tbuckley/cabot-search huggingface dataset:
Abstract 3512: Ikaros regulation of the <i>BCL6/BACH2</i> axis and its clinical relevance in acute lymphoblastic leukemia
Authors: Chunhua Song, Zheng Ge, Jianyong Li, Baoan Chen, Elanora Dovat, Katarina Dovat, Jonathon Payne, Sinisa Dovat
Journal: Cancer Research (2017)

Abstract B-Cell CLL/Lymphoma 6 (BCL6) is a proto-oncogene that is highly expressed in acute lymphoblastic leukemia (ALL). BTB and CNC Homology 1 Basic Leucine Zipper Transcription Factor 2 (BACH2) is a suppressor of transcription. The BACH2-BCL6 balance controls selection at the pre-B cell receptor checkpoint by regulating p53 expression. However, the underlying mechanism and the clinical relevance of the BCL6/BACH2 axis are unknown. Here, we found that Ikaros, a tumor suppressor encoded by IKZF1, directly binds to both the BCL6 and BACH2 promoters where it suppresses BCL6 and promotes BACH2 expression in B-cell ALL (B-ALL) cells. Casein kinase 2 (CK2) inhibitors increase Ikaros function thereby inhibiting BCL6 and promoting BACH2 expression in an Ikaros-dependent manner. We also found that the expression of BCL6 is higher while BACH2 expression is lower in patients with B-ALL than normal bone marrow control. High BCL6 and low BACH2 expression is associated with high leukemic cell proliferation, unfavorable clinical and laboratory features, and inferior outcomes. Moreover, IKZF1 deletion is associated with high BCL6 and low BACH2 expression in B-ALL patients. CK2 inhibitors increase Ikaros binding to the promoter of BCL6 and BACH2 and suppress BCL6 while promoting BACH2 expression in the primary B-ALL cells. Our data indicates that Ikaros regulates expression of the BCL6/BACH2 axis in B-ALL. High BCL6 and low BACH2 expression are associated with Ikaros dysregulation and have a potential effect on the development of B-ALL. Citation Format: Chunhua Song, Zheng Ge, Jianyong Li, Baoan Chen, Elanora Dovat, Katarina Dovat, Jonathon Payne, Sinisa Dovat. Ikaros regulation of the BCL6/BACH2 axis and its clinical relevance in acute lymphoblastic leukemia [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 3512. doi:10.1158/1538-7445.AM2017-3512
Abstract 2010: BTK inhibitor BGB-3111 demonstrates anti-tumor activity in solid tumor models
Authors: Nan Hu, Jiye Zhang, Min He, Shuo Zhang, Yong Liu, Lai Wang
Journal: Cancer Research (2017)

Abstract Background BGB-3111 is a novel, irreversible, second generation BTK inhibitor with better selectivity profile and DMPK property compared to ibrutinib. It has demonstrated promising anti-tumor activities in patients with advanced B cell malignancies. Given BTK is expressed in all hematopoietic lineages except for T lymphocytes, it is reasonable to explore the immune modulatory effect of BGB-3111. In this study, we sought to investigate the anti-tumor activity of BGB-3111 in solid tumor models. Methods Cell viability was assessed with Cell Titer Glo® assay and half maximal inhibitory concentrations (IC50) were estimated. In vivo activity was assessed in subcutaneous mouse xenograft models. Treatments were administered by oral gavage and individual body weight and tumor volume was recorded twice weekly. Results In vitro studies showed that MDA-MB-436 cells are insensitive to BGB-3111, which do not expresse BTK. In both human breast cancer MDA-MB-436 and human A431 epidermoid carcinoma subcutaneous xenograft models, the tumor cells were co-injected with peripheral blood mononuclear cells (PBMCs) of healthy donors. In MDA-MB-436 model, BGB-3111 (15 mg/kg, BID) single agent significantly induced tumor growth inhibition (TGI) of 55%, whereas showed no anti-tumor effect if no PBMCs co-injected. Furthermore, co-treatment of BGB-3111 (15 mg/kg, BID) and anti-PD-1 antibody BGB-A317 (10 mg/kg, QW) demonstrated enhanced therapeutic effect in A431 allogeneic model. Interestingly, in BCLU200 and BCLU054 NSCLC primary tumor xenograft models (without PBMC co-injection), BGB-3111 (15 mg/kg, BID) also demonstrated significant anti-tumor activity. Conclusions In summary, BGB-3111 showed interesting activity in solid tumor models, suggesting BTK inhibitor might have potential to be used beyond hematology malignancies. . Citation Format: Nan Hu, Jiye Zhang, Min He, Shuo Zhang, Yong Liu, Lai Wang. BTK inhibitor BGB-3111 demonstrates anti-tumor activity in solid tumor 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 2010. doi:10.1158/1538-7445.AM2017-2010
Abstract 1742: Cancer cell-selective transcriptome analysis reveals new colorectal cancer molecular subtypes with improved biological resolution and superior predictive and prognostic performance
Authors: Claudio Isella, Sara E. Bellomo, Francesco Brundu, Francesco Galimi, Elisa Ficarra, Luigi Marchionni, Livio Trusolino, Andrea Bertotti, Enzo Medico
Journal: Cancer Research (2017)

