bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract IA-008: Etiology of chromosomal rearrangements, and other DNA double-strand break repair outcomes
Authors: Stark Jeremy M.
Published: April 2021

Defining the factors that influence chromosomal double-strand breaks (DSBs) outcomes important for developing radiosensitization strategies that target the DNA damage response (DDR). In a main project in the lab, we have used Cas9 to study mechanisms of end joining (EJ) repair that affect diverse outcomes, ranging from short insertion/deletion (indels) mutations, to large chromosomal rearrangements. In particular, we have sought to define the relative contributions of canonical non-homologous end joining (C-NHEJ), and alternative end joining (ALT-EJ), on such DSB repair outcomes. For instance, I will present evidence that C-NHEJ is absolutely required for EJ between distal ends of two Cas9-induced chromosomal breaks that are joined without causing insertion/deletion mutations (No Indel EJ). Namely, C-NHEJ does not appear to be intrinsically prone to causing indels, relative to the ALT-EJ pathway. Furthermore, using No Indel EJ as a hallmark of C-NHEJ, I will present our current directions for understanding the mechanism and regulation of C-NHEJ and ALT-EJ, and targeting these pathways by DDR inhibitors. I suggest that establishing how the DDR affects distinct EJ events will reveal the ideal contexts for using DDR inhibitors during cancer therapy and inform the development of biomarkers of response.

Citation Format: Jeremy M. Stark. Etiology of chromosomal rearrangements, and other DNA double-strand break repair outcomes [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-008.
Abstract IA-013: Integrating radiation therapy with immunotherapy
Authors: Crittenden Marka
Published: April 2021

We have shown that when studied in isolation, radiation therapy functions poorly as an endogenous vaccine, and that many of the promising therapeutic approaches of radiation in combination with immunotherapy depends on a pre-existing immune response. Therefore, focusing primarily on radiation as an in situ vaccine strategy may yield limited results. We have identified that the ability of radiation therapy to function as a vaccine is dependent on its ability to activate the cDC1 subpopulation of dendritic cells in the tumor and that a lack of endogenous adjuvant and/or active suppression following radiation resulting in lack of maturation of cDC1 may be a major factor that limits control of poorly radioimmunogenic tumors. However, where radiation therapy and immunotherapy combinations work well, radiation therapy cannot be adequately replaced by a potent tumor vaccine, demonstrating that radiation therapy provides critical effects beyond priming new T cell responses. In addition to potential vaccine effects of radiation, it also modifies the cancer cells in the field to make them a better target for control by immune cells. We recently demonstrated that one of the major roles that radiation can play in controlling tumors when combined with immunotherapy is to increase the susceptibility of surviving cancer cells to CD8+ T cells through induction of MHC-I through genetic upregulation of the MHC-I transactivator NLRC5. These data support the critical role of local modulation by radiation in improved tumor control with combination immunotherapy.

Citation Format: Marka Crittenden. Integrating radiation therapy with immunotherapy [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-013.
Abstract IA-026: Gaps alone kill BRCA deficient cancer cells
Authors: Cantor Sharon B. , Panzarino Nicholas
Published: April 2021

Defects in DNA repair and/or the protection of stalled DNA replication forks are thought to underlie the chemosensitivity of tumors deficient in the hereditary breast cancer genes, BRCA1 and BRCA2 (BRCA). Challenging this assumption, recent findings indicate that chemotherapies such as cisplatin used to treat BRCA-deficient tumors do not initially cause DNA double-strand-breaks (DSBs). Here, we show that single stranded DNA (ssDNA) replication gaps underlie the hypersensitivity of BRCA-deficient cancer, and we propose that defects in homologous recombination (HR) or fork protection (FP) do not. Specifically, in BRCA-deficient cells, ssDNA gaps develop because replication is not effectively restrained in response to stress. Gap suppression by either restoration of fork restraint or gap filling confers therapy resistance in tissue culture and BRCA patient tumors. In contrast, restored FP and HR can be uncoupled from therapy resistance when gaps are present. Moreover, we find that DSBs are not detected after therapy when apoptosis is inhibited, supporting a framework in which DSBs are not directly induced by genotoxic agents, but rather from cell death nucleases. Together, this data indicate that ssDNA replication gaps underlie the BRCA cancer phenotype, “BRCAness,” and we propose are fundamental to the mechanism-of-action of genotoxic chemotherapies.

Citation Format: Sharon B. Cantor, Nicholas Panzarino. Gaps alone kill BRCA deficient cancer 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 IA-026.
Abstract IA-028: Interaction of radiotherapy and immunotherapy: Maybe not what you think
Authors: Weichselbaum Ralph R.
Published: April 2021

Immunotherapy has altered the cancer therapy landscape and has engendered significant investigative interest in the context of the basic mechanisms and clinical applications of radiotherapy/immunotherapy combinations from accomplished investigators, many of whom have presented at this conference. Despite high quality preclinical data and some intriguing hints of efficacy, most of the clinical trials to date have failed to show a benefit to radiotherapy/immunotherapy combinations except for small subsets of patients treated in phase 1 clinical trials. The often cited “PACIFIC” trial in stage 3 lung cancer shows that immunotherapy can safely be given after chemoradiotherapy and provides significant patient benefit in terms of progression free and overall survival but does not demonstrate a positive dependent interaction between radiotherapy and immunotherapy. I will critically review select clinical trials and present data from our (and other) laboratories that may in part explain the discrepancies between the encouraging preclinical data and the somewhat disappointing clinical results.

