bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B106: A minimal driver pair for a spontaneous high-grade serous ovarian cancer mouse model: Myc and p53-R270H
Authors: Delaney Joe R 
Published: March 2024

Abstract
Genetically engineered mouse models (GEMM) have fundamentally changed how ovarian cancer etiology, early detection, and treatment can be understood. One challenge of the last decade has been to provide evidence for which cells are responsible for the origin of epithelial ovarian cancer. Different promoters, including Pax8, Lgr5, Ogvp1, and others have allowed for expression of transgenes in specific epithelial compartments in mice. Ovgp1 has been shown to be specific for fallopian tube epithelium (FTE), which most HGSOC is now thought to originate from. Pairing Ovgp1 with multiple homozygous deletions of powerful tumor suppressors like Brca1, Trp53, Rb1, and Nf1 yields murine disease after a year of age. However, human tumors do not contain homozygous deletions of these many tumor suppressors. Others have utilized Pax8 to knock out Trp53 and Pten to yield tumors at 3-8 months of age, but human tumors rarely have PTEN knockouts and Pax8 drives kidney and thyroid expression as well. We postulated that it is possible to strictly mimic human HGSOC genetics in a mouse model and nonetheless drive oncogenesis within the lifespan of a mouse. Here, we describe the OvTrpMyc model, Trp53em1Jdel_Tg(Ovgp1-Trp53*R270H-Myc), in which p53-R270H and Myc expression are driven by the Ovgp1 promoter. The transgene was inserted at the endogenous Trp53 locus, predicting that this design would allow for loss of the opposing wild-type chromosome 11 (syntenic to chromosome 17 in humans) to better mimic human HGSOC genetics. This model generated lethal disease at a median of 15.6 months of age. Dissected metastatic tumors were peritoneal and expressed Pax8, consistent with human disease. Immunohistochemical staining of the fallopian tube, ovary, and uterus indicated clear nuclear staining of p53 and Myc on the FTE. Notably, pockets of intraepithelial metastases expressing p53 and Myc were also found on the uterine epithelium. Cells grown ex vivo from uterus or fallopian tube dissections were analyzed for transcriptomes. RNA-seq revealed a clustering of these extracted cancer cells with human HGSOC and p53 mutant serous endometrial cancers. Loss of heterozygosity at the p53 locus was universal in these ex vivo grown cancer cells, as was extensive aneuploidy. The OvTrpMyc model requires only a single transgene for its breeding strategy, better enabling cancer detection, prevention, and treatment experiments. Taken together, the OvTrpMyc model of p53-R270H mutation and Myc expression driven by Ovgp1 is sufficient to recapitulate cancer hallmarks of HGSOC and, surprisingly, p53 mutant serous uterine cancer as well.
Citation Format: Joe R Delaney. A minimal driver pair for a spontaneous high-grade serous ovarian cancer mouse model: Myc and p53-R270H [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B106.
Abstract B108: Zinc finger protein 217 (ZNF217) promotes ovarian cancer metastasis through interaction with estrogen
Authors: Wardrup Kathryn , Padmanabhan Achuth 
Published: March 2024

Abstract
ZNF217 is a transcription factor located at chromosomal region 20q13.2 which is frequently amplified in many human cancers, including ovarian. Consistently, ZNF217 mRNA is overexpressed in epithelial ovarian cancer and is negatively correlated with 5-year survival predictions. Despite this connection, little is known about the role of ZNF217 in the development of epithelial ovarian cancer. To explore the role of ZNF217 in this context, we generated ovarian cancer cell lines that stably overexpress ZNF217 to prolife in vitro pro-metastatic phenotypes. We found that increased expression of ZNF217 led to increases in cell proliferation, cell migration, adhesion, and transwell invasion. Subsequent gene expression analysis revealed alterations consistent with the induction of epithelial to mesenchymal transition (EMT). Depleting ZNF217 resulted in abrogation of these phenotypes. Consistent with these in vitro data, both intraperitoneal and ovary intrabursal xenograft models demonstrated that increased levels of ZNF217 rapidly enhanced the rate of tumorigenesis in vivo. RNA sequencing analyses revealed significant alterations in expression of genes involved in estrogen signaling, such as ESR1 and ESR2. We found that in vitro the presence of 17β-estradiol synergistically increased cell proliferation and invasion when compared to cells in media lacking estrogens. In vivo, ovariectomized mice supplemented with a subcutaneous slow release 17β-estradiol tablet in combination with high-ZNF217 expressing cells displayed an increased rate of tumorigenesis and an increase in disease severity as compared to controls lacking estrogens. The findings reveal a novel transcription factor that is key in promoting ovarian cancer progression and metastasis and highlights a functional role for estrogen in promoting ZNF217-driven metastasis.
Citation Format: Kathryn Wardrup, Achuth Padmanabhan. Zinc finger protein 217 (ZNF217) promotes ovarian cancer metastasis through interaction with estrogen [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B108.
Abstract IA001: Placing our bets to make a difference
Authors: Bowtell David D. 
Published: March 2024

