bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 912: Macrophage inhibitory factor (MIF), osteopontin (OPN) and anti-interleukin-8 (IL-8) autoantibodies (AAb) complement CA125 for detection of early-stage ovarian cancer
Authors: Guo Jing , Yang Wei-lei , Celestino Joseph , Lu Karen , Lokshin Anna E. , Lu Zhen , Bast Robert C.
Published: August 2019

Background: Early detection of ovarian cancer promises to reduce mortality. At present, only 20 percent of ovarian cancer is found in early stage (I-II). CA125 is found in sera from approximately 60% of patients with early stage disease. Greater sensitivity could be observed with a panel of blood tests.

Methods: A panel of 10 antigen biomarkers (MIF, Leptin, IL-6, IL-8, TNFa, OPN, FGF2, HE4, TGFa and a panel of autoantibodies (AAbs) against 12 antigens (IL-8, MDM2, c-myc, PLAT, EpCAM, HOXA7, ENO1, PDI, HSPA5, HSPA8, ANXA2, Cathepsin D) were analyzed in sera of 77 ovarian cancer patients with early stage (I-II), 50 patients with late stage (III-IV), and 216 healthy women from the Normal Risk Ovarian Cancer Screening Study (NROSS) using Luminex-based immunoassays. Serum levels of serum tumor marker CA-125 were routinely measured in all patients using a Roche assay. The most promising markers (CA125, MIF, OPN, and anti-IL-8 autoantibodies were validated using an independent panel with sera from 69 early stage and 50 late ovarian cancer patients and 200 healthy controls.

Result: Serum level of CA125, MIF, OPN and IL-8 AAb were elevated in early stage (I-II) and late stage (III-IV) ovarian cancer patients compared with healthy controls. Analyzing the positive biomarkers in combination with CA125 increased detection of early stage disease from 62% with CA125 alone to 92% a panel of CA125, MIF, OPN and IL-8 AAb at 98% specificity. For patients with late stage disease sensitivity increased from 90% to 98% with the panel. Complementarity of CA125 with MIF, OPN and IL-8 AAb was confirmed with an independent validation set, where sensitivity for early stage disease was improved from 84% to 91% at 98% specificity.

Conclusion: MIF, OPN and IL8 AAb could be used in combination with CA125 to distinguish ovarian cancer patients from health controls with high sensitivity.

Citation Format: Jing Guo, Wei-lei Yang, Joseph Celestino, Karen Lu, Anna E. Lokshin, Zhen Lu, Robert C. Bast. Macrophage inhibitory factor (MIF), osteopontin (OPN) and anti-interleukin-8 (IL-8) autoantibodies (AAb) complement CA125 for detection of early-stage ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 912.
Abstract 95: Synthetic essentiality of chromatin remodeling factor CHD1 in PTEN deficient cancer
Authors: Zhao Di
Published: August 2019

Prostate cancer (PCa) is one of the most common cancer types in mem. Advanced PCa, especially metastatic castration resistant prostate cancer (mCRPC), has high morbidity and mortality. ~50% advanced PCa shows PTEN deletion or mutation, therefore, identification of specific therapeutic targets for PCa harboring PTEN deficiency holds hope for patients with advanced PCa. Taking advantage of the vast public available prostate cancer genome database, we recently explored a novel approach to identify potential therapeutic targets by screening for “synthetic essential” genes that were occasionally deleted in cancer but always retained in the context of tumor suppressor gene deficiency. Using this method, we identified the chromodomain-helicase-DNA-binding protein 1 (CHD1) as a synthetic essential gene in PTEN-deficient PCa. Both human PCa xenograft models and genetically engineered PCa mouse models suggested that depletion of CHD1 suppresses the tumor growth and progression of PTEN-deficient PCa, but has minimal effects on normal prostate tissue or PTEN-intact PCa. Importantly, CHD1 inhibition leads to a significantly prolonged overall survival in PTEN-loss PCa mouse model. Mechanistically, we found that PTEN-PI3K-AKT-GSK3βpathway regulates CHD1 phosphorylation, followed by ubiquitination and degradation via β-TrCP mediated proteasome pathway. The ChIP-seq and transcriptional profiling analyses uncovered that, in PCa with PTEN loss, CHD1 is stabilized and interacts with epigenetic marker H3K4me3, resulting in the transcriptional activation of NF-κB network genes. Furthermore, immunophenotyping using Mass Cytometry (CyTOF) and functional validation suggested that CHD1 contributes to the immunosuppressive tumor microenvironment in PCa through stimulating the expansion and activation of myeloid-derived suppressor cell (MDSCs) and reducing tumor-infiltrating CD8+ T-cells. Together, this study demonstrated that CHD1 plays important roles in tumor initiation and progression of PTEN-deficient PCa, and presents a promising context-specific therapeutic target in PCa. In addition, the novel approach of “synthetic essentiality” we proposed provides a good tool to identify context-specific therapeutic targets for undruggable tumor suppressor deficiency in cancer genome.

