bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 273: Synergistically suppressive effects by combination of glycolytic inhibitor with TRAP1-depletion in colorectal cancer
Authors: Tsai Hong-Yuan , Chen Miao-Hsueh , Senavirathna Herath Lakmini , Yun Jihye , Pan Sheng , Chen Ru 
Published: April 2023

Abstract
Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial homolog of HSP90 chaperones. It plays an important role in protection against oxidative stress and apoptosis by regulating reactive oxidative species (ROS). Recent studies have suggested TRAP1 as a regulator of metabolism and mitochondrial homeostasis in diverse pathological states, including cancer. To further elucidate the mechanistic role of TRAP1 in regulating tumor cell survival, we used gamitrinib-triphenylphosphonium (G-TPP) to inhibit TRAP1 signaling pathways in colon cancer. Inhibition of TRAP1 disrupted redox homeostasis and increased ER stress in colon cancer. To confirm the G-TPP effects of TRAP1 inhibition in colon cancer, we performed TRAP1 CRISPR/Cas9 to deplete TRAP1 expression in colon cancer cell line CT26. TRAP1-depleted cells were found to acquire several distinct phenotypes: induction of reactive oxidative species (ROS) level, reduction of cell growth, and lower pH value of culture medium. In addition, proteomic data showed that depletion of TRAP1 induced significant metabolism alteration in CT26 cells. Using seahorse assay to access mitochondrial respiration and glycolysis, we found that TRAP1-depleted cells were insensitive to Oxidative Phosphorylation (OXPHOS) inhibitor treatment and significantly increased extracellular acidification rate (ECAR) compared to parental cells. Furthermore, higher glucose consumption rate and higher lactic acid level of culture medium were observed in TRAP1-depleted cells. On the other hand, Glycolytic inhibitor (2DG) led to excessive ROS production, reduction of glucose uptake and exacerbated cell death in TRAP1-depleted cell compared to parental cells. Taken together, depletion of TRAP1 induces mitochondrial dysfunction and modulates metabolic switch toward aerobic glycolysis in TRAP1-depleted colon cancer cells. Dual inhibition of TRAP1 and glycolytic signaling may increase therapeutic efficiency through induction of excessive ROS production in colon cancer.
Citation Format: Hong-Yuan Tsai, Miao-Hsueh Chen, Herath Lakmini Senavirathna, Jihye Yun, Sheng Pan, Ru Chen. Synergistically suppressive effects by combination of glycolytic inhibitor with TRAP1-depletion in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 273.
Abstract 3029: Barriers to optimal breast cancer screening modalities for high-risk patients in the primary care setting
Authors: Jan Yu Jen , Lam Prudence B. 
Published: April 2023

Abstract
Background: Annual screening breast MRIs are endorsed by current breast cancer screening guidelines as an adjunctive screening modality for high-risk patients (defined by more than 20% lifetime risk) in addition to a screening mammogram. Recent studies showed screening breast MRI remained underutilized despite the current recommendations. On the other hand, validated breast cancer risk models for identifying high-risk patients also remained under-recognized among primary care providers. This study aims to identify the potential barriers for primary care providers (PCPs) to using breast cancer risk models and referring high-risk patients to breast MRI for screening.
Methods: An anonymous survey was distributed via email to the PCPs and OB/GYN providers in the network of Mount Auburn Hospital, a community teaching hospital affiliated with Harvard Medical School in Cambridge, Massachusetts. The survey included questions regarding breast cancer screening in average-risk and high-risk patients, providers’ understanding of breast cancer risk models, and current referral status of breast MRIs and high-risk/genetic clinics.
Results: The survey was sent to 104 providers, and 43 responses were received. When asked about performing breast cancer risk assessments, 58% reported “Always (91-100%)” and 33% said “Often (71-90%)”. For factors to consider when performing risk assessments, most of the providers considered personal medical history (98%), family history (100%), genetic syndrome history (86%), and previous breast biopsy results (90%). When asked about breast cancer risk models, 58% of the providers had not heard of or used one. 33% of the providers have used the Gail model, and 26% have used the Tyrer-Cuzick model. 51% of the providers correctly identified high-risk as lifetime risk &gt;20%. 56% correctly answered annual mammograms with MRI for breast cancer screening for high-risk patients. The majority of the providers (84%) would prefer to refer patients to the high-risk clinic for risk assessment and screening management. For barriers to referring to MRI, the insurance approval process (49%) was reported to be the largest barrier. 72% of the providers prefer not ordering it and defer to the high-risk/genetic clinic for ordering the test.
Conclusions: Our survey has shown different barriers to breast cancer screening in high-risk patients in the primary care setting, including knowledge and logistic barriers. Further education for PCPs is needed for correctly identifying high-risk patients, utilizing risk models, and referring high-risk patients for breast MRI screening.
Citation Format: Yu Jen Jan, Prudence B. Lam. Barriers to optimal breast cancer screening modalities for high-risk patients in the primary care setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3029.
Abstract 315: HPV-related genome rearrangements in head and neck cancer cell lines
Authors: Mukhina Vera , Anderson Alexa , Gaykalova Daria A. 
Published: April 2023

