tbuckley/cabot-search huggingface dataset:
Abstract 3455: Cystatin C decreases proliferation of melanoma cells by affecting mitosis length
Authors: Hanna Wallin, Kersti Alm, Magnus Abrahamson
Journal: Cancer Research (2017)

Abstract Cystatin C is a small secreted protein, produced by most cells in the body and found in significant quantities in all body fluids. It is the major inhibitor of extracellular cysteine protease activity in mammals because of its rapid binding to virtually all known cysteine proteases of families C1 (cysteine cathepsins) and C13 (mammalian legumain). Cystatin C has also been shown to inhibit viral replication within cells and display protective effects against cancer cell invasion. The protein has recently been shown to get internalized into cancer cells, providing an explanation to possible intracellular effects of the inhibitor. The purpose of the present study was to elucidate possible direct effects of cystatin C on cancer cell growth, by use of holometric imaging to analyze proliferation rate as well as to monitor the mitosis phase in real-time. Human A375 melanoma cells were cultured with and without addition of physiological quantities of cystatin C added to the culture medium (1 micromolar final concentration). The cultures were monitored for up to 3 days in a standard incubator using a HoloMonitor M4 instrument. Settings were optimized to allow accurate counting of cells throughout the experiment by analysis of images captured, revealing an inhibitory effect on overall cell proliferation rate by cystatin C addition to the cultures. To analyze the migration and cell division of individual cells, images were captured at short intervals allowing tracking and monitoring of cell morphology with respect to parameters such as thickness/density and area. Parameters could be set to define start of the mitosis phase indicated by a distinct rounding-up of cells and followed until a natural stop at cytokinesis, whereafter the daughter cells could be continuously tracked. These analyses revealed qualitative differences in the normal migration behavior of the A375 cells under study as a result of cystatin C addition. Moreover, the mitosis phase was considerably prolonged in cells grown in cystatin C containing medium, indicating that the proliferation-inhibiting effect of the protease inhibitor may be through its direct action on proteolytic processes in the actual mitosis phase. This finding justifies in-depth studies on additional cancer cell types to reveal how general the anti-proliferative effect of cystatin C is and how it can be explored to possibly control cancer cell growth and spread. The use of real-time holometric imaging of growing cells should be a most useful tool in such studies. Citation Format: Hanna Wallin, Kersti Alm, Magnus Abrahamson. Cystatin C decreases proliferation of melanoma cells by affecting mitosis length [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 3455. doi:10.1158/1538-7445.AM2017-3455
Abstract 5598: Adenosine signaling through A2AR limits the efficacy of anti-CTLA4 and chemotherapy in preclinical models
Authors: Po Ho, Meng-Yin Hsieh, Andrew Hotson, Richard Miller, Ian McCaffery, Stephen Willingham
Journal: Cancer Research (2017)

Abstract Elevated levels of extracellular adenosine within the tumor microenvironment create an immunosuppressive niche that promotes tumor growth and metastasis. Adenosine signaling via the A2A receptor (A2AR) on immune cells suppresses anti-tumor immunity and has been shown to limit the efficacy of immunotherapies such as anti-PD-L1 or anti-PD-1 monoclonal antibodies (mAbs). CPI-444 is a potent and selective oral A2AR antagonist that is currently being investigated in Phase 1/1b clinical trials alone and in combination with an anti-PD-L1 antibody (Atezolizumab) in selected solid tumors. New preclinical data suggests that combining CPI-444 with anti-CTLA-4 mAbs as well as chemotherapy treatment are also promising therapeutic strategies in solid tumors, suggesting a broad role for adenosine as an immune suppressive mechanism. The efficacy of CPI-444 + anti-CTLA-4 mAb treatment was evaluated in MC38 and CT26 syngeneic mouse tumor models. In CT26, combination treatment eliminated established tumors in up to 90% of mice approximately 2 weeks after treatment was initiated. In MC38, combination CPI-444 and anti-CTLA-4 