Citation Format: Di Zhao. Synthetic essentiality of chromatin remodeling factor CHD1 in PTEN deficient cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 95.
Abstract CT017: A Phase Ib of a combination of two chimeric (Trastuzumab-like and Pertuzumab-like) HER-2 B cell peptide vaccine emulsified in ISA 720 and nor-MDP adjuvant in patients with advanced solid tumors
Authors: Bekaii-Saab Tanios , Wei Lai , Wesolowski Robert , Ahn Daniel , Wu Christina , Lustberg Maryam , Mortazavi Amir , Ramaswamy Bhuvaneswari , Overholser Jay , Kaumaya Pravin
Published: August 2019

Background: HER-2 is a transmembrane receptor that is overexpressed in multiple epithelial tumors. We have previously shown that a first generation HER-2 B-cell peptide vaccine targeting epitopes (628-647) and (316-339) was safe and relatively active. We recently developed a novel B-cell epitope specific vaccine (HER-Vaxx) consisting of epitopes derived from the extracellular domain of HER-2 that correspond to amino acid sequences 597-626 (pertuzumab binding site) and 266-296 (trastuzumab binding site).

Methods: This first-in-human Phase 1b study evaluated the safety, optimal immunologic/biologic dose (OID/OBD) and immunogenicity of HER-Vaxx. Using a 3+3 dose escalation design, 3 patients (pts) were treated at each dose level (DL). If <2 pts experience dose-limiting toxicity (DLT), we required an additional 3 pts to be entered at that DL for OID/OBD assessment (defined as the dose level inducing a strong immunogenic response for 5 out of 6 patients). We also required that at least 6 patients at each DL to receive 3 inoculations of the combination vaccines at 3-week intervals and that < 2 of the 6 pts experience DLT before dose escalation. DLs were 1.0 mg (DL1), 1.5 mg (DL2), 2.0 mg (DL3) and 2.5 mg (DL4) of each peptide. Each dose contained 0.025 mg of n-MDP.

Results: 49 patients with metastatic and/or recurrent solid tumors and a median of 4 prior lines of chemotherapy received at least one inoculation of HER-vaxx. Common related toxicities include injection site reactions (56% grade 1/2 and 5% grade 3/4). There were no DLTs. The OID/OBD was found to be DL 2 (1.5 mg of each peptide vaccine).A total of 28 patients received ≥ 3 vaccinations including 2 with a partial response and 14 with stable disease. Of those, 6 patients received at least one 6-month boost. The vaccine generated sustained humoral response eliciting HER-2 specific antibodies in the majority of responding patients.

Conclusion: We demonstrate that HER-Vaxx is well tolerated and able to generate sustained anti-HER-2 immune response. Given the promise, continuous development of the vaccine is ongoing at the suggested OBD in HER-2 overexpressing tumors.

Citation Format: Tanios Bekaii-Saab, Lai Wei, Robert Wesolowski, Daniel Ahn, Christina Wu, Maryam Lustberg, Amir Mortazavi, Bhuvaneswari Ramaswamy, Jay Overholser, Pravin Kaumaya. A Phase Ib of a combination of two chimeric (Trastuzumab-like and Pertuzumab-like) HER-2 B cell peptide vaccine emulsified in ISA 720 and nor-MDP adjuvant in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT017.
Abstract CT085: Pharmacodynamic correlates in a phase I study of INCMGA00012, a PD-1 antagonistic monoclonal antibody
Authors: Condamine Thomas , Owens Sherry , Feldman Patricia , Motte-Mohs Ross La , Muth John , Sumrow Bradley , Moore Paul , Newton Robert
Published: August 2019

Background: The role of the PD-1 / PD-L1 axis in limiting T cell activity has been well established. Effective blockade of this pathway has been demonstrated to lead to an increase in T cell activity and to yield clinical activity in cancer patients. INCMGA00012 is a humanized IgG4 monoclonal antibody that binds to human PD-1 and blocks its interaction with PD-L1/PD-L2. This therapeutic antibody has demonstrated acceptable tolerability with evidence of clinical activity in a phase 1 study in patients with solid tumors (NCT03059823). Pharmacodynamic markers demonstrating biological activity of INCMGA0012 were assessed in samples collected during the study.

Methods: Blood samples were collected at baseline and at various time points following treatment from patients receiving doses of either 3mg/Kg (Q2W) in the tumor-specific expansion cohort or a flat-dose of 500 or 750mg (Q4W) in the tumor-agnostic expansion cohort. Receptor occupancy was measured on circulating T cells by flow cytometry and serum cytokine levels were measured using either a proximity extension assay or immunoassays. In addition, circulating immune cell phenotyping was analyzed using flow cytometry and PBMC functionality evaluated using ex-vivo re-stimulation.

Results: All tested doses of INCMGA0012 evaluated demonstrated a full saturation of the PD-1 receptor at trough on circulating CD4 and CD8 T cells. In all tested cohorts, an increase in serum CXCL9 and CXCL10 was observed following infusion with INCMGA0012. Moreover, an increase in the proliferation of circulating T cells was observed on treatment compared to baseline. Concurrently, following ex vivo re-stimulation, T cells isolated from peripheral blood mononuclear cells demonstrated an increased capacity to secrete cytokines.

Conclusion: These results provide evidence that INCMGA0012 is biologically active and leads to an increase in IFNγ-related protein levels (i.e. CXCL9 and CXCL10) and in T cell proliferation. The clinical activity of INCMGA0012 is undergoing further evaluation in several indications, including endometrial cancer, Merkel cell carcinoma and squamous carcinoma of the anal canal. Several combination studies have also been initiated.

