tbuckley/cabot-search huggingface dataset:
Abstract 3049: Tracing the origin of disseminated tumor cells in breast cancer using single-cell sequencing
Authors: Jonas Demeulemeester, Parveen Kumar, Elen K. Møller, Silje Nord, David C. Wedge, April Peterson, Randi R. Mathiesen, Renathe Fjelldal, Masoud Z. Esteki, Koen Theunis, Elia F. Gallardo, Jason Grundstad, Elin Borgen, Lars O. Baumbusch, Anne-Lise Børresen-Dale, Kevin P. White, Vessela N. Kristensen, Peter Van Loo, Thierry Voet, Bjørn Naume
Journal: Cancer Research (2017)

Abstract Background. Single-cell micro-metastases of solid tumors often occur in the bone marrow. These disseminated tumor cells (DTCs) may resist therapy and lay dormant or progress to cause overt bone and visceral metastases. The molecular nature of DTCs remains elusive, as well as when and from where in the tumor they originate. Here, we apply single-cell sequencing to identify and trace the origin of DTCs in breast cancer. Results. We sequence the genomes of 63 single cells isolated from six non-metastatic breast cancer patients. By comparing the cells’ DNA copy number aberration (CNA) landscapes with those of the primary tumors and lymph node metastasis, we establish that 53% of the single cells morphologically classified as tumor cells are DTCs disseminating from the observed tumor. The remaining cells represent either non-aberrant ‘normal’ cells or ‘aberrant cells of unknown origin’ that have CNA landscapes discordant from the tumor. Further analyses suggest that the prevalence of aberrant cells of unknown origin is age-dependent, and that at least a subset is hematopoietic in origin. Evolutionary reconstruction analysis of bulk tumor and DTC genomes enables ordering of CNA events in molecular pseudo-time and traced the origin of the DTCs to either the main tumor clone, primary tumor subclones, or subclones in an axillary lymph node metastasis. Conclusions. Single-cell sequencing of bone marrow epithelial-like cells, in parallel with intra-tumor genetic heterogeneity profiling from bulk DNA, is a powerful approach to identify and study DTCs, yielding insight into metastatic processes. A heterogeneous population of CNA-positive cells is present in the bone marrow of non-metastatic breast cancer patients, only part of which are derived from the observed tumor lineages. Citation Format: Jonas Demeulemeester, Parveen Kumar, Elen K. Møller, Silje Nord, David C. Wedge, April Peterson, Randi R. Mathiesen, Renathe Fjelldal, Masoud Z. Esteki, Koen Theunis, Elia F. Gallardo, Jason Grundstad, Elin Borgen, Lars O. Baumbusch, Anne-Lise Børresen-Dale, Kevin P. White, Vessela N. Kristensen, Peter Van Loo, Thierry Voet, Bjørn Naume. Tracing the origin of disseminated tumor cells in breast cancer using single-cell sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3049. doi:10.1158/1538-7445.AM2017-3049
Abstract 4108: Targeting IL-6 signaling overcomes cetuximab resistance in head and neck squamous cell carcinoma
Authors: Rachel A. O'Keefe, Neil Bhola, Toni M. Brand, Yan Zeng, Daniel E. Johnson, Jennifer R. Grandis
Journal: Cancer Research (2017)

