bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PO-038: Hide and Seq: Radiation-induced immunogenicity of patient tumors revealed by single cell analysis
Authors: Chow Jacky L. , Hoffend Nicholas , Gaudieri Madeline , Abrams Scott , Schwaab Thomas , Singh Anurag , Muhitch Jason 
Published: April 2021

Abstract
Robust preclinical investigations into radiation-induced immunogenicity has led to increased enthusiasm for combining radiation with immunotherapy. Promising results in a limited number of patients treated with radiotherapy and immune-activating strategies has supported the initiation of over 150 ongoing clinical trials. Yet, due to reduced availability of patient samples following treatment, tumor tissue in particular, there has been sparse investigation of the impact of radiation on immunogenicity in human malignancies. While murine models have revealed important insights into understanding radiation-induced immunogenic mechanisms, inherent differences in radiation sensitivity between mice and humans limit translation to patients. To determine the impact of radiation on patient tumor cells we analyzed samples from renal cell carcinoma (RCC) patients treated with stereotactic body radiation therapy (SBRT) in a pilot study (NCT01892930). Previous data showed radiation induced surface presentation of tumor-associated antigens in resected irradiated tumors. Bulk transcriptomic data of in situ-irradiated tumors showed evidence of immune activation, including increased interferon-gamma (IFNG) signaling, as well as increased T cell clonality and higher abundance of T cells clones with similar binding affinities predicted by dominant motif analysis. We hypothesized that the tumor response to in situ irradiation included increased transcript abundance for tumor antigen genes and antigen-presentation machinery, as well as a response to IFNG signaling. Tumor cell comparisons following single-cell RNA sequencing uncovered RCC cell-specific responses to in situ irradiation. Irradiated RCC tumor cells expressed higher levels of genes encoding MUC-1 and carbonic anhydrase 9, as well as higher expression of calreticulin and genes encoding MHC class 1 molecules: HLA-A, HLA-B, and HLA-C; furthermore, gene set enrichment identified enhancement of antigen processing and presentation pathways. Additionally, irradiated tumor cells expressed higher levels of the IFNG receptor, its downstream targets, and the enrichment of several interferon response gene sets. Collectively, these results indicate radiation may improve tumor recognition through both increased antigen expression and surface presentation as well as sensitize tumor cells to immunogenic cytokines and T cell-mediated cytolysis in human malignancies, such as RCC.
Citation Format: Jacky L. Chow, Nicholas Hoffend, Madeline Gaudieri, Scott Abrams, Thomas Schwaab, Anurag Singh, Jason Muhitch. Hide and Seq: Radiation-induced immunogenicity of patient tumors revealed by single cell analysis [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-038.
Abstract PO-039: Radiation therapy enhances anti-tumor activity of a MET CAR T-based immunotherapy approach for glioblastoma multiforme
Authors: Hovhannisyan Lusine , Aebersold Daniel M. , Maher John , Ochsenbein Adrian F. , Riether Carsten , Medova Michaela , Zimmer Yitzhak 
Published: April 2021

