tbuckley/cabot-search huggingface dataset:
Abstract 2980: Effects of cetuximab and CD-3379 on cytokine/chemokine balance in the tumor micro-environment (TME) of squamous cell carcinoma of the head and neck (SCCHN)
Authors: Dongsheng Wang, Sreenivas Nannapaneni, Gregory B. Lesinski, Dong M. Shin, Nabil F. Saba, Georgia Z. Chen
Journal: Cancer Research (2020)

Abstract Background: The Anti-EGFR agent cetuximab has shown promising outcomes and remains to be the only FDA-approved non-immunotherapeutic targeted agent for the treatment of squamous cell carcinoma of the head and neck (SCCHN). There is evidence that immune modulation represents a mechanism by which cetuximab elicits its clinical activity in SCCHN. As resistance inevitably occurs to cetuximab, there is a need to further elucidate the biological mechanisms by which cetuximab affects immune effectors in the tumor microenvironment (TME). We aimed to explore the effect of EGFR inhibition on the cytokine/chemokine balance in the TME. Methods: Three SCCHN cancer cell lines UM-SCC47 (HPV positive), JHU022 (HPV negative), and SCC-1C (HPV negative and resistant to cetuximab) were treated with cetuximab, CD-3379 (a HER3 inhibitor), and their combination. After 48 and/or 72 hours, the supernatants of the treated and untreated cells were collected and subjected to multiplexed immunoassay [Meso Scale Discovery (MSD) U-PLEX Assays] to study the cytokine/chemokine alteration. Changes in immune suppressive chemokines were confirmed by ELISA. A potential effect of a chemokine neutralizing antibody on apoptosis was further evaluated using patient-derived organotypic cancer spheroids (PDOCSs). Results: Our results identified 10 down regulated cytokines/chemokines, including IL6, IL-8, IL-2, IL-12, IL-27, IL-4, IL-5, TGF-β, GM-CSF, and IFN-γ in at least one SCCHN cell line. Three cytokines/chemokines were up regulated, including IL-15, MCP-3, and MCP-1. MCP-1 (CCL2) is a modulator of myeloid-derived suppressor cells (MDSCs). Enhancing MCP-1 by cetuximab and/or CD-3379 in the SCCHN cell lines was confirmed by ELISA. Treating multiple PDOCSs with the same combination along with MCP-1 neutralizing antibody enhanced apoptosis in comparison to cetuximab, CD-3379, or the cetuximab/CD-3379 combination. Conclusions: Our findings suggest that cetuximab in combination with HER3 inhibition affects secretion of cytokines/chemokines which are both immune stimulatory and suppressive in the TME of SCCHN. Alteration of the selected cytokines/chemokines may enhance the clinical activity of EGFR targeting in SCCHN. Citation Format: Dongsheng Wang, Sreenivas Nannapaneni, Gregory B. Lesinski, Dong M. Shin, Nabil F. Saba, Georgia Z. Chen. Effects of cetuximab and CD-3379 on cytokine/chemokine balance in the tumor micro-environment (TME) of squamous cell carcinoma of the head and neck (SCCHN) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2980.
Abstract 2502: Genetic and functional heterogeneity of DCIS as predictors of invasive cancer
Authors: Angelo Fortunato, Diego Mallo, Lorraine King, Timothy Hardman, Allison Hall, Jeffrey R. Marks, Shelley Shelley Hwang, Carlo C. Maley
Journal: Cancer Research (2020)

Abstract Genetic diversity both between and within individual tumors constitutes a challenge to personalized cancer medicine. Intra-tumor heterogeneity provides the genetic fuel for natural selection in clonal evolution and cancer progression. Tumors with high levels of genetic heterogeneity are hypothesized to be more likely to demonstrate aggressive behavior and progress to invasion and metastasis. We analyzed the mutational loads from separate areas of pure DCIS and compared this to genetic heterogeneity in DCIS lesions found adjacent to invasive and metastatic cancer. Two spatially distinct areas of DCIS from each case were macro-dissected and the DNA extracted from FFPE samples. To analyze the data, we developed new bioinformatics methods that allowed analysis of small amounts of degraded DNA extracted from FFPE samples across multiple regions. Our bioinformatics pipeline was optimized on a series of 28 independent technical replicates of the same DNA sample sequenced twice, as training tools to find the best filtering parameters. Whole exome sequencing was performed on each of the two geospatially separated samples for each case. Minimum coverage for inclusion in this study was 40X over at least 50% of the exome. We used the ratio of private mutations (only in 1 area) to public (found in both areas) mutations as a measure of intra-tumor heterogeneity. We present an approach to measure clonal heterogeneity using a bulk sequencing strategy applied to geospatially distinct foci of DCIS. We found statistically significant difference between DCIS adjacent to invasive disease and metastatic patients' genetic divergence (t-test, p=0.013). Our findings suggest that genetic and functional heterogeneity may play an important evolutionary role as a driver for invasive progression. Citation Format: Angelo Fortunato, Diego Mallo, Lorraine King, Timothy Hardman, Allison Hall, Jeffrey R. Marks, Shelley Shelley Hwang, Carlo C. Maley. Genetic and functional heterogeneity of DCIS as predictors of invasive cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2502.
Abstract 3527: Paraneoplastic glomerulonephropathies associated with solid tumor: A review of published literature
Authors: Xiaojie Zhang, Asit K. Paul
Journal: Cancer Research (2020)

