bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B26: The natural history of ovarian high-grade serous carcinoma from time effects of ovulation inhibition and progesterone clearance of p53-defective lesions
Authors: Chu Tang-Yuan , Wu Na-Yi Yuan , Wang Jing 
Published: September 2020

Abstract
High-grade serous carcinoma (HGSC) is the most common and devastating type of ovarian cancer; its etiology, mechanism of malignant transformation, and origin remain controversial. Recent studies have identified secretory cells at the fimbria of the fallopian tube as the cell of origin of HGSC, initiating TP53 mutation, evolving to tubal precursor lesions, including “p53 signature” and serous tubal intraepithelial carcinoma (STIC), and metastasizing to the ovary as clinically evident ovarian cancer. The etiologic mechanisms associated with the known epidemiologic risk factors, i.e., ovulation and retrograde menstruation, have also been unveiled. Mutagens and transforming growth factors, such as reactive oxygen species and IGF axis proteins, as well as the apoptosis-rescuing protein hemoglobin are abundantly present in the ovulatory follicular fluid and peritoneum fluid, which bathes the fimbrial epithelium, and induces malignant transformation after repeated exposure. Meanwhile, in accordance with the proposed therapeutic effect of progesterone from studies on oral contraceptive (OC) use or term pregnancy, our recent study indicated that the p53-null tubal epithelial cells are selectively cleared by progesterone depending on its progesterone receptor (PR). In this report, by analyzing different time-effects of OC use or pregnancy in the prevention of ovarian cancer and by aligning them with the carcinogenic and therapeutic clearance concepts of ovulation and P4, as well as the fact of progressive loss of PR during tubal transformation, we deduced the natural history of ovarian HGSC. The natural history begins at the first ovulation and spans more than 30 years, taking 10 years from the normal tubal epithelium to the “p53 signature” status, another 15 years to PR(-) STIC, and a final 5+ years to HGSC. The estimated natural history may help understand the pathogenesis of HGSC and defines the window for early detection and chemoprevention.
Citation Format: Tang-Yuan Chu, Na-Yi Yuan Wu, Jing Wang. The natural history of ovarian high-grade serous carcinoma from time effects of ovulation inhibition and progesterone clearance of p53-defective lesions [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B26.
Abstract B62: Integrating highly-multiplexed imaging with multi-omics data to uncover immunologic vulnerabilities in high-grade serous ovarian cancer
Authors: Kilkkila Miikka K. , Casado Julia , Jacobson Connor , Hakkinen Antti , Erkai Erdogan , Dai Jun , Zhan Kaiyang , Maliga Zoltan , Carpen Olli , Lehtonen Rainer , Hautaniemi Sampsa , Sorger Peter , Vaharautio Anna , Farkkila Anniina 
Published: September 2020

Abstract
A key event in cancer progression is the establishment of an immunosuppressive environment that prevents the immune system from effectively attacking the cancer cells. In this study we aim to characterize the cellular determinants and the spatial features of immune suppressive mechanisms in high-grade serous ovarian cancer (HGSOC) via integrating tissue Cyclic Immunofluorescence (tCycIF), a novel highly multiplexed single-cell spatial proteomics platform with multi-omics data, including state-of-the-art single-cell RNA sequencing. We have conducted a comprehensive analysis of a unique dataset consisting of 23 HGSOC samples, including 7 pairs of treatment-naïve and post-chemotherapy samples, using tCycIF, single-cell, and bulk RNA sequencing coupled with novel deconvolution algorithms and whole-genome sequencing. All samples were prospectively collected from patients treated at Turku University Hospital, Finland, as a part of the HERCULES consortium. Our preliminary findings suggest that tCycIF can reliably capture tumor microenvironment composition in HGSOC. Overall, there was a good correlation with tumor purity between all the methods used. In tCycIF, scRNAseq and bulk deconvolution macrophages were the most common immune cell type in the HGSOC microenvironment. However, specific immune subpopulations, such as CD8+T-cells, had a larger proportion in tCycIF compared to single-cell RNA sequencing and bulk-deconvoluted RNAseq data. Further, the immune profiling based on RNAseq deconvolution algorithm showed highly variable results based on the algorithm used. We are in the process of using our complete dataset to compare state-of-the-art methods and improve algorithms for HGSOC immunophenotyping. tCycIF’s spatial proteomic data in single-cell resolution allows us to gain new insights into the tumor microenvironment and discover the previously latent cell-to-cell interactions that make up the immunosuppressive milieus in HGSOC tumors. The improvement of novel reliable single-cell immunophenotyping methods is critical to develop more effective immunotherapies to improve the outcomes and survival of patients with HGSOC.
Citation Format: Miikka K. Kilkkila, Julia Casado, Connor Jacobson, Antti Hakkinen, Erdogan Erkai, Jun Dai, Kaiyang Zhan, Zoltan Maliga, Olli Carpen, Rainer Lehtonen, Sampsa Hautaniemi, Peter Sorger, Anna Vaharautio, Anniina Farkkila. Integrating highly-multiplexed imaging with multi-omics data to uncover immunologic vulnerabilities in high-grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B62.
Abstract B64: Targeting the pH regulators in the tumor microenvironment for ovarian cancer treatment
Authors: Kulshrestha Arpita , Katara Gajendra K. , Schneiderman Sylvia , Riehl Valerie E. , Young Alexandria N. , Levine Shayna , Ibrahim Safaa , Bilal Mahmood , Gilman-Sachs Alice , Beaman Kenneth D. 
Published: September 2020