Abstract
Cancer-associated papillomavirus (HPV) infection often leads to genomic rearrangements such as the integration of viral DNA into the human genome or formation of extrachromosomal DNA (ecDNA) circles with human-HPV DNA fusions, copy number alterations, translocations, inversions, or all at once. Such structures play a key role in cancer formation and progression by altering the expression of human and viral genes. They can also potentially increase genomic instability promoting new rearrangements, but little is known about how these rearrangements evolve during cancer. Unfortunately, short-read sequencing and standard assembly methods often fail to reconstruct HPV-induced rearrangements because of their repetitive nature. Long-read technology can potentially help to overcome this limitation.Here, we used Nanopore long-read whole genome sequencing to explore HPV structures in head and neck cancer cell line UPCI-SCC-090, known for its complex HPV rearrangements. We tested several protocols and methods on this cell line to estimate their impact on rearrangement detection. To study the dynamics of HPV rearrangements, we compared data from UPCI-SCC-090 to another cell line isolated later from the same patient (UPCI-SCC-152).As a result, we discovered a core set of UPCI-SCC-090 rearrangements involving chr 2,3,6 and 9, which remain robust across different tested protocols and methods, and these structures were consistent with previous studies. At the same time, we identified new minor rearrangements in UPCI-SCC-090 indicating heterogeneity within this cell line. The comparison with the UPCI-SCC-152 cell line demonstrated that most rearrangements were kept, but the overall profile of rearrangements changed. For example, UPCI-SCC-152 missed all HPV-induced alterations on chr 6.We concluded that the long-read approach failed to reconstruct all rearrangements completely but allowed us to study them in more detail on a single-molecule level and detect heterogeneity of HPV integrations within and between cell lines. We demonstrated that HPV-induced rearrangements formed a stable core that could persist for a long time with a minor group of variable rearrangements.
Citation Format: Vera Mukhina, Alexa Anderson, Daria A. Gaykalova. HPV-related genome rearrangements in head and neck cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 315.
Abstract 3171: Detecting ploidy specific vulnerability to resource restriction: An integrated in vitro and in silico approach
Authors: Beck Richard J. , Ilter Didem , Gomes Ana P. , Andor Noemi 
Published: April 2023

Abstract
Changes in the number of copies of the genome, i.e. changes in ploidy are widespread among cancer cells. Increased ploidy is thought to benefit cancer cells by conferring robustness against deleterious consequences of genomic instability. However, whether there are any potential costs associated with increased ploidy has not been sufficiently investigated. One hypothesis holds that high ploidy cells may exhibit increased sensitivity to limitations in resources, due to the extra energy required for the replication of a larger genome. To address this hypothesis, we developed an integrated in vitro and in silico system to investigate the response to glucose restriction in diploid and tetraploid cells.
Near diploid (2N) SUM159 breast cancer cells were fused to generate an isogenic tetraploid (4N) cell line. 2N or 4N cells were plated with varying initial concentrations of glucose. Cells grew for five days and media was not refreshed, so cells depleted the glucose in the media until they eventually died. Throughout the experiments, glucose concentration was measured at 24 hour intervals, and images were taken at 8 hour intervals allowing quantification of the number of alive or dead cells over time. These in vitro data were then used as inputs to the in silico portion of our system, which consists of an Ordinary Differential Equation (ODE) model of cancer cell growth. ODE model parameters were estimated using the measured outputs from the in vitro experiments. Parameters estimated from the ODE model gave insight into differences between the 2N and 4N cell lines.
We found that 4N cells outcompeted 2N cells at high glucose concentrations, due to their ability to divide more rapidly when glucose was abundant. However, 2N cells were able to outcompete 4N cells at lower glucose concentrations. The advantage of 2N cells at low glucose was not due to an increased proliferative capacity. Instead, 2N cells were more resistant to cell death when glucose was limited. Our next steps will be to expand our system to assess ploidy specific sensitivity to other resources, such as phosphate or oxygen. The ODE model we have developed allows us to identify resource conditions that will select for tumor cells based on ploidy. In future this knowledge can be used to suggest therapeutics that can modulate resource availability within tumors, in order to steer tumor evolution towards less aggressive phenotypes.
Citation Format: Richard J. Beck, Didem Ilter, Ana P. Gomes, Noemi Andor. Detecting ploidy specific vulnerability to resource restriction: An integrated in vitro and in silico approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3171.
Abstract 3285: Targeting TBK1 to overcome resistance to cancer immunotherapy
Authors: Sun Yi , Revach Or-Yam , Anderson Seth , Jenney Anne , Mills Caitlin E. , Tiwari Payal , Manguso Robert T. , Jenkins Russell William 
Published: April 2023