Abstract Molecular classification of colorectal cancer (CRC) based on gene expression profiling of tumor samples is known to be heavily affected by transcripts of stromal origin. As a consequence, current CRC transcriptional subtypes reflect an admixture of cancer cell-intrinsic traits and tumor microenvironment features. Whether selective analysis of the cancer cell transcriptome could improve CRC subtyping, remains an open issue. In patient-derived xenografts (PDXs), human transcripts only originate from cancer cells, because stromal transcripts are of mouse origin. We therefore assessed cancer-cell intrinsic transcriptional features of CRC by generating human-specific expression profiles of 515 PDXs from 244 CRC patients, and performing unsupervised class discovery. We identified five “CRC intrinsic subtypes” (CRIS A-E) only partially overlapping with the current ones, and robustly enriched for distinct molecular, functional and phenotypic traits: (i) CRIS-A: mucinous, glycolytic, CIMP, and enriched for microsatellite instability or mutations in KRAS; (ii) CRIS-B: marked TGF-β pathway activity, epithelial-mesenchymal transition and poor prognosis; (iii) CRIS-C: MSS, elevated EGFR signaling and sensitivity to EGFR-targeted treatments; (iv) CRIS-D: MSS, WNT activation, and IGF2 overexpression and amplification; (v) CRIS-E: MSS, Paneth cell-like phenotype and higher frequency of TP53 mutation. CRIS subtypes successfully categorized independent sets of primary and metastatic CRCs and cell lines, for a total of over 3000 samples profiled by microarrays and RNAseq. The new subtypes displayed unprecedented predictive and prognostic performances, indipendent from known markers including stromal signatures, whose integration with CRIS further enhanced prognostic significance. Citation Format: Claudio Isella, Sara E. Bellomo, Francesco Brundu, Francesco Galimi, Elisa Ficarra, Luigi Marchionni, Livio Trusolino, Andrea Bertotti, Enzo Medico. Cancer cell-selective transcriptome analysis reveals new colorectal cancer molecular subtypes with improved biological resolution and superior predictive and prognostic performance [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 1742. doi:10.1158/1538-7445.AM2017-1742
PML nuclear bodies are juxtaposed to DNA-DSBs following IR-induced DNA damage
Authors: Kenneth Tse, Farid Jalali, Ramya Kumareswaran, Graham Dellaire, David Bazett-Jones, Robert Bristow
Journal: Cancer Research (2008)