Abstract
Glioblastoma multiforme (GBM) is the most prevalent primary malignant brain tumor, which has an aggressive phenotype and mostly fatal recurrence after standard therapy. MET, the hepatocyte growth factor (HGF) receptor is a relevant target for GBM treatment as it is expressed in up to 50% of cases and its expression, which may be induced by radiation therapy (RT), can potentially contribute to RT-resistance of GBM stem cells, and tumor recurrence. MET-based chimeric antigen (CAR) T cell therapy is currently being evaluated in several solid tumor working settings. A combination of T cell-based therapies with RT may improve the efficacy of the CAR T cell therapy through by the RT-induced immune activation via release of cytokines and induction of antigen expression, similarly as has been observed when combining RT with immune checkpoint inhibitors. Here we investigated the combination of MET-targeting CAR T cells with RT for GBM treatment, hypothesizing enhanced anti-tumor effects. The current study used a panel of MET-proficient and MET-deficient human GBM and GBM stem-like cell lines. Cells have been irradiated with a single dose of 0, 2, 5, or 10 Gy and RT impact on MET expression has been assessed at various time points after RT administration. Results show MET increase after RT in some cell lines. To test MET-targeting CAR T effect on the GBM cell lines, CAR constructs that are based on HGF-MET binding elements have been introduced into virus-producing cells and used for human T cells transduction to generate MET-targeting CAR T cells. CAR T cells co-cultured with GBM cell lines in vitro have specifically and significantly decreased viability of MET-positive cancer cells. Data resulting from combination of RT and CAR T cells treatment suggest that radiation exhibits an enhancement of CAR T cells anti-tumor killing activity, indicating a synergism between the two modalities. In conclusion, our data are the first to indicate the efficacy of a MET-based CAR T immunotherapy approach in GBM cell lines. The results also demonstrate a basis for the combination of a MET CAR T modality together with RT. The mechanisms for understanding the interaction between RT and the MET CAR T cells are under investigation.
Citation Format: Lusine Hovhannisyan, Daniel M. Aebersold, John Maher, Adrian F. Ochsenbein, Carsten Riether, Michaela Medova, Yitzhak Zimmer. Radiation therapy enhances anti-tumor activity of a MET CAR T-based immunotherapy approach for glioblastoma multiforme [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-039.
Abstract PO-041: An immunologic niche of antigen presenting cells and stem-like CD8+ T-cells is present in non-small cell lung cancer brain metastases
Authors: Jansen Caroline S. , del Balzo Luke , Prabhu Roshan , Logan Suzanna , Chappa Prasanthi , Patel Kirtesh , Wilkinson Scott , Lake Ross , Shu Hui-Kuo G. , Zhong Jim , Dhere Vishal , Olson Jeffrey , Sowalsky Adam G. , Khan Mohammad K. , Kissick Haydn T. , Buchwald Zachary S. 
Published: April 2021

Abstract
Background: Non-small cell lung cancer (NSCLC) patients with brain metastases have a very poor prognosis. The first line treatments for NSCLC brain metastases are typically surgery and pre- or post-operative stereotactic radiosurgery (SRS) or SRS alone. However, subsequent intra-cranial failure and death is common. Importantly, we have previously shown that a unique immune niche in genitourinary malignancies correlates with the risk for disease recurrence. Accordingly, here we investigated whether this immune niche was present in brain metastases, whether it correlated with patient outcomes, and whether it was modulated by SRS. Methods: Formalin fixed paraffin embedded brain metastases were stained by immunofluorescence for CD8, PD-1, TCF-1, MHC-II and DAPI. Following successful image acquisition using fluorescent whole slide scanning, we used a custom quantitative analysis pipeline to measure the cellularity, relative cellular locations, local cellular density, and marker staining intensity. Results: We identified immune niches consisting of both stem-like TCF-1+ CD8+ T-cells and antigen presenting cells (MHC-II+) in brain metastases. TCF-1+ CD8+ T-cells were found at in areas of higher MHC-II+ cell density than the TCF-1 CD8+negative T-cells. The amount of tumor issue occupied by immune niches correlated with TCF1+ CD8+ T-cell infiltration, as well as with total CD8+ T-cell and MHC-II+ cell infiltration. Importantly, we found that higher MHC-II+ cell density correlated with longer overall survival in this cohort of patients. Additionally, we found this immune niche is preserved following pre-operative SRS. Conclusions: Our study is the first to demonstrate stem-like CD8+ T-cells in brain metastases and that these cells form an immune niche similar to those described extra-cranial tumor sites. Additionally, we report that the immune niche is preserved following SRS, which is highly clinically relevant to the use of combinatorial strategies between SRS and checkpoint blockade.
Citation Format: Caroline S. Jansen, Luke del Balzo, Roshan Prabhu, Suzanna Logan, Prasanthi Chappa, Kirtesh Patel, Scott Wilkinson, Ross Lake, Hui-Kuo G. Shu, Jim Zhong, Vishal Dhere, Jeffrey Olson, Adam G. Sowalsky, Mohammad K. Khan, Haydn T. Kissick, Zachary S. Buchwald. An immunologic niche of antigen presenting cells and stem-like CD8+ T-cells is present in non-small cell lung cancer brain metastases [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-041.
Abstract PO-056: Sonographic and photoacoustic monitoring of radiation-induced parenchymal and vascular injury to salivary glands
Authors: Bolookat Eftekhar Rajab , Vincent-Chong Vui King , Singh Anurag K. , Seshadri Mukund 
Published: April 2021