Citation Format: Thomas Condamine, Sherry Owens, Patricia Feldman, Ross La Motte-Mohs, John Muth, Bradley Sumrow, Paul Moore, Robert Newton. Pharmacodynamic correlates in a phase I study of INCMGA00012, a PD-1 antagonistic monoclonal antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT085.
Abstract CT161: A Phase II study of the polo-like kinase (PLK1) inhibitor onvansertib in combination with abiraterone (abi) and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC)
Authors: Einstein David J. , Choudhury Atish , Saylor Philip , Werner Lillian , Erlander Mark , Ridinger Maya , Bubley Glenn
Published: August 2019

Background: mCRPC remains a leading cause of cancer-related deaths worldwide. Although abi increases survival, resistance is universal and generally occurs within 9-16 months of initiating treatment. PLK1, a serine/threonine kinase, is a master regulator of cell-cycle progression and is highly upregulated in prostate cancer following castration. PLK1 inhibition enhances the efficacy of abi in cell line models and patient-derived tumor xenografts. Onvansertib (PCM-075; Trovagene, Inc.) is the first orally available PLK1-specific inhibitor. In Phase I testing, onvansertib demonstrated a manageable safety profile, with transient hematologic effects as its most prominent, yet reversible, toxicity.

Methods: The goal of this Phase II study (NCT03414034) is to observe the effects of onvansertib in combination with abi + prednisone on disease control, as assessed by prostate-specific antigen (PSA) decline or stabilization after 12 weeks of study treatment, in subjects with mCRPC and early resistance to abi. Patients are enrolled at time of PSA progression while on standard abi and treated with onvansertib (24 mg/m2 orally on days 1-5 of a 21-day cycle) plus abi (administered orally and continuously once daily with prednisone) until time of radiographic or symptomatic progression. The safety lead-in of 3 subjects showed no dose-limiting toxicities or new toxicities from the combination of onvansertib with abi. A 29-patient expansion phase is ongoing, with 11 patients enrolled as of January 2019. With 32 patients, there will be 90% power to detect a change in disease-control rate from 10% (null) to 30% (alternative). Based on a Simon’s two-stage optimal design, the study will terminate early if <2 of the first 13 patients achieve disease control. Toxicity and PSA levels are monitored during treatment. Exploratory analyses include quantification of circulating tumor cells, evaluation of PLK1 inhibition in vivo and evaluation of predictive genomic biomarkers in circulating tumor DNA, such as alterations in oncogenes and tumor suppressors.

Citation Format: David J. Einstein, Atish Choudhury, Philip Saylor, Lillian Werner, Mark Erlander, Maya Ridinger, Glenn Bubley. A Phase II study of the polo-like kinase (PLK1) inhibitor onvansertib in combination with abiraterone (abi) and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT161.
Abstract CT165: Phase II open label trial of minnelide™ in patients with chemotherapy refractory metastatic pancreatic cancer
Authors: Propper David , Han Haiyong , Hoff Daniel Von , Borazanci Erkut , Reya Tannishtha , Ghergurovich Jonathan , Pshenichnaya Irina , Antal Corina , Condjella Rachel , Sharma Shreya , O'Dwyer Peter , Littlewood Trevor , Patel Hitendra , Saluja Ashok , Velagapudi Mohana , Yang Lifeng , Downes Michael , Evans Ronald , Evan Gerard
Published: August 2019

BackgroundTriptolide and its water-soluble prodrug, Minnelide™, have shown promising activity against pancreatic ductal adenocarcinoma (PDAC) in both in vitro and in vivo experiments. Triptolide induces apoptosis in pancreatic cancer cells by different pathways, including caspase-dependent apoptotic death and caspase -independent autophagic death. It inhibits the activity of the TFIIH general transcription factor complex and modulates the transcriptional landscape of both the stroma and cancer cell compartments. In the epithelial tumour compartment, triptolide down-regulates key transcription factors such as c-MYC. In the phase I clinical trial of Minnelide™ significant activity in highly refractory metastatic pancreatic carcinoma was observed. Hence we undertook this study in patients with chemotherapy refractory metastatic PDAC.

MethodsEligibility criteria include stage IV PDAC that has progressed on standard chemotherapy, Karnofsky performance status ≥ 70%, and measurable disease. Planned sample size is up to 35 patients with interim analysis after the first 18 evaluable patients, aiming for at least a 20% difference in DCR (10% v 30%). Minnelide™ 0.67 mg/m2 is administered intravenously over 30 minutes on days 1-21, followed by a 7 day rest period in a 28 day cycle. Exploratory objectives include: analysis of tumor texture on radiologic scans as a non-invasive biomarker for response, as well as analyses of paired tumour biopsies for changes in immune cell infiltration, stromal activation, chromatin accessibility, phopshoproteomics and metabolism. # NCT03117920The trial opened 4/2017 and as of 12/2018, 18 patients have been treated. Supported by SU2C, Cancer Research UK, Lustgarten Foundation

Citation Format: David Propper, Haiyong Han, Daniel Von Hoff, Erkut Borazanci, Tannishtha Reya, Jonathan Ghergurovich, Irina Pshenichnaya, Corina Antal, Rachel Condjella, Shreya Sharma, Peter O'Dwyer, Trevor Littlewood, Hitendra Patel, Ashok Saluja, Mohana Velagapudi, Lifeng Yang, Michael Downes, Ronald Evans, Gerard Evan. Phase II open label trial of minnelide™ in patients with chemotherapy refractory metastatic pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT165.
Abstract DDT01-02: Discovery and first structural disclosure of AZD7648: A potent and selective DNA-PK inhibitor
Authors: Goldberg Frederick W. , Cadogan Elaine , Finlay Raymond , Montoya Antonio Ramos , Beattie David , Lamont Gillian , Fallan Charlene , Fok Jacqueline , Vazquez-Chantada Mercedes , Barratt Derek , Dean Emma , Norris Jane , Campbell Andrew , Cronin Anna , Harding Joanna , Ting Attilla , Hollingsworth Simon , Davies Barry
Published: August 2019

