tbuckley/cabot-search huggingface dataset:
Abstract 4343: Molecular identification of bladder cancer gene expression subtypes
Authors: In-Sun Chu, Bic-Na Song, Sun-Hee Leem
Journal: Cancer Research (2018)

Abstract Bladder urothelial carcinoma (BLCA) comprises two main types: non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). To discovery the subtype of BLCA, we used gene expression data from 165 patient cohort (102 NMIBC, 63 MIBC). Three other gene expression data sets including the Sweden 1 cohort (97 NMIBC, 45 MIBC), the Sweden 2 cohort (213 NMIBC, 93 MIBC), and 408 MIBC sample from The Cancer Genome Atlas (TCGA) and 476 sample (460 NMIBC, 16 MIBC, the multicenter European UROMOL consortium). For selection of subtype-specific gene set, we used significance analysis of microarrays (SAM). Then, subtype-specific genes were trained by prediction analysis for microarrays (PAM) to build a classifier. Clustering analyses were applied to gene expression data of training set identified four molecular subtypes with different clinical outcomes. The majority of patients with class 1 were the low-grade NMIBC and associated with the prognosis of NMIBC, for cancer-specific survival (P =0.003, log-rank test). Class 2 patients, characterized by FGFR3 overexpression and downregulated immune pathways, showed the intermediate prognosis. Class 3 tumors showed high expression of cell-cycle genes and downregulated notch signaling pathway. Furthermore, high-grade NMIBC were predominantly found in class 3, indicating that NMIBC patients classified as class 3 would be more likely to progress to MIBC. Class 4 tumors, mainly composed of MIBC, were characterized by high expression of immune-related genes which is positively associated with potential response to immunotherapy. We further validated the BLCA subtypes in four independent data sets (n = 1,471), including the RNA-seq data set, by applying the 786-gene classifier onto the data sets. As expected, the progression rate of NMIBC patients classified as class 3 was significantly increased compared with other three classes in the RNA-seq data set (P &amp;lt; 0.001, log-rank test). Citation Format: In-Sun Chu, Bic-Na Song, Sun-Hee Leem. Molecular identification of bladder cancer gene expression subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4343.
Significance of Late Diastolic Potential Preceding Purkinje Potential in Verapamil-Sensitive Idiopathic Left Ventricular Tachycardia
Authors: TakeshiTsuchiya, KenOkumura, ToshihiroHonda, TakashiHonda, AtsushiIwasa, HirofumiYasue, ToshifumiTabuchi
Journal: Circulation (1999)

Background—Verapamil-sensitive idiopathic left ventricular tachycardia (VT) is due to reentry with an excitable gap. A late diastolic potential (LDP) is recorded during endocardial mapping of this VT, but its relation to the reentry circuit and significance in radiofrequency (RF) ablation remain to be elucidated. Methods and Results—Sixteen consecutive patients with this specific VT were studied (12 men and 4 women; mean age, 32 years). In all patients, sustained VT was induced and during left ventricular endocardial mapping, LDP preceding Purkinje potential (PP) was recorded at the basal (11 patients), middle (3 patients), or apical septum (2 patients). The area with LDP recording was confined to a small region (0.5 to 1.0 cm2) in each patient and was included in the area where PP was recorded (2 to 3 cm2). The relative activation times of LDP, PP, and local ventricular potential (V) at the LDP recording site to the onset of QRS complex were −50.4±18.9, −15.2±9.6, and 3.0±13.3 ms, respectively. The earli...
Abstract 12133: Prehospital Advanced Life Support and Survival After Traumatic Out-of-Hospital Cardiac Arrest: A Cohort Study From the Japanese National Registry
Authors: Tatsuma Fukuda, Naoko Ohashi-Fukuda, Yutaka Kondo, Takeshi Wada, Kei Hayashida, Ichiro Kukita
Journal: Circulation (2017)

Introduction: There has been controversy as to which is superior, advanced life support (ALS) or basic life support (BLS), for traumatic out-of-hospital cardiac arrest (OHCA), although many studies...
Effect of Verapamil on Long-Term Tachycardia-Induced Atrial Electrical Remodeling
Authors: Shih-HuangLee, Wen-ChungYu, Jun-JackCheng, Chi-RenHung, Yu-AnDing, Mau-SongChang, Shih-AnnChen
Journal: Circulation (2000)

