tbuckley/cabot-search huggingface dataset:
Abstract 820: Enzymatic Methyl-Seq: methylome analysis of challenging DNA samples
Authors: Louise Williams, V K Chaithanya Ponnaluri, Brittany S. Sexton, Lana Saleh, Katherine Marks, Mala Samaranayake, Laurence Ettwiller, Shengxi Guan, Heidi E. Church, Nan Dai, Esta Tamanaha, Erbay Yigit, Bradley Langhorst, Zhiyi Sun, Thomas C. Evans, Romualdas Vaisvila, Eileen Dimalanta, Theodore B. Davis
Journal: Cancer Research (2019)

Abstract DNA isolated from blood draws (cell-free DNA (cfDNA)) or from archival material like formalin fixed paraffin embedded (FFPE) tissues have advanced the field of cancer genetics. DNA methylation (5-methylcytosines (5mC) and 5-hydroxymethylcytosines (5hmC)) is a key epigenetic factor that plays an important role in cellular processes and it’s misregulation results in diseased states like cancer. Advances in the field of sample preparation from biological matrices and genomics have enabled cancer biomarker identification based on methylation profiling. Bisulfite sequencing is the standard method to detect methylation and has been employed for both targeted and whole genome methylation analysis. However, the chemical based bisulfite conversion of cytosines to uracils also results in DNA damage which subsequently results in shorter DNA insert sizes as well as introducing bias into the data. Robust biomarker detection relies primarily on the ability to profile methylation accurately. Analysis of DNA methylation from cfDNA and FFPE DNA is challenging as the DNA is typically of low quality and quantity. To overcome the drawbacks of bisulfite sequencing, we developed an enzyme based methylation detection technology, called NEBNext Enzymatic Methyl-Seq (EM-Seq). DNA damage is minimized enabling longer insert sizes, lower duplication rates and minimal GC bias resulting in more accurate quantification of methylation in the sample DNA. Using EM-Seq, we profiled cfDNA and FFPE DNA from multiple tissue types. Results for these challenging DNA types showed that the EM-Seq libraries had longer inserts, lower duplication rates, higher percentages of mapped reads and less GC bias compared to WGBS libraries. These libraries also identified a higher number of CpG’s and the estimated global methylation levels were in good agreement with the absolute levels quantified using LC/MS. In conclusion, EM-Seq libraries have superior sequencing metrics resulting in robust methylation profiling for these types of challenging DNA samples. Citation Format: Louise Williams, V K Chaithanya Ponnaluri, Brittany S. Sexton, Lana Saleh, Katherine Marks, Mala Samaranayake, Laurence Ettwiller, Shengxi Guan, Heidi E. Church, Nan Dai, Esta Tamanaha, Erbay Yigit, Bradley Langhorst, Zhiyi Sun, Thomas C. Evans, Romualdas Vaisvila, Eileen Dimalanta, Theodore B. Davis. Enzymatic Methyl-Seq: methylome analysis of challenging DNA samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 820.
Health-Related Quality of Life and Symptom Burden in Chronic Myeloid Leukemia Patients Treated with First Line with Imatinib Versus Those Treated with Dasatinib: First Results of the Leonidas Study
Authors: Fabio Efficace, Michele Baccarani, Fabio Stagno, Alessandra Iurlo, Elisabetta Abruzzese, Luigi Scaffidi, Massimo Breccia, Fausto Castagnetti, Emilio Usala, Monica Crugnola, Isabella Capodanno, Bruno Martino, Mario Tiribelli, Gianluca Gaidano, Alberto Bosi, Luigia Luciano, Patrizia Pregno, Francesco Cottone, Patrizia Tosi, Nicola Cascavilla, Gianni Binotto, Susanne Saussele, Claudio Fozza, Micaela Bergamaschi, Rosaria Sancetta, Giovanni Caocci, Gianantonio Rosti
Journal: Blood (2017)
Abstract 4340: A novel fluoride (ChlA-F) transcriptionally upregulates miR494 via a HuR/JunB axis to inhibit cell invasion in human bladder cancers
Authors: Zhongxian Tian, Xiaohui Hua, Jiheng Xu, Junlan Zhu, Jingxia li, Chuanshu Huang
Journal: Cancer Research (2019)