DNA-dependent kinase (DNA-PK) plays an important role in the cellular response to DNA damage through the detection and repair of double strand breaks, and is a critical component of the DNA damage response (DDR). Double strand breaks can be induced by a range of agents, including chemotherapy, radiation or PARP inhibitors such as olaparib (Lynparza), and thus a DNA-PK inhibitor is likely to sensitise to these agents. DNA-PK inhibitors may also be effective as monotherapy in tumours with high endogenous levels of DNA damage resulting from defects in other DNA repair pathways. Our screening strategy focussed on identifying hits with good selectivity versus structurally related kinases. Significant improvements were made to permeability, metabolic stability and PK properties, whilst improving potency and selectivity with a structure-guided approach. This optimisation resulted in AZD7648, which is a potent inhibitor of DNA-PK (0.6 nM in biochemical assay, 89 nM in A549 cells) and >100x selective against 396 other kinases in a Thermofisher selectivity panel. In addition, AZD7648 has good crystalline solubility, metabolic stability and predictable pharmacokinetics in preclinical species. In murine xenograft models, PD was assessed using pRPA (S4/8) and was potently inhibited (in vivo IC50 = 52 nM). Tumour growth inhibition was observed with AZD7648 as monotherapy, and regressions were observed in combination with either olaparib or radiation. The efficacy observed when combining AZD7648 with olaparib was correlated to free cover over the in vivo IC90. AZD7648 is a potent and highly selective DNA-PK inhibitor, with good crystalline solubility, permeability and metabolic stability, good bioavailability and predictable pharmacokinetics in preclinical species, and potent knockdown of pRPA and regressions in murine xenograft models when combining with olaparib or radiation. These features make AZD7648 a suitable clinical candidate, and clinical studies evaluating AZD7648 as a potential cancer treatment are planned in 2019.

Citation Format: Frederick W. Goldberg, Elaine Cadogan, Raymond Finlay, Antonio Ramos Montoya, David Beattie, Gillian Lamont, Charlene Fallan, Jacqueline Fok, Mercedes Vazquez-Chantada, Derek Barratt, Emma Dean, Jane Norris, Andrew Campbell, Anna Cronin, Joanna Harding, Attilla Ting, Simon Hollingsworth, Barry Davies. Discovery and first structural disclosure of AZD7648: A potent and selective DNA-PK inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr DDT01-02.
Abstract LB-037: A novel zebrafish platform for deciphering the mutations co-operation in driving acute myeloid leukaemia
Authors: Cheng Yik Ling Bowie , He Bai Liang , Wang Dan Dan , Leung Yu Hung Anskar
Published: August 2019

Background and Objectives: Acute myeloid leukaemia (AML) is a highly genetically heterogenous disease. Patients carry unique genetic mutational profile that affect their clinical outcome. Remarkably, there are common patterns of co-occurring mutations, indicating their potential cooperativity in driving leukaemia. This project presents a novel zebrafish platform that allows quick and traceable evaluation of the impact of different genetic mutation combinations on leukemogenesis and drug response, paving the way for personalized medicine.

Experimental Procedures and Results: Zebrafish embryos were co-injected with combination of mutations FLT3 ITD with IDH2R140Q, IDH2R172K, IDH1R132H and DNMT3AR882H), and their effect on the expression pattern and intensity of different myeloid lineage markers including pu.1 (myeloid progenitor), mpo (macrophage), c-myb (haematopoietic stem cell; HSC) and Sudan Black B staining (neutrophils or granulocytes) were evaluated. Consistent with TCGA database, which showed FLT3 ITD mutation only co-occurred with IDH2R140Q or DNMT3AR882H, overexpression of FLT3 ITD and IDH2R140Q in zebrafish embryo promoted expansion of myeloid progenitors and granulocytes, while co-expression of FLT3 ITD and DNMT3AR882H promoted expansion of HSCs and granulocytes. No combinatory effects were observed between FLT3 ITD and IDH2R172K or IDH1R132H. To establish a zebrafish-based platform for predicting differential drug responses for unique mutational profiles, zebrafish embryos were injected with FLT3 ITD and IDH2R140Q and a list of FDA approved and preclinical drugs were examined for their efficacy on rescuing FLT3 ITD/IDH2R140Q-induced myeloid expansion. Although FLT3 ITD inhibitor was able to rescue FLT3 ITD-induced myeloid expansion, the effect was alleviated if FLT3 ITD and IDH2R140Q were co-expressed, indicating specific mutation patterns affected drug responses. To further validate our findings and study the long-term effect of mutation combinations, transgenic fish lines with FLT3 ITD/IDH2R140Qand FLT3 ITD/IDH2R172K under Runx1 promoter (HSC lineage) were established with Tol2 transgenesis. At 6 months of age, Tg(Runx1:FLT3 ITD, IDH2R140Q) showed increased percentage of myeloid precursors compared to WT and single mutant group.

Conclusion: Our result show that zebrafish can serve as an effective platform to study the cooperative effect of mutations in acute myeloid leukaemia and predict a better option for patients carrying unique genetic mutational profiles, paving the way for personalized medicine.