Abstract
The presentation will focus genomics of high grade serous ovarian cancer (HGSC). I will briefly describe TRACEBACK, a study aimed at identifying deceased high-risk mutation carriers, and how a novel approach to patient ascertainment and testing may serve as a model for other familial cancer diseases. I will discuss some of key questions and directions arising from our studies of end-stage BRCA-related HGSC using samples collected through a rapid autopsy program. The major focus of the presentation will be on analyses of patients with exceptionally poor or favorable overall survival, including a cohort of BRCA1/2 patients with an unusually poor response to treatment and survival, and HGSC patients who survive more than 10 years following their diagnosis.
Citation Format: David D. Bowtell. Placing our bets to make a difference [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr IA001.
Abstract IA005: Regional combating of immunosuppressive forces in the ovarian tumor microenvironment
Authors: Powell Daniel J. 
Published: March 2024

Abstract
The accumulation of intraepithelial T cells in ovarian cancer is prognostic for increased survival while the accumulation of immunosuppressive cells, such as tumor associated macrophages, are associated with poor outcomes. These clinical findings provide the rationale for the development of immunotherapeutic approaches that locally augment T cell responses while circumventing immunosuppressive forces. Clinical trials of systemic immunotherapy have shown encouraging clinical responses in a subset of treated patients; however tumor regression does not occur in most treated patients, some patients experience immune related adverse effects and patients with immunologically cold tumors are unlikely to respond. One central objective of researchers is to understand the basis of natural immune recognition and to use this knowledge to rationally bolster anti-tumor immunity. One modality to augment anti-cancer immunity is to administer adoptive T cell therapy (ACT), thereby increasing the net number of tumor-reactive T cells in a patient. While ACT is effective and approved for the treatment of various hematological cancers, there is no approved immunotherapeutic agent for the treatment of ovarian cancer, including ACT. With significant advances in synthetic biology and large-scale cell manufacturing, it is now possible to generate patient-specific T cell products that specifically recognize and kill antigen expressing cancer cells; to outfit those T cells with supraphysiological properties that overcome immunosuppressive forces in the tumor microenvironment; and to safely promote local recruitment of endogenous T cell responses to markedly enhance the overall immune response against ovarian cancer. Using these techniques, overexpressed antigens can be targeted, immunosuppressive tumor associated macrophages can be selectively eliminated, the tumor microenvironment can be polarized to an inflammatory state, endogenous T cell recruited, and T cells made to proliferate robustly at the tumor site in response to tumor recognition. This knowledge and these approaches provide a guidepost and the infrastructure to begin creating safe and effective immunotherapy for ovarian cancer.
Citation Format: Daniel J. Powell. Regional combating of immunosuppressive forces in the ovarian tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr IA005.
Abstract IA006: Friend or foe: Reevaluating the therapeutic potential of monocytes and tumor-associated macrophages in ovarian cancer
Authors: Yeku Oladapo 
Published: March 2024