Citation Format: Ralph R. Weichselbaum. Interaction of radiotherapy and immunotherapy: Maybe not what you think [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-028.
Abstract PO-009: Targeting a unique electrochemical vulnerability in a pediatric brain tumor to potentiate proton beam radiotherapy
Authors: Krummel Daniel Pomeranz , Kallay Laura , Bhattacharya Debanjan , Gawali Vaibhavkumar , Donatien Kamdem T. , Ahmed Taukir , Cook James M. , Lamba Michael , Wells Susanne , Vatner Ralph E. , Sertorio Mathieu , Ionascu Dan T. , Sengupta Soma
Published: April 2021

Medulloblastoma (MB) is the most common malignant (WHO Grade IV) primary brain cancer in children, adolescents, and young adults. Radiotherapy (RT) is a mainstay of MB treatment, as it is for most childhood and adult cancers. RT dose and frequency needed to achieve efficacy in MB patients severely impacts survival outcomes and is the cause of long-term cognitive deficits. To improve on short-term side effects and long-term complications, scanning beam proton therapy is employed, when available. While this recent technological advance significantly reduces damage to surrounding healthy brain tissue, survivors continue to experience induced radiation damage, including neurocognitive sequelae. To impact survivors’ health-related quality of life and caregivers’ emotional and financial burden, it is critical to identify approaches that reduce RT dose to mitigate side-effects without impacting RT effectiveness. We are investigating targeting a unique MB electrochemical vulnerability as a means to sensitize MB tumor cells to RT. There are four MB molecular subgroups: wingless, sonic-hedgehog, Group 3, and Group 4. Our analysis of 763 MB tumor transcriptomes reveals that all Group 3 MB tumors share an enhanced expression of genes-coding for subunits of the Type-A GABA receptor (GABAAR), a chloride channel. Using patch-clamp electrophysiology, we found that GABAARs conduct Cl− in MB cells and that a brain-penetrant benzodiazepine (BZ) enhances this effect and triggers cytotoxic responses commensurate with mitochondrial depolarization. We find that BZ combined with RT, even at a sub-lethal dose, is highly effective in impairing the viability of MB tumor cells, greater than RT alone. Our BZis capable of penetrating the blood-brain barrier in minutes, is metabolically stable, and showed no toxicity in a primate model. We are investigating its suitability to be used concomitant with proton beam radiotherapy, replacing standard of care vincristine, to reduce radiation-induced brain toxicity experienced by MB patients and survivors while not decreasing RT effectiveness.

Citation Format: Daniel Pomeranz Krummel, Laura Kallay, Debanjan Bhattacharya, Vaibhavkumar Gawali, Kamdem T. Donatien, Taukir Ahmed, James M. Cook, Michael Lamba, Susanne Wells, Ralph E. Vatner, Mathieu Sertorio, Dan T. Ionascu, Soma Sengupta. Targeting a unique electrochemical vulnerability in a pediatric brain tumor to potentiate proton beam radiotherapy [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-009.
Abstract PO-012: Ultra-high dose rate (FLASH) irradiation does not alter microhomology mediated recombination under varying oxygen tension when compared to standard clinical dose rates
Authors: Barghouth Paul , Ollivier Jonathan , Montay-Gruel Pierre , Loo Billy W. , Vozenin Marie-Catherine , Limoli Charles , Frock Richard
Published: April 2021

The mechanism(s) driving the enhanced therapeutic ratio of ultra-high dose-rate radiotherapy (FLASH-RT) over slower conventional (CONV) ionizing radiation (IR) dose-rate are not known. However, attenuated DNA damage and transient oxygen depletion are among a number of proposed models. In this study, we employ high-throughput genome-wide translocation sequencing (LAM-HTGTS), a highly-sensitive assay used to identify “prey” DNA double strand breaks (DSBs) via their translocation to a single CRISPR-Cas9 “bait” DSB break, to investigate the potential differences in DSBs and repair generated by 10 Gy delivered at CONV (0.13 Gy/s) or FLASH (5.106 Gy/s) dose rates with the eRT6 (PMB-Alcen, CHUV). Investigations were conducted under different oxygen tensions. IR exposure in HEK293T cells at normoxic (21% O2) conditions increased both the proportion and total number of translocations from the junctions recovered, as expected, but were indistinguishable between CONV-RT and FLASH-RT dose-rates. Although, increased proportions of translocations were observed as cells were acutely transitioned to either physioxic (4%) or hypoxic (<2%) conditions alone, the combined decrease in oxygen tension with IR dose-rate modulation did not reveal overt differences in the level of increased translocations nor in junction structures, which were predominantly increased in microhomology utilization. We discuss these findings with other related LAM-HTGTS studies.

