tbuckley/cabot-search huggingface dataset:
Abstract 2251: Gene expression analysis by RNA-sequencing highlights differential regulated pathways involved in cell cycle and inflammation in orbitofacial neurofibromas
Authors: Eddie L. Imada, Deepak P. Edward, Antje Arnold, Hailah Al-Hussain, Diego Strianese, Luigi Marchionni, Fausto J. Rodriguez
Journal: Cancer Research (2021)

Abstract Although most commonly benign, neurofibromas (NFs) can have devastating functional and cosmetic effects in addition to the possibility of malignant transformation. Orbitofacial NFs in particular may cause progressive, disfiguring tumors of the lid, brow, temple, face and orbit, and anecdotal evidence suggest that they may have increased local aggressiveness compared to NFs developing at other sites. The purpose of this study was to identify biological differences between orbitofacial NFs and those occurring at other anatomic sites. We performed global RNA-sequencing in orbitofacial (n=10) and non-orbitofacial (n=9) NFs. A total of 880 mRNA transcripts were differentially expressed between the two groups (adjusted p&amp;gt;0.05), The top 10 genes relatively overexpressed in orbitofacial NF included NEFL, TREM2, CST1, GAP43, ADORA3, MIA, SYT6, FCGR3A, SPP1, and FCGR1A. The top 10 genes relatively underexpressed in orbitofacial NF included XG, WISP2, MMP27, CXCL14, MFAP5, APLNR, MYOC, SLITRK6, STMN2, and TDRD1. Gene enrichment analyses demonstrated a variety of gene sets differentially affected including pathways involved in cell proliferation, interferon and immune related pathways. Comparisons with publicly available databases of various Schwann cell tumors and models using CAT plots demonstrated the highest overlap with differentially expressed genes in plexiform NF vs MPNST (&amp;gt;10%). In summary, we identified gene expression differences between orbitofacial NF and NFs occurring at other anatomic locations. Further investigation may be warranted, given that orbitofacial NF are notoriously difficult to treat and associated with disproportionate morbidity. Citation Format: Eddie L. Imada, Deepak P. Edward, Antje Arnold, Hailah Al-Hussain, Diego Strianese, Luigi Marchionni, Fausto J. Rodriguez. Gene expression analysis by RNA-sequencing highlights differential regulated pathways involved in cell cycle and inflammation in orbitofacial neurofibromas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2251.
Abstract 2039: The role of HORMAD1 in DNA damage repair in squamous cell carcinomas
Authors: Jennifer Gantchev, Amelia Martinez Villarreal, Brandon Ramchatesingh, Ivan V. Litvinov
Journal: Cancer Research (2021)

Abstract Genomic instability is a prominent hallmark of cancer, however the dynamic mechanisms that drive and sustain genomic instability remain elusive. Research demonstrates that numerous cancers with increased levels of genomic instability express meiosis genes and undergo a process called meiomitosis. Cancer meiomitosis is the orchestrated activation of both mitotic and meiotic machineries in neoplastic cells that confer a selective advantage. Specifically, meiCT (meiosis-specific cancer/testis) genes that specialize in the reductional division of germ cells in meiosis I are ectopically expressed in several cancers, particularly in squamous cell carcinomas. The meiCT gene, HORMAD1 is a meiosis specific protein that functions to ensure that a sufficient number of DSBs are formed for appropriate meiotic progression and to maintain genome integrity throughout homologous recombination. Studies show that HORMAD1 is significantly upregulated in several cancers and is regarded as a potentially important oncogene that plays a role in sustaining increased genomic instability. With the use of shRNA mediated knockdown of HORMAD1, we evaluated the effects ofHORMAD1 on genomic instability and survival in squamous cell carcinomas (SCCs). Our results demonstrate that HORMAD1 knockdown in SCC cancer cell lines leads to an increase in genomic instability denoted by an increase in double strand breaks, micronuclei formation and ploidy. Furthermore, shHORMAD1 results in increased sensitivity to etoposide treatment leading to increased centrosome formation and reduced cell survival. We also demonstrate thatHORMAD1 modulates a functional and balanced level of genomic instability by eliciting an DNA damage response through homologous recombination mechanisms that allows SCCs to thrive following DNA damage. Citation Format: Jennifer Gantchev, Amelia Martinez Villarreal, Brandon Ramchatesingh, Ivan V. Litvinov. The role of HORMAD1 in DNA damage repair in squamous cell carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2039.
Abstract SY01-03: The gold standard cancer diagnosis: Studies of physician variability, interpretive behavior, and the impact of AI
Authors: Joann Elmore
Journal: Cancer Research (2021)