Background—The effect of verapamil on long-term tachycardia-induced atrial electrical remodeling has not been reported. Methods and Results—Forty-eight dogs were randomly divided into verapamil and control groups. The dogs in the verapamil group received verapamil 120 mg every day, those in the control group did not receive verapamil. Atrial effective refractory period (AERP), inducibility of atrial fibrillation (AF), and duration of AF were assessed before and after complete atrioventricular junction ablation with 1-day, 1-week, or 6-week rapid atrial pacing (780 bpm). AERP shortening, AERP dispersion, AERP maladaptation, and inducibility of AF after 1-day pacing was significantly attenuated by verapamil. However, verapamil did not have any significant effect on these parameters in the dogs with 1-week or 6-week pacing. Verapamil did not have any significant effect on the conduction velocity in the dogs with 1-day, 1-week, or 6-week pacing. Before rapid atrial pacing, verapamil significantly prolonged th...
Abstract 2456: The PIWI-interacting RNA pathway in prostate is regulated by vitamin D and altered in cancer
Authors: Bethany Baumann, Shang Gao, Giovanni Lugli, Larisa Nonn
Journal: Cancer Research (2018)

Abstract Low serum vitamin D is a risk factor for aggressive prostate cancer. piRNAs and their interacting partners, PIWI-like (PIWIL) proteins, are aberrantly expressed in many cancers, but few studies have focused on piRNAs in the prostate. We used laser-capture microdissected (LCM) human prostate epithelium from frozen samples collected for a clinical trial of high dose vitamin D to examine the small non-coding RNA population by next-generation sequencing. The 8 patients for this study were selected for having either high (avg=48.7pg/ml) or low (avg=21.4pg/ml) prostatic vitamin D (1,25(OH)2D) levels. VDR ChIP-seq was performed as well, using human primary epithelial cells treated for 3hr with EtOH or 50nM vitamin D. In LCM-collected prostate epithelium unexpectedly piRNAs represented ~20% of the mapped reads. Of all the small RNA species investigated, piRNAs were the most affected by vitamin D status, increasing in abundance in tissues wish high vitamin D (p=0.036, t-test). The LCM data were compared to small-RNA sequencing data from benign prostate available from The Cancer Genome Atlas (TCGA), which represent whole prostate tissue and may contain stromal bias. The LCM-collected samples had a distinct, more consistent profile of small RNAs than TCGA samples. Two unambiguous piRNAs that were highly expressed in LCM data, but not in TCGA data, were verified as epithelial-specific in prostate by in situ hybridization. Several piRNA-biogenesis genes lie within 100kb of VDR ChIP peaks, including TDRKH, which was found to be vitamin D-regulated experimentally. The expression of piRNA-interacting PIWIL proteins was assessed by RT-qPCR, immunoblot and immunofluorescence on a tissue microarray containing paired benign and cancer tissues (N=23). Of the 4 human PIWIL proteins, PIWIL1, 2 and 4 were present in normal prostate epithelial cells by PCR. PIWIL1 protein was also detected in PrE and RWPE-1 benign cells, but PIWIL1 was not detected in the PC3 prostate cancer cell line. By immunofluorescence, PIWIL1 protein in prostate epithelium significantly decreased in prostate cancer (p=0.016, paired t-test). In conclusion, vitamin D status associated with the expression of piRNA in prostate epithelium in clinical trial samples. PIWIL1 protein levels were lower in prostate cancer, suggesting a pro-differentiation role for the PIWI pathway that may be affected in vitamin D-deficient patients. Citation Format: Bethany Baumann, Shang Gao, Giovanni Lugli, Larisa Nonn. The PIWI-interacting RNA pathway in prostate is regulated by vitamin D and altered in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2456.
Abstract 4844: Evidence of PARP-1 dependent cytotoxic agents with low target affinity
Authors: Laura Puentes, Sean Reilly
Journal: Cancer Research (2018)

