bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA-004: The impact of gut microbiota on the radiotherapy-induced antitumor immune response
Authors: Uribe-Herranz Mireia , Rafail Stavros , Beghi Silvia , Verginadis Ioannis , Mesaros Clementina , Koumenis Costantinos , Facciabene Andrea 
Published: April 2021

Abstract
Alterations in gut microbiota impact the pathophysiology of several diseases, including cancer. Radiotherapy (RT), an established curative and palliative cancer treatment, exerts potent immune modulatory effects, inducing tumor-associated antigen (TAA) cross-priming with antitumor CD8+ T cell elicitation and abscopal effects. We tested whether the gut microbiota modulates antitumor immune response following RT distal to the gut. Vancomycin, an antibiotic that acts mainly on gram-positive bacteria and is restricted to the gut, potentiated the RT-induced antitumor immune response and tumor growth inhibition. This synergy was dependent on TAA cross presentation to cytolytic CD8+ T cells and on IFN-γ. Notably, butyrate, a metabolite produced by the vancomycin-depleted gut bacteria, abrogated the vancomycin effect. In conclusion, depletion of vancomycin-sensitive bacteria enhances the antitumor activity of RT, which has important clinical ramifications.
Citation Format: Mireia Uribe-Herranz, Stavros Rafail, Silvia Beghi, Ioannis Verginadis, Clementina Mesaros, Costantinos Koumenis, Andrea Facciabene. The impact of gut microbiota on the radiotherapy-induced antitumor immune response [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-004.
Abstract IA-015: Hypoxia-induced SETX links replication stress with the unfolded protein response
Authors: Hammond Ester M. 
Published: April 2021

Abstract
Tumor hypoxia is associated with poor patient prognosis and radiation resistance. A unique transcriptional response is initiated by hypoxia which includes the rapid activation of numerous transcription factors in a background of reduced global transcription. Here, we show that the biological response to hypoxia includes the accumulation of R-loops and the induction of the RNA/DNA helicase SETX. In the absence of hypoxia-induced SETX, R-loop levels increase, DNA damage accumulates, DNA replication rates decrease and radiosensitivity increases. Importantly, we show that the mechanism of SETX induction is reliant on the PERK/ATF4 arm of the unfolded protein response. These data not only highlight the unique cellular response to hypoxia, which includes both a replication stress-dependent DNA damage response and an unfolded protein response but uncover a novel link between these two distinct pathways.
Citation Format: Ester M. Hammond. Hypoxia-induced SETX links replication stress with the unfolded protein response [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-015.
Abstract IA-020: Optimizing stem cell niche for post-irradiation regeneration
Authors: Coppes Rob P. 
Published: April 2021

Abstract
Radiotherapy involves unavoidable co-irradiation of the normal tissue, often resulting in side effects that limit the dose to the tumor and/or reduce quality of life of cancer survivors. The response of normal tissues to irradiation is mainly determined by the survival and regenerative potential of the tissue stem cells, and modulated by inflammatory processes, vasculature damage, altered neuronal innervation and fibrosis. Indeed, transplantation of tissue specific stem cells has been shown to restores tissue homeostasis and prevent late radiation effects. However, the radiation-induced senescence, fibrosis, and chronic inflammation may chance the stem cell niche engender an unfavorable environment for the regenerative potential of the tissue’s stem cells. Here changes in the salivary gland stem cell niche will be discussed using irradiated murine submandibular salivary gland tissue and derived organoids. Recently, we have developed methods to culture murine and patient specific tissue resembling salivary gland organoids (SGO). SGO contain all the glandular lineages, are able to extensively self-renew and up on transplantation rescue salivary gland function, allowing the study of radiation responses. The role of stemness factors, senescence and inflammatory processes in stem cell self-renewal and differentiation and post-irradiation regeneration will be discussed. Using SGO formation efficiency (OFE) as a measure of regenerative potential it is shown that stem cell potency after in vivo irradiation, is time dependent reduced. Interestingly, the conditioned medium of irradiated SGO reduced the OFE of unirradiated SGO. The potential role of radiation-induced senescence-associated secretory phenotype, hippo-signaling and inflammation through activation of cytosolic DNA sensing pathways on stem cells function will be addressed. Radiation-induced environmental changes in the stem cells niche have a severe impact on stem cell function. Modulation of these effect may enhance regenerative potential of surviving stem cells and improve engraftment and regeneration after stem cell transplantation. Supported by the Dutch Cancer Society (KWF, grant No. 10650 and 12092) and The Netherlands Organisation for Health Research and Development (ZonMw, Grant nrs. 11.600.1023 and 40-43600-98-14003).
Citation Format: Rob P. Coppes. Optimizing stem cell niche for post-irradiation regeneration [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-020.
Abstract PO-001: HDAC6 inhibitors sensitize non-mesenchymal triple-negative breast cancer cells to cysteine deprivation
Authors: Alothaim Tahiyat , Charbonneau Morgan , Tang Xiaohu (Mark) 
Published: April 2021