Abstract Head and neck squamous cell carcinoma (HNSCC), the sixth most common cancer worldwide, has a five-year survival rate of only 50%. The first targeted agent FDA approved for treatment of HNSCC was cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR). Despite EGFR overexpression in up to 90% of HNSCC tumors and ample evidence supporting EGFR as a therapeutic target in HNSCC, the response rate for single-agent cetuximab is below 20%, and resistance to cetuximab-containing therapy remains a major obstacle in the effective treatment of HNSCC. Identification and targeting of mediators of cetuximab resistance is needed to improve patient outcomes. Secretion of the cytokine interleukin 6 (IL-6) has been proposed as a mechanism of resistance to cetuximab in HNSCC, and inhibition of signal transducer and activator of transcription 3 (STAT3), a downstream mediator of IL-6 signaling, has been shown to overcome cetuximab resistance in preclinical HNSCC models. Thus, we hypothesize that IL-6 signaling mediates resistance to cetuximab and that co-treatment with agents targeting the IL-6 pathway will enhance the therapeutic efficacy of cetuximab in HNSCC. We have generated cetuximab-resistant variants of the cetuximab-sensitive HNSCC cell lines Cal33 and PE/CA-PJ49. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis indicated that IL6 expression is increased 3.5- to 8-fold in cetuximab-resistant variants compared to the parental cells from which they were derived. In addition, a colony formation assay revealed that, as expected, cetuximab-treated parental cells formed fewer colonies than vehicle-treated cells, while cetuximab treatment had no effect on the ability of cetuximab-resistant PE/CA-PJ49 variants to form colonies. In contrast, treatment with tocilizumab, an IL-6 receptor-neutralizing monoclonal antibody, markedly reduced the colony-forming ability of the cetuximab-resistant variants, but not parental cells. These results suggest that targeted inhibition of IL-6 signaling may effectively inhibit proliferation in cetuximab-refractory HNSCC cells. Citation Format: Rachel A. O'Keefe, Neil Bhola, Toni M. Brand, Yan Zeng, Daniel E. Johnson, Jennifer R. Grandis. Targeting IL-6 signaling overcomes cetuximab resistance in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4108. doi:10.1158/1538-7445.AM2017-4108
Abstract 2497: Differential requirement of amino acids on cell survival of ovarian cancer cells
Authors: Akiko Furusawa, Jun Inoue, Hitoshi Tsuda, Naoyuki Miyasaka, Johji Inazawa
Journal: Cancer Research (2017)

Abstract Amino acids (AAs) are traditionally classified into nutritionally essential AAs (EAAs) or nonessential AAs (NEAAs) for animals and humans. Recent studies have demonstrated that not only EAAs but also NEAAs play important roles on energy metabolisms in cancer cells. However, which AAs are indispensable for human cancer cell survival has not been fully elucidated. The purposes of this study were 1) to determine the indispensable AAs for ovarian cancer (OVC) cells and 2) to investigate the relationship between the AAs synthetase and cancer cell survival. Firstly, OVC cell lines were cultured with different medium in which each AA was depleted and cancer cell survival was examined. Among 17 OVC cell lines, EAAs were required in 12 cell lines, whereas others did not require EAAs for cell survival. Interestingly, cancer cell lines which required EAA also required at least one NEAAs, including arginine, cystine, glutamine, serine and tyrosine. Although extracellular glutamine has been known to be a critical factor for cancer cell survival and growth, 3 OVC cell lines did not require extracellular glutamine. Hence, we next examined glutamine synthetase (GS) gene, which is a critical enzyme for production of endogenous glutamine from glutamate. In OVC cell lines which did not require extracellular glutamine, GS expression level was positively correlated with cell survival rate under glutamine-depleted condition. Furthermore, we found that the expression of GS protein was negative in 38 of 645 primary OV tumors (5.9 %). Taken together, these results suggest that GS-down-regulated OVC cells require extracellular glutamine for their survival. Therefore, uptake inhibition of extracellular glutamine or reduction of extracellular glutamine level may be a novel therapeutic strategy for patients with ovarian cancer with “GS down-regulation”, as well as development of an AA-based precision medicine of OVC. Citation Format: Akiko Furusawa, Jun Inoue, Hitoshi Tsuda, Naoyuki Miyasaka, Johji Inazawa. Differential requirement of amino acids on cell survival of ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2497. doi:10.1158/1538-7445.AM2017-2497
Over-the-scope clip is an effective therapy for postbanding ulcer bleeding after initially successful transjugular intrahepatic portosystemic shunt therapy
Authors: Oscar Cahyadi, Karel Caca, Arthur Schmidt
Journal: Endoscopy (2017)

Postbanding ulcer bleeding (PBUB) is a potential deadly complication after esophageal variceal banding (EVB) in patients with portal hypertension, with a reported incidence of 2.6 % – 7.3 % [1]. Various treatment possibilities for PBUB, such as cyanoacrylate injection, self-expandable metal stents, and transjugular intrahepatic portosystemic shunt (TIPS), are commonly applied. Rebleeding from a postbanding ulcer after initially successful TIPS is rare, and no clear treatment algorithm is available. Here, we report on the successful application of an over-the-scope clip (OTSC) to treat a PBUB after successful TIPS not amenable to EVB or hemoclip.
Invasive Mold Infections in Acute Leukemia Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Sheng-Hsuan Chien, Yao-Chung Liu, Nai-Wen Fan, Chia-Jen Liu, Tzeon-Jye Chiou, Jyh-Pyng Gau, Jin-Hwang Liu
Journal: Blood (2016)
Abstract 3954: Single-cell misregulation of NRF2 in basal-like breast cancer
Authors: Elizabeth Pereira, Kevin Janes
Journal: Cancer Research (2017)

