tbuckley/cabot-search huggingface dataset:
Abstract 3602: Validation and implementation of next-generation sequencing in liquid biopsies by a novel NGS platform: Focus on non-small cell lung cancer
Authors: Atil Bisgin, Ozge Sonmezler, Ibrahim Boga
Journal: Cancer Research (2018)

Abstract Introduction: Liquid biopsy as a novel and non-invasive test for the surveillance of cancer is rapidly growing, by next-generation sequencing (NGS) technologies with multi-gene panels. Objective: The aim of this study was to describe the validation and implementation of a cell free tumor DNA (cfDNA) from the patients with non-small cell lung cancer (NSCLC), to sequence for 19 genes and copy number variation analyses for 5 genes via a novel NGS platform; GeneReader NGS System. Materials and Methods: We performed the complete NGS workflow with modifications, and sequenced the cfDNA extracted from 100 NSCLC patients. The multi-gene panel includes 19 lung cancer related genes (AKT1, ALK, BRAF, DDR, ERBB2, ESR1, KIT, KRAS, MAP2K1, NRAS, NTRK, PDGFRA, PIK3CA, PTEN and ROS) to sequence and additional copy number variations of 5 genes (RICTOR, EGFR, MET, FGFR1 and ERBB2) that all were selected to represent the most actionable genes for the clinical oncology and molecular diagnostics. The sequencing was performed using a novel NGS platform (GeneReader NGS System, Qiagen). Results: The validation process and the implementation of genetic testing from the cfDNA by this novel NGS system have been utilized for the clinical use. After quality assessment, the data from this NGS system was bioinformatically processed and a tertiary analysis was performed using QCI-Analyze and QCI-Interpret bioinformatics tools. The data was then reviewed on alterations and those reported in different mutation databases. The clinically relevant alterations were identified and reported due to the testing indications. Overall, actionable variants in EGFR, ALK, KRAS, PIK3CA, MET, FGFR1 and ERBB2 genes were detected and reported in 62 % of all NSCLC patients while the majority were in EGFR. Conclusions: For each of the 100 samples tested thus far, at least one variant was detected showing the high sensitivity and specificity of both the multi-gene panel and this novel NGS platform. Our evaluation yielded good results for the actionable multi-gene panel selected and provides a comprehensive NGS analysis and workflow for this new platform. Citation Format: Atil Bisgin, Ozge Sonmezler, Ibrahim Boga. Validation and implementation of next-generation sequencing in liquid biopsies by a novel NGS platform: Focus on non-small cell lung 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 3602.
Maturation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes by Soluble Factors from Human Mesenchymal Stem Cells
Authors: Shohei Yoshida, Shigeru Miyagawa, Satsuki Fukushima, Takuji Kawamura, Noriyuki Kashiyama, Fumiya Ohashi, Toshihiko Toyofuku, Koichi Toda, Yoshiki Sawa
Journal: Molecular Therapy (2018)

In this study, we proposed that the functionality or phenotype of differentiated cardiomyocytes derived from human induced pluripotent stem cells (iPSC-CMs) might be modified by co-culture with mesenchymal stem cells (MSCs), resulting in an improved therapeutic potential for failing myocardial tissues. Structural, motility, electrophysiological, and metabolic analyses revealed that iPSC-CMs co-cultured with MSCs displayed aligned myofibrils with A-, H-, and I-bands that could contract and relax quickly, indicating the promotion of differentiation and the establishment of the iPSC-CM structural framework, and showed clear gap junctions and an electric pacing of >2 Hz, indicating enhanced cell-cell interactions. In addition, soluble factors excreted by MSCs, including several cytokines and exosomes, enhanced cardiomyocyte-specific marker production, produced more energy under normal and stressed conditions, and reduced reactive oxygen species production by iPSC-CMs under stressed condition. Notably, gene ontology and pathway analysis revealed that microRNAs and proteins in the exosomes impacted the functionality and maturation of iPSC-CMs. Furthermore, cell sheets consisting of a mixture of iPSC-CMs and MSCs showed longer survival and enhanced therapeutic effects compared with those consisting of iPSC-CMs alone. This may lead to a new type of iPSC-based cardiomyogenesis therapy for patients with heart failure.Graphical abstract
Abstract 3838: Inhibition of the spectraplakin protein MACF1 sensitizes glioblastomas to BCNU
Authors: Danielle Borlay, Kala Bonner, Orica Kutten, Katelyn Atkinson, Quincy A. Quick
Journal: Cancer Research (2018)

