bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A63: Whole-genome CRISPR/CAS9 screen using patient samples reveals JunB as a unique genetic liability
Authors: Takahashi Nobuhiro , Keys Heather , Mohan Raghav , Zhang Lihua , Li Yi , Saatcioglu Hatice D. , Nagykery Nicholas , Donahoe Patricia K. , Sabatini David , Pépin David
Published: September 2020

Background: Epithelial ovarian cancers are the fifth leading cause of cancer-related deaths in American women, with a five-year overall survival rate for patients diagnosed at advanced stages of less than 30%. High-grade serous ovarian cancers (HGSOCs), the most common histologic subtype, often initially responds to platinum-based chemotherapy. However, over 80% of patients experience chemoresistant recurrence in advanced-stage disease.

Methods: We have established over 40 patient-derived HGSOC cell lines from ascites of patients with recurrences and hypothesized that these refractory HGSOC cell lines may each possess genetic liabilities and be dependent on unique pathways for survival that can be identified using an unbiased screening approach for the development of personalized therapies. In one such example, we identified candidate genes that are uniquely essential to a single HGSOC patient (ptD), as proof of concept, using a genome-wide lentiviral sgRNA library, containing 187,536 sgRNAs targeting 18,543 protein-coding human genes and 1,504 nontargeting control sgRNAs in a Cas9-containing vector.

Results: The unbiased CRISPR screen identified BRAF (p=2E-6) as a specific susceptibility of ptD, confirming the known oncogene addiction of this primary cell line carrying a V600E mutation, as well as a significant sensitivity to JUNB deletion (p=6E-6). Knockout of the JUNB gene, using lentiviruses expressing guide RNAs and Cas9 protein targeted to JUNB, repressed cell proliferation in vitro in ptD cells but not other primary cell lines. Moreover, in a xenograft mouse model, JUNB KO ptD cells displayed slower tumor growth than control JUNB WT cells.

Conclusion: We have confirmed in a single patient cell line our ability to identify and validate unique genetic liabilities, suggesting the approach can be scaled to rapidly screen primary HGSOC samples for personalized therapy.

Citation Format: Nobuhiro Takahashi, Heather Keys, Raghav Mohan, Lihua Zhang, Yi Li, Hatice D. Saatcioglu, Nicholas Nagykery, Patricia K. Donahoe, David Sabatini, David Pépin. Whole-genome CRISPR/CAS9 screen using patient samples reveals JunB as a unique genetic liability [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 A63.
Abstract B14: Atovaquone targets STAT3 in ovarian cancer spheroids
Authors: Neil Kayli E. , Lacroix Sarah J. , Walker David F. , Liu Suhu , Frank David A. , Walker Sarah R.
Published: September 2020

Ovarian cancer remains a deadly disease for countless women. Recent evidence demonstrates that ovarian cancer cell clusters, spheroids, are important in promoting ovarian recurrence and metastasis. Often these spheroids are resistant to therapy. Therefore, we were interested in identifying drugs that could target ovarian cancer spheroids. To do this, we wanted to identify pathways that were activated in cells growing in three-dimensional (3D) clusters. Analysis of gene expression from 2D and 3D growing cells identified STAT3 as a pathway enriched in 3D growing cells. STAT3 is a transcription factor that is activated by tyrosine phosphorylation. In ovarian cancer cells, activation usually occurs from interleukin 6 (IL-6) binding to the IL-6 receptor and recruiting the signal transducer molecule (GP130, IL6ST). This activates Jak kinases that then tyrosine phosphorylates STAT3. Once activated, STAT3 dimerizes, translocates into the nucleus, and regulates the expression of target genes. Using shRNA targeting STAT3 and the upstream signaling molecule, GP130, we found that reduction of both STAT3 and its upstream signaling molecule GP130 reduced the growth of spheroids. This suggested that targeting STAT3 or an upstream signaling molecule might be a viable treatment option. Atovaquone, used normally for the treatment of malaria or the prevention of pneumocystis pneumonia, inhibits STAT3 activation by inhibiting the expression of GP130 on the cell surface. Therefore, we hypothesized that atovaquone would have efficacy in ovarian cancer spheroids. Treatment of ovarian spheroids with atovaquone reduced their growth and viability. Importantly, atovaquone inhibited STAT3 tyrosine phosphorylation and target gene expression, demonstrating that atovaquone is inhibiting STAT3 in ovarian spheroids. Preliminary data suggest that overexpression of STAT3 partially rescues the effects of atovaquone on spheroid growth. As spheroids are also involved in ovarian cancer metastasis, we are currently assessing the effects of atovaquone on spheroid-mediated ovarian cancer metastasis. Taken together, our data suggest that atovaquone may be a beneficial treatment for ovarian cancer patients.

Citation Format: Kayli E. Neil, Sarah J. Lacroix, David F. Walker, Suhu Liu, David A. Frank, Sarah R. Walker. Atovaquone targets STAT3 in ovarian cancer spheroids [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 B14.
Abstract B21: Oncogenic BRAF and KRAS mutations in endosalpingiosis
Authors: Chui M. Herman , Shih Ie-Ming
Published: September 2020