Abstract
Triple-negative breast cancer (TNBC) accounts for 15% ~ 20% of overall breast cancer cases and exhibits earlier age of onset, high metastasis, and aggressiveness with poor clinical outcomes shown by higher relapse and lower survival rates than other types of breast cancer. TNBC contributes to the major mortality of breast cancer patients. Treatments of TNBC patients are still limited to surgery, chemotherapy, or radiation since the absence of cell receptors makes targeted hormonal therapies impossible. Targeting cysteine-dependence is an emergent strategy to treat the mesenchymal TNBC. However, many TNBC cells are non-mesenchymal and irresponsive to cysteine deprivation. To overcome such resistances, three selective HDAC6 inhibitors (Tubacin, CAY10603, and Tubastatin A), identified by epigenetic compound library screening, can synergize with cysteine deprivation to induce cell death in the non-mesenchymal TNBC. Despite the efficacy of the HDAC6 inhibitor, knockout of HDAC6 did not mimic the synthetic lethality induced by its inhibitors, particularly tubacin, indicating that HDAC6 is not the actual target of HDAC6 inhibitor in this context. Instead, transcriptomic profiling showed that tubacin triggers an extensive gene transcriptional program in combination with erastin, a cysteine transport blocker. Notably, the zinc-related gene response and an increase of labile zinc were induced in cells by the combination treatment. We found that the disturbance of cellular zinc homeostasis was driven by PKCγ activation, which revealed that the PKCγ signaling pathway is required for HDAC6 inhibitor-mediated synthetic lethality. Overall, our study identifies a novel function of HDAC6 inhibitors that function as potent sensitizers of cysteine deprivation. HDAC6 inhibitors are capable to overcome cysteine independence in non-mesenchymal tumor cells, which allows the application of targeted cysteine-dependence therapy in various subtypes of breast cancer.
Citation Format: Tahiyat Alothaim, Morgan Charbonneau, Xiaohu (Mark) Tang. HDAC6 inhibitors sensitize non-mesenchymal triple-negative breast cancer cells to cysteine deprivation [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-001.
Abstract PO-007: 18O-substituted nucleosides combined with proton beam: “Theranostic transformation.”
Authors: Rich Tyvin , Pan Dongfeng , Chordia Mahendra , Keppel Cynthia , Jung Mira , Pang Dalong , Beylin David , Grindrod Scott , Dritschilo Anatoly 
Published: April 2021