Abstract The current gold standard for cancer diagnoses is based on pathologists' visual inspection of tissue sections. However, our research has found concerning levels of inter-observer and intra-observer variability among pathologists. Our prior work in melanoma shows that current diagnoses within the disease spectrum from benign nevi to melanoma in situ to invasive melanoma are neither reproducible nor accurate, yielding estimates that ~17% of all diagnoses for melanocytic lesions in the US are incorrect (Elmore et al. BMJ 2017). A study conducted by our team in breast pathology quantified the magnitude of diagnostic agreement among pathologists compared with a gold standard consensus reference: among DCIS cases, 16% of interpretations were discordant, while among atypia cases 52% of interpretations were discordant (Elmore et al. JAMA 2015). While computer systems, such as computer aided detection (CAD) tools, have been widely integrated into clinical practice to aid the interpretative and diagnostic process, our work has also found that the use of CAD can be associated with increases in potential harms, including higher recall and biopsy rates for screening mammography (Fenton et al. NEJM 2007). Given the critical need to improve the quality of our current diagnostic and prognostic capabilities, our multidisciplinary research team is conducting several studies that involve the development and integration of AI/machine learning and eye-tracking across clinical contexts. The challenges and implications associated with “gold standard” definitions for diagnoses, with data sharing infrastructure and with the eventual impact of AI on the human interface will be discussed. Citation Format: Joann Elmore. The gold standard cancer diagnosis: Studies of physician variability, interpretive behavior, and the impact of AI [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr SY01-03.
Abstract 493: A novel humanized B-hPD-1/hPD-L1/hTIGIT mouse model reveals enhanced efficacy of combined TIGIT and PD-L1 blockade against cancer
Authors: Chonghui Liu, Xiaofei Zhou, Yanan Guo, Eugene Lin, Luke (Zhaoxue) Yu, Yuelei Shen
Journal: Cancer Research (2021)

Abstract Immune checkpoint blockade targeting PD-1/PD-L1 has enjoyed tremendous success in the clinic against various advanced stage cancers, unleashing potent and durable immune-mediated control of tumors while vastly improving patient survival. However, only a portion of patients truly benefit, while other cancers, such as breast, prostate, pancreatic, and colon cancers, are largely resistant to PD-1/PD-L1 therapy alone. Targeting additional immunosuppressive proteins could boost the efficacy of anti-PD-1/PD-L1 therapy and bring the benefits of immunotherapy to more patients. TIGIT is a recently identified immune checkpoint protein mainly expressed by T and NK cells. CD155 (PVR) is a high-affinity receptor of TIGIT, while CD112 and CD113 bind it with weaker affinity. CD155 and CD112 can engage CD226, an NK activating receptor also expressed on some CD8+ T cells, and trigger killing of tumors. Competitive binding of TIGIT to CD155 and CD112 would prevent signaling through CD226. Therefore, anti-TIGIT blocking antibodies may enhance the function of NK cells and T cells. Preclinical studies have shown that inhibition of TIGIT promotes proliferation and function of T cells. Combined blockade of both TIGIT and PD1/PD-L1 has also shown superior efficacy over monotherapy against tumors in early phase clinical trials. Given the intensive interest in combined TIGIT and PD-1/PD-L1 therapies for cancer, Biocytogen has established a novel human PD-1/PD-L1/TIGIT triple knock-in (TKI) mouse as a vital tool to pre-clinically evaluate the in vivo efficacy of combined human TIGIT and PD1/PD-L1 blocking agents against tumors compared to either alone. Exon 2 of the mouse PD-1 gene, exon 3 of mouse PD-L1, and exon 2 of mouse TIGIT were replaced by their human homologs in B-hPD-1/hPD-L1/hTIGIT mice. Human PD-1, PD-L1, and TIGIT proteins were expressed in homozygous B-hPD-1/hPD-L1/hTIGIT but not wildtype mice. Immune profiles of B-hPD-1/hPD-L1/hTIGIT mice were similar to those in wild-type C57BL/6 mice, and abnormalities were not observed. Importantly, we showed that combining anti-human PD-L1 and anti-human TIGIT antibodies significantly inhibited the growth of MC38-hPD-L1 tumor cells implanted into B-hPD-1/hPD-L1/hTIGIT mice. Thus, our novel hPD-1/hPD-L1/hTIGIT TKI mice will be very useful for investigating the in vivo efficacy of TIGIT antibodies currently in company pipelines both alone and combined with PD1/PD-L1 antibody drugs. Citation Format: Chonghui Liu, Xiaofei Zhou, Yanan Guo, Eugene Lin, Luke (Zhaoxue) Yu, Yuelei Shen. A novel humanized B-hPD-1/hPD-L1/hTIGIT mouse model reveals enhanced efficacy of combined TIGIT and PD-L1 blockade against cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 493.
Abstract 597: Comprehensive analysis of blood-based biomarkers to immunotherapy using circulating tumor cells, peripheral blood cells and circulating tumor DNA in advanced non-small cell lung cancer
Authors: Cheol-Kyu Park, Hyun-Ju Cho, In-Jae Oh, Young-Chul Kim
Journal: Cancer Research (2021)