Abstract Cancer is driven by a complex and heterogeneous combination of genes and pathways, many of which are not explicitly oncogenic on their own. These so-called non-oncogenes are required for maintenance of the tumorigenic state, but they are not mutated themselves. One way to identify “non-oncogene” pathways is to evaluate how proliferating cells adjust to variable and evolving environments. By examining heterogeneous transcriptional regulatory states of single cells in a 3D culture model of breast epithelial organization, we uncovered NRF2 as a candidate transcription factor upstream of an important regulatory state for morphogenesis. NRF2 is a known oncogene in lung cancer, but mutations in the transcription factor are uncommon in breast cancer. To examine the functional impact of NRF2 signaling, we engineered several triple-negative breast cancer cell lines with inducible short hairpin RNA to knock down NRF2. In claudin-low MDA-MB-231 cells, knockdown of NRF2 caused dramatic reduction in stellate invasion compared with shGFP control. In basal-like HCC-1806 cells, knockdown of NRF2 caused a reduction in “ruptured” tumorspheres, in which cells disseminate from their originating site. In a non-transformed breast epithelial cell line, overexpression of a non-degradable form of NRF2 caused greater variation in the size of acini, while knockdown of NRF2 narrowed the size distribution of acini. Therefore, knockdown of NRF2 substantially normalizes the size and shape of both non-transformed and cancerous 3D structures. We also analyzed expression levels of the genes in the provisional NRF2-regulated cluster after NRF2 knockdown or overexpression. Upon NRF2 knockdown, the p53-regulated transcripts CDKN1A (p21) and RPS27L were strongly induced, suggesting that p53 may be activated after NRF2 loss. Our results suggest a functional importance for NRF2 in multiple breast-epithelial and TNBC contexts, and raise the possibility of interplay between NRF2 and p53. A detailed understanding of NRF2 regulation and dynamics could enable new strategies to disrupt this non-oncogene addiction and re-sensitize cancer cells to their environment and to chemotherapy. Citation Format: Elizabeth Pereira, Kevin Janes. Single-cell misregulation of NRF2 in basal-like breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3954. doi:10.1158/1538-7445.AM2017-3954
Action is needed to avoid NHS staffing crisis in Scotland, audit finds
Authors: Bryan Christie
Journal: BMJ (2017)

Urgent action is needed to improve workforce planning in Scotland to ensure that the health service has enough staff to meet future demands, auditors have warned.

A report from Audit Scotland criticised the Scottish government and NHS boards for failing to plan future staffing needs against the expected long term demand for healthcare.1 It added that current responsibility for workforce planning is “confused,” being split between the government, boards, and …
Abstract 5705: Analytical validation of Guardant360 v2.10
Authors: James Vowles, Justin Odegaard, Stefanie Mortimer, Stephen Fairclough, Marcin Sikora, Diana Abdueva, Reza Mokhtari, Arthur Baca, AmirAli Talasaz
Journal: Cancer Research (2017)