Abstract
The hostile tumor microenvironment in ovarian cancer is an active deterrent to the efficacy of immunotherapeutic agents such as immune checkpoint inhibitors, Chimeric Antigen Receptor (CAR) T-cells, and Bispecific T-cell Engagers (BiTEs). Tumor-associated macrophages (TAMs) and Myeloid-Derived Suppressor Cells (MDSCs) have been shown to promote an immunosuppressive metabolic and cytokine tumor microenvironment that is detrimental to cytotoxic effector T-cell activity in ovarian cancer. These immunosuppressive cells are also associated with poor prognostic outcomes. The ideal approach to modulating TAMs and MDSCs is unknown. Data from preclinical models support reprogramming these cells to a more inflammatory phenotype or removing them from the tumor microenvironment entirely. However, neither approach has translated to clinical benefits. We have previously demonstrated that CAR-T cells modified to secrete IL-18 exerted their therapeutic effects partly via polarization of bone marrow macrophages towards an M1 phenotype. We also found that the depletion of TAMs improved CAR-T cell efficiency, even when these CAR-T cells were co-modified to secrete IL-12. Because of the propensity for monocytes to be recruited to the ovarian cancer tumor microenvironment, we evaluated the efficacy of monocytes genetically modified to secrete BiTEs. First, we designed and evaluated BiTEs that recognize the retained portion of MUC16 (Muc16-ecto) and CD3+ T-cells and showed that these BiTEs were efficacious in vitro and in vivo in a xenograft model of ovarian cancer. We validated that monocytes transduced to secrete Muc16-specific BiTEs (Mono-BiTEs) could effectively lyse tumor cells in vitro and suppress xenograft ovarian cancer cells in vivo. Adding IFN-alpha and IFN-gamma to Mono-BiTEs significantly improved Mono-BiTEs antitumor efficacy over BiTE therapy or unmodified monocyte therapy alone. Adoptive cell therapy with genetically engineered autologous monocytes could provide an alternative approach to reprograming or eliminating myeloid-derived cells in ovarian cancer.
Citation Format: Oladapo Yeku. Friend or foe: Reevaluating the therapeutic potential of monocytes and tumor-associated macrophages in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr IA006.
Abstract IA009: Epigenetic approaches to endometriosis-associated ovarian cancer
Authors: Zhang Rugang 
Published: March 2024

Abstract
The past decade has brought unprecedented progress in understanding the genetics of epithelial ovarian cancer (EOC), but cures remain elusive due to the lack of insights into mechanisms that can be leveraged to develop new therapies. EOC is genetically heterogeneous and, therefore, it is imperative that therapeutic strategies become personalized by targeting distinct molecular subsets of EOC. Despite the importance of epigenetic regulators in EOC, the mechanism of action for these epigenetic regulators and the associated vulnerabilities exposed by their dysregulations have remained elusive for most of them. Here we will discuss our recent work on how to leverage epigenetic mechanisms to address unmet clinical needs in endometriosis-associated ovarian cancer through integrated approaches.
Citation Format: Rugang Zhang. Epigenetic approaches to endometriosis-associated ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr IA009.
Abstract P30: Therapeutic activation of pre-B-cell receptor signaling in high-risk pediatric ALL: exploiting TCF3 and MYC-linked vulnerabilities
Authors: Leo Isabelle R , Post Frederik , Struyf Nona , Qi Xuekang , Aswad Luay , Nguyen Thao TT , Tamai Minori , Akahane Koshi , Pokrovskaja-Tamm Katja , Erkers Tom , Inukai Takeshi , Lehtiö Janne , Jafari Rozbeh 
Published: March 2024