Abstract Background: This study aimed to investigate the feasibility of liquid biopsy using circulating tumor cells (CTCs), peripheral blood cells (PBCs) and circulating tumor DNA (ctDNA) as predictive blood-based biomarkers to immunotherapy in advanced non-small cell lung cancer (NSCLC). Methods: This study included patients with advanced NSCLC receiving pembrolizumab or atezolizumab from July 2019 to June 2020. Blood was collected in K2-EDTA tube before each administration from cycle 1 to 4 (C1-4), and PBC counts (absolute neutrophil count[ANC], neutrophil-to-lymphocyte ratio[NLR], derived NLR[dNLR], platelet-to-lymphocyte ratio[PLR]) were calculated at each cycle. CTCs were enriched by using CD-PRIMETM system, the antibody-independent size-based isolation method, and identified by single positive cells (EpCAM/CK+CD45-) in BioViewCCBSTM system. Cell-free DNA was purified and extracted from plasma at baseline and C4 or end-of-treatment. Results: Among 83 response-evaluable patients, objective response rate was 19% and durable clinical benefit (DCB) were 34%. Baseline (C1) CTC, PBC count and ctDNA amount did not show a significant difference according to best response and DCB. However, patients with lower NLR, dNLR, PLR and ctDNA level at C1 showed significant benefit in progression-free survival (PFS) and overall survival (OS) (p&amp;lt;0.05 for all). Patients with decreased CTC at C2 compared to C1 showed benefit in median PFS (6.2 vs 2.3, p=0.078) and OS (not reached [NR] vs 6.8, p=0.021) than those with increased CTC count. Low dNLR (≤2.0) at C1 and decreased CTC at C2 compared to C1 were the independently significant factors for survival. Conclusion: Comprehensive analysis of CTC, PBC count and ctDNA amount at baseline and their changes during treatment could be potential biomarkers to predict the survival benefit and may help risk-group stratification in patients with advanced NSCLC who received anti-PD-1/PD-L1 immunotherapy. Citation Format: Cheol-Kyu Park, Hyun-Ju Cho, In-Jae Oh, Young-Chul Kim. Comprehensive analysis of blood-based biomarkers to immunotherapy using circulating tumor cells, peripheral blood cells and circulating tumor DNA in advanced non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 597.
Abstract 2903: The exosome marker CD63 and Caveolin-1 in breast cancer patients
Authors: Erina Iwabuchi, Yasuhiro Miki, Ayako Kanai, Takanori Ishida, Hironobu Sasano
Journal: Cancer Research (2021)