Abstract Guardant360 is a cell-free circulating tumor DNA (ctDNA) test that genotypes all guideline-recommended solid tumor somatic genomic treatment targets from a single non-invasive blood draw. The new version, v2.10, was redesigned to enhance sensitivity and specificity across 73 cancer-related genes. It detects all four major variant classes (single nucleotide variants, SNVs, in all 73 genes; indels in 23 genes; gene amplifications, CNAs, in 18 genes; and fusions in 6 genes). Analytical performance was assessed throughout the reportable range via multiple serial dilution studies of orthogonally-characterized contrived and patient samples. Analytical specificity was assessed by calculating the false positive rate in pre-characterized healthy donor sample mixtures serially diluted. Positive predictive value (PPV) was estimated as a function of allelic fraction/copy number from pre-characterized samples and prevalence-adjusted using a cohort of 2,585 consecutive clinical samples. Confirmation was performed using ddPCR. Analytical specificity was 100% for SNVs, fusions, and CNAs and 96% for indels across 25 defined samples. Relative to Guardant360v2.9, v2.10 demonstrated 20-50% increase in fusion molecule recovery. Retrospective in silico analysis of 2,585 consecutive clinical samples demonstrated a 15% increase in actionable fusion detection, a 6%-15% increase in actionable indel detection (excluding newly reportable indels), and a 3%-6% increase in actionable SNV detection. AlterationsReportable Range95% Limit of DetectionAllelic Fraction / Copy NumberAnalytical SensitivityAllelic Fraction / Copy numberPPVSNVs≥0.04%0.25%≥0.25%&amp;gt;99.9%≥0.25%98.7%0.05–0.25%63.8%&amp;lt;0.25%92.3%Indels≥0.02%0.2%≥0.25%&amp;gt;99.9%≥0.25%98.4%0.05–0.25%67.8%&amp;lt;0.25%88.5%Fusions≥0.04%0.4%≥0.3%100%any100%&amp;lt;0.3%83.0%CNAs≥2.12 copies2.24-2.93 copies2.3 copies95.0%any100% Guardant360 analytical performance characteristics based on standard cfDNA input (30ng). Analytical sensitivity/limit of detection estimates are provided for clinically actionable variants and may vary by sequence context and cfDNA input. PPV is estimated across entire reportable panel space (PPV was 100% for clinically actionable variants). Conclusion: Guardant360 v2.10 comprehensively detects all adult solid tumor guideline-recommended somatic genomic variants with unparalleled sensitivity, accuracy, and specificity. Citation Format: James Vowles, Justin Odegaard, Stefanie Mortimer, Stephen Fairclough, Marcin Sikora, Diana Abdueva, Reza Mokhtari, Arthur Baca, AmirAli Talasaz. Analytical validation of Guardant360 v2.10 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5705. doi:10.1158/1538-7445.AM2017-5705
Abstract 2625: Clinicopathological features of programmed cell death ligand 1 (PD-L1) expression in resected non-small cell lung cancers
Authors: Yoshihito Ohhara, Ichiro Kinoshita, Utano Tomaru, Kanako C. Hatanaka, Yutaka Hatanaka, Rio Honma, Satoshi Takeuchi, Yasushi Shimizu, Kichizo Kaga, Yoshihiro Matsuno, Hirotoshi Dosaka-Akita
Journal: Cancer Research (2017)

Abstract Background: Antibodies against programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) have recently demonstrated a survival benefit in several types of cancer, including melanoma and non-small cell lung cancer (NSCLC). PD-L1 expression has provided a predictive biomarker for anti-PD-1/PD-L1 therapy. However, the relationship between PD-L1 expression and clinical and clinicopathological characteristics remains unclear in NSCLCs. The aim of this study was to investigate the relevance of PD-L1 expression to clinical and clinicopathological factors in resected NSCLCs. Materials and Methods: PD-L1 expression was evaluated in 154 surgically resected NSCLC specimens by immunohistochemistry (IHC) using the SP142 antibody. Before the IHC of clinical samples, we performed a concordance study of Western blot analysis and IHC in 17 lung cancer cell lines. We evaluated the relationship between PD-L1 expression and clinical and clinicopathological factors by univariate and multivariate analyses. Survival curves were estimated by the Kaplan-Meier methods, and differences in survival distributions were evaluated by the log-rank test. Results: PD-L1 expression was well concordantly observed in Western blot analysis and IHC in the lung cancer cell lines analyzed. PD-L1 expression was observed in 51 of 154 (33%) surgically resected NSCLCs. PD-L1 expression was significantly correlated with male, heavy smoking history, squamous cell carcinoma, and moderate/poor differentiation of tumors by univariate analysis. In multivariate analysis, tumor differentiation had a strong relationship with PD-L1 expression (odds ratio: 6.32, 95% CI: 1.70-23.49, P = 0.006). The survival was not statistically different between patients with high and low PD-L1 expression (5-year survival rate: 44.1% versus 58.1%, P = 0.22). PD-L1 expression was not an independent prognostic factor in univariate and multivariate analyses. Conclusion: PD-L1 expression was strongly associated with tumor differentiation in resected NSCLCs. PD-L1 expression was not a prognostic factor in this cohort of resected NSCLCs. Citation Format: Yoshihito Ohhara, Ichiro Kinoshita, Utano Tomaru, Kanako C. Hatanaka, Yutaka Hatanaka, Rio Honma, Satoshi Takeuchi, Yasushi Shimizu, Kichizo Kaga, Yoshihiro Matsuno, Hirotoshi Dosaka-Akita. Clinicopathological features of programmed cell death ligand 1 (PD-L1) expression in resected non-small cell lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2625. doi:10.1158/1538-7445.AM2017-2625
Abstract 2803: The NCI mouse repository: Cancer models and miRNA-ES cell resource
Authors: Parirokh Awasthi, Fitzgerald Debra, Jones N. Stephen
Journal: Cancer Research (2017)