Endosalpingiosis, or ectopic fallopian tube epithelium, frequently involves the peritoneum and lymph nodes in patients with ovarian low-grade serous borderline tumor or carcinoma, but the pathogenic significance of these microscopic lesions remains unclear. Using laser-capture microdissection and digital droplet PCR, we investigated whether endosalpingiosis harbors the driver mutations in BRAF and KRAS, commonly seen in low-grade serous tumors. Of 21 women with endosalpingiosis associated with a synchronous or metachronous ovarian low-grade serous tumor, mutations were identified in 11 (52%) cases and the identical mutation was shared between the tumor and endosalpingiosis in 10/11 cases. In contrast, of 12 cases of endosalpingiosis not associated with an ovarian tumor, only 1 harbored a KRAS mutation. Across mutation-positive cases, the median mutant allelic frequency was 37% (range: 12 – 67%). Ki-67 immunohistochemical staining revealed significantly decreased proliferative index in endosalpingiosis relative to low-grade serous tumors, but no difference with eutopic tubal epithelium. BRAF or KRAS-mutated endosalpingiosis had significantly lower Ki-67 index compared to lesions lacking mutations in both genes. Functional studies using fallopian tube epithelial cell cultures demonstrate that enforced expression of KRAS-G12V causes phosphorylation of downstream ERK, with associated growth impairment and induction of p21, suggesting oncogene-induced senescence. We demonstrate that endosalpingiosis represents a striking example of cancer driver mutations in deceptively normal-appearing cells, signifying this innocuous-appearing lesion as a monoclonal proliferation with neoplastic potential.

Citation Format: M. Herman Chui, Ie-Ming Shih. Oncogenic BRAF and KRAS mutations in endosalpingiosis [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 B21.
Abstract B27: Cellular retinoic acid binding protein 2 (CRABP2) is a novel biomarker and potential therapeutic target for high-grade serous ovarian carcinomas
Authors: Feng Yi , Gillette Michael , Kuhn Eric , Klinkebiel David , Mitchell Marilyn A. , Doberstein Kai , Chaves-Moreira Daniele , Sato Sho , Xu Haineng , Bomwell Brett , Hirsch Michelle S. , Reyes Carolina , Karpf Adam R. , Birrer Michael J. , Skates Steven J. , Carr Steven A. , Drapkin Ronny
Published: September 2020

Ovarian cancer ranks fifth in cancer deaths among women in the United States, accounting for more deaths than any other gynecologic cancer. There is an unmet medical need for biomarkers that can detect high-grade serous ovarian carcinoma (HGSOC) at an early stage. Our laboratory evaluated the biomarker potential of cellular retinoic acid binding protein 2 (CRABP2). Using Western blots (WB) and immunohistochemistry (IHC), we show that CRABP2 is expressed and secreted by HGSOC cells and tissues and is absent in normal fallopian tube (FT) epithelium. CRABP2 expression was associated with poor overall survival in patients with HGSOC. Proteomic analyses quantified specific secretion of CRABP2 in conditioned media from HGSOC cell lines, primary ascites-derived tumor cells, and serum from HGSOC patients. Expression of CRABP2 was positively associated with CRABP2 copy number amplifications by mining The Cancer Genome Atlas database. In addition, DNA methylation studies identified a putative enhancer downstream of CRABP2 that is hyper-methylated in fallopian tube epithelia (FTE) tissue and hypomethylated in HGSOC cells and tissues that expressed CRABP2. Inhibition of DNA methylation with DNA methytransferase (DNMT) inhibitors resulted in robust expression of CRABP2 protein in FT cell lines. Finally, a finding supported by CRABP2 knockdown experiments showed that CRABP2 loss triggers cell death in HGSOC cell lines. In conclusion, CRABP2 may serve as a novel biomarker for HGSOC with clinical potential as a therapeutic target.

Citation Format: Yi Feng, Michael Gillette, Eric Kuhn, David Klinkebiel, Marilyn A. Mitchell, Kai Doberstein, Daniele Chaves-Moreira, Sho Sato, Haineng Xu, Brett Bomwell, Michelle S. Hirsch, Carolina Reyes, Adam R. Karpf, Michael J. Birrer, Steven J. Skates, Steven A. Carr, Ronny Drapkin. Cellular retinoic acid binding protein 2 (CRABP2) is a novel biomarker and potential therapeutic target for high-grade serous ovarian carcinomas [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 B27.
Abstract B34: LINC00886, a risk locus-associated long noncoding RNA, promotes ovarian cancer progression
Authors: Nakamura Koji , Reid Brett M. , Sellers Thomas A. , Karreth Florian A.
Published: September 2020

Background: Recent genome-wide association studies (GWAS) have identified a plethora of SNPs that cluster at loci associated with increased epithelial ovarian cancer (EOC) risk. The functional validation of genes in such risk loci focused primarily on the protein-coding space while long noncoding RNAs (lncRNAs) were disregarded. Given the emerging evidence that lncRNAs can act as oncogenes and tumor suppressors, we seek to evaluate the functional role of EOC risk locus-associated lncRNAs in EOC development.

Methods: We interrogated GWAS for EOC and the FANTOM-CAT database for lncRNAs to identify EOC risk-associated SNPs that lie within lncRNA regulatory regions. We first prioritized the lncRNAs that are associated with EOC risk loci using public databases including GTEx and TCGA. To assess the oncogenic potential of these lncRNAs, we performed in vitro functional assays such as proliferation, colony formation, anchorage-independent growth and migration by overexpressing and silencing candidate lncRNAs in fallopian tube secretory epithelial and ovarian cancer cells. To validate our findings in vivo, we intraperitoneally injected OVCAR-8 cells into immunocompromised mice and evaluated tumor growth. LncRNA subcellular localization was evaluated based on qPCR from cytoplasmic and nuclear RNA. Further, we investigated expression changes upon lncRNAs overexpression in OVCAR-8 and FT282 cells by RNA sequencing (RNA-seq) and predicted shared microRNAs (miRNA) binding sites using LncBase Predicted v.2 and TargetScanHuman 7.2.