4317   The promyelocytic leukemia (PML) tumor suppressor protein aggregates in discrete PML nuclear bodies (PML-NBs) that are detectable by immunofluorescenct microscopy. PML foci number can change as a function of the cell cycle and various cell stresses, including DNA damage. γ-H2AX nuclear foci are commonly used as an indicator of DNA double strand breaks (DNA-DSBs). γ-H2AX foci increase in response to DNA-DSBs in a time- and dose-responsive fashion and resolve to background level upon the repair of DNA-DSBs. Our labs have previously published (Dellaire et al., JCB, 2006) the post-irradiation kinetics of γ-H2AX and PML foci in asynchronous cell populations. In the minutes following DNA damage, PML foci increased in number especially in S-phase cells. However, whether PML-NBs were associated with exogenous or endogenous (e.g. DNA replication associated) damage was unclear. In a detailed study, we have determined the number and intra-nuclear locale of γ-H2AX and other DNA repair biomarkers (e.g. 53BP1, RAD51, RPA, MRE11, TRF2 and MDC1) in relation to PML foci, within G0-G1 synchronized normal human fibroblasts (GM5757) to solely characterize PML responses to exogenous DNA damage. Following a clinically-relevant dose of 2Gy, PML foci number remained constant over 24 hours in contrast to initial induction and resolution kinetics of the known DNA-DSB biomarkers. In other studies, PML foci number was independent of radiation dose and in contrast to γ-H2AX and 53BP1, did not show increased residual foci at 24 hours in 180BR (NHEJ-deficient) cells or following DNA-PKcs biochemical inhibition with KU-7440. However, 3-D confocal microscopy studies showed that PML bodies juxtaposed to the sites of γ-H2AX-associated DNA-DSBs suggesting involvement in unique chromatin-based locales of DNA repair. Ongoing experiments are testing whether this juxtaposition is in euchromatin or heterochromatin and whether S-phase cells differ in this PML-associated biology. The effect of hypoxia is also being investigated on PML/DNA-DSB juxtaposition and will be reported. Our studies support that PML-NBs are juxtaposed with DNA-DSBs following both exogenous and endogenous DNA damage and may be preferential intranuclear sites of DNA repair.
Pathology of a Transplantable Spontaneous Hepatoma in a C3H Mouse&lt;xref ref-type="fn" rid="fn1"&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/xref&gt;
Authors: Jesse E. Edwards, Albert J. Dalton, Howard B. Andervont
Journal: JNCI Journal of the National Cancer Institute (1942)

Journal Article Pathology of a Transplantable Spontaneous Hepatoma in a C3H Mouse Get access Jesse E. Edwards, Jesse E. Edwards research fellow National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar Albert J. Dalton, Albert J. Dalton cytologist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar Howard B. Andervont Howard B. Andervont principal biologist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 2, Issue 6, June 1942, Pages 555–563, https://doi.org/10.1093/jnci/2.6.555 Published: 01 June 1942
Abstract 4945: Axl-hi DTCs in the bone marrow of a genetically engineered mouse model of prostate cancer exhibit decreased proliferation
Authors: Haley D. Axelrod, Kenneth C. Valkenburg, Brian W. Simons, Kenneth J. Pienta
Journal: Cancer Research (2017)

Abstract The majority of prostate cancer (PCa) deaths are attributed to bone metastases, which may not arise until years after the primary tumor has been removed. Disseminated tumor cells (DTCs) have been shown to already be present in the bone marrow of patients at the time of prostatectomy, and it is thought that they undergo a period of dormancy, allowing them to remain undetected for years before manifesting into clinically detectable metastases. It is not known what allows PCa DTCs to undergo and persist in this dormant state, but it is likely that factors in the bone marrow niche play an essential role. Previously our group has shown that one of these niche factors, Gas6, can regulate growth of PCa cells. The growth restraining effects of Gas6 on PCa cells is likely mediated through the tyrosine kinase receptor Axl, whose expression was found to be increased on dormant DTCs compared to proliferating metastases in a xenograft mouse model. Here, we utilized the TRAMP model, a genetically engineered mouse model of spontaneous PCa progression, to compare the frequency of Axl-hi and Axl-low bone marrow DTCs that are proliferating versus non-proliferating. Further, we also compared Axl expression and proliferation in matched primary tumors. To investigate the functional significance of Gas6/Axl signaling in mediating PCa dormancy, we have generated Axl knockout PCa cells to test the requirement of Axl in maintaining dormancy, and Axl overexpressing PCa cells to test the sufficiency of Axl in mediating dormancy. Determining the role of Axl and any other regulatory mechanisms of PCa DTC dormancy will be crucial in efforts to prevent lethal and incurable metastasis. Citation Format: Haley D. Axelrod, Kenneth C. Valkenburg, Brian W. Simons, Kenneth J. Pienta. Axl-hi DTCs in the bone marrow of a genetically engineered mouse model of prostate cancer exhibit decreased proliferation [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 4945. doi:10.1158/1538-7445.AM2017-4945
Periodontal plastic surgery of gingival recessions at single and multiple teeth
Authors: Francesco Cairo
Journal: Periodontology 2000 (2017)