Abstract
Therapeutic protons (PRT) cause atomic transmutation of 18O to 18F producing positrons and release neutrons. We hypothesize that targeted production of 18F may be achieved with an 18O containing nucleoside that incorporates into DNA and when exposed to PRT alters local chemical behavior. PRT radiation sensitization (RS) was tested in SQ20-B squamous carcinoma and PC3 prostate cancer cells treated with 18O substituted C2-18O-thymidine (18O-TD), C2-18O-Uridine (18O-UD) and also the thymidine analogs IUdR and substituted 5’-18O-5-iododeoxyuridine (18O-IUdR). Proton RS data are reported for Log phase cells exposed to these substituted nucleosides at physiologic concentrations of 5 -10 µM for 48 hours and re-plated in fresh media. PRT 24 hours later delivered 1 to 9 Gy using an 85 MeV beam at the Bragg peak. Survival fractions were determined by colony assays in triplicate for combined treatment vs. PRT alone. The single hit multi-target model was applied to demonstrate RS with dose modification factors of 1.2 for 18O-TD, 1.3 for IUdR, and 1.5 for 18O-IUdR. RS was not seen with 18O-TD, 18O-UD, or H218O irradiated with gamma rays, nor those treated with 18O-UD or H218O combined with PRT (no changes in D0). PRT of H218O with 10 Gy yielded positron emission tomography images in vitro initiated &gt;45 minutes after PRT with a decay signal with T1/2 of ~111 min. We conclude that 18O-substituted nucleosides activated by therapeutic PRT create in situ 18F that may open up new strategies for RS. A wide PRT therapeutic window could result from the metabolic, physical, and chemical effects of “theranostic transmutation” with 18O labelled nucleosides.
Citation Format: Tyvin Rich, Dongfeng Pan, Mahendra Chordia, Cynthia Keppel, Mira Jung, Dalong Pang, David Beylin, Scott Grindrod, Anatoly Dritschilo. 18O-substituted nucleosides combined with proton beam: “Theranostic transformation.” [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-007.
Abstract PO-016: Changes in the expression levels of DNAJAs in triple negative breast cancer cells exposed to cytotoxic chemotherapy
Authors: Freeny Devon 
Published: April 2021

Abstract
Triple Negative Breast Cancer (TBNC) lacking biological targets results in limited therapeutic options and leads to high mortality rates. The last therapy is Doxorubicin (Cytotoxic chemotherapeutic drug), an anti-tumor therapeutic alternative; which has bad side effects (cardiotoxicity), due to dose dependence, leading to drug resistance. There are three primary mechanisms of action for doxorubicin: Intercalation into DNA, which directly affects transcription and replication. Inhibition of topoisomerase II activity during the double-strand break, which prevents the binding portion of the ligation reaction that topoisomerase II catalyzes, by stabilizing the DNA-topoisomerase II alpha complex. Lastly, generating free radicals as it cycles between its quinone and semi-quinone structures during metabolic reactions, which generates reactive oxygen species. Research says heat shock proteins (HSPs) help to protect cells using heat-shock response. Several HSPs have been tested, with limited knowledge of HSP40s (DNAJAs). We will determine which DNAJA (1 to 4) assists in the survival response to doxorubicin by observing the domains and expression of the proteins being exposed to chemotherapy. The J domain has shown to be a critical area for increasing cell sensitivity while reducing cardiotoxicity. Expression levels were analyzed via RT-PCR and Western Blots, and relevant domains via COSMIC database. In conclusion the first step to reducing cardiotoxicity with chemotherapeutics is by modifying HSP40 functionality in human cancer cells, providing an alternative to hypersensitization to chemotherapy, allowing for lower dosage with less side effects.
Citation Format: Devon Freeny. Changes in the expression levels of DNAJAs in triple negative breast cancer cells exposed to cytotoxic chemotherapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-016.
Abstract PO-023: Impact of a novel Ku-DNA binding inhibitor on the IR-induced DNA damage response
Authors: Mendoza-Munoz Pamela , Gavande Navnath S. , VanderVere-Carozza Pamela S. , Pawelczak Katherine S. , Dynlacht Joseph R. , Garrett Joy , Turchi John J. 
Published: April 2021