Abstract
Salivary gland dysfunction is a common side effect of radiation therapy (RT) in patients with head and neck cancer and is a consequence of direct damage to glandular parenchyma along with inflammatory changes and vascular injury following radiation. However, dynamic functional imaging of changes in salivary gland vascularity and oxygenation following RT has not been previously reported. Here, we employed bimodal photoacoustic imaging (PAI) with co-registered ultrasound (US) to non-invasively monitor radiation-induced parenchymal and vascular injury to salivary glands in vivo. Experimental imaging studies revealed parenchymal damage on B-mode US and early increase in vascular resistance on contrast-enhanced US (within 24h following radiation). Notably, this was accompanied by a reduction in oxygen consumption of salivary glands on dynamic PAI following parasympathetic stimulation with pilocarpine. Temporal kinetics of radiation-induced vascular injury was dependent on the host immune status and correlates with stimulated salivary secretion. These findings demonstrate the ability of US-PAI to monitor the dynamic changes in neurovascular coupling of salivary glands following radiation injury and highlight its potential utility to identify drugs or therapeutic approaches that could protect or mitigate radiation-induced vascular damage.
Citation Format: Eftekhar Rajab Bolookat, Vui King Vincent-Chong, Anurag K. Singh, Mukund Seshadri. Sonographic and photoacoustic monitoring of radiation-induced parenchymal and vascular injury to salivary glands [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-056.
Abstract PO-058: Acute total body ionizing radiation induces long-term cardiac effects and immediate changes in oxidative carbonylation of cardiac troponin T in the rat
Authors: Rosen Elliot 
Published: April 2021

Abstract
Radiation-induced heart disease represents a significant health risk in the event of an accidental radiation exposure as well as to cancer patients who receive acute doses of irradiation as part of radiation therapy. We utilized the Wistar-Kyoto and spontaneously hypertensive rat models, previously shown to demonstrate drug-induced cardiomyopathy, to evaluate the acute and long-term effects of sub-lethal total body irradiation at two, four, and fifty-two weeks. We examined irreversible oxidative protein carbonylation in the heart immediately following irradiation. Both males and females sustained reduced growth and anemic conditions over a one-year period as reflected by reduced body weight and low red blood cell count. Increased inflammation was detected via elevated IL-6 serum levels selectively in males at four weeks. Serum cardiac troponin T and I analyses revealed signs of cardiomyopathy at earlier timepoints, but high variability was observed, especially at one year. Echocardiography at two weeks following 5.0 Gy treatment revealed inflammation and a decrease in cardiac output in the short term, but significant differences were not observed at the one-year timepoint. Cardiac output was decreased in both males and females after two weeks, and statistically significant in females. Following 10.0 Gy irradiation, the heart tissue showed an increase in total protein oxidative carbonylation accompanied by DNA damage indicated γ-H2AX. Using proteomic analyses, several novel proteins showed a marked carbonylation profile including those associated with mitochondrial homeostasis and cardiac contractility, most notably, cardiac troponin T. Overall, we present findings of acute oxidative protein, DNA damage, and long-term cardiomyopathy in the irradiated animals, along with oxidative proteomic markers of acute damage.
Citation Format: Elliot Rosen. Acute total body ionizing radiation induces long-term cardiac effects and immediate changes in oxidative carbonylation of cardiac troponin T in the rat [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-058.
Abstract PO-062: Why drug and radiation combination synergism or antagonism can be quantitatively determined with the mass-action law based pharmacodynamics equation, algorithm and computer simulation
Authors: Chou Ting-Chao 
Published: April 2021