Results: We identified 5 candidate risk locus-associated lncRNAs (CATG00000115318.1, HAGLR, LINC00886, CATG00000117550.1, and CTD-2521M24.8). Functional assays showed that LINC00886 promoted cancer cell proliferation and colony formation in vitro. Overexpression of LINC00886 in OVCAR-8 cells significantly promoted peritoneal dissemination in a xenograft model. LINC00886 was mainly localized to the cytoplasm, suggesting it could function by decoying miRNAs. Interestingly, we observed that LINC00886 overexpression increased the levels of several oncogenes, of which several (ROR2, TNFSF14, GPNMB, LTB, and ZBTB20) share miRNA binding sites with LINC00886.

Conclusion: LINC00886, a risk loci-associated lncRNA, promotes an aggressive phenotype in ovarian cancer, suggesting an oncogenic function. We are currently investigating the molecular mechanism of LINC00886 as a ceRNA in ovarian cancer progression.

Citation Format: Koji Nakamura, Brett M. Reid, Thomas A. Sellers, Florian A. Karreth. LINC00886, a risk locus-associated long noncoding RNA, promotes ovarian cancer progression [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 B34.
Abstract B40: Characterization of TP53 mutations in Pap test DNA of women with and without serous ovarian cancer
Authors: Krimmel-Morrison Jeffrey D. , Lian Shenyi , Zhang Yuezheng , Fredrickson Jeanne , Nachmanson Daniela , Baker Kathryn T. , Radke Marc R. , Hun Enna , Norquist Barbara , Emond Mary J. , Swisher Elizabeth M. , Risques Rosa Ana
Published: September 2020

Objective: The development of Pap tests as a molecular diagnostic for serous ovarian cancer is a promising concept, but previous studies reported limited sensitivity. In addition, the presence of cancer-associated somatic mutations in normal tissue is increasingly recognized as a specificity challenge for mutational tests. We aimed to determine the diagnostic performance of Pap tests for ovarian cancer detection using ultra-accurate deep sequencing.

Methods: We used CRISPR-DS, a novel duplex sequencing method that employs CRISPR-based target enrichment to increase efficiency and reduce DNA input. We performed ultra-accurate deep sequencing (mean 2000x) of the TP53 gene in 30 Pap tests from 21 women without cancer and 9 women with serous ovarian cancer with known TP53 driver mutations. Mutations were annotated using the Seshat web service and compared to those in the UMD TP53 cancer database.

Results: The tumor-derived mutation was identified in 3 of 9 Pap tests from women with ovarian cancer (33% sensitivity). In addition, 221 low-frequency (≲0.001) mutations were identified in the coding region of TP53 in Pap tests from women with ovarian cancer (94 mutations) and without ovarian cancer (127 mutations). In both groups these mutations showed evidence of positive selection as indicated by clustering in exons 5 to 8, preferential location in hotspot codons and CpG dinucleotides, common presence in cancer database, impact on protein activity, and predicted pathogenicity. These “cancer-like” features were significantly more frequent in mutations identified in women with ovarian cancer than in women without cancer.

Conclusions: Pap tests have low sensitivity for ovarian cancer detection and carry abundant low-frequency TP53 mutations. These mutations are more frequently pathogenic in women with ovarian cancer and determining whether their presence is associated with an increased gynecologic cancer risk warrants further study.

Citation Format: Jeffrey D. Krimmel-Morrison, Shenyi Lian, Yuezheng Zhang, Jeanne Fredrickson, Daniela Nachmanson, Kathryn T. Baker, Marc R. Radke, Enna Hun, Barbara Norquist, Mary J. Emond, Elizabeth M. Swisher, Rosa Ana Risques. Characterization of TP53 mutations in Pap test DNA of women with and without 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 B40.
Abstract B46: Trends in stage at diagnosis for ovarian, fallopian tube, and serous primary peritoneal cancers, 2004–2015
Authors: Townsend Julie S. , Puckett Mary C. , Stewart Sherri L.
Published: September 2020

Introduction: Timely diagnosis is key to reducing distant stage ovarian cancer. The purpose of this study was to examine trends in the proportion of women diagnosed with ovarian cancer by stage and predictors of distant stage diagnosis, comparing two time periods: 2004–2009 and 2010–2015.

Methods: We analyzed newly diagnosed malignant ovarian, fallopian tube, and serous primary peritoneal cancers reported to population-based central cancer registries funded by CDC’s National Program of Cancer Registries (NPCR) or the NCI’s Surveillance, Epidemiology, and End Results Program (SEER). We conducted a descriptive analysis examining demographic and clinical characteristics by SEER summary stage at diagnosis (localized, regional, distant, unstaged). We compared women diagnosed between 2004–2009 and 2010–2015 by stage, histology, race/ethnicity, and stage. We built a logistic regression model to examine predictors of a distant stage diagnosis.

Results: In 2004, 18% of women were diagnosed at regional stage, which increased to 23% in 2015. There was a slight increase in local stage tumors (14% to 15%). Unstaged tumors declined from 10% to 7% over the same time period, and distant stage tumors declined from 58% to 56%. Only American Indian/Alaska Native (AI/AN) women did not experience a statistically significant decline in distant stage tumors over the two time periods. A greater proportion of serous tumors were diagnosed in the 2010–2015 time period compared to the first (53.2% vs. 50.5%). Predictors of distant stage diagnosis included being diagnosed between 2004–2009, older age (those over age 65), residence in the southern and western U.S., black race, serous histology, and residence in high-poverty census tracts.

Conclusion: In the 2010–2015 time period, a smaller proportion of ovarian cancers were distant or unstaged at diagnosis compared to 2004–2009, and most subpopulations of women experienced a decline in distant ovarian cancer. More efforts are needed to increase timely diagnosis and access to specialized care in the southern and western US, high-poverty areas, and among black women.