Abstract Bladder cancer (BC) is a commonly occurring cancer and characterized by a low 5-year survival rate particularly in patients with invasive BCs. Here we investigated the chemotherapeutic activity of ChlA-F, a novel C8 fluoride derivative of cheliesisin A (ChelA) with potent anti-neoplastic properties. ChlA-F treatment upregulated miR494 expression and significantly suppressed cell invasion in human BC cell lines. Mechanistically, ChlA-F-induced upregulation of miR494 expression was due to a HuR-mediated increase in JunB mRNA stabilization and protein expression, which led to an increase in miR494 transcription via direct binding to the miR494 promoter region. After ChlA-F treatment, upregulated miR494 was found to bind to the 3’ UTR region of c-Myc mRNA, resulting in decreased c-Myc mRNA stability and protein expression. This, in turn, led to decreased transcription of a c-Myc downstream-regulated gene, MMP-2 and ultimately, inhibition of BC invasion. Here we provide the first evidence showing that our newly synthesized compound, ChlA-F, has a profound inhibitory effect on human BC invasion and elucidate the mechanisms underlying this anti-neoplastic activity. Our data suggest that ChlA-F may be a promising therapeutic alternative for treatment of invasive and metastatic human BC in patients. Citation Format: Zhongxian Tian, Xiaohui Hua, Jiheng Xu, Junlan Zhu, Jingxia li, Chuanshu Huang. A novel fluoride (ChlA-F) transcriptionally upregulates miR494 via a HuR/JunB axis to inhibit cell invasion in human bladder cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4340.
Selecting the Appropriate Patients for Proton Pump Inhibitor Discontinuation
Authors: Kevin D. Platt, Sameer D. Saini, Jacob E. Kurlander
Journal: JAMA Internal Medicine (2019)

This Teachable Moment examines the case of a man in his 70s who presented to the emergency department 2 weeks after discontinuation of proton pump inhibitors (PPIs) to caution against abrupt PPI discontinuation in patients with multiple risk factors for peptic ulcer disease.
Abstract 16717: Relationship Between Survival and Duration of Hypotension in Rat Fixed Pressure Hemorrhagic Shock Model: The First Critical 30 Minutes
Authors: Wangde Dai, Jianru Shi, Juan Carreno, Sharon Hale, Robert A Kloner
Journal: Circulation (2017)

Background: Hemorrhagic shock is a leading killer of soldiers in the battle field. In order to develop a reliable experimental hemorrhagic model for developing new therapeutic strategies for preven...
Abstract 3123: Targeting SHP2 and RAS MAPK pathway in neuroblastoma
Authors: Ivette Valencia-Sama, Teresa Adderley, Lynn Kee, Gabriella Christopher, Yoshihito Kano, Michael Ohh, Meredith Irwin
Journal: Cancer Research (2019)

Abstract Introduction: Neuroblastoma (NB), the most common pediatric extra-cranial solid tumor, recurs in &amp;gt;50% of patients who present with metastases. Strategies to treat relapsed NB, which is often fatal, include targeting relapse-specific signaling pathways. Recently, sequencing studies have revealed that 78% of mutations detected in relapse samples are predicted to activate the RAS-MAPK pathway, suggesting there may be opportunities to pharmacologically target this pathway to treat recurrent NB. Experimental Design: Our lab previously reported that the PTPN11-encoded tyrosine phosphatase SHP2 is an activator of the RAS pathway, and pharmacologic inhibition of SHP2 inhibited glioblastoma growth in vivo. To determine whether inhibiting SHP2 in NB would impact tumor growth we treated a panel of NB cells with diverse genetic backgrounds, including mutations in NRAS, with different SHP2 inhibitors (SHP099 and II-B08) alone and in combination with additional drugs that target RAS-MAPK signaling. Results: In comparison to NB cell lines harboring endogenous NRAS mutations (NRASmt), cells with NRAS wild-type (NRASwt) were more sensitive to SHP2 inhibitors. In addition, NRASwt cells engineered to overexpress NRASmt were more resistant to SHP099 than cells with endogenous or overexpressed NRASwt, as demonstrated by higher levels of proliferation, increased survival, and diminished apoptosis. Furthermore, SHP099 effectively inhibited SHP2 in both NRASwt and NRASmt cells, but only failed to inactivate the downstream RAS effector ERK1/2 in NRASmt cells, suggesting that SHP099 treatment alone is ineffective in cells harboring NRAS mutations. To determine whether SHP099 resistance in NRASmt cells could be overcome with combination strategies, sensitive and resistant NB cells were treated with SHP2 inhibitors alone or in combination with other RAS-MAPK pathway inhibitors (vemurafenib, trametinib and ulixertinib). Interestingly, in comparison to SHP099 or II-B08 alone, all three combinations significantly reduced survival and IC50 values in both NRASwt and NRASmt cells. Using the Bliss independence model we determined all three combinations were synergistic. Conclusions: Our studies demonstrate that NRAS mutations are associated with resistance to SHP2 inhibitors, and that in certain tumors, based on the genetic status of RAS-MAPK-SHP2 signaling components, combinations of drugs targeting this pathway could be effective strategies for relapsed NB. Citation Format: Ivette Valencia-Sama, Teresa Adderley, Lynn Kee, Gabriella Christopher, Yoshihito Kano, Michael Ohh, Meredith Irwin. Targeting SHP2 and RAS MAPK pathway in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3123.
Dietary factors determining diabetes and impaired glucose tolerance
Authors: E.J.M. Feskens, S.M. Virtanen, L. Rasanen, J. Tuomilehto, J. Stengard, J. Pekkanen, A. Nissinen, D. Kromhout
Journal: Diabetes Care (1995)