Abstract Glioblastoma heterogeneity and diversity is recognized as a major contributing factor to the resistance of these cancers to clinical chemo- and radiotherapy treatment regimens. This diversity is attributed in part to a plethora of novel unevaluated proteins whose functions participate in glioblastoma etiology, progression, and recurrence. One such protein is the cytoskeletal cross-linker, Microtubule Actin Crosslinking Factor 1 (MACF1), which we have previously shown was expressed at high levels in glioblastoma tissue as compared to its absence in normal brain tissue. In support of these findings immunoblotting expression analysis in this study showed that MACF1 protein expression was upregulated in response to BCNU exposure in glioblastoma cells. Subsequently, experiments were conducted to assess the combinatorial effect of MACF1 inhibition in conjunction with BCNU treatment. A CRISPR-Cas9 genome editing approach was used to inhibit MACF1 function prior to drug exposure. Cell proliferation analysis revealed a cooperative synergistic effect of MACF1 inhibition and BCNU treatment on the reduction of glioblastoma cells as compared to cells treated with either BCNU or CRISPR inhibition of MACF1 alone. In conclusion, upregulation of MACF1 in response to BCNU suggests that this spectraplakin protein may play a role in the mechanistic resistance of glioblastomas to BCNU and the therapeutic prognosis of glioblastomas treated with this drug. Additionally, this study demonstrated that MACF1 inhibition is a novel neoadjuvant approach that enhances the therapeutic efficacy of BCNU. Citation Format: Danielle Borlay, Kala Bonner, Orica Kutten, Katelyn Atkinson, Quincy A. Quick. Inhibition of the spectraplakin protein MACF1 sensitizes glioblastomas to BCNU [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 3838.
Abstract 5315: Frequent downregulation of <i>SALL3</i> by recurrent genetic and epigenetic alterations is involved in triple-negative breast cancers
Authors: Yosuke Matsushita, Masato Komatsu, Kazuma Kiyotani, Tetsuro Yoshimaru, Hiromu Suzuki, Yasuo Miyoshi, Mitsunori Sasa, Toyomasa Katagiri
Journal: Cancer Research (2018)

Abstract Triple negative breast cancers (TNBC), defined by the lack of estrogen and progesterone receptors and HER2 gene amplification, is a heterogeneous and clinically aggressive disease due to the lack of beneficial therapeutic targets. Even though one of the most major risk for the development of TNBC is carrying a deleterious germline and somatic mutations of BRCA1 are not frequently found in sporadic cases of TNBC. Therefore, we aimed to search genomic alterations in TNBC cases by whole-exome sequencing analysis of genomic DNAs from 36 Japanese patients with TNBC compared with their corresponding normal. We identified 36 genes that were recurrently mutated (&amp;gt;10% of cases) in TNBC cases, including TP53 and PIK3CA as described in the previous next generation sequencing analysis of TNBC cases. Remarkably, we identified a number of epigenetic-related genes involved in histone modification and DNA methylation, which were mutated in 20 out of 36 (55.6%) cases. Among them, we focused on spalt like transcription factor 3 (SALL3) gene which shows recurrent somatic mutations, and are most frequently downregulated in TNBC cases. Nonsense-mutation of SALL3 (E169X) completely abolish its binding to DNAMT3A. Ectopic overexpression of the wildtype SALL3, but not the somatically mutated SALL3 into BT549 breast cancer cells, which expresses low level of SALL3 gene, caused the significant suppression of cell growth. Importantly, SALL3 gene was frequently hypermethylated and transcriptionally silenced in only TNBC cases, but not in other types of breast cancer using TCGA data sets. Moreover, the expression of SALL3 was restored after treatments of 5-aza-2'-deoxycitidine (5-aza-dC) in TNBC cell line, HCC1937. Notably, siRNA-mediated knockdown of SALL3 expression in BT20 cells enhanced chemoresistance against paclitaxel and docetaxel, respectively. Moreover, low expression of SALL3 was associated with significantly shorter relapse free survival. Our findings provide the evidence of a pathophysiological role for SALL3 as a tumor suppressor which is possibly associated with carcinogenesis for TNBC. Citation Format: Yosuke Matsushita, Masato Komatsu, Kazuma Kiyotani, Tetsuro Yoshimaru, Hiromu Suzuki, Yasuo Miyoshi, Mitsunori Sasa, Toyomasa Katagiri. Frequent downregulation of SALL3 by recurrent genetic and epigenetic alterations is involved in triple-negative breast cancers [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 5315.
Abstract CT067: A phase Ib study of Toca 511, a retroviral replicating vector, followed by Toca FC in patients with advanced cancer
Authors: Jaime Merchan, Jordi Rodon, Gerald Falchook, Shree Venkat, Derek Ostertag, Dalissa Tejera, Thian Kheoh, Douglas J. Jolly, Harry E. Gruber, Jolene S. Shorr
Journal: Cancer Research (2018)