Abstract
The high mortality rate in ovarian cancer (OVCA) is currently the most pressing concern despite the research advancements. It is still not clear how to effectively treat OVCA patients to prevent a relapse or to treat the relapse tumors that display a drug-resistant profile. To address this issue, this study targets a uniquely expressed pH regulator in the tumor microenvironment as a strategy to treat ovarian cancer. In order to survive the metabolic acidosis, cancer cells overexpress pH regulators on their surface to pump out excess protons/lactic acid. This, in turn, acidifies the tumor microenvironment and promotes tumor invasion/chemoresistance. The a2-Vacuolar-ATPases (V-ATPases) are the major pH-sensing unit of the V-ATPase proton pumps and are abundantly expressed on the surface of ovarian cancer cells. To establish the clinical importance, our findings show that a2-V-ATPases are overexpressed in all morphologic subtypes and stages of human OVCA and are absent on normal ovarian tissues. We further examined the therapeutic potential of monoclonal antibody against a2-V-ATPase (V0a2-mab) in controlling tumor growth in the preclinical mouse model. In vivo V0a2-mab treatment (300μg in PBS; i.p) resulted in a significantly delayed tumor growth compared to control, with no apparent in vivo toxicity in athymic nude mice xenograft model. The delayed tumor growth was attributed to high immune infiltration with increased leukocyte population and an enhanced iNOS expression compared to control mice. These results show that V-ATPases are overexpressed in the tumor microenvironment and their inhibition impairs OVCA growth by interfering with tumor acidification that enhances the antitumor responses. In conclusion, the study demonstrates that targeting V-ATPase pH regulators is an effective treatment strategy in ovarian cancer.
Citation Format: Arpita Kulshrestha, Gajendra K. Katara, Sylvia Schneiderman, Valerie E. Riehl, Alexandria N. Young, Shayna Levine, Safaa Ibrahim, Mahmood Bilal, Alice Gilman-Sachs, Kenneth D. Beaman. Targeting the pH regulators in the tumor microenvironment for ovarian cancer treatment [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B64.
Abstract B71: Investigating the role of PAX8 in modulating the tumor microenvironment of high-grade serous ovarian cancer
Authors: Salvi Amrita , Hardy Laura , Watry Samantha , Pergande Melissa , Cologna Stephanie M. , Burdette Joanna E. 
Published: September 2020