Abstract
Despite the success of PD-1 blockade in melanoma and other cancers, effective treatment strategies to overcome resistance to cancer immunotherapy are lacking. We identified the innate immune kinase TANK-binding kinase 1 (TBK1) as a candidate immune evasion gene in a pooled genetic screen. Using a suite of genetic and pharmacologic tools across multiple experimental model systems, we confirm a role for TBK1 as an immune evasion gene. Targeting TBK1 enhances response to PD-1 blockade by lowering the cytotoxicity threshold to effector cytokines (TNFα/IFNγ). TBK1 inhibition in combination with PD-1 blockade also demonstrated efficacy using patient-derived tumor models. Cancer cells lacking TBK1 are primed to undergo RIPK- and caspase-dependent cell death in response to TNFα/IFNγ in a JAK/STAT-dependent manner. Taken together, our results demonstrate that targeting TBK1 is a novel and effective strategy to overcome resistance to cancer immunotherapy.
Citation Format: Yi Sun, Or-Yam Revach, Seth Anderson, Anne Jenney, Caitlin E. Mills, Payal Tiwari, Robert T. Manguso, Russell William Jenkins. Targeting TBK1 to overcome resistance to cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3285.
Abstract 3288: A novel and defined TLR3 agonist based anticancer therpay
Authors: Kim Dongho , Lee Sungwhan 
Published: April 2023

Abstract
Synthetic dsRNA analogs recognized by TLR3 are an attractive adjuvant candidate for fight against intracellular pathogens or tumors, because of their enhanced T cell-mediated and humoral immunities. Although poly(I:C) is a representative dsRNA with potent adjuvanticity, its clinical application has been severely limited due to heterogenicity, inconsistent activity, poor stability, and toxicity. In spite of numerous clinical trials, few products have been approved for human use. To overcome these limitations, we try to develop a novel defined form of TLR3 agonist. A single 275-kDa homogeneous molecule was selected as an alternative of poly IC and its derivatives and named NexaVant (NVT). The analytical analyses including reverse phase-HPLC analysis demonstrated that NVT is homologous without a lot-to-lot variation. NVT appears to be stable since its appearance, concentration, and molecular size were unaffected under 6 months of accelerated storage conditions. Moreover, preclinical evaluation of toxicity under good laboratory practices showed that NVT is a safe substance without signs of serious toxicity. NVT increases the expression of dsRNA sensors such as TLR3, MDA-5, and RIG-I. Together with a potent apoptotic cell death to several cancer cell lines, NVT substantially induced the phenotypic markers of DC maturation and activation including MHC-II, CD40, CD80, and CD86 together with IFN-alpha production. Several poly IC and its derivatives are used as a in situ anticancer agent in clinical trials. NexaVant was tested as an in-situ cancer therapy reagent in several animal models. When NVT is injected into tumors, it induces and recruits diverse immune cells with a potent anti-cancer effect. Combined with anit-PD-1 antibody, it shows the increase number of DC and T-cells, especially CD8 T cells and decrease that of Tregs. Using human PD-1 knock-in mouse model, NVT has shown the synergistic anti-cancer effect with anti-PD-1 antibody. Several animal efficacy data target to head and neck cancer, triple-negative breast cancer, and melanoma would be presented.
Citation Format: Dongho Kim, Sungwhan Lee. A novel and defined TLR3 agonist based anticancer therpay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3288.
Abstract 3302: KLK7 expression in human tumors: A tissue microarray study on 13,447 tumors
Authors: Kind Simon , Castillo Carolina , Uhlig Ria , Gorbokon Natalia , Lennartz Maximilian , Rico Sebastian Dwertmann , Reiswich Viktor , Viehweger Florian , Kluth Martina , Hube-Magg Claudia , Bernreuther Christian , Büscheck Franziska , Clauditz Till , Fraune Christroph , Hinsch Andrea , Krech Till , Lebok Patrick , Steurer Stefan , Burandt Eike , Minner Sarah , Marx Andreas , Simon Ronald , Wilczak Waldemar , Sauter Guido , Menz Anne , Jacobsen Frank 
Published: April 2023