Abstract This manuscript aims to review periodontal plastic surgery for root coverage at single and multiple gingival recessions. Techniques are assessed based on biological principles, surgical procedures, prognosticative factors and expected clinical and esthetic outcomes. The use of coronally advanced flap, laterally sliding flap, free gingival graft, the tunnel grafting technique, barrier membranes, enamel matrix derivative, collagen matrix and acellular dermal matrix are evaluated. The clinical scenario and practical implications are analyzed according to a modern evidence‐based approach.
Abstract LB-211: Phenotypic change specific to tumor-infiltrating regulatory T cells by LFPRLR knockdown
Authors: Kuan-Hui E. Chen, Ameae Walker
Journal: Cancer Research (2017)

Abstract The clinical relevance and prognostic significance of tumor-infiltrating Tregs in different types of cancers makes them appealing therapeutic targets. However, targeting all Tregs initiates autoimmune disease. In the current study, we have found that knockdown of the long form of the prolactin receptor (LFPRLR) inhibits the function of tumor Tregs with no functional change in peripheral Tregs. Knockdown of the LFPRLR was by splice modulating oligomer (SMO), tested in the syngeneic 4T1-Balb/c immune-competent breast cancer model. Similar effects would be predicted to occur in prostate and ovarian cancer. Knockdown reduced tumor output of CCL17, a chemokine regulated by the major LFPRLR signaling Jak2/Stat5 pathway. Reduced CCL17 output in turn resulted in impaired Treg recruitment into tumors, allowing enhanced CD4+ and CD8+ T cell activities within the tumor and reducing metastasis to distal organs. Also observed was a reduction in Tregs at metastatic sites. RNAseq transcriptomic analysis of LFPRLR SMO-treated tumor Tregs revealed that among immune-suppressive cytokines, expression of IL-10 and TGF-β was not affected, but EBI3, a component of IL-35, became undetectable. Of cytokines known to promote metastasis, IL-6, IL23a and IL34 were reduced. When tumor Tregs, isolated from LFPRLR SMO-treated animals, were co-cultured with 4T1 breast cancer cells, they failed to drive epithelial to mesenchymal transition, while tumor Tregs isolated from control SMO-treated animals did transform 4T1 cells into a more mesenchymal phenotype. Although tumor T regs were reduced by treatment, other major components of the tumor microenvironment, including B cells, CD8+ T cells, macrophages, NK T cells, dendritic cells, myeloid-derived suppressor cells, and fibroblasts were not changed by LFPRLR knockdown, while effector CD4+ T cells were increased and tumor endothelial cells were decreased. Although the population of CD8+ T cells was not changed, their activity was enhanced, as determined by their production of IL-2 and IFN-γ when stimulated. Examination of splenic Tregs from animals treated with LFPRLR- or control SMO for 28 days showed normal suppressive activity of anti-CD3-stimulated T cell proliferation. In conclusion, systemic LFPRLR knockdown has direct and indirect effects on tumor Tregs that modify their cytokine profile and reduce their suppressive capability and ability to drive epithelial to mesenchymal transition of tumor cells. Citation Format: Kuan-Hui E. Chen, Ameae Walker. Phenotypic change specific to tumor-infiltrating regulatory T cells by LFPRLR knockdown [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 LB-211. doi:10.1158/1538-7445.AM2017-LB-211
Abstract 4429: An exhaled microRNA panel interrogation and validation as risk biomarkers for lung cancer
Authors: Simon D. Spivack
Journal: Cancer Research (2017)