Citation Format: Julie S. Townsend, Mary C. Puckett, Sherri L. Stewart. Trends in stage at diagnosis for ovarian, fallopian tube, and serous primary peritoneal cancers, 2004–2015 [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 B46.
Abstract B47: Physical activity and survival following diagnosis with ovarian cancer
Authors: Wang Tianyi , Townsend Mary , Eliassen Heather , Terry Kathryn , Song Mingyang , Tworoger Shelley
Published: September 2020

Among the limited studies assessing the association between physical activity and ovarian cancer survival, results have been inconsistent. Therefore, we investigated the relation of pre- and postdiagnosis physical activity with risk of death among women with ovarian cancer in two prospective cohort studies, the Nurses’ Health Study (NHS) and NHSII. Analyses included 1,113 women with confirmed invasive, stage I-III epithelial ovarian cancer (611 ovarian cancer specific deaths). We used Cox proportional hazards regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for ovarian cancer-specific mortality by physical activity levels, adjusting for age and year of diagnosis, tumor stage, histologic subtype, body mass index, and nonsteroidal anti-inflammatory use (postdiagnosis models only). Neither prediagnosis physical activity (assessed a median of 12 months before diagnosis) nor postdiagnosis physical activity (assessed a median of 19 months after diagnosis) was significantly associated with risk of ovarian cancer death. For example, comparing women participating in ≥27 vs. <3 MET-hours/week of physical activity, HRs were 1.19 (95%CI: 0.91-1.56) for prediagnosis activity and 0.74 (95%CI: 0.51-1.08) for postdiagnosis activity. In analyses stratified by tumor stage, higher physical activity before and after diagnosis was associated with lower ovarian cancer-specific mortality among stage I/II patients (≥27 vs. <3 MET-hours/week, HR=0.43, 95%CI: 0.21-0.88 for prediagnosis activity, HR=0.31, 95%CI: 0.13-0.72 for postdiagnosis activity), while an increased risk of death or no association was observed among stage III patients (≥27 vs. <3 MET-hours/week, HR=1.37, 95%CI: 1.02-1.84 for prediagnosis activity, HR=0.84, 95%CI: 0.56-1.25 for postdiagnosis activity). Results did not vary significantly by histologic subtype (serous vs. nonserous/unknown). Future analyses will evaluate prediagnosis physical activity reported at least four years prior to ovarian cancer diagnosis and postdiagnosis physical activity within four years after diagnosis. Overall, our analyses suggest that, among all stage I-III ovarian cancer patients, higher levels of physical activity, either before or after diagnosis, are not associated with improved survival. However, physical activity in women with early-stage disease may be related to improved outcomes.

Citation Format: Tianyi Wang, Mary Townsend, Heather Eliassen, Kathryn Terry, Mingyang Song, Shelley Tworoger. Physical activity and survival following diagnosis with 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 B47.
Abstract B66: Paracrine interactions with microenvironmental fibroblasts promote ovarian cancer metastasis through downregulation of miR-4454
Authors: Dasari Subramanyam , Pandhiri Taruni , Grassi Tommaso , Visscher Daniel W. , Multinu Francesco , Agarwal Komal , Mariani Andrea , Shridhar Viji , Mitra Anirban K.
Published: September 2020

Metastasis causes poor prognosis and yet remains the least understood aspect of cancer. To identify key regulators of ovarian cancer metastasis that drive early colonization and are also essential for advanced metastasis, we have applied a novel, comprehensive approach of combining the analysis of an organotypic 3D culture model of early metastasis with ovarian cancer patient tumors. Using matched primary and metastatic tumors from 42 OC patients, we have compared the fully formed metastatic tumors with the primary tumor of the same patient. Since this is an end-point analysis and reveals little about the intermediated regulatory steps, we have also studied the changes occurring during early metastatic colonization as a result of the interactions with the metastatic microenvironment by using an organotypic 3D culture model of omental metastasis. By combining these two approaches, we have identified key master regulators of metastasis that are essential for early metastatic colonization and remain important in the fully formed metastatic tumor. We specifically focused on microRNAs because of their pleotropic effects through translational inhibition of multiple targets, and also our previous studies have demonstrated their important role in metastasis. Using this approach, we identified a novel microRNA miR-4454, downregulated in the metastasizing ovarian cancer cells through their specific paracrine interactions with fibroblasts in the metastatic microenvironment. The downregulation of miR-4454 promoted high-grade serous ovarian cancer cell migration, invasion, proliferation, and clonogenic growth as well as metastasis in xenografts. The targets of miR-4454 were identified by RNA-seq in high-grade serous ovarian cancer cells overexpressing the microRNA. SPARC and BAG5 were found to be the functional effectors of miR-4454. SPARC activated FAK signaling and promoted metastasis, while BAG5 inhibited apoptosis and helped the metastasizing cancer cells tide over adverse conditions in the microenvironment. Since miR-4454 is essential for early metastatic colonization as well as in advanced metastasis, targeting it is a promising approach to treat metastatic ovarian cancer.