Abstract Introduction: Inhibition of nuclear protein poly (ADP-ribose) polymerase-1 (PARP1) is synthetically lethal in BRCA mutated cancers. However, the mechanism by which PARPi exert cytotoxic effects is not fully understood. In this study, we compare 16 olaparib analogs and measured their potency in a radioligand binding assay to measure their affinity for PARP1, and in a cytotoxicity assay to measure their ability to serve as a chemotherapeutic. Methods: Compounds were prepared by replacing the piperazine core on olaparib with a series of diazaspiro ring systems. PARP1 affinity was assessed using radioligand binding competition assays. In vitro cytotoxicity was performed on BRCA1 methylated and PARP1-/- ovarian cancer cell lines to evaluate the relative potency of the analog compounds. Results: The 16 analogs displayed lower affinity to PARP1 but comparable or higher potency in cell kill assays when compared to olaparib. Of the 16 compounds, those that contained the diazaspiro core with an N-Boc-functional group displayed the highest degree of potency. Cytotoxicity assays were performed for each compound using PARP1 -/- and PARP2 -/- cells to assess off-target effects. Dose response curves for PARP1-/- cells resulted in a rightward shift; no changes in the dose-response curves were detected for PARP2 -/- cells. Conclusion: Radioligand binding assays demonstrated that these compounds have low PARP1 affinity. Evaluation of the relative potency of these compounds revealed that compounds having a lower PARP1 affinity relative to olaparib still retained a high potency in cell kill assays. In vitro cytotoxicity assays on PARP1 -/- and PARP2 -/- cells confirmed that these compounds are PARP1 but not PARP2 dependent. Future studies will focus on assessing catalytic inhibition of PARP1 and PARP1 trapping in order to better elucidate the antiproliferative effects of these compounds. Citation Format: Laura Puentes, Sean Reilly. Evidence of PARP-1 dependent cytotoxic agents with low target affinity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4844.
Abstract 5638: A tetanus-way of improving synthetic long peptide tumor vaccination
Authors: Jan Wouter Drijfhout, Erika Fletcher, Justyna Leja-Jarblad, Iliana Kerzeli, Robert Cordfunke, Gunilla Tornqvist, Frida Lindqvist, Greta Hultqvist, Rob Valentijn, Sam Ladjervardi, Michael Haggman, Gustav Ullenhag, Sara Mangsbo
Journal: Cancer Research (2018)

Abstract We have previously identified a natural B cell epitope derived from tetanus toxin named Minimal Tetanus Toxin Epitope (MTTE)[1]. Most healthy individuals have IgG1 antibodies to this peptide sequence but no IgM antibodies. We have assessed the possibility to apply this MTTE sequence in drug development with the intention to create immune complexes and use them as vehicles to carry antigen-material into dendritic cells. Thru a conjugation method three MTTE sequences and a longer synthetic peptide stretch harboring T cell epitopes are linked together. As immune complexes are efficient carriers of antigen material and can promote cross-presentation the aim is to use these conjugates for therapeutic purposes in diseases where a strong cellular immune response should be induced. To further evaluate the MTTE peptide conjugates in drug development we have investigated how a diphtheria, tetanus, pertussis (DTP) vaccination induces antibody titers against the linear tetanus sequence. Herein we have studied the MTTE location in the tertiary structure of the protein, how cancer patients respond with antibody titers against MTTE along with a subsequent T cell response and in vivo anti-tumor responses (mice). In addition we have studied safety in terms of cytokine release assessment pre and post a DTP vaccination. We found that the MTTE sequence is part of an alpha-helix that is externally oriented and thereby accessible for peptide binding. We found that not helper epitope is part of the MTTE sequence and that healthy individuals as well as cancer patients can mount IgG titers against the epitope, this also result in more efficient induction of recall responses post a DTP booster than pre boost. Mice seropositive to the MTTE sequence can mount anti-tumor responses, while this is not seen in seronegative animals. In addition, a cytokine release assessment using a modified chandler loop model with intact complement does not display a broad immediate cytokine release pre or post a DTP booster. We conclude that it is efficacious and safe to make use of a peptide conjugate in a drug development project with the aim to use it as a vaccine strategy. [1] Mangsbo et al. In press. Molecular Immunology 2017 Citation Format: Jan Wouter Drijfhout, Erika Fletcher, Justyna Leja-Jarblad, Iliana Kerzeli, Robert Cordfunke, Gunilla Tornqvist, Frida Lindqvist, Greta Hultqvist, Rob Valentijn, Sam Ladjervardi, Michael Haggman, Gustav Ullenhag, Sara Mangsbo. A tetanus-way of improving synthetic long peptide tumor vaccination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5638.
Abstract 4393: Electrochemotherapy with irreversible electroporation and FOLFIRINOX improves survival in murine pancreatic adenocarcinoma by increasing apoptosis and decreasing tumor cell proliferation
Authors: Neal Bhutiani, Harshul Pandit, Qianqian Zheng, Suping Li, Yan Li, Robert C. Martin
Journal: Cancer Research (2018)