Abstract Toca 511 (vocimagene amiretrorepvec) is an investigational, conditionally lytic retroviral replicating vector (RRV) that selectively infects cancer cells. Toca 511 spreads through tumors, stably delivering an optimized cytosine deaminase (CD) gene that converts the prodrug, Toca FC (investigational, extended-release 5-FC), into 5-FU. Based on preclinical studies, 5-FU kills infected dividing cancer cells and diffuses and kills surrounding cancer cells, myeloid derived suppressor cells, and tumor associated macrophages, thus reestablishing tumor immunity. In a previous Phase 1 study, intravenous (IV) injection of Toca 511 successfully delivered and expressed CD protein to high grade glioma tumors. In animal models of metastatic colorectal cancer, IV Toca 511 infected metastatic sites, and subsequent 5-FC treatment resulted in decreased tumor size and improved survival. Toca 6 is a Phase 1b, multicenter, open-label study in patients with advanced solid tumors or lymphoma (NCT02576665) designed to investigate changes in immune activity after treatment with Toca 511 &amp; Toca FC. Vector deposition and transgene expression in tumor tissue following IV delivery of Toca 511 also is followed. Toca 511 is injected IV daily for 3 days, with subsequent injection either intratumorally after biopsy or, in the brain tumor setting, into resection cavity walls following resection. Oral Toca FC is started approximately 4 weeks later and repeated every 4-6 weeks. A total of 30 patients are planned to be enrolled. In patients treated to date, viral RNA, DNA, and CD protein expression after IV Toca 511 delivery have been detected in liver metastases from colorectal cancer and mesenteric lymph node metastases from pancreas cancer, demonstrating IV delivery of virus to and transgene expression in tumor. Preliminary data indicate treatment has been generally well tolerated to date, with few related adverse events. Data on changes from baseline in immune activity in tumor (infiltrating T-cell subpopulations, B cells, monocytes) and peripheral blood (effector, memory, Treg, and myeloid lineage cells), viral and CD protein expression in tumor, and safety will be presented. Citation Format: Jaime Merchan, Jordi Rodon, Gerald Falchook, Shree Venkat, Derek Ostertag, Dalissa Tejera, Thian Kheoh, Douglas J. Jolly, Harry E. Gruber, Jolene S. Shorr. A phase Ib study of Toca 511, a retroviral replicating vector, followed by Toca FC in patients with advanced 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 CT067.
Abstract 5930: Oral siRNA delivery for colorectal liver metastases cancer therapy
Authors: Sung-Hun Kang, Vishnu Revuri, Sungpil Cho, In-Kyu Park, Kwang Jae Cho, Woo Kyun Bae, Yong-Kyu Lee
Journal: Cancer Research (2018)