Citation Format: Subramanyam Dasari, Taruni Pandhiri, Tommaso Grassi, Daniel W. Visscher, Francesco Multinu, Komal Agarwal, Andrea Mariani, Viji Shridhar, Anirban K. Mitra. Paracrine interactions with microenvironmental fibroblasts promote ovarian cancer metastasis through downregulation of miR-4454 [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 B66.
Abstract B78: Improving chemotherapy response of immunologically cold high-grade serous ovarian cancer with loss of PTEN using STING agonist
Authors: Shakfa Noor , Lightbody Elizabeth , Afriyie-Asante Afrakoma , Kannen Vinicius , Koti Madhuri
Published: September 2020

High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy, with high rates of chemotherapy resistance and poor outcomes. We previously showed that tumors from chemotherapy-resistant patients show an immunologically cold phenotype, exhibiting lower density of CD8+ T cells and low expression of interferon genes. Subsequently, using the ID8-Trp53−/− murine model of HGSC, we further demonstrated the potential of Stimulator of Interferon Genes (STING) pathway activation in enhancing response of HGSC to carboplatin chemotherapy. Currently, we aim to better characterize the effect of cancer cell genotype on response to treatment in HGSC. The evolution of the tumor immune microenvironment (TIME) as immunologically hot or cold can be to some extent dictated by cancer cell-specific genetic alterations. While loss of the tumor suppressor TP53 is a universal mutation (>96% of cases), previous reports in HGSC have shown that patients with BRCA1 mutations (~25% of cases) have higher CD8+ T-cell infiltration and higher chemosensitivity. In contrast, loss of PTEN (seen in ~20% of cases) is associated with poor outcomes and chemoresistance. We hypothesized that HGSC tumors with loss of PTEN expression can benefit via immunomodulatory treatment approaches that activate the STING pathway following chemotherapy. C57/BL6 mice were implanted with either ID8-Trp53−/−; Brca1−/− cells or ID8-Trp53−/−; Pten−/− cells and subjected to one of three treatment groups: vehicle, carboplatin, or carboplatin + STING agonist. Characterization of the TIME generated from ID8-Trp53−/−; Brca1−/− cells, and those from ID8-Trp53−/−; Pten−/− cells, through local and systemic immune profiling, showed significant immunologic differences between different genotypes. Addition of STING agonist significantly increased chemosensitivity and improved overall response in ID8-Trp53−/−; Pten−/− injected mice compared to those treated with carboplatin alone. This study helps to determine the potential of STING pathway activation in inducing an activated tumor immune state in genotypes of HGSC that result in a “cold” TIME, such as loss of PTEN, to augment responses to chemotherapy and prolong survival.

Citation Format: Noor Shakfa, Elizabeth Lightbody, Afrakoma Afriyie-Asante, Vinicius Kannen, Madhuri Koti. Improving chemotherapy response of immunologically cold high-grade serous ovarian cancer with loss of PTEN using STING agonist [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 B78.
Abstract B80: Predictive treatment response models for epithelial ovarian cancer: Comparison of 2D, 3D, and in vivo models
Authors: Nourmoussavi Melica , Carmona Euridice , Mes-Masson Anne-Marie
Published: September 2020

Introduction: Epithelial ovarian cancer (EOC) is still a deadly disease, with a 5-year overall survival of 45%. Current research focuses on the development of new targeted and personalized therapies to improve survival in these patients. The drug discovery pipeline is dependent on preclinical models, which have mostly focused on 2D systems because of time and cost efficiency. However, it is currently unclear whether they accurately reflect patient response and whether other in vitro models may better predict therapeutic response. Preliminary data from our laboratory suggest that the sensitivity to carboplatin chemotherapy varies between 2D and 3D in vitro models. We hypothesize that the 3D model will more closely reflect therapeutic response. The primary objective of this study is to characterize the sensitivity to carboplatin of our EOC cell lines in 2D monolayers and 3D spheroids and compare them to their in vivo response using our xenograft mouse models.

Methods: We are injecting NOD-RAG mice with 7 EOC cell lines (TOV112D, TOV21G, OV4485, OV4453, OV1946, OV90, OV3133). At 200mm3, weekly carboplatin treatments (group1 = control, group 2= 25mg/kg, group 3= 50mg/kg, group 4= 75mg/kg) are given up to 6 cycles. Tumor volume and survival curves are used to categorize chemosensitivity between cell lines. Furthermore, the same cell lines are seeded in ultra-low attachment microplates to form spheroids over 48hr and are thereafter treated with 24hr of carboplatin. Flow cytometry analyses are done to classify cell lines.

Results: The results for the 2D models using clonogenic assays (IC50) of the 7 cell lines have previously been published. Thus far, we have completed a first set of in vivo experiments for TOV21G showing a nonsignificant tumor growth suppression after 6 doses (no difference between the 3 treated and the nontreated group). Tumor growth suppression for OV90 was statistically significant with 50mg/kg and 75mg/kg of carboplatin after 6 doses. This demonstrates thus far that the most resistant cell line in 2D is more sensitive in an in vivo model.

Conclusion: The results will help define the most reliable preclinical model with the highest translational potential to predict treatment response.

Citation Format: Melica Nourmoussavi, Euridice Carmona, Anne-Marie Mes-Masson. Predictive treatment response models for epithelial ovarian cancer: Comparison of 2D, 3D, and in vivo models [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 B80.
Abstract IA09: Challenges in the identification of inherited risk of ovarian cancer
Authors: Norquist Barbara M.
Published: September 2020

We have come a long way since the 1990s in our understanding of inherited risk and in the genetic testing options that are available to our patients. Despite the clear benefits of identifying inherited risk, there are many barriers in place to genetic testing, and most women with ovarian cancer are still not undergoing these tests. The need for genetic testing currently exceeds the availability of genetic counselors, and creative solutions will need to be explored. The Stand Up To Cancer Ovarian Cancer Dream Team is conducting the MAGENTA (MAking GENetic Testing Accessible) trial. MAGENTA utilizes genetic testing at home with a mailed kit, electronic results delivery, and telephonic genetic counseling. This and other ideas will have to be explored in order to increase genetic testing rates. With the recent publication of SOLO-1 demonstrating a large benefit for PARP inhibitor maintenance therapy in the primary setting for women with advanced BRCA-mutated OC, identifying germline and somatic BRCA1 and BRCA2 mutations at the time of diagnosis is paramount and likely to soon be considered standard of care for treatment planning. The most optimal method for detecting both germline and somatic mutations is currently up for debate. Our University of Washington Department of Laboratory Medicine is currently offering tumor and germline sequencing in parallel using both tumor and blood samples, allowing for simultaneous detection of germline and somatic mutations, with methods optimized for each approach. Data from this ongoing project will be presented. Finally, in order to optimize the identification of inherited risk, we need to better understand which genes are implicated in ovarian cancer risk and treatment response. The advent of multiplex gene testing has allowed us to detect mutations in many genes using a single test, increasing efficiency and decreasing costs. The primary downside of multiplex testing is that as more genes are sequenced, the likelihood of identifying uncertain results also increases, either in the form of variants of uncertain significance (VUS) or damaging mutations in genes with uncertain contributions to cancer risk. Available data on risks of ovarian cancer with mutations in genes other than BRCA1 and BRCA2 will be reviewed.