mAb treatment prolonged survival of 80% of mice compared to only 40% of mice that received CPI-444 or anti-CTLA-4 mAbs alone. The effect of CPI-444 + anti-CTLA-4 treatment on T-cell proliferation, T cell activation, and TREG function will be discussed. Chemotherapy releases adenosine and ATP into the tumor microenvironment (TME). Multiple chemotherapies have also been shown to up-regulate the ecto-enzymes CD39 and CD73 that produce adenosine and further suppress immune function. In the MC38 model, CPI-444 treatment synergized with doxorubicin and eliminated established tumors 80% of treated mice. CPI-444 treatment was also synergistic with cyclophosphamide, inhibiting the growth of RENCA tumors, a model that is considered resistant to chemotherapy. Ongoing studies are evaluating the effect of CPI-444 + chemotherapy on tumor infiltrating lymphocyte localization, activation, and expression of CD73 and CD39. These results suggest that blockade of the adenosine signaling pathway may be vital for enhancing anti-tumor responses in solid tumors that show an incomplete response to anti-CTLA4 therapy or chemotherapy. Citation Format: Po Ho, Meng-Yin Hsieh, Andrew Hotson, Richard Miller, Ian McCaffery, Stephen Willingham. Adenosine signaling through A2AR limits the efficacy of anti-CTLA4 and chemotherapy in preclinical models [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 5598. doi:10.1158/1538-7445.AM2017-5598
Abstract 2162: MEK signaling marks resistance to synthetic lethality induced by PI3K/Akt and BCL-XL inhibition in PTEN-mutant cancers
Authors: Raghav Joshi, Wenying Ren, Paul Mathew
Journal: Cancer Research (2017)

Abstract Background: Loss of PTEN represents one of the most common disruptions of tumor suppressor activity in the progression of human neoplasia. There are no established precision medicine approaches defined in PTEN-deficient neoplasms which include prostate, breast, glioblastoma (GBM) and uterine cancers. In PTEN-mutant prostate cancer cells, the PI3K/Akt pathway collaborates with BCL-XL specifically, to regulate the apoptotic threshold (Ren, MCR 2016). Whereas single agent PI3K/Akt inhibitors are ineffective in inducing cell death, combined inhibition of PI3K/Akt and BCL-XL in PTEN-mutant prostate cancer cells results in synergistic apoptosis suggesting a novel therapeutic strategy with translational potential in this important subset of disease. Hypothesis: We hypothesized that synthetic lethality following combinatorial PI3K/BCL-XL inhibition is conserved across the range of PTEN-mutant cancers. Methods: PTEN-mutant cell lines (ATCC), validated for PTEN-loss and p-Akt expression, were assessed in apoptosis (cleaved Parp) and cell-viability assays following combined PI3K (Buparlisib, SelleckChem) and BCL-XL (A-1331852, AbbVie) inhibition (1µM each, 24h). Since MEK signaling has been associated with resistance to PI3K pathway inhibition, p-Erk was profiled as a candidate marker of resistance. The contribution of MEK signaling to the apoptotic threshold in p-Erk expressing PTEN-mutant cells was tested with pharmacological MEK inhibition (Trametinib, SelleckChem; 1,3,5 µM 48h) in combination. Results: MEK signaling and PI3K/BCL-XL inhibition in PTEN-mutant cancersSourceCell linePTENp-Aktp-ErkSynergistic Apoptosis with PI3K / BCL-XL inhibitionLoss of cell viabilityp-Erk suppression with MEK inhibitionApoptosis with concomitant MEK inhibitionProstatePC3AbsentPresentAbsentYesYesN/AN/AProstateLNCaPAbsentPresentAbsentYesYesN/AN/AProstateC4-2BAbsentPresentAbsentYesYesN/AN/ABreastZR-75-1AbsentPresentWeakYesYesN/AN/AUterineSK-UT-1AbsentPresentPresentNoNoYesYesGBMA-172AbsentPresentPresentNoNoYesNoCervixC33-AAbsentPresentPresentNoNo-- Conclusions: Synthetic lethality in PTEN-mutant tumor cells with PI3K/BCL-XL inhibition was confined to tumor cells without active MEK signaling. MEK inhibition inconsistently overcomes resistance to therapy suggesting heterogeneity of survival pathways in p-erk expressing PTEN-deficient tumors. These data have implications for precision medicine approaches in PTEN-deficient tumors as absence of p-Erk expression may predict for a responsive phenotype. Citation Format: Raghav Joshi, Wenying Ren, Paul Mathew. MEK signaling marks resistance to synthetic lethality induced by PI3K/Akt and BCL-XL inhibition in PTEN-mutant 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 2162. doi:10.1158/1538-7445.AM2017-2162