Abstract The tetraspanin CD63, a proposed exosome marker, has been reported to be expressed in solid tumors. For instance, CD63 status in carcinoma cells was reported to be a significant independent prognostic factor in gastric cancer patients, with its overexpression causing adversity in patients with gastrointestinal stromal tumors. However, the expression of CD63 has remained virtually unknown in breast cancer pathological specimens. In addition, the detection of high levels of exosomes expressing CD63 and Caveoloin-1 in the plasma of melanoma patients was reported as a novel tool for the clinical management of cancer patients. Caveolin-1 has also been reported to negatively regulate the endocytosis of exosomes. Tetraspanin proteins are shown to form complicated interaction networks in cells to exert their functions. In this study, we immunolocalized CD63 and Caveolin-1 in the surgical pathology specimens of 88 breast cancer patients. CD63 was immunolocalized in the cytoplasm of both the cancer and stromal cells. The number of CD63-positive cancer cells was significantly higher in HER2-positive patients and the levels of CD63-positive stromal cells were also significantly higher in those with high pathologic T factor (pT) and proliferation marker protein Ki-67 labeling index and low pathologic N factor (pN). The number of CD63-double-positive cancer cells and stromal cells was associated with high histological grade, high pT, and high Ki67 expressions. CD63-positive cancer cells and Caveolin-1-positive cancer cells were both significantly higher in Estrogen receptor-positive breast cancer patients with high histological grade and pT. To the best of our knowledge, this is the first study demonstrating the significance of CD63 in breast cancer. Our results indicated that CD63-double-positive cancer cells and stromal cells could be involved in clinically and biologically aggressive subtypes of breast cancer. Further studies are required to clarify the clinical significance of the associations between CD63 and Caveolin-1 in patients with breast cancer. Citation Format: Erina Iwabuchi, Yasuhiro Miki, Ayako Kanai, Takanori Ishida, Hironobu Sasano. The exosome marker CD63 and Caveolin-1 in breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2903.
Radiation therapy‐associated toxicity: Etiology, management, and prevention
Authors: Kyle Wang, Joel E. Tepper
Journal: CA A Cancer Journal for Clinicians (2021)

Abstract Radiation therapy (RT) is a curative treatment for many malignancies and provides effective palliation in patients with tumor‐related symptoms. However, the biophysical effects of RT are not specific to tumor cells and may produce toxicity due to exposure of surrounding organs and tissues. In this article, the authors review the clinical context, pathophysiology, risk factors, presentation, and management of RT side effects in each human organ system. Ionizing radiation works by producing DNA damage leading to tumor death, but effects on normal tissue may result in acute and/or late toxicity. The manifestation of toxicity depends on both cellular characteristics and affected organs' anatomy and physiology. There is usually a direct relationship between the radiation dose and volume to normal tissues and the risk of toxicity, which has led to guidelines and recommended dose limits for most tissues. Side effects are multifactorial, with contributions from baseline patient characteristics and other oncologic treatments. Technological advances in recent decades have decreased RT toxicity by dramatically improving the ability to deliver RT that maximizes tumor dose and minimizes organ dose. Thus the study of RT‐associated toxicity is a complex, core component of radiation oncology training that continues to evolve alongside advances in cancer management. Because RT is used in up to one‐half of all patients with cancer, an understanding of its acute and late effects in different organ systems is clinically pertinent to both oncologists and nononcologists.
Nuclear Aurora kinase A triggers programmed death‐ligand 1‐mediated immune suppression by activating MYC transcription in triple‐negative breast cancer
Authors: Shulan Sun, Wei Zhou, Xiaoxi Li, Fei Peng, Min Yan, Yajing Zhan, Fan An, Xiaoyan Li, Yunyong Liu, Quentin Liu, Haozhe Piao
Journal: Cancer Communications (2021)