Abstract Introduction: Combining gemcitabine (gem) with irreversible electroporation (IRE) has been shown to result in increased tumor cell apoptosis in a murine model of pancreatic adenocarcinoma (PDAC). However, it remains unclear whether this effect can be augmented locally and systemically by utilizing more active chemotherapies. The objective of this study was to evaluate the efficacy of IRE+FOLFIRINOX (FOL: 5-FU, leucovorin, irinotecan, and oxaliplatin). Methods: Athymic nude mice underwent intrapancreatic injection with S2-013 PDAC cells. After 7-10 days, tumors were confirmed with ultrasound and mice were treated with chemotherapy (gem or FOL), IRE, or chemotherapy+IRE. Four hours after last chemotherapy, pancreas was evaluated histologically. Levels of irinotecan and its active metabolite (SN-38) were evaluated in organs of mice treated with FOL and IRE+FOL. Experiments were repeated and survival analyses performed to evaluate long-term efficacy. Pancreas was harvested for histology and evaluation of apoptotic machinery, cell cycle proteins, and tumor cell proliferation. Results: IRE+FOL (ECT) resulted in increased tumor cells apoptosis compared to gem, gem+IRE, or FOL (apoptotic index (AI) 34.6% vs. 3.8%, 7.3%, 5.8%, respectively, p&amp;lt;0.001). High performance liquid chromatography (HPLC) demonstrated a 1.5-2-fold increase in irinotecan and SN-38 in the pancreas and a 4-fold increase of both compounds in the liver in mice treated with ECT vs. FOL. ECT significantly improved overall survival when compared to mice treated with IRE or FOL (median 7 days ECT vs. 4 days IRE vs. 3 days FOL, p=0.03). Histology demonstrated increased tumor cell apoptosis at time of death (AI = 34.2% ECT vs. 13.2% IRE vs. 4.4% FOL, p=0.026). Western blot demonstrated an increase in active caspase 3 (0.14 ECT vs. 0.00 IRE vs. 0.03 FOL fold change/GAPDH, p=0.02). ECT resulted in lower cell proliferation compared to IRE or FOL (0.2% vs. 0.3% vs. 0.9, p&amp;lt;0.001). Conclusions: ECT with IRE and FOL causes significant tumor cell apoptosis, decreases tumor cell proliferation, enhances systemic FOL exposure, and improves overall survival. Human Phase 1 trials have been initiated to evaluate safety and efficacy of this therapeutic modality. Citation Format: Neal Bhutiani, Harshul Pandit, Qianqian Zheng, Suping Li, Yan Li, Robert C. Martin. Electrochemotherapy with irreversible electroporation and FOLFIRINOX improves survival in murine pancreatic adenocarcinoma by increasing apoptosis and decreasing tumor cell proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4393.
Targeting WEE1 to enhance conventional therapies for acute lymphoblastic leukemia
Authors: Andrea Ghelli Luserna Di Rorà, Neil Beeharry, Enrica Imbrogno, Anna Ferrari, Valentina Robustelli, Simona Righi, Elena Sabattini, Maria Vittoria Verga Falzacappa, Chiara Ronchini, Nicoletta Testoni, Carmen Baldazzi, Cristina Papayannidis, Maria Chiara Abbenante, Giovanni Marconi, Stefania Paolini, Sarah Parisi, Chiara Sartor, Maria Chiara Fontana, Serena De Matteis, Ilaria Iacobucci, Pier Giuseppe Pelicci, Michele Cavo, Timothy J. Yen, Giovanni Martinelli
Journal: Journal of Hematology & Oncology (2018)