Abstract 2981: Identification of circulating stroma-related biomarkers for pancreatic ductal adenocarcinoma
Authors: Andrea Resovi, Luca Porcu, Alessia Anastasia, Paola Allavena, Paola Cappello, Anna Falanga, Giulia Taraboletti, Mariarosa Bani, Dorina Belotti, Raffaella Giavazzi
Journal: Cancer Research (2017)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive epithelial malignancies characterized by a relevant amount of tumor stroma. It is usually diagnosed late and has limited treatment options. Plasmatic markers capable of detecting the disease in its early stages and monitoring treatment effectiveness might change the fate of PDAC patients. This study investigates the potential value of circulating stroma-related molecules as PDAC biomarkers capable to detect the disease and to monitor treatment response. Thirty-eight stroma-related candidate biomarkers were selected from published proteomic studies on PDAC. Levels of these molecules were tested by ELISA and Multiplex Luminex assays in a first cohort of plasma samples from PDAC patients and healthy subjects. Thirteen molecules -extracellular matrix proteins and proteolytic fragments, matrix-degrading enzymes and their inhibitors, growth factors and adhesion molecules-, were found to be differentially expressed in PDAC plasma compared to healthy subjects. A second analysis in an independent cohort of PDAC patients, chronic pancreatitis patients and healthy controls confirmed the previous findings and allowed restricting the number of biomarkers up-regulated in the plasma of PDAC patients. The plasma analysis of two genetically engineered mouse models of pancreatic cancer [Pdx-1-Cre;LSL-KrasG12D and Pdx-1-Cre;LSL-KrasG12D/+;LSL-Trp53R172H/+] revealed an up-regulation of four markers in association with PanIN development, indicating their potential role in the early diagnosis of pancreatic cancer. These markers were also elevated in the plasma of mice bearing patient derived orthotopic PDAC xenografts (PDAC-PDX), but not in a mouse model of caerulein-induced chronic pancreatitis. Their level was associated with PDAC-PDX tumor growth and response to gemcitabine combined with nab-paclitaxel. In conclusion this analysis has identified a panel of stroma-related potential biomarkers associated with tumor progression and drug response of PDAC. Supported by Associazione Italiana per la Ricerca sul Cancro (AIRC 5 per mille grant n. 12182) and Fondazione “Eugenio Morandi” ONLUS per lo studio e la cura dei tumori del pancreas. Citation Format: Andrea Resovi, Luca Porcu, Alessia Anastasia, Paola Allavena, Paola Cappello, Anna Falanga, Giulia Taraboletti, Mariarosa Bani, Dorina Belotti, Raffaella Giavazzi. Identification of circulating stroma-related biomarkers for pancreatic ductal adenocarcinoma [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 2981. doi:10.1158/1538-7445.AM2017-2981
Abstract 2542: MSI2 binds LncRNAs and promotes self-renewal and oncogenesis through MYC expression
Authors: Hifzur Siddique, Padmani Narayan, Vasu Punj, Douglas E. Feldman, Keigo Machida
Journal: Cancer Research (2017)

Abstract Backgrounds and Aims: RNA-binding protein MSI2 is elevated in several cancers and is linked to poor prognosis. Here, we sought to elucidate the role of MSI2 in regulating the expression of proto-oncogenes or tumor suppressor genes in hepatocellular carcinoma (HCC). Methods: We performed RIP-seq using anti-MSI2 antibody in tumor-initiating stem-like cells (TICs) and subsequent validation by qPCR analysis. Results: Among the MSI2-bound RNAs, MYC mRNA and long noncoding RNA (LncRNA) miR22 host gene (MIR22HG) and MARAT1 were identified by RIP-qPCR analysis. MSI2-MARAT1 binding dereppresses polycomb reppressor to recruit E2F1 in MYC promoter regions. It is known that the 5’-untranslated region of MYC contains an internal ribosome entry sequence (IRES) which allows IRES-dependent translation initiation along with canonical cap-dependent mechanisms. Our data show that MSI2 acts as an IRES trans-acting factors for MYC mRNA translation. MSI2 does not have any effect on the steady state level of MYC mRNA but significantly increases MYC protein levels, indicating that MSI2 regulates MYC at the post-transcriptional level. Further, we observed that MSI2 reduced the level of mature miR22 derived from MIR22HG