Citation Format: Barbara M. Norquist. Challenges in the identification of inherited risk of 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 IA09.
Abstract IA23: Therapeutic approaches for ARID1A-mutated ovarian cancer
Authors: Zhang Rugang
Published: September 2020

Ovarian cancer remains the most lethal gynecologic malignancy in the developed world. Despite the unprecedented progress in understanding the genetics of ovarian cancer, cures remain elusive due to a lack of insight into the mechanisms that can be targeted to develop new therapies. SWI/SNF chromatin remodeling complexes are genetically altered in ~20% of all human cancers. SWI/SNF alterations vary in different histologic subtypes of ovarian cancer, with ARID1A mutation occurring in ~50% of ovarian clear-cell carcinomas. Given the prevalence of ARID1A mutation, ovarian cancer represents a paradigm for investigating the molecular basis and exploring therapeutic strategies for SWI/SNF alterations. The presentation will discuss our recent efforts in understanding SWI/SNF alterations in ovarian cancer and specifically focuses on ARID1A mutation in endometriosis-associated clear cell and endometrioid histologic subtypes of ovarian cancer. Understanding the molecular underpinning of ARID1A mutation in ovarian cancer will provide mechanistic insights into how ARID1A inactivation contributes to ovarian cancer. In addition, how these newly gained insights can be leveraged to develop urgently needed therapeutic strategies in a personalized manner for ovarian cancer will be discussed.

Citation Format: Rugang Zhang. Therapeutic approaches for ARID1A-mutated 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 IA23.
Abstract PR03: Single-cell proteomic analysis of the tumoral heterogeneity in response to PARP inhibitor
Authors: Kendsersky Nicholas D. , Ma Hongli , Fang Yong , Campbell Lydia G. , Eng Jenny , Lee Sanghoon , Chin Koei , Westin Shannon N. , Mills Gordon B. , Labrie Marilyne
Published: September 2020

Although poly (ADP-ribose) polymerase (PARP) inhibitors have shown efficacy in the treatment and maintenance of ovarian cancer patients, development of PARP inhibitor resistance is frequent. Our group and others have demonstrated that the cancer cells’ adaptive responses to PARP inhibitor can be detected at the protein level and targeting these adaptive responses increases the depth and duration of treatment and might prevent the development of drug resistance. However, it is still unclear if these adaptive responses are conserved across cancer cells from the same tumor and across cells from different lesions. Having a better understanding of the heterogeneity of adaptive responses might help develop better approaches of PARP-based combination therapies. The objective of this study was to develop a single-cell proteomic approach to investigate the heterogeneity of adaptive responses in ovarian cancer tumors. We developed a cyclic-immunofluorescence antibody panel and measured the expression of more than 40 proteins at the single-cell level in several ovarian cancer tumors that have been treated with PARP inhibitors. We also performed reverse-phased protein array (RPPA) analysis on protein extracted from the tumors and measured the activity of several pathways know to be altered in response to PARP inhibitors. Overall, our results demonstrated that adaptive responses can be detected at the single-cell level through cyclic immunofluorescence. Furthermore, although RPPA assays capture the main pathway alterations in response to PARP inhibitors, cyclic immunofluorescence adds complementary information by allowing a spatial-oriented analysis of the different cell populations as well as their frequency. Overall, this approach might lead to a better understanding of how cancer cells try to survive therapeutic stress and improve the decision-making process in the treatment of ovarian cancer patients.

This abstract is also being presented as Poster A19.

Citation Format: Nicholas D. Kendsersky, Hongli Ma, Yong Fang, Lydia G. Campbell, Jenny Eng, Sanghoon Lee, Koei Chin, Shannon N. Westin, Gordon B. Mills, Marilyne Labrie. Single-cell proteomic analysis of the tumoral heterogeneity in response to PARP inhibitor [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 PR03.
ДИЗАЙН ЕКСПЕРИМЕНТУ ПРИ ПРОВЕДЕННІ ДОСЛІДЖЕНЬ ІЗ СТВОРЕННЯ ТАБЛЕТОВАНИХ ЛІКАРСЬКИХ ЗАСОБІВ
Authors: Hroshovyi T. A. , Demchuk M. B. , Beley N. M. , Nayda Yu. V. , Pavliuk B. V.
Published: August 2020

Мета роботи. Аналіз і систематизація даних літератури щодо дизайну досліджень із використанням математичного планування експерименту при створенні та вдосконаленні технології таблетованих лікарських засобів. 

Матеріали і методи. В роботі використано методи інформаційного пошуку, аналізу даних літератури щодо дизайну експерименту на етапі вивчення якісних факторів при проведенні досліджень зі створення таблетованих лікарських засобів.