Abstract The NCI Mouse Repository, located at the Frederick National Laboratory for Cancer Research (FNLCR), Frederick, Maryland, is an NCI-funded resource of approximately 150 genetically-engineered mouse cancer models and associated strains, including mice bearing conditional and point-mutant alleles in cancer-related genes. In addition, the Repository houses a unique collection of over 1500 different mouse ES cell clones bearing conditionally-activated miRNA transgenes to facilitate in vivo exploration of miRNA functions. The NCI Mouse Repository makes strains and mESCs available to all members of the scientific community (academic, non-profit, and commercial). The mouse models and ES cell clones are cryo-archived and distributed as frozen germplasm or cells. Requests may be placed through the NCI Mouse Repository website (https://ncifrederick.cancer.gov/Lasp/MouseRepository/Default.aspx). In addition to the request form, this website includes detailed description for each strain accepted into the Repository and the associated publications provided by the donating scientist. The miR-harboring ESCs, originally generated at the Cold Spring Harbor Laboratories for the NCI, are described in full detail and include validation data for each miRNA ES cell clone. These resources are available for nominal cost to NCI, NIH, and other US government-funded investigators, as well as to Investigators at non-profit organizations. Citation Format: Parirokh Awasthi, Fitzgerald Debra, Jones N. Stephen. The NCI mouse repository: Cancer models and miRNA-ES cell resource [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2803. doi:10.1158/1538-7445.AM2017-2803
Abstract 3546: LIN28B/MYC loop regulates aerobic glycolysis and tumor acidic microenvironment to promote cancer stemness and cancer progression
Authors: Chong Chen, Lipeng Bai, Fengqi Cao, shengnan wang, Yan Liu, Jian Guo, Qin Si, Rong Xiang, Yunping Luo
Journal: Cancer Research (2017)

Abstract Substantial evidences have proven that targeting cancer addictive metabolism could suppress tumor progression. Tumor microenvironment (TME) supports the development of metabolic reprograming of tumor cells. The function of cancer stem cells (CSCs) closely related with its own metabolic alteration. However, the relationship between CSCs’ metabolic reprograming and their supportive TME, as well as underlying mechanism remains largely unknown. In this study, we have demonstrated a novel mechanism that the LIN28B/MYC positive regulation loop could promote the aerobic glycolysis of cancer cells and glycolysis-derived lactate and further enhance the cancer stemness to facilitate tumor progression. 1) Metabolic analysis revealed that glycolysis (ECAR) was suppressed after LIN28B was knocked down in MDA-MB-231 or H1299 cancer cells respectively. Consistently, both the glucose-uptake and lactate-secretion were attenuated in shLIN28B cancer cells. Importantly, either the glucose accumulation in cancer tissues or lactate secretion in serum was reduced in mouse injected with shLIN28B cancer cells. 2) Metabolic analysis revealed that CSCs possessed higher ECAR and higher level of LIN28B, MYC and HIF1a. Furthermore, glycolysis-derived lactate not only increase the proportion of ALDH+ cells, but also enhance the tumorsphere forming ability and mobility of cancer cells. 3) MicroRNAs screening analysis revealed that 6 miRNAs were up-regulated above 2 folds after LIN28B was knocked down in MDA-MB-231 cells. Metabolic analysis revealed that miR-34a-5p could suppress the aerobic glycolysis (ECAR) in MDA-MB-231 cells. 4) LIN28B inhibitor could reduce the expression of LIN28B and MYC in vitro and then suppressed tumor growth and metastasis in vivo. Taken together, our study demonstrated that LIN28B/MYC loop could sustain the aerobic glycolysis of cancer cells and then enhance the function of CSCs via regulating the tumor acid microenvironment, thus, established the LIN28B/MYC as a central node in connecting tumor metabolism and tumor microenvironment, and could serve as a therapeutical target. Citation Format: Chong Chen, Lipeng Bai, Fengqi Cao, shengnan wang, Yan Liu, Jian Guo, Qin Si, Rong Xiang, Yunping Luo. LIN28B/MYC loop regulates aerobic glycolysis and tumor acidic microenvironment to promote cancer stemness and cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3546. doi:10.1158/1538-7445.AM2017-3546