processing. We showed that miR22 suppresses the expression of MYC thorough a 3’-UTR dependent process. Overexpression of MSI2 promotes TIC self-renewal and tumor initiation property in xenograft tumor mouse models, whereas silencing MSI2 reduces this occurrence. Conclusion: we demonstrate that MSI2 promotes liver tumorigenesis by maintenance of MYC expression through dereppression of polycomb repressor and an IRES-dependent translation mechanism and possibly by inhibition of miR22 processing. Thus, MSI2 may be a useful prognostic factor for HCC and MSI2 targeted therapy and thus may be beneficial in the treatment of HCC patients. Citation Format: Hifzur Siddique, Padmani Narayan, Vasu Punj, Douglas E. Feldman, Keigo Machida. MSI2 binds LncRNAs and promotes self-renewal and oncogenesis through MYC expression [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 2542. doi:10.1158/1538-7445.AM2017-2542
Abstract 2227: Fgf2 from visceral adipose tissue stimulates neoplastic transformation of nonmalignant epithelial cells
Authors: Debrup Chakraborty, Vanessa Benham, Elena Y. Demireva, Blair Bullard, Jamie J. Bernard
Journal: Cancer Research (2017)

Abstract Background: Adiposity plays a crucial role in the pathogenesis and prognosis of different types of cancers. Epidemiological evidence suggests visceral adipose tissue (VAT) and high-fat diets (HFD) are associated with increased cancer risk however the mechanism is not understood. The aim of this study was to explore the factors in VAT that stimulate neoplastic transformation. Methods: We modeled visceral adiposity-stimulated neoplastic transformation using our novel ex vivo system of VAT-condition medium stimulated epithelial cell transformation (measured by growth in soft agar) and our in vivo murine lipectomy model of ultraviolet light B (UVB)-induced, VAT promoted skin tumor formation. FgfR1(-/-) stable cells were generated by using CRISPR-Cas9 technology and were used to investigate the role of fibroblast growth factor-2 (FGF2) and FGFR1 dependent signaling in neoplastic transformation, both in vitro and in vivo. Results: Only the VAT of obese mice fed a HFD [not VAT from low-fat diet (LFD) fed mice] stimulated neoplastic transformation of skin epithelial cells. Furthermore, human VAT stimulated both skin and mammary epithelial cell transformation. The differences in VAT activity between LFD and HFD fed mice and human donors were associated with the levels of FGF2. Circulating levels of FGF2 were associated with non-melanoma tumor formation in vivo. Human and mouse VAT failed to stimulate transformation in FgfR1(-/-) cells and do not form tumors when injected in Nude mice in vivo. Conclusion: Collectively, our data show FGF2 released from VAT and its interaction with FGFR1 is a novel and potential direct path of VAT-enhanced tumorigenesis. Blocking the FGFR1 induced signaling in VAT of abdominally obese individuals may be an important cancer prevention strategy as well as an adjuvant therapy for improving outcomes following cancer diagnosis. Citation Format: Debrup Chakraborty, Vanessa Benham, Elena Y. Demireva, Blair Bullard, Jamie J. Bernard. Fgf2 from visceral adipose tissue stimulates neoplastic transformation of nonmalignant epithelial 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 2227. doi:10.1158/1538-7445.AM2017-2227
Resistant<i>Staphylococcus aureus</i>
Journal: New England Journal of Medicine (1967)

Catalase. negative; Meticill resistance Summary The wide dissemination of a major epidemic meticillin-resistant Staphylococcus aureus (MRSA) clone in Brazilian hospitals (Brazilian clone) limits the value of molecular typing techniques such as pulsed-field gel elec- .in trophoresis (PFGE) for outbreak investigation. We report the first outbreak of a catalase-negative strain of MRSA, which was initially detected by the unusual result of this phenotypical test. The outbreak occurred in the Hospital Sanatorinhos de Carapicuiba, a 237-bed secondary hospital located in Sao Paulo, Brazil. From May to August 2002, a total of 11 MRSA isolates were recovered from four patients in the intensive care unit. A11 the isolates were catalase negative and susceptible only to vancomycin and linezolid. Three of the four patients eventually died. Molecular typing dernonstrated an indistinguishable PFGE pattern among the 11 isolates, with similarities to the Brazilian clone and the hospital's usual MRSA strain. This report empha- sizes the importance of an uncommon phenotypical result as a marker for initiating an outbreak investigation and should encourage clinical labora- tories to recognize and report such isolates. O 2006 The Hospital Infection Society. Published by Elsevier Ltd. All rights reserved