Abstract
High-risk pediatric Acute Lymphoblastic Leukemia (ALL) is insufficiently addressed by current treatment options, and generally patients may benefit from safety and efficacy improvements if eligible for targeted therapies. Using a comprehensive panel of 84 pediatric ALL cell lines representing diverse molecular phenotypes, we developed a platform combining multi-omics profiling and drug response screening to link these molecular phenotypes with mechanisms of treatment response. Our results revealed that PKC activation leads to significant toxicity for specific cell line models, with an especially notable efficacy in cells harboring MEF2D rearrangements and TCF3-HLF fusions. We conducted a comprehensive analysis using quantitative, functional and chemical proteome profiling to investigate the impact of pre-B-cell receptor (BCR) signaling activation, identifying a link between activated pre-BCR signaling toxicity and a TCF3 and MYC driven differentiation program. This vulnerability aligns with observed parallels in apoptosis mechanisms during B- and T- lymphocyte development, suggesting a therapeutic angle that exploits a developmental checkpoint. Further, we observed that resistant cell lines have similar induction of toxicity effector responses during PKC activation, but are protected by induction of TCF3 bHLH domain functions and histone acetylation changes. A synergy screen was conducted between PKC activator bryostatin-1 and 528 clinically approved or investigational oncology compounds, using normal bone marrow responses as a healthy reference. This revealed that non-responsive leukemia cell lines can be sensitized to PKC activation effects when combining PKC activation with epigenetic modifiers, indicating an enhanced therapeutic potential. The activation of pre-BCR signaling is a compelling candidate as a chemotherapy-independent targeted treatment modality, offering a promising new avenue which could be especially relevant in the management of high-risk pediatric ALL subtypes and providing a foundation for further translational investigation. Our cell line profiling resource is an exciting ongoing effort with significant potential for identification and evaluation of new treatment opportunities and the molecular phenotypes underlying sensitivity.
Citation Format: Isabelle R Leo, Frederik Post, Nona Struyf, Xuekang Qi, Luay Aswad, Thao TT Nguyen, Minori Tamai, Koshi Akahane, Katja Pokrovskaja-Tamm, Tom Erkers, Takeshi Inukai, Janne Lehtiö, Rozbeh Jafari. Therapeutic activation of pre-B-cell receptor signaling in high-risk pediatric ALL: exploiting TCF3 and MYC-linked vulnerabilities [abstract]. In: Proceedings of the Blood Cancer Discovery Symposium; 2024 Mar 4-6; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(2_Suppl):Abstract nr P30.
Behavioral Bias for Exploration Is Associated with Enhanced Signaling in the Lateral and Medial Frontopolar Cortex
Authors: Güldener Lasse , Pollmann Stefan 
Published: March 2024

Abstract
Should we keep doing what we know works for us, or should we risk trying something new as it could work even better? The exploration–exploitation dilemma is ubiquitous in daily life decision-making, and balancing between the two is crucial for adaptive behavior. Yet, we only have started to unravel the neurocognitive mechanisms that help us to find this balance in practice. Analyzing BOLD signals of healthy young adults during virtual foraging, we could show that a behavioral tendency for prolonged exploitation was associated with weakened signaling during exploration in central node points of the frontoparietal attention network, plus the frontopolar cortex. These results provide an important link between behavioral heuristics that we use to balance between exploitation and exploration and the brain function that supports shifts from one tendency to the other. Importantly, they stress that interindividual differences in behavioral strategies are reflected in differences in brain activity during exploration and should thus be more in the focus of basic research that aims at delineating general laws governing visual attention.
The Role of Letter–Speech Sound Integration in Native and Second Language Reading: A Study in Native Japanese Readers Learning English
Authors: Yan Dongyang , Seki Ayumi 
Published: March 2024

Abstract
The automatic activation of letter–speech sound (L-SS) associations is a vital step in typical reading acquisition. However, the contribution of L-SS integration during nonalphabetic native and alphabetic second language (L2) reading remains unclear. This study explored whether L-SS integration plays a similar role in a nonalphabetic language as in alphabetic languages and its contribution to L2 reading among native Japanese-speaking adults with varying English proficiency. A priming paradigm in Japanese and English was performed by presenting visual letters or symbols, followed by auditory sounds. We compared behavioral and event-related responses elicited by congruent letter–sound pairs, incongruent pairs, and baseline condition (symbol–sound pairs). The behavioral experiment revealed shorter RTs in the congruent condition for Japanese and English tasks, suggesting a facilitation effect of congruency. The ERP experiment results showed an increased early N1 response to Japanese congruent pairs compared to corresponding incongruent stimuli at the left frontotemporal electrodes. Interestingly, advanced English learners exhibited greater activities in bilateral but predominantly right-lateralized frontotemporal regions for the congruent condition within the N1 time window. Moreover, the enhancement of P2 response to congruent pairs was observed in intermediate English learners. These findings indicate that, despite deviations from native language processing, advanced speakers may successfully integrate letters and sounds during English reading, whereas intermediate learners may encounter difficulty in achieving L-SS integration when reading L2. Furthermore, our results suggest that L2 proficiency may affect the level of automaticity in L-SS integration, with the right P2 congruency effect playing a compensatory role for intermediate learners.
A comparative study on the transbrachial and transfemoral approaches for the treatment of superior mesenteric artery lesions
Authors: Guo Wenying , Chen Li , Li Xiaoye , Zhu Longtu , Zhang Hao , Wu Biao , Lu Qingsheng , Xia Shibo , Ding Zhichen , Zhang Lei 
Published: March 2024