Citation Format: Paul Barghouth, Jonathan Ollivier, Pierre Montay-Gruel, Billy W. Loo Jr., Marie-Catherine Vozenin, Charles Limoli, Richard Frock. Ultra-high dose rate (FLASH) irradiation does not alter microhomology mediated recombination under varying oxygen tension when compared to standard clinical dose rates [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-012.
Abstract PO-021: Single-cell DNA sequencing as a means to directly examine the size and frequency of radiation-induced mutations - An exploratory study
Authors: Mathew Felix , Yeo Jonathan , Galarneau Luc , Ybarra Norma , Tonin Patricia , Wang Yu Chang , Ragoussis Ioannis , Kildea John
Published: April 2021

This study examines if single-cell DNA sequencing may be used to study the mutational effects of ionizing radiation. As the action of ionizing radiation is a stochastic process, each cell in an irradiated sample experiences its own unique radiation-induced DNA damage. As a result, conventional sequencing methods such as bulk cell sequencing cannot be used to identify individual mutations. In this work, Epstein-Barr virus (EBV) transformed B-lymphoblastoid cells were irradiated with 6 MV X-ray radiation using a medical linear accelerator. Four samples of cells from the same population (400,000 cells/ml) were exposed to sham irradiation (0 Gray [Gy]; control), 0.5 Gy, 1.5 Gy and 3.0 Gy respectively at a common dose rate of about 600 cGy/min. Irradiated samples were incubated for 24 hrs and subsequently underwent single-cell whole-genome DNA sequencing to characterize the radiation impact. Mutational profiles of approximately 500 cells, randomly selected from each sample, were individually analyzed and compared to identify the variation of several mutational parameters as a function of dose. We quantified the copy number variations (CNV) for each cell in our samples. Additionally, we segregated insertion CNVs and deletion CNVs and independently analyzed their dose dependences. We found that the total number of CNVs (insertion and deletion combined) increased with dose, and the number of deletion CNVs consistently increased most. We have repeated the experiment and a new round of single-cell DNA sequencing is underway. If confirmed, our results will demonstrate that the mutational effects of ionizing radiation may be examined directly using single-cell sequencing.

Citation Format: Felix Mathew, Jonathan Yeo, Luc Galarneau, Norma Ybarra, Patricia Tonin, Yu Chang Wang, Ioannis Ragoussis, John Kildea. Single-cell DNA sequencing as a means to directly examine the size and frequency of radiation-induced mutations - An exploratory study [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-021.
Abstract PO-030: The harmala alkaloid harmine as a novel cancer cell radiosensitizer
Authors: Smack Caleb R.P. , Lafargue Audrey , Lam Christine , Carrieri Francesca A. , Siddiqui Ismaeel , Wang Hailun , Tran Phuoc T.
Published: April 2021

Radiation therapy resistance remains a persistent clinical challenge in the treatment of multiple different cancer types. Better appreciation of novel molecular targets to improve radiation therapy efficacy is needed. TWIST1 is an epithelial-mesenchymal transcription factor whose expression is linked to therapy resistance, including radioresistance, in cancer. We have shown previously that the harmala alkaloid harmine degrades TWIST1 and possess anti-tumor activity. We hypothesized that harmine may radiosensitize cancer cells via downregulation of TWIST1. We examined the effects of harmine combined with radiation (RT) on two TWIST1 overexpressing tumor cell lines, A549 human non-small cell lung cancer (NSCLC) cells and the LMT mouse-derived hepatocellular cancer cell line (HCC), both with doxycycline-inducible Twist1 expression. We also used the LM mouse-derived HCC cell line without Twist1 expression as a control. In vitro assays for clonogenic survival, apoptosis, cell cycle distribution, γH2AX foci kinetics, and protein expression in pathways important for cancer cell survival and radioresistance were performed. Harmine alone exhibited anti-cancer activity irrespective of Twist1 expression as shown by decreased clonogenic survival. Harmine caused a supra-additive radiosensitization in all cancer cell lines with radiation enhancement ratios between 1.05 – 3.04. In vivo we are evaluating tumor growth delay and effects of combined harmine and RT treatment in a NSCLC hind-flank tumor growth model. Mechanistic elucidation of these results, studies on normal cells, and in vivo validation are ongoing.

Citation Format: Caleb R.P. Smack, Audrey Lafargue, Christine Lam, Francesca A. Carrieri, Ismaeel Siddiqui, Hailun Wang, Phuoc T. Tran. The harmala alkaloid harmine as a novel cancer cell radiosensitizer [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-030.
Abstract PO-033: Papaverine derivative smv-32 alleviates tumor hypoxia and radiosensitizes tumors by inhibiting mitochondrial metabolism
Authors: Benej Martin , Wu Jinghai , Kreamer McKenzie , Vibhute Sandip , Papandreou Ioanna , Denko Nicholas C.
Published: April 2021

Radiation therapy is a standard type of treatment modality used to achieve local control in more than 50% of all cancer patients. However, tumor hypoxia reduces the effectiveness of radiation therapy by limiting the biologically effective dose. We identified that FDA-approved phosphodiesterase 10A (PDE10A) inhibitor papaverine (PPV) has an off-target effect inhibiting mitochondrial oxygen consumption (OCR) leading to acute reduction of tumor hypoxia and significant radiosensitization of model tumors. Our data suggests that PDE10A does not contribute to the radiosensitizing effect. Based on PPV’s structure, we used biomedicinal chemistry approach to engineer its novel derivative SMV-32 with reduced PDE10A inhibition. We used Seahorse metabolic flux analyzer to determine the effect of PPV and SMV-32 on mitochondrial OCR in vitro. Near-infrared optical spectroscopy and pODD-luciferase in vivo reporter system was used for pharmacodynamics analyses and dose response evaluation. Local radiation therapy was delivered using Small Animal Radiation Research Platform (SARRP). We compared intraperitoneal (IP) and intravenous (IV) delivery and optimized dosing using pODD luciferase reporter system. SMV-32 showed superior OCR inhibition in vitro and enhanced hypoxia reduction in vivo compared to PPV. A single clinically relevant dose of PPV or SMV-32 significantly reduced the hypoxic fractions of heterotopic and orthotopic tumors in mice and sensitized the tumors to radiation therapy. PPV and SMV-32 appear to be ideal candidates for clinical radiosensitization. PPV is already in phase I clinical trial for treatment of non-small cell lung cancer combined with stereotactic body radiation therapy.