Abstract Background: Paraneoplastic glomerulonephropathies (PGN) are paraneoplastic syndromes associated with solid tumors and hematologic malignancies. PGN is difficult to differentiate from other forms of glomerulonephropathies and standard management of glomerulonephropathies is often ineffective. A delay in diagnosis may lead to significant morbidity and mortality. To date, no retrospective or prospective data on PGN have been published. We reviewed clinical variables, treatment, and outcome in published case reports of PGN associated with solid tumors over the past three decades. Methods: We conducted a search to identify published case reports on solid tumors associated with PGN in English PubMed-indexed journals. Keywords used included: “solid tumor”, “lung cancer”, “gastrointestinal cancer”, “gynecological cancer”, “genitourinary cancer”, “paraneoplastic nephropathy,” “paraneoplastic glomerulopathy,” “minimal change disease,” “IgA nephropathy,” “membranoproliferative,” “membranous,” “nephropathy” and “glomerulonephropathy”. Published articles from January 1st, 1987 to November 30,2019 were screened. Included were the patients who had laboratory and/or biopsy proven nephrotic syndrome in association with a solid tumor diagnosis. Results: We identified 95 patients who fulfilled the inclusion criteria. The median age of the patients were 58 years. The majority of the patients were male (65%). Among them, 37 (39%) were diagnosed with PGN prior to the diagnosis of cancer. Membranous nephropathy (41%) was the most common subtype, followed by minimal change disease (17%), focal segmental glomerulonephritis (14%) and IgA nephropathy (11%). Genitourinary cancers (36%) followed by lung cancers (30%), gastrointestinal cancers (15%) and gynecological cancers (13%) are the common cancers associated with PGN. Among the patients, 44 (46%) had non-metastatic tumors, 39 (41%) had metastatic tumors and 12 (13%) were unspecified. Treatment information were available for 79 of 95 (83%) patients. Overall, PGN improved in 76% of patients who received definitive or systemic therapy with or without steroid compared to 57% of patients who were treated with steroid alone. Definitive and systemic treatment alone led to improvement of PGN in 24 of 29 (83%) patients without metastasis and 13 of 17 (76%) patients with metastasis. Conclusions: PGNs associated with solid tumors are rare and can happen in both non-metastatic and metastatic cancers. Diagnosis of PGN might precede the diagnosis of cancer. Definitive or systemic anticancer therapies improved PGN in most cases and were more effective than steroid alone. Citation Format: Xiaojie Zhang, Asit K. Paul. Paraneoplastic glomerulonephropathies associated with solid tumor: A review of published literature [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3527.
An Atypical Case of Vasovagal Cardioinhibitory Syncope in a Young Male Soldier—Stand Up, Be Counted
Authors: Elizabeth R. Doman, Adam J. Kisling, Emilio Fentanes
Journal: JAMA Internal Medicine (2020)

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Abstract 3519: Genetically predicted plasma N-glycans and prostate cancer risk: Analysis of over 140,000 European descendants
Authors: Tianying Zhao, Jingjing Zhu, Lang Wu
Journal: Cancer Research (2020)