Результати й обговорення. У роботі наведено дані літератури та власних досліджень щодо використання математичного планування експерименту при вивченні якісних факторів на етапі розробки складу та технології таблеток. Наведено приклади використання планів латинських, греко-латинських і гіпер-греко-латинських квадратів при вивченні якісних факторів з однаковим числом рівнів. Для вивчення якісних факторів із різним числом рівнів розглянуто приклади використання планів латинських кубів і паралелепіпедів.

Висновки. Дизайн якості є важливим та широко використовуваним прийомом при розробці лікарських засобів. Його методи використовують експериментатори на різних етапах дослідження – від формування цілей до характеристики готового препарату. Особливо це важливо у процесі створення та дослідження таблеток, який є багатостадійним. Застосування математичного планування експерименту на стадії планування досліджень дозволяє впровадити принцип «дизайн якості» як в наукових, так і в промислових умовах при створенні таблетованих лікарських засобів. Наведені приклади проведення досліджень із вивчення якісних факторів з однаковим і різним числом рівнів, методи побудови планів дисперсійного аналізу, їхнього статистичного аналізу та інтерпретації результатів експериментальних досліджень.
КОМПЕТЕНЦІЇ МЕДИЧНОЇ СЕСТРИ В ДОГЛЯДІ ЗА ХВОРИМИ ГЕПАТОЛОГІЧНОГО ПРОФІЛЮ
Authors: Dunda D. S. , Prokopchuk O. V. , Danchak S. V.
Published: August 2020

У статті висвітлено сучасні дані щодо професійної компетентності та професійної мобільності молодшого медичного персоналу при догляді за пацієнтами із захворюваннями печінки в сучасних умовах, маніпуляції, які використовують у даній професії, та специфіку їх проведення. Розвиток системи професійної підготовки медичних працівників є важливим питанням сьогодення та вимагає перегляду з метою удосконалення сестринської справи.
ПРОБЛЕМА ГУМАНІТАРНОЇ ПІДГОТОВКИ МАЙБУТНІХ ФАХІВЦІВ МЕДИЧНОЇ ГАЛУЗІ
Authors: Kulchytskyj V. Y. , Nevinska L. M.
Published: August 2020

У статті розглянуто проблему гуманітарної підготовки майбутніх фахівців медичної галузі на засадах міждисциплінарної інтеграції.
КВАРЦ. УЛЬТРАФІОЛЕТОВЕ ВИПРОМІНЮВАННЯ. ОЗОН. ВПЛИВ НА ВІРУС COVID-19
Authors: Bai U. A.
Published: August 2020

У статті проаналізовано вплив ультрафіолетового випромінювання, кварцу та озону як на людський організм, так і на мікроорганізми. Пояснено, що внаслідок дезактивації ДНК бактерій, вірусів та інших патогенних мікроорганізмів руйнується їх здатність до розмноження та виникнення хвороби, що робить доцільним використання ультрафіолетового випромінювання з метою дезінфекції, особливо в період такої вірусної епідемії, як COVID-19.
ВИКОРИСТАННЯ ΙННОВАЦΙЙНИХ ТЕХНОЛОГΙЙ У ПРОЦЕСΙ ПΙДГОТОВКИ МАЙБУТНІХ ФАХΙВЦΙВ МЕДИЧНОЇ ГАЛУЗΙ
Authors: Zhavrichenko K. V.
Published: August 2020

У статті розглянуто необхідність впровадження інноваційних технологій у навчальний процес для покращення якісних показників навчальних досягнень студентів.
НАПРЯМИ РОБОТИ З ІН’ЄКЦІЙНИМИ СПОЖИВАЧАМИ НАРКОТИКІВ
Authors: Yavkina I. V.
Published: August 2020

У статті розкрито основні напрями роботи з ін’єкційними споживачами наркотиків. Узагальнено роботу служби «Довіра».
ПРОФІЛАКТИКА ТА ДОПОМІЖНЕ ЛІКУВАННЯ ГОСТРИХ РЕСПІРАТОРНИХ ЗАХВОРЮВАНЬ ДІТЕЙ І ДОРОСЛИХ ЗА ДОПОМОГОЮ БІОПТРОН-ПАЙЛЕР-СВІТЛА
Authors: Ґуляр С. О.
Published: August 2020

Огляд містить короткі відомості про нові аспекти фізіотерапії (фотобіомодуляції) із застосуванням поляризованого світла апарату БІОПТРОН. Палітра активних біофізичних чинників налічує 12 полі- та монохроматичних видів світла від галогенних і світлодіодних джерел. Їхня протизапальна, протибольова, репаративна та імунонормалізуюча ефективність доведена експериментально та клінічно. Серед основних показів є також різноманітні види патології шкіри та слизових оболонок, лікування ран і наслідків травм, оптимізація реабілітаційних процесів та інші стани, що підлягають фізіотерапевтичному лікуванню. Додаткові специфічні терапевтичні можливості виникають за рахунок створення монохроматичних (лазероподіб-них) діапазонів, модифікації світла фуллереном із тороїдною поляризацією та розширений діапазон із додаванням ближнього ультрафіолетового світла. ПАИЛЕР-світло впливає як місцево на клітини та світлочутливі молекули, нормалізуючи в них електромагнітний баланс, так і системно через дію на структури крові та точки акупунктури.

Експериментально доведено бактерицидну та противірусну ефективність БІОПТРОН-світла. Під час холодного сезону безконтактна неінвазивна профілактика та лікування застудних захворювань із застосуванням БІОПТРОН-світлотерапії є суттєвою для зменшення негативних проявів без фармакологічного навантаження на організм. Наведено апробовані протокольні схеми профілактики та лікування гострих респіраторних захворювань. Серед засобів індивідуального захисту доцільно зменшення світлового навантаження та створення механічних перепон для захисту очей шляхом застосування окулярів з фуллереновими фільтрами.