Abstract
Biological system-analysis by the mass-action law with biophysical, biochemical and mathematical induction-and-deduction leads to the derivation of &gt;300 reaction rate equations. These derived equations led to general biodynamics/pharmacodynamics and bioinformatics (MAL-BD/PD/BI) general paradigms for “Dose” and “Effect”. 1. Median-Effect Eq. (MEE) for single drug or entity, regardless, in vitro, in animals or in human, where Dm and m values signify the median-effect dose “potency” and “shape” (dynamic order), respectively. 2. Combination Index Eq. (CIE), where CI&lt;1, =1, and &gt;1 indicates synergism, additive effect and antagonism, respectively, in combinations. Since all terms in MEE and CIE are relativity ratios, they are dimensionless quantities. Therefore, MEE and CIE are fundamental MAL-BD/PD/BI/CI principle independent to entity’s physical nature (chemicals, biologicals, natural products, radiation, liquid, or gas); independent to unit (ug, nM, mg/ml. mg/kg, IU, rad or multiples of infection); and independent to mode or mechanism of actions (competitive, noncompetitive, uncompetitive, sequential, ordered, ping-pong or random). Comprehensive details are available in Chou TC, Pharmacol. Rev. 58: 621-681, 2006 (specifically on p.655 and p.660), It also discussed in Chou, Integrative Biol. 3: 548-559, 2011, and many more recent papers on chemotherapy and radiation therapy combinations, as indicated in Google scholars. The above 2006 Chou article, as of January 12, 2021, has 3,835 citations in 1,054 biomedical journals internationally, encompassing nearly all disciplines in biomedical sciences.
Citation Format: Ting-Chao Chou. Why drug and radiation combination synergism or antagonism can be quantitatively determined with the mass-action law based pharmacodynamics equation, algorithm and computer simulation [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-062.
Abstract PO-087: Novel high-throughput screen in a breast cancer cell line to identify potent radiosensitizers
Authors: Landry Madeleine R. , DuRoss Allison N. , Choi Eunseo , Jozic Antony , Nelson Dylan , Sun Conroy 
Published: April 2021

Abstract
There is a need for more broadly applicable radiosensitizers independent of disease state and DNA protein repair status. High throughput screens hold potential for identifying new classes of radiosensitizers from libraries of small molecules. Our group has developed an in vitro high throughput screen identifying radiosensitizers using high content imaging. Due to chromatin condensation, G2/M is acknowledged as the most radiosensitive phase of the cell cycle. We therefore dosed 4T1 breast cancer cells with a library of 1430 FDA approved drugs, then using the high content images, assessed ability to stall in G2/M. We initially eliminated drugs with less than 30% viability from consideration to negate toxicity effects on the CCI. With a CCI cutoff of two standard deviations from the mean, we attained a hit rate of 2.8% with 40 hits. The screen identified both known and novel radiosensitizers belonging to previously unidentified classes. This methodology of cell cycle analysis was confirmed by the more classical flow cytometry assay and a selected hit from the screen was assessed for radiosensitizing ability by clonogenic and γH2AX assays, and in vivo studies. Based on the clonogenic survival fractions, the radiation enhancement ratio was found to be &gt;1 at all doses between 2-6 Gy for the selected drug, with the highest values at 4 and 5 Gy of 4.5. Furthermore, we found two 10 µM doses of the novel radiosensitizer paired with two fractions of 2 Gy was sufficient to significantly decrease 4T1 tumor volume growth in BALB/c mice.
Citation Format: Madeleine R. Landry, Allison N. DuRoss, Eunseo Choi, Antony Jozic, Dylan Nelson, Conroy Sun. Novel high-throughput screen in a breast cancer cell line to identify potent radiosensitizers [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-087.
Abstract PR-003: Radiosensitization by targeting the NPM1/RAD51 axis
Authors: Freeman Michael L. , Traver Geri , Sekhar Konjeti R. , Crooks Peter A. 
Published: April 2021