Abstract
The DNA-dependent protein kinase (DNA-PK) plays a critical role in the non-homologous end joining (NHEJ) double stand break (DSB) repair pathway and the DNA damage response (DDR). Consequently, blocking DNA-PK kinase activity is a novel anti-cancer therapeutic strategy in combination with ionizing radiation (IR). Towards developing a series of a new class of DNA-PK inhibitors, our laboratory has exploited the mechanism of DNA-PK activation which requires binding to DNA termini via the Ku 70/80 heterodimer. We recently reported the development of Ku-DNA binding inhibitors (Ku-DBi’s) that act via this novel mechanism of action to inhibit DNA-PK catalytic kinase activity. Ku-DBi’s display nanomolar activity in vitro, possess cellular DNA-PK and NHEJ inhibitory activity and sensitize non-small cell lung cancer (NSCLC) cells to chemotherapeutics bleomycin and etoposide. In this study, we demonstrate that pre-incubation of our novel Ku-DBi’s can potentiate the cellular effects of IR. We demonstrate that the increase in IR sensitivity is preceded by a decrease in DNA-PKcs autophosphorylation events at the S2056 (pS2056) cluster. Using a combination of Western blot and immunofluorescence assays in the NSCLC NCI-H460 cell line, Ku-DBi 245 treatment in combination with IR showed a significant reduction of phosphorylation of DNA-PKcs at S2056 compared to IR alone. Analysis of gH2A.X also showed an inhibition of the DDR as a function of 245 treatment, evidenced by reduction of S139 phosphorylation. These results demonstrate that Ku-DBi 245 blocks DNA-break dependent DNA-PKcs autophosphorylation, resulting in an increased in radiation sensitivity. These data are consistent with Ku-DBi’s possessing a novel mechanism of action that abrogates autophosphorylation of DNA-PKcs and DDR signaling as part of an anticancer therapeutic strategy in combination with IR.
Citation Format: Pamela Mendoza-Munoz, Navnath S. Gavande, Pamela S. VanderVere-Carozza, Katherine S. Pawelczak, Joseph R. Dynlacht, Joy Garrett, John J. Turchi. Impact of a novel Ku-DNA binding inhibitor on the IR-induced DNA damage response [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-023.
Abstract PO-024: Paclitaxel induced apoptosis through ROS production and eliminated cellular senescence in PC9-MET cells
Authors: Mohiuddin Md , Kasahara Kazuo 
Published: April 2021

Abstract
Background: Paclitaxel is used as first-line and subsequent therapy for the treatment of various cancers. However, the mechanisms by which paclitaxel exerts its anticancer activity against non-small cell lung cancer (NSCLC) are not well understood. This study aimed to investigate paclitaxel's role in cell proliferation, apoptosis, and cellular senescence of PC9-MET (gefitinib-resistant) cells and reveal the underlying mechanisms. Methods: PC9-MET cells were treated with paclitaxel for 72 h and then evaluated by cell viability assay, Giemsa staining, DAPI staining, apoptosis assay, SA-β-Gal staining, ROS assay, TUNEL assay and western blotting. Results: Our results revealed that paclitaxel significantly reduced the viability of PC9-MET cells and induced morphological signs of apoptosis. The apoptotic effects of paclitaxel were observed by increased levels of cleaved caspase-3, cleaved caspase-9 and cleaved PARP. Additionally, paclitaxel increased ROS production, leading to DNA damage. Importantly, paclitaxel eliminated cellular senescence, which was observed by SA-β-Gal staining. Conclusion: In light of these findings, paclitaxel could be a promising agent for cancer treatment against human PC9-MET (gefitinib-resistant) cells.
Citation Format: Md Mohiuddin, Kazuo Kasahara. Paclitaxel induced apoptosis through ROS production and eliminated cellular senescence in PC9-MET cells [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-024.
Abstract PO-025: Radiation-induced and FACS-sorted senescent tdTOMp16+ cells upregulate profibrotic genes in C57BL/6 stromal target cells
Authors: Mukherjee Amitava , Epperly Michael , Shields Donna , Hou Wen , Fisher Renee , Hamade Diala , Greenberger Joel S. 
Published: April 2021