To investigate the role of diet as a predictor of glucose intolerance and non-insulin-dependent diabetes mellitus (NIDDM). DESIGN AND METHODS--At the 30-year follow-up survey of the Dutch and Finnish cohorts of the Seven Counties Study, in 1989/1990, men were examined according to a standardized protocol including a 2-h oral glucose tolerance test. Information on habitual food consumption was obtained using the cross-check dietary history method. Those 338 men in whom information on habitual diet was also available 20 years earlier were included in this study. Subjects known as having diabetes in 1989/1990 were excluded from the analyses. RESULTS--Adjusting for age and cohort, the intake of total, saturated, and monounsaturated fatty acids and dietary cholesterol 20 years before diagnosis was higher in men with newly diagnosed diabetes in the survey than in men with normal or impaired glucose tolerance. After adjustment for cohort, age, past body mass index, and past energy intake, the past intake of total fat was positively associated with 2-h postload glucose level (P < 0.05). An independent inverse association with the past intake of vitamin C was observed (P < 0.05). These associations were independent of changes in the intake of fat and vitamin C during the 20-year follow-up. An increase in the consumption of vegetables and legumes, potatoes, and fish during the 20-year follow-up was inversely related with 2-h glucose level (P < 0.05). CONCLUSIONS--Although the regression coefficients were in general not very large, these results indicate that a high intake of fat, especially that of saturated fatty acids, contributes to the risk of glucose intolerance and NIDDM. Foods such as fish, potatoes, vegetables, and legumes may have a protective effect. In addition, the observed inverse association between vitamin C and glucose intolerance suggests that antioxidants may also play a role in the development of derangements in glucose metabolism.
HIF-2α Upregulates CCR1 to Promote Dissemination of Plasma Cells in Multiple Myeloma
Authors: Mara N Zeissig, Duncan R. Hewett, Sally Martin, Krzysztof M Mrozik, Chee Man Cheong, Peter Diamond, Luen Bik To, Stan Gronthos, Daniel J Peet, Peter I Croucher, Kate Vandyke, Andrew C. W. Zannettino
Journal: Blood (2017)
Abstract 4071: A novel combination therapy of high intensity focused ultrasound and PDL1 blockades against advanced breast cancer
Authors: Shinya Abe, Takuya Osada, Kensuke Kaneko, Pei Zhong, Herbert K. Lyerly
Journal: Cancer Research (2019)