Abstract
Background: Kallikrein-related peptidase 7 (KLK7) is a chymotrypsin-like serine protease which is essential for the desquamation of corneocytes and thus plays a pivotal role in maintaining skin homeostasis. In cancer, KLK7 overexpression was suggested to represent a route for metastasis through cleavage of cell junction and extracellular matrix proteins of cancer cells.
Methods: To comprehensively determine KLK7 protein expression in normal and neoplastic tissues, a tissue microarray containing 13,447 samples from 147 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry.
Results: KLK7 positivity was found in 64 of 147 tumor categories, including 17 tumor categories with at least one strongly positive case. The highest rate of KLK7 positivity was found in squamous cell carcinomas from various sites of origin (positive in 18.1%-63.8%), ovarian and endometrium cancers (4.8%-56.2%), salivary gland tumors (4.8%-13.7%), bilio-pancreatic adenocarcinomas (20.0%-40.4%), and adenocarcinomas of the upper gastrointestinal tract (3.3%-12.5%). KLK7 positivity was linked to nodal metastasis (p=0.0005), blood vessel infiltration (p=0.0037), and lymph vessel infiltration (p&lt;0.0001) in colorectal adenocarcinoma, nodal metastasis in hepatocellular carcinoma (p=0.0382), advanced pathological tumor stage in papillary thyroid cancer (p=0.0132), and low grade of malignancy in a cohort of 719 squamous cell carcinomas from 11 different sites of origin (p&lt;0.0001).
Conclusions: These data provide a comprehensive overview on KLK7 expression in normal and neoplastic human tissues. The prognostic relevance of KLK7 expression and the possible role of KLK7 as a drug target need to be further investigated.
Citation Format: Simon Kind, Carolina Castillo, Ria Uhlig, Natalia Gorbokon, Maximilian Lennartz, Sebastian Dwertmann Rico, Viktor Reiswich, Florian Viehweger, Martina Kluth, Claudia Hube-Magg, Christian Bernreuther, Franziska Büscheck, Till Clauditz, Christroph Fraune, Andrea Hinsch, Till Krech, Patrick Lebok, Stefan Steurer, Eike Burandt, Sarah Minner, Andreas Marx, Ronald Simon, Waldemar Wilczak, Guido Sauter, Anne Menz, Frank Jacobsen. KLK7 expression in human tumors: A tissue microarray study on 13,447 tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3302.
Abstract 3403: Leveraging a p53 “super-tumor suppressor” to understand mechanisms of lung adenocarcinoma regression
Authors: Wang Mengxiong , Kaiser Alyssa , Bieging-Rolett Kathryn , Brady Colleen , Attardi Laura 
Published: April 2023

Abstract
Lung cancer is the leading cause of cancer deaths worldwide, and lung adenocarcinoma (LUAD) comprises the majority of lung cancer cases. Inactivation of the TP53 tumor suppressor gene, which encodes the p53 transcription factor, is observed in ~50% of human LUADs and is associated with poor prognosis and therapeutic responses. Hence, pharmacological restoration of p53 is an appealing strategy for LUAD treatment. Previous studies have demonstrated that p53 reactivation in mouse LUAD models leads to tumor regression. Here, we seek to understand the molecular mechanisms through which p53 restoration promotes tumor regression. To this end, we sought to better understand the transcriptional programs underlying tumor regression by leveraging an allelic series of transcriptional activation domain (TAD) mutants. We generated mouse models of LUAD initiated by oncogenic Kras and loss of p53, followed by reactivation of wild-type p53 or p53 TAD mutants, including the TAD1 (p5325,26), TAD2 (p5353,54), and TAD1/2 (p5325,26,53,54) mutants. We find that restoration of wild-type p53 induces significant regression of established tumors. Interestingly, we find that restoration of the p5353,54 mutant induces tumor regression even more potently than wild-type p53, reminiscent of our previous findings showing this mutant is a “super” tumor suppressor in pancreatic cancer. In contrast, the transcriptionally-dead TAD1/2 mutant, p5325,26,53,54, is unable to drive tumor regression. To understand the basis of tumor suppression, we are currently analyzing antiproliferative cellular responses in tumors, including cell cycle arrest, apoptosis, autophagy and differentiation. We have also developed a complementary in vitro system to further explore the molecular mechanisms of p53 action in LUAD regression. RNA-sequencing analysis in this system has revealed transcriptional programs underlying the enhanced tumor regression with the p5353,54 mutant. Collectively, these findings have illuminated the individual contributions of each p53 TAD to LUAD regression. In particular, elucidating the mechanisms by which the “super” tumor suppressor p5353,54 mutant induces tumor regression will provide great insight for developing therapeutic strategies to restore and amplify p53 function.
Citation Format: Mengxiong Wang, Alyssa Kaiser, Kathryn Bieging-Rolett, Colleen Brady, Laura Attardi. Leveraging a p53 “super-tumor suppressor” to understand mechanisms of lung adenocarcinoma regression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3403.