Citation Format: Martin Benej, Jinghai Wu, McKenzie Kreamer, Sandip Vibhute, Ioanna Papandreou, Nicholas C. Denko. Papaverine derivative smv-32 alleviates tumor hypoxia and radiosensitizes tumors by inhibiting mitochondrial metabolism [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-033.
Abstract PO-066: Relationship between KEAP1/NFE2L2 pathway activation and radiation resistance in oral cavity cancer
Authors: Guan Li , Cao Hongbin , Hui Angela , Kwok Shirley , Viswanathan Vignesh , Nambiar Dhanya , Eyben Rie V. , Holmes Brittany , Kong Christina , Diehn Maximilian , Le Quynh-Thu
Published: April 2021

Radiotherapy (RT) is one of the primary treatment modalities for head and neck squamous cell carcinoma (HNSCC) either in the definitive or the adjuvant setting. Unfortunately, despite therapeutic and technological advances in radiotherapy, some patients will have persistence tumor or develop locoregional failure, resulting in significant morbidity and mortality. Presently, there is no biomarker that can reliably identify HNSCC that is resistant to RT. Recent genomic sequencing studies show that mutations in the KEAP1/NFE2L2 pathway exist in HNSCC. However, very little data is available with regards to the relationship between RT resistance and activating mutation or pathway hyperactivation of this pathway in HNSCC. Moreover, the mechanism by which dysregulation of this pathway can lead to RT resistance in HNSCC is poorly understood. Therefore, the project is aimed to study the relationship between KEAP1/NFE2L2 mutations and patient outcomes in HNSCC. To address this aim, DNA sequencing strategies and tissue microarray (TMA) are used to identify mutations and/or a hyperactivation protein signature of the KEAP1/NFE2L2 oxidative stress pathway in an oral cavity cancer patient cohorts (N = 69[MOU1]) treated with surgery and adjuvant RT. In addition, identified mutations are introduced into HNSCC cell lines and mouse xenografts to study the effect of these mutations on radiation response and to identify the mechanism by which they mediate radiation resistance. Here we find that 6% of oral cavity cancer patients harbor mutation in this pathway, primarily in a hotspot in the NFE2L2 gene. NFE2L2 mutation is associated with 100% in-field recurrence after radiotherapy. Strong co-expression of two downstream targets of this pathway (HO1 and NQO1) in tumor cells on the TMA strongly correlates with NFE2L2 mutation and in-field recurrence after RT. Finally, overexpression of the mutated NFE2L2 gene in HNC cell lines lead to increased ROS and radioresistance. Our findings suggest oral cavity cancers harboring activating mutation or a hyperactivation protein signature of the KEAP1/NFE2L2 pathway are more radioresistant. Work is ongoing to validate these findings in other types of HNSCC and to determine how to enhance radiation effectiveness in mutated tumors.

Citation Format: Li Guan, Hongbin Cao, Angela Hui, Shirley Kwok, Vignesh Viswanathan, Dhanya Nambiar, Rie V. Eyben, Brittany Holmes, Christina Kong, Maximilian Diehn, Quynh-Thu Le. Relationship between KEAP1/NFE2L2 pathway activation and radiation resistance in oral cavity cancer [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-066.
Abstract PO-070: Boost tumor response to radiation therapy: What can we learn from PTEN-deficient models?
Authors: Fan Xinyi , Qiu Miaoyan , Formenti Silvia C. , Shen Wen H.
Published: April 2021

PTEN is among the most frequently mutated genes in nearly all types of cancer. TCGA studies reported mutation or deletion of the PTEN gene in 11% of breast invasive carcinoma and 9% of colorectal adenocarcinoma. Cancer-associated PTEN deficiency is associated with worse prognosis as well as tumor resistance to therapies, including chemotherapy and immunotherapy. However, it is largely controversial, as there is no consensus regarding how PTEN deficiency alters tumor response to radiation therapy (RT). RT elicits anti-cancer efficacy through both cell-autonomous and non-cell-autonomous mechanisms by disrupting the cancer genome and by promoting immune responses. Similarly, loss of PTEN results in genomic instability and immune deregulation, which may lead to a tumor-specific net outcome of growth and response to RT. In order to characterize a pan-cancer phenotype of RT sensitivity, we created multiple isogenic pairs of tumor cells of different tissue origins. Our studies, using both a breast cancer model and a colon cancer model, demonstrate that PTEN deficiency confers an enhanced RT efficacy through a non-cell autonomous mechanism. Specifically, orthotopically implanted tumors lacking PTEN regressed significantly following single-dose RT that was less effective in suppressing PTEN-proficient tumors. A more efficient regimen (3*8Gy) became ablative and achieved 100% tumor-free survival only in the hosts of PTEN-deficient tumors. The RT sensitivity manifested in PTEN-mutant tumors in vivo is likely due to enhanced immunogenicity, because in vitro, PTEN-deficient cancer cells not only lost such vulnerability but often exhibited RT resistance. Our data suggest that PTEN-deficient tumor phenotypes may be exploited to achieve the highest cancer elimination rate, using a combinatorial strategy to promote non-cell-autonomous immunogenicity and to concurrently overcome cell-autonomous RT resistance.