Abstract Background: There is a need for non-invasive airway-based biomarkers in lung carcinogenesis for both risk assessment of the ex-smoker, and earlier diagnosis. Recent studies have revealed that microRNAs play important regulatory roles in carcinogenesis. Exhaled breath condensate (EBC) contains airway lining fluid molecules, including nucleic acids, presumably in part from epithelial cellular origins. Here we further develop and begin validation of the detection of microRNAs in EBC from lung cancer patients and controls. Methods: Exhaled breath condensate (EBC) was collected non-invasively, using a handheld device in ambulatory subjects. MicroRNA expression profiling using RNA-specific RT-qPCR was performed in EBC in an initial batch (E) of 88 individuals (41 lung cancer cases, 47 controls), and a second batch D of 88 individuals (41, cases and 47 controls). We generated a 39 miR panel based on literature-derived microRNAs, combined with a lung tissue-based discovery effort we have performed using microRNA-seq on lung tumors and surrounding non-tumor tissue. The qPCR primers were designed using our previously published RNA-specific realtime RT-PCR technique. All samples were run twice with positive and negative controls. Results: Qualitative analyses of the first donor batch E was performed on 39 microRNAs measured in 41 cases and 47 controls. Chi-square analysis (univariate) within the training set (batch E) revealed that exhaled miR-31, 33, 105, 200b, 944, 1269a were significantly different between the initial set of cases and controls; their absence marked the cases. In the validation batch (D) preliminary analysis, exhaled miRs 200b (this time present in cases, p=0.044) and 944 (again absent in cases, p=0.052) were case-control discriminant. In addition, test set batch D showed case-control discrimination for additional miRs 130b-3p (present in cases, p=0.035), 212 (absent in cases, p=0.009), 1910a (absent in cases, p=0.006) and other microRNAs that were not seen in the qualitative training set (batch E). Importantly, multi-miR discriminant signatures, quantitative analysis, and risk ROC/modelling analyses are pending as of this AACR abstract deadline. Conclusion: This new exhaled biomarker platform can yield case-control discriminant microRNA sets, including a subset of miRs that can validate in test sets. Once further distilled and validated, our goal is to apply this non-invasive biomarker approach to prospective cohorts for non-invasive lung cancer risk assessment, in order to better select higher risk individuals who should undergo CT screening. Note: This abstract was not presented at the meeting. Citation Format: Simon D. Spivack. An exhaled microRNA panel interrogation and validation as risk biomarkers for lung 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 4429. doi:10.1158/1538-7445.AM2017-4429
Abstract 3896: Exosomes derived from CD133+hepatocellular carcinoma (HCC) cell promote the acquisition of stem cell-like properties of the targeted HCC cell via the Akt/GSK 3β/Snail and cyclin D1 pathways
Authors: Pengyi Guo, Haitao Yu, Xiaozhai Xie, Yi Wang, Gang Chen
Journal: Cancer Research (2017)

Abstract Backgrounds and Aims: Liver cancer stem cells are closely related to the recurrence and metastasis of hepatocellular carcinoma (HCC). However, the mechanism underlying the reciprocity between liver cancer stem cells and HCC cells in the tumor microenvironment remains unclear. Exosomes act as natural shuttles to deliver bioactive molecules that alter the behavior of the recipient cells, offering a new means of cell-cell communication for physiological and pathological processes in the liver. This study aimed to clarify whether the exosomes derived from the liver stem cells could facilitate the acquisition of stem cell-like properties of the adjacent HCC cells, thereby promoting the malignant process of HCC. Methods: CD133+ liver cancer stem cells were isolated from the highly invasive HCC-LM3 cells or tumor tissues of HCC patients using flow cytometry and were identified using qPCR and immunofluorescence. The exosomes from CD133+ liver cancer stem cells were identified using CD133 and other stem cell markers, and they were then used to treat HepG2 and Hep3B cells. The cell viability, invasion ability, sphere formation and tumorigenesis abilities of the treated HepG2 and Hep3B cells were analyzed to reveal the effect of CD133+ exosomes, and the underlying molecular mechanism was further explored. Results: CD133+ liver cancer stem cells were successfully isolated from HCC-LM3 cells and HCC patients’ tumor tissues, which were able to release CD133+ exosomes. The intake of CD133+ exosomes promoted the putative stem cell phenotype of Hep3B and HepG2 cells, as evidenced by significantly enhanced cell proliferation, invasion and sphere formation abilities in vitro and tumorigenesis in vivo. In additional, we found that CD133+ exosomes activated the PI3K/Akt/GSK3β/Snail and cyclin D1 pathway, thereby reducing the expression of E-Cadherin and promoting the epithelial-mesenchymal transition (EMT) of HCC cells. Conclusions: Our results suggest that exosomes derived from CD133+ HCC cells can change the malignant behavior and promote the acquisition of stem cell-like properties of targeted HCC cells via the Akt/GSK 3β/Snail and cyclin D1 pathways. Note: This abstract was not presented at the meeting. Citation Format: Pengyi Guo, Haitao Yu, Xiaozhai Xie, Yi Wang, Gang Chen. Exosomes derived from CD133+ hepatocellular carcinoma (HCC) cell promote the acquisition of stem cell-like properties of the targeted HCC cell via the Akt/GSK 3β/Snail and cyclin D1 pathways [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 3896. doi:10.1158/1538-7445.AM2017-3896