Citation Format: Yik Ling Bowie Cheng, Bai Liang He, Dan Dan Wang, Yu Hung Anskar Leung. A novel zebrafish platform for deciphering the mutations co-operation in driving acute myeloid leukaemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-037.
Abstract LB-100: HNF4G overexpression promotes PDAC progression and confers metformin sensitivity in patients with SMAD4-loss of function
Authors: Wang Chengcheng , Wu Chen , Lin Dongxin , Zhao Yupei
Published: August 2019

BACKGROUND: Genome-wide association studies (GWAS) have identified several genetic regions associated with risk of pancreatic ductal adenocarcinoma (PDAC) while the underlying mechanisms remain largely unknown. This study investigated the functions of genes in these genetic regions and their roles as potential biomarkers or therapeutic targets for PDAC.

METHODS: We reanalyzed our previous GWAS data based on referring the 108 risk loci reported in published PDAC GWAS to seek for all susceptibility genes in the Chinese population and found 44 potential risk genes. A siRNA library was used to silence these genes in PDAC cell lines and the malignant phenotypes were examined by using a high content screen method followed by a series of functional assays.

RESULTS: Among the 44 genes, HNF4G was the top one who’s silencing significantly repressed PDAC cell migration and invasion. Functional assays showed that HNF4G regulates cell-cell junction pathway, which may be the underlying mechanism for its action. HNF4G was upregulated by SMAD4 loss of function and frequently overexpressed in PDACs. PDAC cell metastasis promoted by the overexpression of HNF4G could be suppressed by metformin, and this effect was seen only in PDAC cells with SMAD4 loss of function, resulting in heterogeneous vulnerability of PDAC to the drug. CONCLUSION: HNF4G overexpression might result in metformin sensitivity in PDAC with SMAD4 loss of function and thus represent as a potential therapeutic target.

Citation Format: Chengcheng Wang, Chen Wu, Dongxin Lin, Yupei Zhao. HNF4G overexpression promotes PDAC progression and confers metformin sensitivity in patients with SMAD4-loss of function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-100.
Abstract LB-226: Utilizing 486 gene assay on a NGS platform to validate guideline-adherent tumor mutational burden (TMB) module to calculate TMB
Authors: AHLUWALIA PANKAJ K. , MONDAL ASHIS , ANANTH SUDHA , HENEIDI SALEH , KOTA VAMSI , KOLHE RAVINDRA
Published: August 2019

Introduction: The quantification of TMB has emerged as a highly promising biomarker in predicting immunotherapeutic responses. The application of whole exome sequencing to measure TMB has shown to predict response to immunotherapy. Multiple studies have shown that TMB quantification using large panels are comparable to whole exome sequencing and are more practical for implementation in clinical care. The QIAseq TMB panel is a new NGS assay designed to detect genetic alterations in 486 genes, along with MSI and TMB score. Methods: The validation was guided by the joint consensus recommendation for validation of NGS assays by the AMP & CAP and NYSDOH. The validation included evaluations of precision, analytic sensitivity, analytic specificity, accuracy, reportable range, and reference range for TMB. DNA from of 60 samples which were characterized on Foundation CGP assay were used during the validation. Libraries were prepared using the QIAseq TMB panel kit and sequenced on NextSeq 550. The TMB module used for calculation of TMB in this validation was designed and developed by QIAGEN. TMB was calculated as the number of somatic mutations (SNVs and Indels only) per megabase (Mb) of the target region (1.2 Mb for QIAseq TMB panel). Results: In silico analysis using the TCGA data by QIAGEN QCI pipeline showed that the QIAseq TMB panel estimates TMB at a high level of concordance with whole exome sequencing (WES). The data show a high correlation (r2 = 0.98) between the TMB values determined using WES data and TMB using the QIAseq TMB panel data. Our validation data shows significant correlation (r2 = 0.94) among TMB values on the QIAseq panel and Foundation one CGP. Conclusions: In this validation we demonstrate that the QIAseq TMB assay can be used to reliably predict TMB across a wide range of cancer types using the QIAGEN QCI TMB module. Our lab’s experience provides an example for others that may wish to implement TMB testing by NGS on a comprehensive panel.

Citation Format: PANKAJ K. AHLUWALIA, ASHIS MONDAL, SUDHA ANANTH, SALEH HENEIDI, VAMSI KOTA, RAVINDRA KOLHE. Utilizing 486 gene assay on a NGS platform to validate guideline-adherent tumor mutational burden (TMB) module to calculate TMB [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-226.
Abstract LB-232: A novel approach for liquid biopsy by using nExo
Authors: Yokoi Akira , Villar-Prados Alejandro , Oliphint Paul Allen , O'Halloran Theresa J. , Roszik Jason , Sood Anil K.
Published: August 2019

Exosomes are small extracellular vesicles secreted from all living cells; its contents are highly varied, including proteins, small RNAs and recently discovered, genomic DNA (gDNA). The presence of nuclear content in exosomes suggests that different cell compartments can contribute to exosome cargo; however, little is known about this sub population of nuclear derived exosomes (nExo). Here, we analyzed nExo isolated from ovarian cancer cells and characterized them to explore potential clinical relevance such as cancer detection and therapeutic response. Exosomes were isolated from ovarian cancer cell lines, normal human fallopian epithelial tube cells and bio-fluids from mouse and human samples. To determine the purity of exosomes, nanoparticle tracking system, immunoblotting assay and cryo-transmission electron microscopy were used. To analyze the content of exosomes, protein mass spectrometry and imaging flow cytometry analysis was performed. First, we determined that mass spectrometry analyses for ovarian cancer cell exosomes revealed that 12.5% of proteins are derived from the cell nucleus sub-population. Additionally, using a novel imaging flow cytometry technique which enables us to identify single exosome and to quantify them, we determined that 10% of exosomes carried gDNA. Conversely, normal cells secreted only 0.2% of nExo. Then we hypothesized that the prevalence of gDNA is affected by genotoxic drugs. Treating cells with either the PARP inhibitor olaparib or topoisomerase inhibitor topotecan increased the proportion of nExo secreted from ovarian cancer cells. In addition, PARP proteins exist in ovarian cancer cell exosomes and 80.4 % of the exosome co-localized with gDNA. Using in vivo preclinical models, serum from ovarian cancer bearing mice contained a higher number of nExo than non-tumor controls, and this population was increased in response to treatment of genotoxic drugs. Furthermore, plasma and ascites from ovarian cancer patients contain around 0.3 % of nExo, which include nuclear proteins and gDNA. We demonstrate that nExo are predominantly secreted from cancer cells and could serve as an important biomarker. Although the subpopulation is relatively rare, their presence in bio-fluids isolated from cancer patients holds the potential of serving as novel biomarkers for early detection and therapeutic response to genotoxic agents.