Citation Format: Xinyi Fan, Miaoyan Qiu, Silvia C. Formenti, Wen H. Shen. Boost tumor response to radiation therapy: What can we learn from PTEN-deficient models? [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-070.
Abstract PO-071: Characterizing transcriptomic indicators of radiosensitivity in cancer and identifying sensitizing therapeutic agents
Authors: Smith Ian , Bell Rachel , Lambie Meghan , Haibe-Kains Benjamin , Bratman Scott
Published: April 2021

While radiation therapy is an integral method for cancer treatment, clinical choices are not currently informed by the genetic and molecular profile of a patient’s tumor. Though it has been shown that genetic features implicate variability, the exact relationship between these features and radiosensitivity is poorly understood. Our work focuses on predicting radiosensitivity of squamous cell carcinoma from molecular features. First, we employ RadioGx, a computational platform for integrative analysis of radiogenomic datasets, to identify a gene expression signature predictive of radiosensitivity. To mitigate the high-dimensionality of gene expression data, we employ pathway-level transcriptomic modeling methods to identify cellular programs associated with radiation sensitivity. Our pancancer radiosensitivity model achieves a Pearson’s correlation of 0.47 with measured radiosensitivity from a radiogenomic dataset using only high level transcriptomic features. Second, we use that gene expression signature to query the Connectivity Map via the PharmacoGx resource and identify candidate radiosensitizers - compounds that may induce the radiosensitivity signature. Further validation is necessary to evaluate the efficacy of these compounds at improving radiosensitivity in both model systems and patient contexts. These results implicate cellular processes in radiosensitivity and advance an approach for identifying radiosensitizing agents through integration of large scale datasets.

Citation Format: Ian Smith, Rachel Bell, Meghan Lambie, Benjamin Haibe-Kains, Scott Bratman. Characterizing transcriptomic indicators of radiosensitivity in cancer and identifying sensitizing therapeutic agents [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-071.
Abstract PO-099: Overexpression of proinflammatory chemokines CCL5 and CCL17 after gene electrotransfer to murine tumors modifies their cytokine expression profile and leads to tumor cures in combination with tumor irradiation
Authors: Sersa Gregor , Bozic Tim , Markelc Boštjan , Cemazar Maja , Brezar Simona Kranjc
Published: April 2021

Proinflammatory chemokines are small signaling proteins, with the ability to induce migration of different types of immune cells. The degree and type of immune cell infiltrate in the tumor microenvironment often correlates with the outcome of immunotherapies in cancer patients. Therefore, combining chemokines with classical, but immune response activating therapy, such as irradiation presents one of the potential approaches in cancer immunotherapy. Through the use of plasmid DNA encoding either proinflammatory chemokine CCL5 or CCL17 we studied their effects on cytokine expression profile in vitro and in vivo in murine breast (4T1, E0771) and colon (CT26, MC38) cancer models. While in vitro plasmid DNA was introduced in the cells using lipofection, gene electrotransfer was utilized in case of tumors in vivo. Viability of all cell lines 48 h after lipofection remained above 80%. Using qRT-PCR expression of 11 cytokines was determined 48 h after lipofection, which showed significantly increased expression of CCL5, CCL17 demonstrating successful transfection. Moreover, increased levels of IL-6 and CXCL10 were also observed in the surviving cells. Gene electrotransfer after intratumoral injection of plasmid DNA encoding either CCL5 or CCL17 in CT26 and 4T1 murine tumor model (animal license: U34401-1/2015/43) resulted in minor tumor growth delay. Concurrent expression analysis of 7 cytokines after gene electrotransfer in tumors showed overexpression of both chemokines, while levels of proinflammatory cytokines IL-6, IL-12 and IFNγ were modestly increased. Obtained altered expression profile, both in vitro and in vivo, is typical for inflammation. Furthermore, irradiation of CT26 and 4T1 tumors combined with gene electrotransfer of plasmids encoding CCL5 or CCL17 resulted in significant tumor growth delay and even tumor cures. Therefore, based on changes in tumor microenvironment after therapy future experiments will be focused towards elucidating the mechanisms of immune response and determining the optimal time window for combined tumor irradiation and gene electrotransfer of plasmids encoding chemokines CCL5 and CCL17.