Abstract Prostate cancer is the second most frequently diagnosed malignancy among males in many countries. There are critical needs to better understand its etiology and identifying effective biomarkers to improve its early detection. Many proteins are modified by glycans that bind to the proteins, a post-translational modification that are critical for normal physiological processes. Studies have linked dysregulation of glycosylation to several human diseases including prostate cancer. Multiple glycan alterations have been identified to be potentially related to prostate cancer, such as changes to PSA glycosylation, sialylation and core fucosylation, O-GlcNacylation, cryptic and branched N-glyans, as well as galectins and proteoglycans. Limited research, however, has been performed to comprehensively evaluate relationship between N-glycans and prostate cancer. To identify novel N-glycans that are potentially associated with prostate cancer risk, we performed a study using a highly novel and cost-efficient approach. Using genetic variants reported to be associated with plasma N-glycan levels in large genome-wide associations studies as instruments, we evaluated associations between plasma N-glycans and prostate cancer risk, using the inverse variance weighted method (IVW). Data generated from 79,194 prostate cancer cases and 61,112 controls of European ancestry included in PRACTICAL/ELLIPSE consortia were used in this analysis, providing sufficient power for our research question of interest. We observed associations between genetically predicted plasma levels of two N-glycans and prostate cancer risk at P&amp;lt;0.05. The odds ratio (OR) and 95% confidence interval (CI) per one standard deviation increase in genetically predicted levels of glycans are: IGP17, 1.05 (1.01-1.10); and IGP41, 0.93 (0.88-0.99). However, these associations became insignificant after adjusting for multiple comparisons. In conclusion, our agnostic analysis does not identify novel N-glycans whose genetically predicted levels in plasma are associated with prostate cancer risk. Further studies are needed to better characterize the relationship between N-glycans and prostate cancer. Citation Format: Tianying Zhao, Jingjing Zhu, Lang Wu. Genetically predicted plasma N-glycans and prostate cancer risk: Analysis of over 140,000 European descendants [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3519.
Abstract 2377: Atm-dependent recruitment of brd7 is required for transcriptional repression and repair at dna breaks flanking transcriptional active regions
Authors: Kaishun Hu
Journal: Cancer Research (2020)

Abstract DNA double-strand break (DSB) is highly cytotoxic and deleterious lesions, causing gross chromosomal rearrangements, genomic instability and tumorigenesis (Meisenberg et al., 2019). In mammalian cells, such damages are mainly repaired through two pathways: non-homologous end joining (NHEJ) and homologous recombination (HR) (San Filippo et al., 2008). To avoid conflicts between ongoing transcription and repair activities, the DNA damage response (DDR) must coordinate the processes of repair signaling and local transcriptional capacity (Adam and Polo, 2014). Cells have evolved the ability of switching off transcription for DSB repair in ATM, DNA-PK and PARP1-dependent manner which is a critical step for maintaining genome-epigenome integrity (Iannelli et al., 2017; Shanbhag et al., 2010; Uckelmann and Sixma, 2017). The mono-ubiquitylation of H2A on K119 is one of the key determinants of transcriptional repression at sites of DNA damage (Kakarougkas et al., 2015; Rona et al., 2018; Shanbhag et al., 2010). However, depletion of these factors did not alleviate completely DSB-induced transcriptional repression, suggesting that additional yet unidentified factors or complexes are involved in the process. Here, we identified that BRD7, another specific subunit of PBAF complex, participated in DNA damage response (DDR) and was recruited to the damaged chromatin via ATM signaling. Mechanistically, BRD7 joined the polycomb repressive complex 2 (PRC2), the nucleosome remodeling and histone deacetylation (NuRD) complex at the damaged DNA and recruited E3 ubiquitin ligase RNF168 to the DSBs. Furthermore, ATM-mediated BRD7 phosphorylation is required for recruitment of the PRC2 complex, DSB sensor complex MRE11-RAD50-NBS1 (MRN) and RNF168 to the active transcription sites at DSBs, resulting in transcriptional repression and DNA repair. Moreover, BRD7 deficiency sensitized cancer cells to PARP inhibition. Collectively, BRD7 is crucial for DNA repair and DDR-mediated transcription repression, which may serve as a therapeutic target. Moreover, our findings have identified the missing link between DNA repair and transcription regulation that maintains genome integrity, as well as highlight the important role of PBAF complex in maintaining genomic integrity. Citation Format: Kaishun Hu. Atm-dependent recruitment of brd7 is required for transcriptional repression and repair at dna breaks flanking transcriptional active regions [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2377.
Abstract 1482: PIM1 promotes angiogenesis via phosphorylation and stabilization of HIF-1α
Authors: Andrea L. Casillas, Shailender S. Chauhan, Rachel K. Toth, Corbin C. Jensen, Noel A. Warfel
Journal: Cancer Research (2020)