Citation Format: Akira Yokoi, Alejandro Villar-Prados, Paul Allen Oliphint, Theresa J. O'Halloran, Jason Roszik, Anil K. Sood. A novel approach for liquid biopsy by using nExo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-232.
Abstract LB-288: CDC7 kinase inhibition by SRA141 induces a potentially novel caspase-dependent tumor cell apoptosis associated with altered DNA replication and cell cycle dynamics
Authors: Jagannathan Veena , Milutinovic Snezana , Hansen Ryan , Strouse Bryan , Hassig Christian , Brown Eric
Published: August 2019

DNA replication is a tightly regulated process required for faithful duplication of the genome. Previous research in lower eukaryotes has demonstrated a requisite role for the CDC7 protein kinase in DNA replication origin firing through phosphorylation of the MCM2-7 helicase complex. Owing to its overexpression in various neoplasms, CDC7 has emerged as an attractive target for cancer treatment. We previously reported that SRA141, a potent and selective CDC7 inhibitor, is cytotoxic to multiple tumor cell lines in vitro and demonstrates robust anti-tumor efficacy in colorectal and leukemia xenograft models. Here, we explored the effects of SRA141 on DNA replication and cell cycle dynamics and how these effects relate to the mechanism of SRA141-induced cell death in colorectal cancer cell lines.

SRA141 treatment caused a complete inhibition of MCM2 phosphorylation and reduced overall cellular DNA synthesis within 3 hours, with the greatest effects observed in late S-phase. Unexpectedly, DNA combing experiments indicated that SRA141 caused a 70-90% increase in the rate of replication fork progression. These findings suggest that SRA141 may indeed limit origin firing, but this effect is compensated for in part by increased replication fork rates. Despite delay, nucleotide analog pulse-chase experiments indicated that SRA141 treated cells ultimately finished S phase and transitioned into mitosis. In contrast to other reports, no evidence of replication fork collapse was observed, indicating that the main mechanism of SRA141 cytotoxicity is not mediated through replication fork collapse. Intriguingly, some of the most pronounced effects of SRA141 treatment were on progression through M phase, as evidenced by an accumulation of mitotic cells and increased Cyclin B levels following treatment. Moreover, inhibition of Aurora B kinase, which regulates mitotic progression, strongly synergized with SRA141 in caspase-dependent cancer cell killing. Taken together, our findings indicate that the mechanism of cytotoxicity of CDC7 inhibitors is distinct from agents that cause replication fork collapse or inhibit CDKs, and thus may define a new class of cancer therapeutic agents that synergize with drugs that target certain mitotic pathways.

Citation Format: Veena Jagannathan, Snezana Milutinovic, Ryan Hansen, Bryan Strouse, Christian Hassig, Eric Brown. CDC7 kinase inhibition by SRA141 induces a potentially novel caspase-dependent tumor cell apoptosis associated with altered DNA replication and cell cycle dynamics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-288.
Abstract LB-302: Whole genome sequencing reveals a significant role of ZNFs-PHLPP2-AKT axis in familial breast cancer of chaoshan area
Authors: Fang Can-Bin , Ye Qian-Qian , Liu Jing , Zhang Guo-Jun
Published: August 2019

Introduction Up to 15% cases of breast cancer are familial. However, the two most prevalent susceptibility genes, BRCA1 and BRCA2, only account for 25% of the familial cases. To this regard, we aimed to identify recurrent variants associated with familial breast cancer in Chaoshan Area of China by whole genome sequencing.

Materials & Methods In the present study, Whole Genome Sequencing was performed in 8 familial breast cancer families with 13 familial breast cancer cases and 25 healthy relatives from Chaoshan Area. All the variants were filtered and prioritized by co-segregation analysis and bioinformatic tools.

Results A total of 714 variants in 609 genes were selected as rare, probably damaging pathogenic mutations after co-segregation and functional prediction analysis in each family. In all the 609 genes, the zinc finger protein family was overlapped in all the 8 families, among which the c.120-130del of ZNF77 was overlapped in 3 families, c.279_791de of ZNF544 and c.T895A of ZNF479 in 2 families respectively, which emphasized the great significance of ZNF family in the mutational spectrum of Chaoshan Area. After that, the KEGG Pathway analysis in KOBAS 3.0 implied the significance of PI3K-Akt pathway in all the mutated 609 genes. At the same time, the PPI analysis by Cytoscape 3.6.1 indicated that all ZNF genes were interacted with one specific gene, PHLPP2, which inhibits the PI3K-Akt pathway similar to PTEN. Furthermore, two website-based bioinformatic tools cBioportal and Oncomine have predicted the positive correlations between ZNF77 and PHLPP2. All the analysis above was demonstrated the great significance of ZNFs-PHLPP2-AKT axis in the mutational spectrum of familial breast cancer of Chaoshan Area, in China.