Background: Superior Mesenteric Artery (SMA) lesions present a significant challenge in endovascular surgery. Both the transbrachial (TBA) and the transfemoral (TFA) approaches have been employed for the treatment of these lesions, but the comparative effectiveness of these methods remains unclear. Materials and methods: A retrospective analysis was conducted on patients who underwent TBA and TFA at a tertiary center between June 2020 and February 2023. Key parameters including technical success, procedural details, and complication rates were examined. Results: In a study of 99 patients, 66 underwent Transfemoral Approach (TFA) and 33 underwent Transbrachial Approach (TBA). No significant age or gender differences were noted between groups. TFA procedures were longer (90.0 vs 63.5 min, p = 0.002) and had higher fluoroscopy times (59.0 vs 43.0 min, p = 0.02) and selective SMA times (366.0 vs 245.0 min, p = 0.038) compared to TBA, especially with a smaller aortomesenteric angle (<90°). Technical success rates were high in both groups (TFA 97%, TBA 93.9%, p = 0.60). Complication rates were similar between groups, with no significant predictors for access site complications identified. Conclusion: Both the TBA and the TFA are effective for the treatment of SMA lesions, with TBA potentially offering advantages in terms of efficiency and patient recovery, particularly in cases with certain anatomy. No significant differences in complication rates were found between the two groups. Further research, including prospective randomized trials, is needed to confirm these findings.
Excellent 2-Year Outcomes of a Midlevel Constrained Liner Used in Stemless Primary TKA
Authors: Hawes Joseph , Ast Michael , Mayman David , Bostrom Mathias , Haas Steven , Chalmers Brian 
Published: March 2024

Introduction: Instability after total knee arthroplasty (TKA) remains a leading cause of revision TKA and can lead to patient dissatisfaction. While many companies have developed midlevel constrained (MLC) polyethylene inserts in primary TKAs, there is little data on their outcomes. Purpose: We sought to analyze short-term outcomes including survivorship, rates of manipulation under anesthesia (MUA), and improvements in patient-reported outcome measures (PROMs) preoperatively to postoperatively in one design of MLC TKA. Methods: We prospectively followed consecutive primary TKA patients who received constrained inserts (Journey II or Legion Genesis II, Smith and Nephew) from 5 surgeons, 2019 to 2020, at a single academic institution. We analyzed revision-free survivorship, MUA rates, and PROMs, preoperatively to postoperatively. Results: A total of 356 patients were included with a mean age of 64 years; 49% were male and the mean body mass index (BMI) was 31 kg/m2. Sixteen patients (4.5%) underwent MUA and 3 patients (0.8%) underwent revision. Two patients underwent polyethylene exchange and patellar resection for patellar loosening. One patient underwent liner exchange for instability. The 2-year revision-free survivorship was 98.5% (95% confidence interval [CI]: 96.6%–100%). Survivorship free from revision for tibial or femoral aseptic loosening was 100% at 2 years. The 2-year survivorship free from MUA was 92.3% (95% CI: 88.6%–96.1%). The mean Knee Osteoarthritis and Injury Outcomes Score Joint Replacement (KOOS JR) was 81 at 2 years follow-up, while the Lower Extremity Activity Score (LEAS) score was 10.5. Conclusion: At a mean of 3 years follow-up, 2 types of MLCs used in primary TKA were associated with a low rate of early revision, low rate of MUA, and reliable improvement in functional outcomes. These MLCs were not associated with early loosening or unique failure modes.