Abstract
NPM1 is a chaperone involved in base excision, translesion synthesis and homologous recombination (HR). In the presence of DNA DSBs pT199 NPM1 co-localizes with H2AX foci, a consequence of binding to K63-linked ubiquitinated histones that surround DSBs via its pT199 domain comprised of an acidic tract and adjacent ubiquitin interacting motif-like domain (1-3). SUMOlyated K263 NPM1 binds to and promotes Rad51 loading onto resected 3-prime DNA at the DSB. Failure to SUMOlyate K263NPM or inhibition of NPM1 reduces Rad51 filament formation, thus inhibiting HR (4). A major effort is underway to develop DNA damage response inhibitors. The novel chemical entity YTR107 is a 5-((N-benzyl-1H-indol-3-yl) methylene) pyrimidine-2, 4,6(1H,3H,5H) trione developed using forward chemical genetics and structure/function screening (5). Colony formation assays revealed that YTR107 radiosensitized 7 NSCLC lines (dose modifying factors of 1.5). Radiosensitization was NPM1-dependent as YTR107 did not radiosensitize an NPM1 null mouse embryo fibroblast cell line (3). Here we show that YTR107 inhibits radiation-induced NPM1 binding to Rad51, Rad 51 foci formation and repair of DNA DSBs.Tumor initiating cells (TICs) were radiosensitized by YTR107. YTR107 inhibited tumor growth (P = 0.027, 2-way ANOVA) and increased the survival of A549 tumor-bearing mice, determined 70 days after the last treatment. Survival of tumor-bearing mice was 60% for mice treated with YTR107and 2.2 Gy(q.d. x 7) vs 20% for mice treated with 2.2 Gy alone (q.d.x 7). Cox Proportional log rank hazard ratio for irradiated vs unirradiated tumor-bearing mice was 0.24 (P = 0.0034) while the log rank hazard ratio for YTR107 plus irradiation vs unirradiated (± YTR107) tumor-bearing mice was 0.17 (P = 0.0023). Thus, these data provide support for development of YTR107 as a therapeutic radiation sensitizer. Supported in part by R44CA228756.
1.Koike A, Nishikawa H, Wu W, Okada Y, Venkitaraman AR, Ohta T.Cancer Res 2010;70:6746-56 2. Sekhar KR, Benamar M, Venkateswaran A, Sasi S, Penthala NR, Crooks PA, et al. Int J Radiat Oncol Biol Phys 2014;89:1106-14 3. Sekhar KR, Reddy YT, Reddy PN, Crooks PA, Venkateswaran A, McDonald WH, et al. Clin Cancer Res 2011;17:6490-9 4. Xu R, Yu S, Zhu D, Huang X, Xu Y, Lao Y, et al. Nat Commun 2019;10:3812 5. Reddy YT, Sekhar KR, Sasi N, Reddy PN, Freeman ML, Crooks PA. Bioorg Med Chem Lett 2010;20:600-2
Citation Format: Michael L. Freeman, Geri Traver, Konjeti R. Sekhar, Peter A. Crooks. Radiosensitization by targeting the NPM1/RAD51 axis [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 PR-003.
ІДЕНТИФІКАЦІЯ ПАРАМЕТРІВ У SIR-МОДЕЛЯХ ЗА РЕЗУЛЬТАТАМИ ПАНДЕМІЇ COVID-19 В ТЕРНОПІЛЬСЬКІЙ ОБЛАСТІ
Authors: Martsenyuk V. P. , Andreychyn M. A. , Sverstiuk A. S. , Kopcha V. S. , Сhaychuk О. Т. , Panychev V. O. 
Published: April 2021

Мета роботи – запропонувати методи аналізу та прогнозування розповсюдження пандемії COVID-19 в Тернопільській області на основі SIR-моделі.
Матеріали і методи. Вхідними даними для аналізу та прогнозування розповсюдження пандемії COVID-19 служили показники Тернопільського обласного лабораторного центру МОЗ України. Аналіз і прогнозування розповсюдження цієї пандемії у Тернопільській області здійснено на основі SIR-моделі в пакеті R.
Результати досліджень. Отримано результати експериментальних досліджень кількості прогнозованих випадків інфікування та осіб, які одужали, з використанням SIR-моделі розповсюдження пандемії COVID-19 на основі лінійних і нелінійних диференціальних рівнянь на 60, 100 та 1000 діб.
Висновки. Абсолютна похибка прогнозування піку пандемії COVID-19 у Тернопільській області на основі SIR-моделі з використанням нелінійних диференційних рівнянь становить 10 діб, що пояснюється введенням своєчасних та ефективних заходів Центром громадського здоров’я МОЗ України та ДУ «Тернопільський обласний лабораторний центр МОЗ України».