Abstract Liver metastasis (CLM) is the lethal secondary hepatic cancer with 5 - 20 months' average survival rate and mostly originated from colorectal cancer (CRC). Surgery and systemic chemotherapy are the currently best options to treat patients. However, over 60% of recurrence rate and severe side effects such as sinusoidal obstruction syndrome and nodular regenerative hyperplasia from the systemic chemotherapy significantly impact on patient's recovery from the treatment. To overcome these side effects and also achieve the synergistic therapeutic effect, we developed a dual padlock system (AR-GT) for oral siRNA delivery to regulate PI3K/Akt signaling pathway, which is highly associated with the progression of CRC to CLM. AR-GT is an about 130 nm nanoparticle consisted of a gold nanoparticle core anchoring siAkt RNA (AR) and a single outer layer of glycol chitosan-taurocholic acid (GT) conjugate. GT layer plays several roles in oral siRNA delivery such as the protection of siRNA in the gastrointestinal (GI) environment, facilitation of ileac uptake of AR-GT in the small intestine and transportation of AR-GT through enterohepatic circulation into the liver. In vitro characterization of AR-GT demonstrated the protection of siRNA under simulated GI pHs for 5 days, facilitation of the trans-epithelial transport in the intestinal Caco2 and ASBT positive cells, and reduction of Akt protein by successful release of siAKT from the AR-GT. Following oral delivery of AR-GT to CLM mouse model, we observed high biodistribution of AR-GT in the ileum, liver, and kidney through intestinal uptake, enterohepatic transportation, and renal excretion. Moreover, CLM mouse after oral delivery of AR-GT (100 μg/kg) manifested about 58 % reduction of the numbers of tumor nodules in the liver and near 100% survival benefit compared to control mouse fed with either saline or AR-Chitosan nanoparticles. Further analysis of liver samples obtained from CLM mouse after oral delivery of AR-GT indicated about 38% reduction of pAkt expression and the enhancement of apoptotic protein expressions such as 2 times or 1.5 times increase of caspase 9 and bax. Theses observation suggests survival benefit and tumor nodule reduction in CLM mouse root on successful AR-GT mediated oral siAkt RNA delivery. we conclude AR-GT oral siRNA delivery system is beneficial in the CLM treatment and further suggest its application to target other cancers. Citation Format: Sung-Hun Kang, Vishnu Revuri, Sungpil Cho, In-Kyu Park, Kwang Jae Cho, Woo Kyun Bae, Yong-Kyu Lee. Oral siRNA delivery for colorectal liver metastases cancer therapy [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 5930.
Abstract 350: Che-1/aatf-induced transcriptionally active chromatin promotes cell growth in multiple myeloma
Authors: Tiziana Bruno, Francesca De Nicola, Frauke Goeman, Matteo Pallocca, Cristina Sorino, Valeria Catena, Gianluca Bossi, Bruno Amadio, Giovanni Cigliana, Enrico Spugnini, Maria Rosaria Ricciardi, Maria Teresa Petrucci, Alfonso Baldi, Mario Cioce, Giancarlo Cortese, Elisabetta Mattei, Roberta Merola, Umberto Gianelli, Francesco Pisani, Svitlana Gumenyuk, Andrea Mengarelli, Katja Hopker, Thomas Benzing, Aristide Floridi, Claudio Passananti, Giovanni Blandino, Simona Iezzi, Maurizio Fanciulli
Journal: Cancer Research (2018)

Abstract Tumor transformation is the result of genetic and epigenetic modifications that alter gene transcription, consequently producing a specific oncogenic program. Multiple myeloma (MM) is a neoplasia characterized by the accumulation of proliferating antibodies producing plasma cells in the bone marrow. This disease is the second most frequent haematological malignancy in the US and Europe. In this study we demonstrate that Che-1 plays a crucial role in the control of transcription and cellular proliferation by regulating the state of the chromatin and by increasing its accessibility, highlighting Che-1 as an essential component of the transcription machinery in MM. Che-1 loss induces a global transcription shut-off, by reducing RNA Pol II recruitment onto the DNA. Most importantly, transcriptional inhibition in Che-1 depleted cells could already be detected at pre-mRNA levels, leading to the hypothesis that Che-1 could regulate RNA pol II activity directly. Our study shows that Che-1 is required for the maintenance of open chromatin in MM cells, and is involved in general histone acetylation. Morever, we found that Che-1 downregulation further sensitizes MM cells to bromodomain and extra-terminal (BET) inhibitors. Indeed Che-1 silencing increased JQ1 sensitivity of MM cells. In summary, our findings identify Che-1 as a key player for maintaining the open chromatin structure required for sustaining MM growth. These findings support Che-1 as a possible target for MM therapy, alone or in combination with BET inhibitors. Citation Format: Tiziana Bruno, Francesca De Nicola, Frauke Goeman, Matteo Pallocca, Cristina Sorino, Valeria Catena, Gianluca Bossi, Bruno Amadio, Giovanni Cigliana, Enrico Spugnini, Maria Rosaria Ricciardi, Maria Teresa Petrucci, Alfonso Baldi, Mario Cioce, Giancarlo Cortese, Elisabetta Mattei, Roberta Merola, Umberto Gianelli, Francesco Pisani, Svitlana Gumenyuk, Andrea Mengarelli, Katja Hopker, Thomas Benzing, Aristide Floridi, Claudio Passananti, Giovanni Blandino, Simona Iezzi, Maurizio Fanciulli. Che-1/aatf-induced transcriptionally active chromatin promotes cell growth in multiple myeloma [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 350.
Evaluation of perioperative therapy for stage II and III rectal cancer in California, 1994-2009.
Authors: Myung Mi Cho, John Morgan, Sumana Chenna, Raymond Knutsen, Kevork Kazanjian
Journal: Journal of Clinical Oncology (2012)