Citation Format: Gregor Sersa, Tim Bozic, Boštjan Markelc, Maja Cemazar, Simona Kranjc Brezar. Overexpression of proinflammatory chemokines CCL5 and CCL17 after gene electrotransfer to murine tumors modifies their cytokine expression profile and leads to tumor cures in combination with tumor irradiation [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-099.
Virus-Like Particle–Drug Conjugates Induce Protective, Long-lasting Adaptive Antitumor Immunity in the Absence of Specifically Targeted Tumor Antigens
Authors: Kines Rhonda C. , Thompson Cynthia D. , Spring Sean , Li Zhenyu , de los Pinos Elisabet , Monks Stephen , Schiller John T.
Published: April 2021

This study examined the ability of a papillomavirus-like particle drug conjugate, belzupacap sarotalocan (AU-011), to eradicate subcutaneous tumors after intravenous injection and to subsequently elicit long-term antitumor immunity in the TC-1 syngeneic murine tumor model. Upon in vitro activation with near-infrared light (NIR), AU-011–mediated cell killing was proimmunogenic in nature, resulting in the release of damage-associated molecular patterns such as DNA, ATP, and HMGB-1, activation of caspase-1, and surface relocalization of calreticulin and HSP70 on killed tumor cells. A single in vivo administration of AU-011 followed by NIR caused rapid cell death, leading to long-term tumor regression in ∼50% of all animals. Within hours of treatment, calreticulin surface expression, caspase-1 activation, and depletion of immunosuppressive leukocytes were observed in tumors. Combination of AU-011 with immune-checkpoint inhibitor antibodies, anti–CTLA-4 or anti–PD-1, improved therapeutic efficacy, resulting in 70% to 100% complete response rate that was durable 100 days after treatment, with 50% to 80% of those animals displaying protection from secondary tumor rechallenge. Depletion of CD4+ or CD8+ T cells, either at the time of AU-011 treatment or secondary tumor rechallenge of tumor-free mice, indicated that both cell populations are vital to AU-011′s ability to eradicate primary tumors and induce long-lasting antitumor protection. Tumor-specific CD8+ T-cell responses could be observed in circulating peripheral blood mononuclear cells within 3 weeks of AU-011 treatment. These data, taken together, support the conclusion that AU-011 has a direct cytotoxic effect on tumor cells and induces long-term antitumor immunity, and this activity is enhanced when combined with checkpoint inhibitor antibodies.
Outcomes of Adolescents and Young Adults Compared with Children with Acute Leukemia after Single-Unit Unrelated Cord Blood Transplantation Using Myeloablative Conditioning without Antithymocyte Globulin
Authors: Zhang Xuhan , Liu Huilan , Zheng Changcheng , Tang Baolin , Zhu Xiaoyu , Wan Xiang , Tong Juan , Yao Wen , Song Kaidi , Sun Zimin
Published: April 2021

Background: Although the use of cord blood transplantation (CBT) is becoming more frequent in acute leukemia, considering the relationship between the low stem cell dose and graft failure, whether use of CBT for adolescents and young adults (AYAs) is appropriate remains uncertain. Methods: A retrospective registry-based analysis of clinical outcomes and immune reconstitution was conducted for 105 AYAs and 187 children with acute leukemia who underwent single-unit CBT using myeloablative conditioning (MAC) without antithymocyte globulin (ATG). Results: Outcomes were similar between AYAs and children, except for nonrelapse mortality (NRM) and recovery rates of neutrophils and platelets. The 30-day cumulative incidence of neutrophil engraftment was similar between AYAs and children, but children had faster rates of neutrophil and platelet recovery than AYAs. The median time to neutrophil engraftment was earlier in children than in AYAs (AYAs, 19 days, 95% confidence interval [CI] 17.3–21.7; children, 16 days, 95% CI 13.1–19.5, p = 0.00003). The incidence of platelet recovery on day 120 was higher in children than in AYAs (AYAs, 80%, 95% CI 71–81%; children, 88%, 95% CI 82–92%, p = 0.037). CD34+ cell dose was the only independent factor influencing both neutrophil and platelet recovery. The cumulative incidence of NRM at 2 years was higher among AYAs than among children (AYAs, 27.5%, 95% CI 20–37%; children, 15%, 95% CI 10–21%, p = 0.008). Conditioning regimen was an independent factor influencing NRM. With respect to immune reconstitution, natural killer cell counts quickly recovered to normal levels 1-month post-CBT in both children and AYAs. CD8+ T-cell counts were higher in children than in AYAs at 1 and 3 months post-CBT. CD4+ T-cell counts were similar in both children and AYAs after CBT. Conclusion: AYAs with acute leukemia have outcomes of single-unit CBT using MAC without ATG that are as good as those of children. Thus, single-unit CBT using modified MAC without ATG is an acceptable choice for both AYAs and children who do not have a suitable donor.
Etiological Analysis of Reactive Gastropathy in an Urban Population
Authors: Kolli Sindhura , Mori Amit , Weissman Simcha , Mehta Tej I. , Dang-Ho Khoi Paul , Shah Jamil , Singh Manpreet , Reddy Madhavi , Suryanarayan Anand
Published: April 2021