Abstract
High-grade serous ovarian cancer (HGSOC), the most common and lethal form of ovarian cancer, is a highly heterogeneous disease. HGSOC is rarely detected early, and likely arises from the fimbriated end of the fallopian tube epithelium (FTE), and in some cases, the ovarian surface epithelium (OSE). PAX8 is a commonly used biomarker for ovarian serous tumors and is expressed in 80-96% of HGSOC. Although the OSE does not express PAX8, murine models of HGSOC derived from the OSE acquire PAX8, suggesting that it is not only a marker of Müllerian origin, but also an essential part of HGSOC progression, potentially from both the OSE and FTE. Previously, we showed that PAX8 deletion by CRISPR and shRNA in HGSOC cell lines caused apoptosis and reduced cell migration and invasion. We performed secretome analysis of PAX8 deleted cells and found a reduction of the extracellular matrix (ECM) component fibronectin. This finding was validated by immunoblotting and immunofluorescence in PAX8 deleted HGSOC cells. We have generated several murine FTE-derived tumor models (PTEN/KRAS/p53 alterations) and knocked down PAX8 in these models. These syngeneic fallopian tube-derived tumor models will be allografted into immune intact FVB mice and the tumors will be used to determine if PAX8 loss impacts immune cell infiltration via changes in ECM. Additionally, we are using a novel high-throughput screening (HTS) assay to identify small molecules that can function to inhibit PAX8 promoter activation and lead to reduced PAX8 expression. We have generated a stable cell line using murine FTE cells expressing the PAX8 promoter-luciferase reporter, which will be used to screen a library of FDA-approved drugs (Prestwick Library, ca. 1,200 members). Overall, this study would help us to validate PAX8 as a regulator of ECM deposition in the tumor microenvironment and identify an effective drug for treatment of ovarian cancers derived from both the FTE and OSE.
Citation Format: Amrita Salvi, Laura Hardy, Samantha Watry, Melissa Pergande, Stephanie M. Cologna, Joanna E. Burdette. Investigating the role of PAX8 in modulating the tumor microenvironment of high-grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B71.
Abstract B73: The search for EGFL6 receptor: Implications for tumor angiogenesis
Authors: Taki Mana , Noh Kyung Hee , Mangala Lingegowda S. , Zhang Ningyan , An Zhiqiang , Sood Anil K. 
Published: September 2020

Abstract
Objective: EGFL6, epidermal growth factor (EGF)-like domain multiple 6, has been found to be an important target for antiangiogenesis approaches. However, its receptor is not fully known and is the focus of the current work.
Method: We first isolated endothelial cells from 10 high-grade serous ovarian cancers, 5 normal ovarian tissues, and 7 healing wound patient samples, and searched for genes selectively expressed in tumor endothelial cells. For receptor studies, we performed an unbiased antibody array for human phospho-RTKs with EGFL6 treatment.
Results: EGFL6 was found to be highly expressed in tumor endothelial cells, but not in wound endothelial cells. EGFL6 promoted tumor angiogenesis by increasing tube formation and migration ability of tumor endothelial cells via Tie2, which is expressed on tumor endothelial cells. Moreover, we developed new EGFL6-blocking antibodies, which reduced tumor angiogenesis and in vivo tumor growth without impairing wound healing. Human phospho-RTK array showed that EGFR could be a candidate receptor for EGFL6. Furthermore, EGL6 activated EGFR expressed on tumor cells and promoted invasion ability of tumor cells by 2-fold. Interestingly, EGFL6 secreted from tumor endothelial cells increased the mRNA expression of EGFL6 in tumor cells, which suggests that there may be a positive regulatory loop between endothelial and tumor cells.
Conclusion: EGFL6 could be a promising target for development of antiangiogenesis therapies.
Citation Format: Mana Taki, Kyung Hee Noh, Lingegowda S. Mangala, Ningyan Zhang, Zhiqiang An, Anil K. Sood. The search for EGFL6 receptor: Implications for tumor angiogenesis [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B73.
Abstract IA04: Drug resistance in end-stage high-grade serous ovarian cancer
Authors: Christie Elizabeth L. , Alsop Kathryn , Au-Yeung George , Pandey Ahwan ,   Australian Ovarian Cancer Study, Bowtell David D.L. 
Published: September 2020