Abstract Background Increasing studies have reported that oncogenes regulate components of the immune system, suggesting that this is a mechanism for tumorigenesis. Aurora kinase A (AURKA), a serine/threonine kinase, is involved in cell mitosis and is essential for tumor cell proliferation, metastasis, and drug resistance. However, the mechanism by which AURKA is involved in immune response regulation is unclear. Therefore, this study aimed to investigate the role of AURKA in immune regulation in triple‐negative breast cancer (TNBC). Methods Peripheral blood mononuclear cells (PBMCs) were co‐cultured with TNBC cells. The xCELLigence Real‐Time Cell Analyzer‐MP system was used to detect the killing efficiency of immune cells on TNBC cells. The expression of immune effector molecules was tested by quantitative real‐time polymerase chain reaction (qRT‐PCR) to evaluate immune function. Furthermore, to validate AURKA‐regulated immune response in vivo, 4T1 murine breast cancer cell line with AURKA overexpression or downregulation was engrafted into BALB/c mice. The distribution and proportion of immune cells in tumors were further evaluated by immunohistochemistry and flow cytometry. Results Downregulation of AURKA in TNBC cells increased immune response by activating CD8 + T cell proliferation and activity. Nuclear rather than cytoplasmic AURKA‐derived programmed death‐ligand 1 (PD‐L1) expression was independent of its kinase activity. Mechanistic investigations showed that nuclear AURKA increased PD‐L1 expression via an MYC‐dependent pathway. PD‐L1 overexpression mostly reversed AURKA silencing‐induced expression of immune effector molecules, including interleukin‐ (IL‐2), interferon‐γ (IFN‐γ), and perforin. Moreover, AURKA expression was negatively correlated with the enrichment and activity of tumor‐infiltrating CD8 + T cells in 4T1 engrafted BALB/c mouse model. Conclusions Nuclear AURKA elevated PD‐L1 expression via an MYC‐dependent pathway and contributed to immune evasion in TNBC. Therapies targeting nuclear AURKA may restore immune responses against tumors.
Abstract 2358: miRNA-483-3p overexpression unleashes invasiveness of metastatic colorectal cancer by NDRG1 targeting and upregulation of the HER3-AKT axis
Authors: Ermes Candiello, Gigliola Reato, Federica Verginelli, Antonio D'Ambrosio, Gennaro Gambardella, Raffaella Albano, Paolo Luraghi, Paolo M. Comoglio, Andrea Bertotti, Livio Trusolino, Carla Boccaccio
Journal: Cancer Research (2021)

Abstract In colorectal cancer, the genetic mechanisms underlying the metastatic switch are still poorly understood. Here we show that overexpression of miRNA-483-3p, encoded by a frequently amplified gene locus encompassing also insulin-like growth factor 2, confers an aggressive phenotype to stem-like cells derived from colorectal cancer metastases (m-colospheres). As result of miRNA-483-3p ectopic overexpression, m-colospheres displayed (i) increased proliferative response to exogenous EGFR family ligands EGF and NRG1; (ii) increased spontaneous and growth factor-induced in vitro invasiveness and epithelial-mesenchymal transition (EMT); (iii) enhanced stem-cell frequency and resistance to differentiation. By transcriptomic analyses and functional validation, we found that miRNA-483-3p targets NDRG1, a known ‘metastasis suppressor', which is responsible for degradation of EGFR family members, in particular HER3. As result, ectopic or native miRNA-483-3p overexpression was associated with hyper-activation of the signaling pathway triggered by HER3, including AKT and GSK3β, responsible for activation of EMT transcription factors. Consistently, treatment of miRNA-483-3p overexpressing m-colospheres with HER3 specific antibodies counteracted their proliferative and invasive phenotype. The pro-invasive role of miRNA-483-3p in patients was further confirmed by (i) analysis of colorectal tumors, where miRNA-483-3p expression levels directly correlated with expression of EMT transcription factors and poor-prognosis, and (ii) downregulation of naturally occurring miRNA-483-3p overexpression, which prevented invasion of tumors formed by m-colosphere transplantation. These results indicate that miRNA-483-3p can support colorectal cancer invasion through a signaling pathway amenable to targeting in human patients. Citation Format: Ermes Candiello, Gigliola Reato, Federica Verginelli, Antonio D'Ambrosio, Gennaro Gambardella, Raffaella Albano, Paolo Luraghi, Paolo M. Comoglio, Andrea Bertotti, Livio Trusolino, Carla Boccaccio. miRNA-483-3p overexpression unleashes invasiveness of metastatic colorectal cancer by NDRG1 targeting and upregulation of the HER3-AKT axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2358.
Evaluation of radio-guided pelvic lymph node dissection in patients with intermediate or high-risk prostate cancer. A French, multicenter, prospective study
Authors: F. Lannes, I. Brenot-Rossi, S. Garcia, M. Soulié, A. Ruffion, T. Rousseau, N. Mottet, D. Rossi, C. Bastide
Journal: European Urology (2021)
Validation of the NCCN-IPI and the Geltamo-IPI in a Large Cohort of Patients Diagnosed of Diffuse Large B-Cell Lymphoma (DLBCL) Treated with R-CHOP/R-CHOP-like in a Single Institution
Authors: Santiago Mercadal, Eva Domingo Domenech, Ana C Oliveira, Maite Encuentra, Fina Climent, Cristina Baca Cano, Marcio Andrade-Campos, Esmeralda De la Banda, Carmen Aguilera, Alberto Fernandez de Sevilla, Anna Sureda, Eva González-Barca
Journal: Blood (2017)