Background: Reactive gastropathy (RG) is an adaptive response to assaults of the gastric mucosa. Demographic information regarding RG as well as the coincidence of RG and gastrointestinal cancer are poorly characterized entities. Objective: Herein, we aim to investigate relationships of RG to both modifiable and nonmodifiable risk factors, as well as conduct a stratified analysis by race in an ethnically diverse, urban population. Methods: In this retrospective study, we queried an urban hospital inpatient pathology database searching for patients with surgical gastric biopsies positive for RG between March 25, 2015, and March 25, 2016. Of the 728 patients with a final diagnosis of RG, 292 were selected based on strict inclusion and exclusion criteria. We explored risk factors and conducted a stratified analysis for associations based on patient demographics. Results: In this urban minority population, nonsteroidal anti-inflammatory drugs (NSAIDs) were the most common medication associated with RG (Fig. 1), as well as the most common cause of RG, followed by chronic bile reflux. In addition, significant differences in demographics and gastropathic characteristics associated with RG, stratified by ethnicity, were found (Fig. 2). Notably, Hispanics, African Americans, and Caucasians had the highest rate of concomitant RG and diabetes, hypertension, and tobacco/alcohol use, respectively. Conclusion: Our study indicated that NSAID usage is the most common cause of RG, followed by bile reflux-mediated mucosal injury, in an ethnically diverse urban US-based population. Of note, few patients had intestinal metaplasia, suggesting it to be a slow or negligent sequela of RG.
Curcumin Reduces Neuroinflammation and Improves the Impairments of Anesthetics on Learning and Memory by Regulating the Expression of miR-181a-5p
Authors: Liu Guizhen , Sun Yuchuan , Liu Fei
Published: April 2021

Objective: The purpose of this study was to explore the role of curcumin (Cur) in isoflurane (ISO)-induced learning and memory dysfunction in Sprague-Dawley rats and further elucidate the mechanism of the protective effect produced by Cur. Methods: Rat models of cognitive impairment were established by inhaling 3% ISO. The Morris water maze test was used to assess the cognitive function of rats. ELISA and qRT-PCR were used to analyze the protein levels of pro-inflammatory cytokines and expression levels of miR-181a-5p, respectively. Results: Cur significantly improved the ISO-induced cognitive dysfunction in rats and alleviated the ISO-induced neuroinflammation. miR-181a-5p was overexpressed in ISO-induced rats, while Cur treatment significantly reduced the expression of miR-181a-5p. Overexpression of miR-181a-5p promoted the cognitive impairment and the release of inflammatory cytokines and reversed the neuroprotective effect of Cur. Conclusion: Cur has a protective effect on ISO-induced cognitive dysfunction, which may be achieved by regulating the expression of miR-181a-5p.
Track and Teach: Identifying Key Movement Patterns in Endoscopic Transurethral Enucleation of the Prostate
Authors: Dressler Franz F. , Gratzke Christian , Miernik Arkadiusz , Schoeb Dominik S.
Published: April 2021

Purpose: We evaluated a system for noninvasive quantitative motion tracking to recognize differences in the movement pattern of experienced surgeons and beginners. Since performing endoscopic procedures requires extensive training, and tissue damage due to disruptive movements with sudden acceleration is possible, the learning curve for beginners is of clinical relevance. Steepening this curve may improve patient outcome. Materials and Methods: We used a commercial gyroscope sensor with a wireless data link, which was attached to the resectoscope handle (RH). After recording, orientation was retrieved by application of the calculated rotation matrices to the RH vector relative to the sensor under the boundary condition of rotational movement around and quasi-constant distance to the pivot point at pelvic floor level. Data alignment, normalization, interpolation, and analysis were performed in custom software scripts. Results: Experienced surgeons and beginners were recorded in n = 36 and n = 14 holmium laser enucleation of the prostate (HoLEP), respectively. Prostate size, patient age, and recorded procedure duration were comparable. Mean lever angle of the individual normalized motion patterns was considerably lower (19.28 ± 0.54° [SEM]) in the advanced than in the beginners’ group (24.52 ± 1.00°; p = 0.0001). Further parameters such as velocity and motion variation demonstrated additional differences between both groups. Conclusions: We demonstrate the feasibility of motion tracking in HoLEP. Pronounced differences exist between different stages of surgeon experience with this procedure. The method can easily be adopted to aide young surgeons in resectoscope handling and identification of improvable motion patterns. Damage to the pelvic floor and surrounding tissue may thus be reduced.
Atypical Congenital Triangular Alopecia (Brauer Nevus): Case Report and Review of Literature in Occipital and Mid-Frontal Localizations
Authors: Rodríguez-Villa Lario Ana , Ferrando Juan , Moreno-Arrones Óscar M. , Gómez-Zubiaur Alba
Published: April 2021

Introduction: Brauer nevus, also known as congenital triangular alopecia (CTA) is a localized alopecia that rarely affects the occipital or mid-frontal region. CTA is a localized follicular hypoplasia, commonly misdiagnosed as alopecia areata. Although named congenital, onset in adulthood is possible. Case Presentation: We present a review of literature of eighteen atypical locations, providing 4 new cases to the 9 previously published, with particular attention to trichoscopy and histopathological descriptions in this exceptional presentation forms. Discussion: Occipital and mid-frontal Brauer nevus are unusual findings with very few cases reported so far. Because of its rarity and atypical presentation, it can often lead to a misdiagnosis. A higher incidence in the male sex stands clear in these locations. Detection at birth is slightly more frequent than in the classical CTA. Histopathological and trichoscopy findings do not differ from the classical entity, although white or hypopigmented hairs do not seem to be an item present in the mid-frontal forms.
Facial Skin Biophysical Profile of Women in Malaysia: Significance of Facial Skincare Product Use
Authors: Goh Choon Fu , Mohamed Faisal Nazirah , Ismail Fatin Najiha
Published: April 2021