Abstract 4627: Prognostic significance and population shift of peripheral monocytes in patients with oropharyngeal squamous cell carcinoma
Authors: Hideyuki Takahashi, Koichi Sakakura, Kazuaki Chikamatsu
Journal: Cancer Research (2017)

Abstract Evidence has accumulated that chronic inflammation plays a critical role in carcinogenesis, tumor growth, and metastasis. To date, several inflammatory biomarkers are considered as potential prognostic factors in various cancers. The aim of the present study was to investigate the prognostic significance of the pretreatment levels of inflammatory biomarkers in patients with oropharyngeal squamous cell carcinoma (OPSCC). A total of 67 patients newly diagnosed as OPSCC was finally included. The neutrophil, lymphocyte, monocyte and platelet counts recorded before treatment was initiated, then lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were calculated. These inflammatory biomarkers and clinical parameters including age, differentiation, T-stage, N-stage, TNM-stage, smoking, and drinking were compared with progression-free survival (PFS) and overall survival (OS) using cox regression. Elevated monocyte count and advanced T-stage were significantly associated with poor PFS; in addition, these were independent prognostic factors for PFS. Elevated monocyte count and low LMR were significantly associated with poor OS; moreover, low LMR was an independent prognostic factor for OS. Of note, monocyte count and LMR were associated with prognosis more intensively in patients with p16-negative OPSCC. Following these results, we evaluated the peripheral blood mononuclear cells of 14 patients with OPSCC collected before treatments. CD14+ CD86+ HLR-DR+ cells were gated as monocytes, then divided into three subsets according to the expression of CD14 and CD16. The proportion of intermediate monocytes was lower and that of classical monocytes was higher in OPSCC patients than in healthy donors, especially in patients with elevated monocyte count. Furthermore, the expression level of PD-L1 was higher in patients than in healthy donors on all subsets. In conclusion, our data suggests that elevated monocyte count and low LMR seem to be useful biomarkers for predicting prognosis of OPSCC; furthermore, the population shift of monocytes may relate to poor prognosis of OPSCC. Citation Format: Hideyuki Takahashi, Koichi Sakakura, Kazuaki Chikamatsu. Prognostic significance and population shift of peripheral monocytes in patients with oropharyngeal 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 4627. doi:10.1158/1538-7445.AM2017-4627
Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomised, controlled, phase 3, non-inferiority trial
Authors: Charlotte E Coles, Clare L Griffin, Anna M Kirby, Jenny Titley, Rajiv K Agrawal, Abdulla Alhasso, Indrani S Bhattacharya, Adrian M Brunt, Laura Ciurlionis, Charlie Chan, Ellen M Donovan, Marie A Emson, Adrian N Harnett, Joanne S Haviland, Penelope Hopwood, Monica L Jefford, Ronald Kaggwa, Elinor J Sawyer, Isabel Syndikus, Yat M Tsang, Duncan A Wheatley, Maggie Wilcox, John R Yarnold, Judith M Bliss, Wail Al Sarakbi, Sarah Barber, Gillian Barnett, Peter Bliss, John Dewar, David Eaton, Stephen Ebbs, Ian Ellis, Philip Evans, Emma Harris, Hayley James, Cliona Kirwan, Julie Kirk, Helen Mayles, Anne McIntyre, Judith Mills, Andrew Poynter, Elena Provenzano, Christine Rawlings, Mark Sculpher, Georges Sumo, Mark Sydenham, Andrew Tutt, Nicola Twyman, Karen Venables, Anna Winship, John Winstanley, Gordon Wishart, Alastair Thompson
Journal: The Lancet (2017)

Local cancer relapse risk after breast conservation surgery followed by radiotherapy has fallen sharply in many countries, and is influenced by patient age and clinicopathological factors. We hypothesise that partial-breast radiotherapy restricted to the vicinity of the original tumour in women at lower than average risk of local relapse will improve the balance of beneficial versus adverse effects compared with whole-breast radiotherapy.