenger RNA From COVID-19 BTN162b2 and mRNA-1273 Vaccines in Human Milk
Authors: Yarden Golan, Mary Prahl, Arianna Cassidy, Christine Y. Lin, Nadav Ahituv, Valerie J. Flaherman, Stephanie L. Gaw
Journal: JAMA Pediatrics (2021)

Evaluation of Messenger RNA From COVID-19 BTN162b2 and mRNA-1273 Vaccines in Human MilkMessenger RNA (mRNA) vaccines against COVID-19 were recently approved under an emergency use authorization. 1 However, there is a paucity of data regarding vaccine safety in pregnant or lactating individuals who were excluded from phase 3 clinical trials, 2,3 and many mothers have declined vaccination or decided to discontinue breastfeeding (temporarily or permanently) due to concern that maternal vaccination may alter human milk.The World Health Organization recommends that breastfeeding individuals be vaccinated and does not advise cessation of breastfeeding following vaccine administration. 4,5The Academy of Breastfeeding Medicine states that there is little plausible risk that vaccine nanoparticles or mRNA would enter breast tissue or be transferred to milk, 6 which could theoretically result in priming of infant immune responses that could alter childhood immunity.However, there are no direct data.To address this knowledge gap, we analyzed milk samples to determine if vaccine-related mRNA was detectable in human milk after vaccination.