Abstract Background: Previous studies have reported that tumor debris and inflammation made by high-intensity focused ultrasound (HIFU) therapy induced the antitumor immune response, however, HIFU as a monotherapy is still not potent enough to eradicate tumors and treat distant metastasis. We have reported that mechanical HIFU (M-HIFU), that will mechanically destroy tumor cells/tissues through acoustic cavitation, induced stronger antitumor immune response compared to conventional thermal HIFU (T-HIFU) that will cause thermal ablation of tumors. In the present study, we established an immune based combination therapy of M-HIFU and immune checkpoint blockade to enhance systemic antitumor immune response and treated distant/metastatic tumors in murine breast cancer models. Methods and Results: HER2 oncogene-dependent murine breast cancer cell line, MM3MG-HER2, was established in our lab. In mice with bilateral implantation of MM3MG-HER2 tumors, M-HIFU monotherapy induced stronger HER2-specific cellular response and inhibited the growth of HIFU-untreated distant tumors as well as HIFU treated-tumors, more potently than T-HIFU. Flow cytometry and immunohistochemical analysis of tumor microenvironment revealed significantly stronger accumulation of activated T cell and NK cells in M-HIFU-treated tumors. On the other hand, M-HIFU induced stronger expression of programmed death-ligand 1 (PD-L1) on various immune cells in both sides of tumors than T-HIFU therapy or no treatment control. Based on these findings, we investigated the combination therapy of M-HIFU and PD-1/PD-L1 axis blockades, and found significantly enhanced tumor-specific cellular immune response compared to each monotherapy, which resulted in improved therapeutic effect against distant tumors as well as HIFU treated-tumors. Furthermore, immune cell depletion studies demonstrated that both CD8+ T cells and NK cells played an essential role for the antitumor efficacy in this combinatory therapy against both HIFU-treated tumors and untreated distant tumors. Conclusion: this study provides strong rational evidence that M-HIFU combined with PD-1/PD-L1 axis blockades could be a promising treatment strategy against advanced breast cancer with metastatic lesion. Citation Format: Shinya Abe, Takuya Osada, Kensuke Kaneko, Pei Zhong, Herbert K. Lyerly. A novel combination therapy of high intensity focused ultrasound and PDL1 blockades against advanced breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4071.
Molecular profiling of primary central nervous system lymphoma as compared to activated B-cell subtype of diffuse large B-cell lymphoma.
Authors: Mohamad Barakat, Maher Albitar, Zijun Xu-Monette, Ken H Young, Haifaa Abdulhaq
Journal: Journal of Clinical Oncology (2019)

7549 Background: The cell of origin of primary central nervous system lymphoma (PCNSL) remains controversial. Data using immunohistochemistry (IHC) and Hans algorithm suggested that both germinal-center B-cell–like (GCB) and activated B-cell-like (ABC) subtypes can be seen in PCNSL. We explored the potential of DNA and RNA molecular profiling in characterizing the biology of PCNSL and compared this profile with ABC subtype of diffuse large B-cell lymphoma (DLBCL). Methods: RNA and DNA were extracted from 30 formalin-fixed paraffin-embedded (FFPE) tissue samples from PCNSL patients and 30 FFPE tissue samples from cases with lymph node DLBCL of ABC subtype. Subtyping of DLBCL cases was performed using IHC and gene expression profiling. We sequenced the DNA using a 275 gene panel (Qiagen) and the RNA using a 1382 gene panel (Illumina). Next Generation Sequencing on Illumina platform was used for detecting mutations and expression profiling. The levels of RNA expression were normalized to that of PAX5. Mutations detected by RNA sequencing were compared to those detected by DNA sequencing. Results: There was no significant difference between DLBCL-ABC and PCNSL in mutation rate of MYD88, CD79B, CARD11 or KMT2D: 33.3%, 10%, 10%, and 13.3%, respectively, in DLBCL-ABC vs 30%, 10%, 10%, and 10%, respectively, in PCNSL. However, NOTCH2 mutations were significantly different and detected in 16.7% of DLBCL-ABC as compared with 3% in PCNSL (P=.001). An algorithm that uses expression profiling of 46 different genes and distinguishes DLBCL-ABC from GCB showed that all PCNSL cases classified as ABC. The GCB classical marker LMO2 was expressed at very low level in both DLBCL-ABC and PCNSL, but was at relatively higher level in PCNSL (P=.002, Kruskal-Wallis ANOVA). There was significantly higher expression of the adhesion molecule CXCR4 (P=.008), activation molecules BTK (P=.0003) and PLCG2 (P=.002), and BCL6 (P=.002) in PCNSL as compared with DLBCL-ABC. There was no significant difference between the two groups in MYC, Ki67, BCL2, CD44, or CD274 (PD-L1) expression. Conclusions: DNA and RNA molecular profiling of PCNSL suggests similarity to DLBCL-ABC subtype. However, PCNSL is unique by expressing higher levels of the adhesion molecule CXCR4 and the activation molecules BTK and PLCG2. The lack of increased expression of MYC and Ki67 suggests that PCNSL is unlikely to be similar to Burkitt lymphoma.
Abstract 1491: Immune resistance emerges from tumor-initiating stem cells
Authors: Yuxuan Miao
Journal: Cancer Research (2019)