1587 Background: Surgical treatment of stage II and III rectal cancer changed little during the past two decades, while ancillary therapies have undergone two evolutionary changes. We sought to evaluate changes in chemoradiation (chemoRT) practices for patients receiving radical operations for stage II and III rectal cancer in California, 1994-2009. Methods: We extracted age, sex, race/ethnicity (R/E), socioeconomic status (SES) (demographic variables) and chemoRT variables for stage II and III rectal cancer cases in California. We used unconditional logistic regression to compute independent odds ratios of receiving preoperative chemoRT (PreOP Tx) to postoperative chemoRT (PostOP Tx) during Early (1994-1999), Middle (2000-2003), and Late (2004-2009) time-periods using the late time-period as the referent group. Results: Logistic regression analyses assessing time-period and demographic variables reveal trends and odds ratios with 95% confidence intervals (OR; CI) for chemoRT variables. Our findings showed a stepwise increase in the odds of PreOP Tx to PostOP Tx across Early, Middle, to Late time-periods (OR Early/Late =0.11; 0.10, 0.13, OR Middle/Late =0.36; 0.32, 0.40). Age &lt;40 and 40-49, independently predicted higher odds of PreOP Tx than PostOP Tx compared to age 50-74, while the findings for subjects age 75+ were similar to those seen in the age 50-74 group (OR &lt;40/50-74 =1.63; 1.30, 2.05, OR 40-49/50-74 =1.18; 1.03, 1.36, OR 75+/50-74 =1.04; 0.90, 1.18). Females showed lower odds of PreOP Tx to PostOP Tx than males (OR Female/Male =0.85; 0.77, 0.93). Odds of PreOP Tx to PostOP Tx were significantly lower among Asian/Other (A/O) and Hispanic relative to Non-Hispanic White (NHW), while findings were similar to NHW for Non-Hispanic Black (NHB) (OR A/O/NHW =0.85; 0.74, 0.98, OR Hispanic/NHW =0.84; 0.73, 0.96, OR NHB/NHW =0.92; 0.73, 1.15). SES did not predict odds of PreOP Tx versus PostOP Tx. Conclusions: These findings depict independent increases in PreOP Tx across the three time-periods among stage II and III rectal cancer patients receiving radical operations. Further analyses will evaluate survival characteristics predicted by changes in perioperative therapies for stage II and III rectal cancer patients.
Abstract 11737: Heart Failure Patients Who Have Knowledge About Their Disease but Don’t Perform Self-Care Have Worse Clinical Outcomes
Authors: NaokoKato, KoichiroKinugawa, TinyJaarsma
Journal: Circulation (2014)

Introduction: Both knowledge and self-care are related to outcomes of heart failure (HF) patients. Some HF patients do not perform self-care even if they have knowledge about the disease and might be in need for special interventions. We aimed at describing characteristics of those patients and assessing their clinical outcomes. Methods: A total of 163 HF outpatients were enrolled (age 64, 70% male, NYHA I or II, 95%) and followed for 2 years. HF self-care risk score was calculated by counting the number of poor adherence to five self-care behaviors (medication, a low-sodium diet, exercise, daily weighing, and help-seeking behavior) (range, 0-6). Knowledge was assessed with a Japanese HF knowledge scale (range, 0-15). Subsequently, we classified patients into 4 groups (A-D) as shown in figure. We analyzed patient’s characteristics in group C (poor self-care but good knowledge) by ANOVA and Chi-square test. To assess clinical outcomes we used Kaplan-Meier method and Cox regression analysis. Results: The me...
Tetrahydrobiopterin Improves Endothelium-Dependent Vasodilation in Chronic Smokers
Authors: ThomasHeitzer, CarstenBrockhoff, BerndMayer, AscanWarnholtz, HankeMollnau, SimoneHenne, ThomasMeinertz, ThomasMünzel
Journal: Circulation Research (2000)

Abstract—Conditions associated with impaired nitric oxide (NO) activity and accelerated atherosclerosis have been shown to be associated with a reduced bioavailability of tetrahydrobiopterin (BH4). We therefore hypothesized that BH4 supplementation may improve endothelial dysfunction of chronic smokers. Forearm blood flow (FBF) responses to the endothelium-dependent vasodilators acetylcholine (ACh; 0.75, 1.5, and 3.0 μg/100 mL tissue/min) or serotonin (5-HT; 0.7, 2.1, and 6.3 ng/100 mL tissue/min), to the inhibitor of endothelial nitric oxide synthase (NOS) NG-monomethyl-l-arginine (L-NMMA; 2, 4, and 8 μmol/min), and to the endothelium-independent vasodilator sodium nitroprusside (SNP; 0.1, 0.3, and 1.0 μg/100 mL tissue/min) were measured by venous occlusion plethysmography in controls and chronic smokers. Drugs were infused into the brachial artery, and FBF was measured before and during concomitant intra-arterial infusion of BH4, tetrahydroneopterin (NH4; another reduced pteridine), or the antioxidant v...