Introduction: At present, there is a lack of baseline data on the facial skin biophysical profile of women in Malaysia. The implications related to the daily habits and facial skincare product use on the skin biophysical condition are, thus, unknown. In this study, we aim to evaluate facial skin biophysical parameters of Malaysian women and examine the influence of demographic characteristics, daily habits, and facial skincare product use on these parameters. Methods: Four skin biophysical parameters – transepidermal water loss (TEWL), melanin content, elasticity, and collagen intensity – were assessed on the cheek of the subjects (20–60 years). Demographic background, daily habits, and skincare product use were gauged through a survey. Only 197 from the 213 subjects recruited initially were used for analysis after the data were screened for normality. Results: The biophysical parameters were similar in different races, except a higher melanin content in Indian female individuals. Elasticity and collagen intensity reduced with age, while melanin content increased in the older age-groups. But no difference was observed in TEWL at different ages. Evaluating the influence of daily habits, we observed that exercise significantly lowered TEWL and increased melanin content, which may be associated with UV radiation exposure. Facial skincare products are popular among the female subjects (>85% users). Products with moisturizing, sunscreening, and other skincare functions (astringent, antiaging, and anti-wrinkle) were preferred by subjects of all ages. These product functions significantly improve skin elasticity and reduce melanin content in the young adults. While aged women recognized the importance of having an additional skin-lightening function in their skincare routine. Although the influence of individual skincare function on skin biophysical parameters was mostly positive, the alteration of these parameters varied at different ages. Conclusion: This is the first report of facial skin biophysical profile of Malaysian women. There is no difference among 3 major races saved for melanin content. This work demonstrated age-dependent influences on the biophysical parameters, except TEWL. The significance of skincare product use is well reflected in the improvement of these parameters at different age-groups based on individual skincare functions.
Distinct Patterns of Tissue Remodeling and Their Prognostic Role in Chronic Rhinosinusitis
Authors: Lee Ho Yun , Pyo Jung-Soo , Kim Su Jin
Published: April 2021

Introduction: Tissue remodeling refers to structural changes that occur in damaged tissue and is associated with disease severity in asthma. However, the characteristics of tissue remodeling and its prognostic role in chronic rhinosinusitis (CRS) remain unclear. In this report, we evaluated the clinical implications of tissue remodeling in CRS. Methods: We performed a retrospective cohort study of adult patients who underwent endoscopic sinus surgery for bilateral CRS. The histopathology of sinus mucosa was determined by evaluating the inflammatory cell count and tissue remodeling markers (squamous metaplasia, subepithelial gland proliferation, basement membrane [BM] thickening, stromal edema, and fibrosis). Eosinophilic CRS (ECRS) was defined as an eosinophil count >15/high-power field in the biopsied tissue. Patient characteristics, allergy test grade, preoperative Lund-Mackay score (LMS), and pre- and postoperative Lund-Kennedy scores (LKSs) were analyzed. Results: Of the identified patients, 59.1% were classified as ECRS and the remaining 40.9% as non-ECRS. Regarding tissue remodeling markers, stromal edema was seen in 90.9%, BM thickening in 63.6%, and stromal fibrosis in 34.1% of patients. In cases with stromal edema and BM thickening, greater tissue eosinophilia was observed, while stromal fibrosis decreased tissue eosinophilia (p < 0.05). Prognostically, subepithelial gland proliferation alone was an independent risk factor for poor postoperative endoscopic findings (odds ratio: 8.250, 95% confidence interval: 1.128–60.319, p = 0.038). Conclusions: Tissue eosinophilia was commonly associated with BM thickening and stromal edema. Subepithelial gland proliferation predicted a poor surgical prognosis in CRS. These findings imply that tissue remodeling provides additional information not only on the CRS endotype but also on the postsurgical prognosis.
Residual Hearing Affects Contralateral Routing of Signals in Cochlear Implant Users
Authors: Stronks H. Christiaan , Briaire Jeroen J. , Frijns Johan H.M.
Published: April 2021

Introduction: Contralateral routing of signals (CROS) can be used to eliminate the head shadow effect. In unilateral cochlear implant (CI) users, CROS can be achieved with placement of a microphone on the contralateral ear, with the signal streamed to the CI ear. CROS was originally developed for unilateral CI users without any residual hearing in the nonimplanted ear. However, the criteria for implantation are becoming progressively looser, and the nonimplanted ear can have substantial residual hearing. In this study, we assessed how residual hearing in the contralateral ear influences CROS effectiveness in unilateral CI users. Methods: In a group of unilateral CI users (N = 17) with varying amounts of residual hearing, we deployed free-field speech tests to determine the effects of CROS on the speech reception threshold (SRT) in amplitude-modulated noise. We compared 2 spatial configurations: (1) speech presented to the CROS ear and noise to the CI ear (SCROSNCI) and (2) the reverse (SCINCROS). Results: Compared with the use of CI only, CROS improved the SRT by 6.4 dB on average in the SCROSNCI configuration. In the SCINCROS configuration, however, CROS deteriorated the SRT by 8.4 dB. The benefit and disadvantage of CROS both decreased significantly with the amount of residual hearing. Conclusion: CROS users need careful instructions about the potential disadvantage when listening in conditions where the CROS ear mainly receives noise, especially if they have residual hearing in the contralateral ear. The CROS device should be turned off when it is on the noise side (SCINCROS). CI users with residual hearing in the CROS ear also should understand that contralateral amplification (i.e., a bimodal hearing solution) will yield better results than a CROS device. Unilateral CI users with no functional contralateral hearing should be considered the primary target population for a CROS device.