Abstract An essential process for the growth and dissemination of solid tumors is angiogenesis, or the formation of new blood vessels. Overexpression of Proviral Integration site for Moloney murine leukemia virus (PIM)-1, a serine-threonine kinase, has been implicated as a driver of aggressive prostate and colon cancer. PIM1 is known to promote tumor growth and survival, and we recently uncovered a role for PIM1 in promoting resistance to anti-angiogenic agents. Here, we identify a novel signaling pathway that directly links PIM to tumor angiogenesis. Immunohistochemical staining of prostate cancer tissue revealed a significant positive correlation between PIM1 and CD31 expression, a marker of endothelial cells. Using prostate cancer as a model, in vitro models of endothelial tube formation and DCE-MRI confirmed that PIM1 overexpression increases tumor angiogenesis. Gene expression analysis of PIM1 overexpressing cells showed that PIM kinases regulates the expression levels of many hypoxia inducible factor-1α (HIF-1α) target genes in normoxic conditions. In vitro, in vivo and kinase assays discovered a novel phosphorylation site within the oxygen-dependent degradation domain (ODDD) of HIF-1α that is a direct target of PIM1. Biochemical analysis demonstrates that phosphorylation of this site increases HIF-1α stability by decreasing PHD binding, hydroxylation, and subsequent proteasomal degradation of HIF-1α. Two CRISPR-generated cell lines with point mutations that mimic phosphorylation of this site were used in xenograft models of colon cancer to confirm the significance of this site to the identified PIM-HIF signaling and tumor angiogenesis. Importantly, we show that the anti-angiogenic and cytotoxic effects of PIM inhibitors are largely dependent on their ability to downregulate HIF-1α signaling. In summary, we uncovered a novel role for PIM1 in promoting tumor angiogenesis and identified a novel phosphorylation site that controls the stability of HIF-1α in normoxic and hypoxic conditions.This research yields important insight into the role of PIM signaling in solid tumors and provides preclinical evidence that to improve the translation of PIM kinase inhibitors in solid tumors. Citation Format: Andrea L. Casillas, Shailender S. Chauhan, Rachel K. Toth, Corbin C. Jensen, Noel A. Warfel. PIM1 promotes angiogenesis via phosphorylation and stabilization of HIF-1α [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1482.
Hepatitis C Virus
Authors: David E. Kaplan
Journal: Annals of Internal Medicine (2020)

Hepatitis C virus (HCV) is the most common bloodborne pathogen in the United States, chronically affecting approximately 2.4 million Americans, most of whom are unaware of the infection. Highly effective, well-tolerated therapies are now available with markedly simplified treatment algorithms. Eradication of HCV is a national goal. Increased efforts to extend access to treatment to populations that traditionally are difficult to treat, such as persons who inject drugs, are critical to achieving eradication. Given the magnitude of the disease burden, an increased role of primary care providers in screening, patient stratification, and treatment will be needed.
Abstract 4059: CRISPR-EXO - genetic deletion tool for treating chronic myelogenous leukemia
Authors: Duško Lainšček, Vida Forstnerič, Špela Malenšek, Mojca Skrbinek, Matjaž Sever, Roman Jerala
Journal: Cancer Research (2020)

Abstract Chronic myeloid leukemia (CML) is a myeloproliferative neoplastic disease, occurring in 1 to 2 cases per 100.000 adults, which accounts for ~ 15 % of newly diagnosed leukemias in adult patients. The diagnosis is based upon the genetic translocation between the t(9;22)(q34;q11.2), resulting in the formation of Philadelphia fusion chromosome, coding for BCR-ABL1 oncoprotein. The life-long treatment relies on tyrosine kinase inhibitors (TKIs). In nearly in 2 % patients develop point mutations, leading to resistance to TKIs treatment. New solutions for treating cancer with genetic etiology are considered. CRISPR/Cas system, composed of guide RNA, targeting endonuclease Cas9 to specific target genomic region has been used before to mediate breakage of Philadelphia chromosome at the site of oncogenic translocation. We present a strategy to couple Cas9 to the exonuclease to promote large deletions at the cancer-specific target genomic site. Cotransfection with EXOIII exhibited the best increase in deletion formation of all tested exonucleases. To further improve the rate of genetic lesion formation, Cas9 and EXOIII were connected via coiled-coil heterodimer forming peptides, bringing the two enzymes into close proximity (CRISPR-EXO). This resulted in a potent increase of deletion formation compared to the standard CRISPR/Cas, cotransfection and genetic fusion. We performed an animal study for the use of the CRISPR-EXO system as a potential anti-cancer therapeutic tool. In case of the CRISPR-EXO system, we showed a significant increase in cell death due to higher genome editing in the BCR-ABL1 region. These findings were confirmed also in an animal cancer model, where animals with tumors, electroporated with CRISPR-EXO system showed improved survival and drastic reduction in tumor size.CRISPR-EXO upgraded CRISPR system based on tethering Cas9 protein to exonuclease EXOIII by heterodimeric coiled-coil forming peptides, resulted in highly efficient editing of BCR-ABL1 fusion gene, leading to enhanced death of CML cancer cells. Citation Format: Duško Lainšček, Vida Forstnerič, Špela Malenšek, Mojca Skrbinek, Matjaž Sever, Roman Jerala. CRISPR-EXO - genetic deletion tool for treating chronic myelogenous leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4059.
Residual Challenges in Radial Approach for Percutaneous Coronary Interventions—Reply
Authors: Michel Le May, George Wells, Aun Yeong Chong
Journal: JAMA Cardiology (2020)

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