Conclusions Zinc finger protein family, especially ZNF77, are frequently mutated in the familial breast cancer of Chaoshan Area, which results in the down regulation of PHLPP2 and subsequently reverse the inhibition of PI3K-Akt pathway, and finally lead to tumorigenesis.

Citation Format: Can-Bin Fang, Qian-Qian Ye, Jing Liu, Guo-Jun Zhang. Whole genome sequencing reveals a significant role of ZNFs-PHLPP2-AKT axis in familial breast cancer of chaoshan area [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-302.
Visual Function after Implantation of a Presbyopia-Correcting Trifocal Intraocular Lens
Authors: Alfonso José F. , Fernández-Vega-Cueto Luis , Fernández-Vega Luis , Montés-Micó Robert
Published: August 2019

Purpose: To evaluate distance, intermediate, and near visual performance in patients implanted with a trifocal aspheric presbyopia-correcting intraocular lens (IOL). Methods: Forty patients were bilaterally implanted with the AcrySofIQ PanOptix IOL after femtosecond laser-assisted lens surgery. Binocular best corrected distance visual acuity (CDVA) (4 m), best distance-corrected near visual acuity (DCNVA) (40 and 30 cm), best corrected distance intermediate visual acuity (DCIVA) (70, 60, and 50 cm), binocular distance contrast sensitivity under photopic conditions (85 cd/m2), and defocus curves were evaluated at 6-months. Results: Six months postoperatively, the mean binocular Snellen decimal CDVA and DCNVA were 0.94 ± 0.10 (ranging from 0.70 to 1.25) and 0.85 ± 0.13 (ranging from 0.63 to 1.00), respectively. At a distance, all patients showed a cumulative binocular distance-corrected visual acuity of 0.8 or better, and about 80% (n = 31) of the patients had a value of 1.0 (20/20). At near and intermediate distances, all patients showed a cumulative distance-corrected visual acuity of 0.5 (20/40) or better at 30, 40, 50, 60, and 70 cm. Specifically, 50 cm showed the highest percentage of patients with larger values of visual acuity (60% [n = 26] with 20/20). Defocus curve showed a wide range of useful vision with two peaks of best visual acuity at distance and at 50 cm, and the binocular distance contrast sensitivity was within normal limits. Conclusions: The outcomes of the present study show that the visual performance obtained with bilateral implantation of the trifocal aspheric AcrySofIQ PanOptix IOL is good at far, intermediate, and near distances.
Life Expectancy: Frequently Used, but Hardly Understood
Authors: Luy Marc , Di Giulio Paola , Di Lego Vanessa , Lazarevič Patrick , Sauerberg Markus
Published: August 2019

Period life expectancy is one of the most used summary indicators for the overall health of a population. Its levels and trends direct health policies, and researchers try to identify the determining risk factors to assess and forecast future developments. The use of period life expectancy is often based on the assumption that it directly reflects the mortality conditions of a certain year. Accordingly, the explanation for changes in life expectancy are typically sought in factors that have an immediate impact on current mortality conditions. It is frequently overlooked, however, that this indicator can also be affected by at least three kinds of effects, in particular in the situation of short-term fluctuations: cohort effects, heterogeneity effects, and tempo effects. We demonstrate their possible impact with the example of the almost Europe-wide decrease in life expectancy in 2015, which caused a series of reports about an upsurge of a health crisis, and we show that the consideration of these effects can lead to different conclusions. Therefore, we want to raise an awareness concerning the sensitivity of life expectancy to sudden changes and the menaces a misled interpretation of this indicator can cause.
Epidemiology and Comorbidities of Psoriasis among Israeli Adolescents: A Large Cross-Sectional Study
Authors: Shreberk-Hassidim Rony , Galili Eran , Hassidim Ayal , Ramot Yuval , Merdler Ilan , Baum Sharon , Zlotogorski Abraham , Barzilai Aviv , Astman Nadav
Published: August 2019

Background and Aims: Although psoriasis can develop at any age, the data regarding its characteristics in adolescents are sparse. This study was designed to determine the psoriasis prevalence and its associations with the body mass index (BMI), lipid profile, and comorbidities in adolescents. Methods: This was a nationwide population-based cross-sectional retrospective study of adolescents (16–18 years old) evaluated for military service between January 1999 and January 2014. Results: Our database included 887,765 adolescents (57.1% males), of whom 3,112 (0.35%) were diagnosed with psoriasis. During the 15-year study period, the psoriasis prevalence increased by 1.4-fold, from 0.3 to 0.42% (1.25-fold for the males and 1.63-fold for the females). Certain comorbidities, such as contact dermatitis, hyperhidrosis, and arthritis, were significantly associated with psoriasis (odds ratios [ORs] of 2.26, 1.51, and 5.3, respectively). The adolescents with psoriasis had significantly elevated BMI and triglyceride values. We found increased ORs of 1.34 (95% confidence interval [CI] = 1.25–1.56) and 1.56 (95% CI = 1.32–1.83) for the overweight and obese adolescents, respectively, while a lower BMI (<20) had an opposite effect with psoriasis (OR = 0.8). Conclusions: Based on our results, the psoriasis prevalence in Israeli adolescents is rising. Dermatological comorbidities and an increased BMI were associated with psoriasis in these adolescents. A better understanding of the distinctive epidemiological characteristics of juvenile psoriasis may allow for the early detection of comorbidities and improve its management.
Multimodal Clinical Imaging Assessment of the Outcome in Mild-to-Moderate Acne: A Prospective Study
Authors: Kyrgidis Athanassios , Becker Markus , Zampeli Vasiliki , Fauger Aurélie , Sayag Michèle , Zouboulis Christos C.
Published: August 2019