Despite the recent progress that has been made in the understanding and treatment of acute lymphoblastic leukemia (ALL), the outcome is still dismal in adult ALL cases. Several studies in solid tumors identified high expression of WEE1 kinase as a poor prognostic factor and reported its role as a cancer-conserving oncogene that protects cancer cells from DNA damage. Therefore, the targeted inhibition of WEE1 kinase has emerged as a rational strategy to sensitize cancer cells to antineoplastic compounds, which we evaluate in this study. The effectiveness of the selective WEE1 inhibitor AZD-1775 as a single agent and in combination with different antineoplastic agents in B and T cell precursor ALL (B/T-ALL) was evaluated in vitro and ex vivo studies. The efficacy of the compound in terms of cytotoxicity, induction of apoptosis, and changes in gene and protein expression was assessed using different B/T-ALL cell lines and confirmed in primary ALL blasts. We showed that WEE1 was highly expressed in adult primary ALL bone marrow and peripheral blood blasts (n = 58) compared to normal mononuclear cells isolated from the peripheral blood of healthy donors (p = 0.004). Thus, we hypothesized that WEE1 could be a rational target in ALL, and its inhibition could enhance the cytotoxicity of conventional therapies used for ALL. We evaluated the efficacy of AZD-1775 as a single agent and in combination with several antineoplastic agents, and we elucidated its mechanisms of action. AZD-1775 reduced cell viability in B/T-ALL cell lines by disrupting the G2/M checkpoint and inducing apoptosis. These findings were confirmed in human primary ALL bone marrow and peripheral blood blasts (n = 15). In both cell lines and primary leukemic cells, AZD-1775 significantly enhanced the efficacy of several tyrosine kinase inhibitors (TKIs) such as bosutinib, imatinib, and ponatinib, and of chemotherapeutic agents (clofarabine and doxorubicin) in terms of the reduction of cell viability, apoptosis induction, and inhibition of proliferation. Our data suggest that WEE1 plays a role in ALL blast's survival and is a bona fide target for therapeutic intervention. These data support the evaluation of the therapeutic potential of AZD-1775 as chemo-sensitizer agent for the treatment of B/T-ALL.
Abstract 1862: CX5461 in combination with radiotherapy I effective against gynecological tumors
Authors: Mohammed Ismael, Roger Webb, Mazhur Ajaz, Helen Coley
Journal: Cancer Research (2018)

Abstract An increased rate of cellular proliferation is a hallmark of cancer and may be accompanied by increase in ribosome biogenesis and dysregulation in rRNA synthesis. In this regard CX-5461 has been developed as a novel RNA POL1 inhibitor and is currently in Phase I/II clinical trials. We have set out to explore the use of this agent in combination with radiation therapy and to understand the associated molecular mechanisms using this approach. A panel of human tumour cell lines treated with CX-5461 indicated a broad spectrum of sensitivity (MTT assay) with IC50 values varying from 25nM - &amp;gt;2µM. No clear relationship between p53 status and sensitivity to CX-5461 was indicated and the mode of cell death was cell context dependent - either via autophagy (LC3I→ LC3II conversion, with P62 sequestosome decrease), sometimes via apoptosis (annexinV staining, caspase-3 activation), also in the presence of increased senescence (β-galactosidase activity). Combination treatment experiments involving CX-5461 alongside radiation therapy (0-16Gy) showed marked synergistic effects for some cancer cell lines, particularly the cervical cancer CASKI line (HPV16+ve). Highly significant effects were seen when low dose radiation and low dose CX-5461 were used together in CASKI cells: combination index CI=&amp;lt; 0.2 with 6nM CX-5461 and 2Gy (isobologram analysis). Cell cycle analysis of CASKI cells treated in combination indicated cell cycle disruption with prolonged S-phase, giving some insight into some of the associated mechanisms involved. In addition, we have found that BRCA-mutant PEO1 ovarian cancer cells were sensitive to CX-5461, IC50 approx. 100nM, whereas carboplatin-resistant PEO1CarbR (with reversed BRCA mutant status) cells gave an IC50 value &amp;gt;3µM In addition, proteomic studies have shown that PEO1CarbR cells overexpress a number of nucleolar proteins and we are investigating the relevance of this in relation to CX-5461 sensitivity. Our further studies aim to identify potential biomarkers of response to CX-5461 and may also inform the design of clinical trials of this novel agent. Citation Format: Mohammed Ismael, Roger Webb, Mazhur Ajaz, Helen Coley. CX5461 in combination with radiotherapy I effective against gynecological tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1862.