Abstract
Background: Acquired drug resistance is the major obstacle in controlling high-grade serous ovarian cancer (HGSC) and leads to poor overall survival. Comparatively little massively parallel sequencing data exist from HGSC patients with recurrent or end-stage disease who have been extensively treated with chemotherapy or newer targeted agents, such as antiangiogenics or PARP inhibitors (PARPi). We previously identified four mechanisms of acquired resistance from whole-genome sequencing (WGS) of 23 HGSC patients with recurrent disease; a resistance mechanism of any kind was only identified in half of the patients.
Aim: To characterize genomic features and identify mechanisms of acquired drug resistance in end-stage HGSC patients.
Methods: Since 2012, we have collected tumor samples from 19 HGSC patients through our rapid-autopsy program. On average, we collect 17 tumor sites per patient during the autopsy, which is performed a median 6 hours after death. SNP array, WGS, and RNA sequencing were performed to detect germline and somatic mutations, copy number alterations and gene expression patterns.
Results: A total of 89 end-stage tumor samples from 15 patients with germline or somatic mutations in components of the homologous recombination (HR) DNA repair pathway have been analyzed by SNP array, and a subset of those have undergone WGS (n=44) and RNAseq (n=47). As expected, all samples had a somatic pathogenic TP53 mutation and have highly aberrant somatic copy number profiles. Prominent mutational signatures (single- and double-base substitutions) are associated with defective HR and prior treatment with platinum drugs. The total single-base substitution mutation burden is similar across tumor samples within patients; however, many mutations are unique to individual tumor samples. Currently, reversion mutations, which are secondary mutations in HR genes, are the most common resistance mechanism identified in our cohort of end-stage patients.
Conclusion: Our data are allowing us to understand HGSC at end stage, by examining the catalogue of resistance mechanisms within an individual patient and reconstructing the natural history of HGSC.
Citation Format: Elizabeth L. Christie, Kathryn Alsop, George Au-Yeung, Ahwan Pandey, Australian Ovarian Cancer Study, David D.L. Bowtell. Drug resistance in end-stage high-grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr IA04.
Abstract IA14: Integrated molecular characterization of the genome, transcriptome, and immune microenvironment in oviductal high-grade serous carcinomas arising in genetically engineered mice
Authors: Cho Kathleen R. 
Published: September 2020

Abstract
Robust preclinical models of ovarian high-grade serous carcinoma (HGSC) are needed to advance our understanding of HGSC pathogenesis and to test novel strategies aimed at improving clinical outcomes for women with the disease. Genetically engineered mouse models of HGSC have been developed that recapitulate the likely cell of origin (fallopian tube epithelium), underlying genetic defects, histology, and biologic behavior of human HGSCs, but the degree to which the mouse tumors acquire the somatic genomic changes, gene expression profiles, and immune microenvironment that characterize human HGSCs remains unclear. We used integrative molecular characterization of oviductal HGSCs arising in the context of Brca1, Trp53, Rb1, and Nf1 (BPRN) inactivation to determine whether the mouse tumors recapitulate human HGSCs across multiple domains of molecular features. Targeted DNA sequencing showed that the mouse BPRN tumors, but not endometrioid carcinoma-like tumors based on different genetic defects (e.g., Apc, Pten, Arid1a), acquire somatic mutations and widespread copy number alterations similar to those observed in human HGSCs. RNA sequencing showed that the mouse HGSCs most closely model the immunoreactive and mesenchymal subsets of human HGSCs. A combined immunogenomic analysis showed that the immune microenvironment of BPRN tumors models key aspects of tumor-immune dynamics in human HGSC, with enrichment of immunosuppressive cell subsets (myeloid-derived suppressor cells and regulatory T cells) as observed in the immunoreactive and mesenchymal subsets of human tumors. These findings, as well as early proof-of-principle studies, support the BPRN model as a robust preclinical experimental platform to help overcome barriers to clinical success in preventing, diagnosing, and treating this lethal cancer.
Citation Format: Kathleen R. Cho. Integrated molecular characterization of the genome, transcriptome, and immune microenvironment in oviductal high-grade serous carcinomas arising in genetically engineered mice [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr IA14.
Abstract IA17: PARP inhibition modulates the tumor immune microenvironment in Brca1-deficient ovarian tumor
Authors: Ding Liya , Wang Qiwei , Kearns Michael , Jiang Tao , Konstantinopoulos Panagiotis , Matulonis Ursula , Zhao Jean 
Published: September 2020