Головною особливістю ЦЕПТЕР-технологій у цілому є їхня здоров'я-зберігаюча сутність, реалізована шляхом багаторівневого антиоксидантного захисту. Все це є необхідним компонентом заходів, що застосовуються при гострих респіраторних захворюваннях.
СИСТЕМНИЙ АНАЛІЗ АКТИВНОСТІ мікроРНК ПРИ ПУХЛИННОМУ ЗРОСТАННІ
Authors: Мінцер О. П. , Заліський В. М. , Малярчук Е. А.
Published: August 2020

Концептуалізовано дані щодо ролі мікроРНК. При аналізі можливих стратегій відновлення нормального рівня р53 і р53-залежних від мікроРНК із метою профілактики злоякісних новоутворень висловлено припущення, що виявлені факти змінили розуміння експресії генів і створили прецедент для розроблення нових методів діагностики та лікування раку. Представляється важливим виявлення додаткових потенЦійних мішеней мікроРНК і розроблення безпечних методів лікування на основі мікроРНК із тим, щоб модуляція мікроРНК стала критичним методом для лікування раку. У цьому плані становить інтерес вивчення варіантів протиракової терапії, пов'язаних із одночасною гіперактивацією двох регуляторів апоптозу — р53 і мікроРНК. У рамках прийнятого математичного моделювання показано потенційно високу антибластомну терапію, мішенню якої є білок-інгібітор р53 як основна ланка петлі позитивного зворотного зв'язку р53 — мікроРНК, а також ініціації метастазування пухлин. Зроблено висновки: 1. МікроРНК являють собою найважливіші регулятори клітинного диференціювання, проліферації і виживання. Зміни в експресії мікроРНК явно пов'язані з прогресуванням численних захворювань людини, зокрема, раку. 2. МікроРНК виконують ключову роль у генезі пухлин як важливі модулятори/демодулятори в клітинних шляхах, регулюючи експресію гена цілі через репресію перекладу або погіршення mRNA. Отже, мікроРНК є привабливими кандидатами на роль прогностичних біомаркерів і терапевтичних мішеней при раку.
СИСТЕМА ДЛЯ ОБЛІКУ ДОНОРСЬКОЇ КРОВІ ТА ЇЇ КОМПОНЕНТІВ
Authors: Стецюк В. З. , Чиж А. М. , Бабінцева Л. Ю. , Чиж М. В. , Муха І. П.
Published: August 2020

Представлено основні компоненти комп'ютерного десктопного програмного забезпечення для оптимізації процесу обліку та автоматизації статистичного аналізу руху донорської крові та її компонентів на станції переливання крові. Об'єктом дослідження стала база даних електронної медичної облікової документації Черкаської обласної станції переливання крові, способи оброблення інформації, спрямовані на отримання оперативної та періодичної статистичної звітності з використанням основних елементів архітектури Microsoft SQL Server.
СУЧАСНІ ТЕХНОЛОГІЇ ДИСТАНЦІЙНОЇ ПІДГОТОВКИ ВИКЛАДАЧІВ ПІСЛЯДИПЛОМНОЇ МЕДИЧНОЇ ОСВІТИ
Authors: Мінцер О. П. , Бабінцева Л. Ю.
Published: August 2020

Питання розвитку післядипломної медичної освіти науково-педагогічних працівників актуалізувалися в зв'язку з модернізацією всієї системи освіти. Констатовано відсутність у державі цілісної системи підготовки та підвищення кваліфікації викладачів післядипломної медичної освіти. Тому існує необхідність обґрунтування системи цілеспрямованих і програмних зусиль для забезпечення традиційної спрямованості розвитку педагогічних і науково-педагогічних працівників на вдосконалення після-дипломного медичного викладання із застосуванням системного підходу. Підкреслено, що підготовка педагогічних і науково-педагогічних працівників у системі післядипломної медичної освіти в період інтенсивного реформування галузі набуває надзвичайного значення. Запропонована спеціальна програма підготовки в рамках стратегії системного безперервного педагогічного розвитку. Важливим індикатором спеціальної програми може стати показник особистого розвитку викладача—векторна характеристика з координатами у вигляді цифрових показників рівня компетенцій, знань, умінь та соціальної активності.
КОМПЛЕКСНЕ ОЦІНЮВАННЯ КОМПЕТЕНТНОСТЕЙ, ЗНАНЬ І ВМІНЬ ЛІКАРЯ В ПРОЦЕСІ БЕЗПЕРЕРВНОГО ПРОФЕСІЙНОГО РОЗВИТКУ. ПРОБЛЕМИ РЕСЕРТИФІКАЦІЇ
Authors: Мінцер О. П. , Ганинець П. П. , Суханова О. О.
Published: August 2020

Розглянуто питання комплексного оцінювання компетентностей, знань, умінь та особливості метрики під час ре-сертифікації. Підкреслюється, що єдиного бачення проблеми атестації лікарів не існує. Відповідно, існують проблеми при зміні лікарем країни: від забезпечення адаптації до досягнень у галузі знань і технологій (процедура ре-сертифікації). Мета дослідження полягала у створенні концептуальних основ кількісної системи оцінювання якості процедур підвищення кваліфікації лікарів. Отримано висновки про те, що існуючі національні практики ресертифіка-ції не забезпечують якість медичної допомоги на міжнародному рівні, оскільки вони оцінюють компетентність і ефективність роботи лікарів лише відповідно до національних стандартів якості. Відсутня єдина методика комплексного оцінювання вдосконалення лікарів у міжнародних системах ресертифікації. Запропонована методика створення багатовимірної шкали оцінювання безперервного професійного розвитку лікаря, що може слугувати ефективним механізмом особистого портфоліо.