Abstract
Acute Radiation Syndrome and the multiorgan failure from delayed effects of acute radiation exposure present challenging consequences of radiation terrorism or a radiological accident. Recent research suggests that radiation-induced cellular senescence plays an important role in radiation-induced pulmonary fibrosis (RIPF), and that clearance of senescent cells (SCs) could be an effective therapeutic strategy. However, the identification and targeted removal of only senescent cells using drugs have been difficult. Here we have established a bone-marrow stromal cell line from a tdTOMp16+ mouse. We show that 5 Gy irradiation induces ~9% cellular senescence in tdTOMp16+ stromal line after 10 days and can be isolated as a pure population of red tdTOMp16+ cells by FACS sorting. To confirm that these irradiated and then sorted red cells are senescent, we cultured them as single cells in 96-well plates and followed for four weeks. None of the 960 irradiated red cells we plated divided after 2 weeks, 137 of these cells remained intact and assumed large and flat cellular morphology. In contrast, 50 of 800 cells that were irradiated but didn’t turn red, divided, as did 104 of 560 nonirradiated control cells (0 Gy) divided. There was significant upregulation of senescent cell markers including SA-ß-gal, p16, and p21 in the irradiated and sorted red cells when compared to irradiated nonred cells. Sorted irradiated red, non-irradiated, or irradiated non-red cells were placed on the top well of transwells. There was a significant induction of fibrotic genes Ctgf, Tgf- ß, collagen 1a, and collagen 3 in C57/B6 stromal target cells in the bottom layer by irradiated red cells, but not the other cell populations irradiated non-red. Thus, radiation-induced biomarkers of fibrosis are induced by senescent cells.
Citation Format: Amitava Mukherjee, Michael Epperly, Donna Shields, Wen Hou, Renee Fisher, Diala Hamade, Joel S. Greenberger. Radiation-induced and FACS-sorted senescent tdTOMp16+ cells upregulate profibrotic genes in C57BL/6 stromal target cells [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-025.
Abstract PO-026: DNA damage response and repair characterization in CHK2-deficient cancers
Authors: Muñoz-Maldonado Carmen , Quintin Aurélie , Aebersold Daniel M. , Zimmer Yitzhak , Medová Michaela 
Published: April 2021

Abstract
Double strand breaks (DSBs) are the most lethal DNA lesions as they can result in chromosomal rearrangements or loss of genetic material. To detect and repair DNA, cells have developed the DNA damage response, a cascade of proteins in which the checkpoint kinase 2 (CHK2) is involved. CHK2-deficient cancers, such as breast, prostate or colon, might have a compromised response to ionizing radiation (IR), arresting cell cycle at checkpoints or inducing apoptosis in presence of irreparable damage. To understand how the lack of CHK2 is affecting DNA damage response and repair, the human isogenic HCT116 colorectal cancer cell lines proficient (CHK2 WT) and deficient (CHK2 KO) for CHK2 have been characterized. Cell cycle distribution and γH2AX foci formation were assessed by flow cytometry and immunofluorescence, respectively, to determine the differences in cell cycle checkpoints and DSBs infliction and resolution upon IR. Traffic Light Reporter, complemented by immunofluorescence of RAD51 foci, was employed in both CHK2 WT and KO cell lines to identify the preferred DSB repair pathway. Our results indicate that CHK2-proficient and -deficient cell lines do not exhibit significant differences in cell cycle distribution upon IR. On the other hand, CHK2 KO cells display a significant increase in γH2AX foci per cell compared to the CHK2 WT. Upon 1Gy of IR, cells lacking CHK2 increment the number of foci per cell, indicating that DSBs detection occurs independently of the CHK2 status. Furthermore, the Traffic Light Reporter revealed higher homologous recombination (HR) to non-homologous end-joining (NHEJ) ratio in the CHK2 KO cells as compared to their CHK2 WT counterparts, suggesting that the lack of CHK2 stimulates a shift in the DSBs repair pathway choice. These results contrast with the RAD51 foci formation, which seems to be compromised in the CHK2 KO cells in both treated and untreated conditions as compared to the CHK2-proficient cells. Our results suggest that CHK2 status considerably affects cellular DNA damage response and these differences in execution of DNA repair could be exploited in CHK2-deficient cancers.
Citation Format: Carmen Muñoz-Maldonado, Aurélie Quintin, Daniel M. Aebersold, Yitzhak Zimmer, Michaela Medová. DNA damage response and repair characterization in CHK2-deficient cancers [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-026.