Abstract
Poly ADP ribose polymerase (PARP) inhibitors have shown promising clinical activities for patients with BRCA mutations and are changing the landscape of ovarian cancer treatment. However, the therapeutic mechanisms of action for PARP inhibition in the interaction of tumors with the tumor microenvironment and the host immune system remain unclear. We recently reported that inhibition with a PARP inhibitor (olaparib) triggers robust local and systemic antitumor immunity involving both adaptive and innate immune responses through a STING-dependent antitumor immune response in Brca1-deficient ovarian tumors. This effect is further augmented when olaparib is combined with PD-1 blockade. However, all PBM-bearing mice treated with olaparib alone or in combination with PD-1 blockade eventually succumbed to the disease. These data indicate that although multiple PARP inhibitors have been approved for the treatment of BRCA-deficient ovarian cancers, eradication of this type of cancer remains a challenge. I will discuss our recent efforts on identifying resistance mechanisms to PARP inhibition and developing potential therapeutic strategy that overcomes the resistance to improve the treatment outcome.
Citation Format: Liya Ding, Qiwei Wang, Michael Kearns, Tao Jiang, Panagiotis Konstantinopoulos, Ursula Matulonis, Jean Zhao. PARP inhibition modulates the tumor immune microenvironment in Brca1-deficient ovarian tumor [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr IA17.
Categorized Genetic Analysis in Childhood-Onset Cardiomyopathy
Authors: Al-Hassnan Zuhair N. , Almesned Abdulrahman , Tulbah Sahar , Alakhfash Ali , Alhadeq Faten , Alruwaili Nadiah , Alkorashy Maarab , Alhashem Amal , Alrashdan Ahmad , Faqeih Eissa , Alkhalifi Salwa M. , Al humaidi Zainab , Sogaty Sameera , Azhari Nawal , Bakhaider Abdulrahman M. , Al asmari Ali , Awaji Ali , Albash Buthaina , Alhabdan Mohammed , Alghamdi Malak A. , Alshuaibi Walaa , Al-Hassnan Raghad Z. , Alshenqiti Abduljabbar , Alqahtani Aisha , Shinwari Zarghuna , Rbabeh Monther , Takroni Saud , Alomrani Ahmed , Albert Brotons Dimpna C. , AlQwaee Abdullah M. , Almanea Waleed , Alfadley Fadel A. , Alfayyadh Majid , Alwadai Abdullah 
Published: September 2020

Background:
Childhood-onset cardiomyopathy is a heterogeneous group of conditions the cause of which is largely unknown. The influence of consanguinity on the genetics of cardiomyopathy has not been addressed at a large scale.

Methods:
To unravel the genetic cause of childhood-onset cardiomyopathy in a consanguineous population, a categorized approach was adopted. Cases with childhood-onset cardiomyopathy were consecutively recruited. Based on the likelihood of founder mutation and on the clinical diagnosis, genetic test was categorized to either (1) targeted genetic test with targeted mutation test, single-gene test, or multigene panel for Noonan syndrome, or (2) untargeted genetic test with whole-exome sequencing or whole-genome sequencing. Several bioinformatics tools were used to filter the variants.

Results:

Two-hundred five unrelated probands with various forms of cardiomyopathy were evaluated. The median age of presentation was 10 months. In 30.2% (n=62), targeted genetic test had a yield of 82.7% compared with 33.6% for whole-exome sequencing/whole-genome sequencing (n=143) giving an overall yield of 53.7%. Strikingly, 96.4% of the variants were homozygous, 9% of which were found in 4 dominant genes. Homozygous variants were also detected in 7 novel candidates (
ACACB, AASDH, CASZ1, FLII, RHBDF1, RPL3L, ULK1
).

Conclusions:
Our work demonstrates the impact of consanguinity on the genetics of childhood-onset cardiomyopathy, the value of adopting a categorized population-sensitive genetic approach, and the opportunity of uncovering novel genes. Our data suggest that if a founder mutation is not suspected, adopting whole-exome sequencing/whole-genome sequencing as a first-line test should be considered.
CARES Act Provider Relief Fund Aid to Otolaryngologists in Small Practices
Authors: Xiao Roy , Rathi Vinay K. 
Published: September 2020

The COVID‐19 pandemic has placed unprecedented financial strain on otolaryngologists. Otolaryngologists employed by small practices may be particularly vulnerable to the effects of ongoing losses because these organizations often have limited financial reserves. We performed a retrospective cross‐sectional analysis of federal direct aid provided to small practices (defined as ≤15 clinicians) employing otolaryngologists, using the Centers for Medicare and Medicaid Services Physician Compare National Downloadable File and the Department of Health and Human Services (HHS) Provider Relief Fund database. As of June 18, 2020, the HHS had allocated nearly $80 million to 966 (88.9%) of 1087 small practices employing 2455 otolaryngologists. The median amount of aid per clinician was $7909 (interquartile range, $4409‐$12,710). These findings suggest that the majority of small practices have received direct aid through the HHS Provider Relief Fund, but aid amounts have thus far been modest relative to the fixed costs of practice.