Abstract The remarkable capacity of the long-lived stem cells-like population to self-renew, initiate and propagate a tumor placed these cancer stem cells (CSC) at the root of tumorigenesis. Many unique molecular features of stem cells endow these key population with specialized properties to drive tumor formation. However, in order to achieve these functions, the neoplastic stem cells must first overcome the immune barrier. Although it has long been postulated that, as the core of a tumor, CSCs must be superior at evading the immune detection, direct evidence is still lacking to demonstrate this stem cell trait. Another important feature of CSCs is that these cells are programed to resist traditional cancer treatments, including chemotherapy and radiation. Yet, it is still unexplored how CSCs react to the immunotherapy, which just start to revolutionize the cancer treatments. In order to address these fascinating questions, we have designed a spontaneous skin squamous cell carcinoma (SCC) mouse model that can be effectively targeted by adoptive cell transfer (ACT)-based immunotherapy, without losing the targeted tumor antigen. Employing this model, we have lineage traced the fate of tumor-initiating stem cells during and after ACT treatment. In this study, we will present data demonstrating that a subset of TGFβ-responding CSCs, residing at the tumor-stromal interface, are always able to survive from the injected CD8+ T cell treatment and give rise to the relapsed tumor. Furthermore, the extensive profiling of ACT surviving stem cells revealed that multiple immune resistant pathways are highly up-regulated in these stem cells. In addition, TGFβ appears to orchestrate these immune resistant processes in the tumor-initiating stem cells. This study highlights CSCs as the core to mediate immune evasion. Citation Format: Yuxuan Miao. Immune resistance emerges from tumor-initiating stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1491.
Efficacy of a therapeutic exercise program on autonomic nervous system function, cardiac function and functional capacity in colorectal cancer survivors: a randomized controlled pilot study
Authors: J. Ruiz-Vozmediano, À. Gutiérrez-Martínez, P. Postigo-Martin, M. Cruz-Fernández, E. González-Flores, I. Cantarero-Villanueva
Journal: Annals of Oncology (2019)
Integrative Molecular Characterization of Resistance to Neoadjuvant Chemoradiation in Rectal Cancer
Authors: Sophia C. Kamran, Jochen K. Lennerz, Claire A. Margolis, David Liu, Brendan Reardon, Stephanie A. Wankowicz, Emily E. Van Seventer, Adam Tracy, Jennifer Y. Wo, Scott L. Carter, Henning Willers, Ryan B. Corcoran, Theodore S. Hong, Eliezer M. Van Allen
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Molecular properties associated with complete response or acquired resistance to concurrent chemotherapy and radiotherapy (CRT) are incompletely characterized. Experimental Design: We performed integrated whole-exome/transcriptome sequencing and immune infiltrate analysis on rectal adenocarcinoma tumors prior to neoadjuvant CRT (pre-CRT) and at time of resection (post-CRT) in 17 patients [8 complete/partial responders, 9 nonresponders (NR)]. Results: CRT was not associated with increased tumor mutational burden or neoantigen load and did not alter the distribution of established somatic tumor mutations in rectal cancer. Concurrent KRAS/TP53 mutations (KP) associated with NR tumors and were enriched for an epithelial–mesenchymal transition transcriptional program. Furthermore, NR was associated with reduced CD4/CD8 T-cell infiltrates and a post-CRT M2 macrophage phenotype. Absence of any local tumor recurrences, KP/NR status predicted worse progression-free survival, suggesting that local immune escape during or after CRT with specific genomic features contributes to distant progression. Conclusions: Overall, while CRT did not impact genomic profiles, CRT impacted the tumor immune microenvironment, particularly in resistant cases.