Background: The quality of outcome assessment in acne studies has been either subjective/insufficient or time consuming through the ordinary lesion counting. Objective: To evaluate the application of multimodal clinical imaging (MCI), a combination of imaging technology and computation, in the assessment of acne lesions in a clinical study setting. Methods: A prospective, monocentric, single-group open study designed to evaluate the efficacy and tolerance of a cosmetic product (IP/SG) in subjects with mild-to-moderate facial acne by classical clinical counting (CCC) – change in the total/inflammatory/noninflammatory acne lesion number compared with baseline (D0) – Investigator Global Assessment (IGA) and self-reported outcomes. Concomitantly, MCI was administered. The study was performed for 12 weeks (D84) with a 4-week follow-up (D112). Results: Mean age of patients (n = 49) was 18.2 ± 3.7 years (range 13–25). The mean acne duration was 3.8 ± 2.8 years. The total number of lesions did not differ significantly between D0/D84 by both CCC and MCI. However, the Cardiff Acne Disability Index (CADI) and uncomfortable feeling improved at D28/D0, the perception of oily skin improved at D14/D0, and the perception of sticky skin improved from D28/D0 to D56/D0. Deterioration was detected between D84/D0 and D112/D0, namely after product discontinuation. Interestingly, a change in trend was recorded for acne lesions at D14/D0 by MCI but not by CCC. Conclusion: MCI, applied for the first time in a small clinical study setting, is at least as reliable as CCC and may allow for a sensitive longitudinal evaluation of single acne lesions and their response to products, especially in conditions where clinical evaluation reaches its limits.
Age Differences in Emotion Regulation and Facial Muscle Reactivity to Emotional Films
Authors: Labuschagne Izelle , Pedder David J. , Henry Julie D. , Terrett Gill , Rendell Peter G.
Published: August 2019

Background: Age-related declines in many cognitive abilities are common in healthy aging. However, the ability to effectively regulate emotions is preserved, and possibly even enhanced, in late adulthood. This capacity has been examined most commonly in relation to low-intensity emotional stimuli that typically involve static pictures. Evidence is suggesting that older adults may become overwhelmed when exposed to emotional cues of heightened intensity. Objective: In the current study, we assessed whether older adults retain the ability to regulate emotions successfully when exposed to more emotionally evocative (e.g., dynamic) stimuli. Methods: Young and older adults were instructed to regulate, using expressive suppression, their outward behavioral expression of emotions while viewing dynamic stimuli involving amusing and sad films. Facial reactivity, as indexed using electromyography, self-rated emotional experience, and memory for the stimuli were assessed. Results: The results showed that, relative to young adults, older adults were unable to suppress zygomaticus (cheek) activity to amusing films or corrugator (brow) reactivity to sad films, which is likely due to their relatively reduced facial muscle reactivity. Expressive suppression did not affect young or older adults’ subjective feelings or memory for the stimuli. Conclusion: Our findings suggest that there are age differences in facial muscle reactivity to amusing and sad cues of heightened intensity. These findings suggest that older adults’ ability to effectively regulate emotions may be limited, at least with expressive suppression, in the context of high-intensity emotional cues. Further research is needed to investigate possible exceptions the preservation of emotion regulation in older adults.
Comparison of Ca2+ Handling for the Regulation of Vasoconstriction between Rat Coronary and Renal Arteries
Authors: Liu Lin , Huang Xin-Wen , Yang Hui , Kuang Su-Juan , Lian Fei-Hong , Zhang Meng-Zhen , Rao Fang , Shan Zhi-Xin , Lin Qiu-Xiong , Yang Min , Lin Ji-Jin , Jiang Sui , Zhou Zhi-Ling , Deng Chun-Yu
Published: August 2019

Background: Ca2+ plays an important role in the regulation of vasoconstriction. Ca2+ signaling is regulated by a number of Ca2+-handling proteins. However, whether differences in Ca2+ handling affect the regulation of vasoconstriction in different arteries remains elusive. Objective: To determine whether differences in Ca2+ handling affect the response to vasoconstrictors in different arteries. Methods: Arterial ring contraction was measured using a Multi Myograph System. Vascular smooth muscle cells (VSMCs) were digested with type 2 collagenase in DMEM, then intracellular calcium concentration was measured with the Ca2+ probe fluo-4/AM in the isolated cells. Calcium-related proteins were assayed by Western blotting. Results: Phenylephrine did not induce ­coronary arterial contraction. There were differences in ­5-hydroxytryptamine, 9,11-dideoxy-11a,9a-epoxymethano-prostaglandin F2a, and endothelin 1-induced vasoconstriction in different solutions between coronary and renal arteries. Vasoconstrictions in the presence of Bay K8644 were stronger in coronary than in renal arteries. Store-operated calcium (SOC) channels could mediate Ca2+ influx in VSMCs of both groups. SOC channels did not participate in the contraction of coronary arteries. In addition, there were significant differences in the expressions of receptors and ion channels between the two groups. Conclusions: Ca2+ handling contributed to the different responses to vasoconstrictors between coronary and renal arteries.