tbuckley/cabot-search huggingface dataset:
Analysis of Pathologic Complete Response 10 Weeks After Radiotherapy—A Radiobiological Sin—In Reply
Authors: David Palma, George Rodrigues, Richard Inculet
Journal: JAMA Oncology (2019)

In Reply We thank all the authors for their thoughtful comments on the Measuring the Integration of Stereotactic Ablative Radiotherapy Plus Surgery for Early Stage Non–Small Cell Lung Cancer (MISSILE-NSCLC) study.1 We wish to briefly discuss some of the main points raised.
Abstract 2642: Antisense oligonucleotide-based induction of dominant-negative variants of STAT3 and EGFR in breast and lung cancer cells
Authors: Prasad Subramaniam, Luca Cartegni
Journal: Cancer Research (2019)

Abstract The signal transducer and activator of transcription 3 (STAT3) is linked to multiple cancers, including breast and lung adenocarcinomas, where it is known to activate multiple oncogenic pathways and serve as a bypass mechanism in drug resistance. For example, STAT3 is known to be a driver in some basal-like Triple-negative breast cancers (TNBC) and a resistance mechanism to EGFR inhibitors in non-small cell lung cancer (NSCLC). Thus STAT3 has become an attractive target in cancer therapeutics. A naturally occurring alternative splicing variant, STAT3-beta, is truncated and lacks the C-terminal trans-activation domain. Stat3-beta can act in a dominant negative fashion. We recently demonstrated that splice-switching oligonucleotides (SSOs) can be used to induce a shift in endogenous expression from the abundant, oncogenic STAT3-alpha to the truncated dominant-negative STAT3-beta isoform. This leads to decreased cell viability in triple-negative breast cancer cells and to tumor regression in mice, as compared to full STAT3 knock-down or controls. Our aim was to test a panel of next-generation SSOs in order to evaluate their efficacy in basal-like breast cancer cells, which are typically refractory to tyrosine kinase inhibitors. Based on our previous studies, we generated a panel of optimized SSOs targeting STAT3, and assayed the extent of the STAT3 alpha-to-beta switch, at the RNA and protein level, and at their efficacy at eliciting cell apoptosis in MDA-MB-468 TNBC cells, and identified one which show a 5-10 fold improvement of activity in vitro, compared to our previous leading published compound. The optimized STAT3 SSO sequence was also tested in RTK inhibitor-resistant H1975 non-small cell lung cancer cells and was found to be effective in killing the cancer cells as compared to Stat3 knockdown. We also used a similar antisense approach to induce the expression of a dominant-negative variant of the EGFR and tested in combination with our STAT3 SSO. While both the SSO-induced dominant negative variants of EGFR or STAT3 were able to effectively kill lung cancer cells individually, we observed a marked synergistic increase in inhibition when the two compounds where used in combination. Citation Format: Prasad Subramaniam, Luca Cartegni. Antisense oligonucleotide-based induction of dominant-negative variants of STAT3 and EGFR in breast and lung cancer 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 2642.
Abstract 4924: High ALDH1 expression in colorectal carcinoma could predict early onset of the disease
Authors: Litika Vermani, N Senthil Kumar, Anuradha Talukdar, Monoj Deka, Ravi Kannan, Rajeev Kumar
Journal: Cancer Research (2019)

Abstract Background: Worldwide there is an increase in the trend of early onset of colorectal carcinoma in individuals who are less than 45 years of age. The composition of young age colorectal cases ranges from 35% to 40% in India. Currently, we do not have the access to any molecular marker that could predict early onset of the disease and its clinical course. Aldehyde dehydrogenase 1 (ALDH1), Twist, E Cadherin and Vimentin are markers for cancer stem cells and epithelial mesenchymal transition. However, there is paucity of data on their clinical significance in terms of their impact on early onset of colorectal carcinoma. This lack of data prompted us to investigate their role in the early onset of the colorectal cancer. Methods: Immunohistochemisty of ALDH1, Twist, E Cadherin and Vimentin was performed in pre treatment biopsy samples collected from 103 colorectal patients who were further divided into 2 groups: viz, less than or equal to 45 years and more than 46 years. Results: Over expression of ALDH1, Twist, E Cadherin and Vimentin was observed in 75.7%, 90.3%, 92.2% and 2.9% of pre treatment colorectal carcinoma tissue specimens respectively. ALDH1 expression was found to have strong correlation with early onset of the disease (patients who were less than or equal to 45 years of age (P=0.003). Women patients were found predominantly non smokers (P=0.001) and non tobacco chewers (P=0.004) with respect to men. Conclusion: High ALDH1 expression correlates with the early onset of colorectal cancer. None of other markers could reach statistical significance with the early or late onset of colorectal cancer. Note: This abstract was not presented at the meeting. Citation Format: Litika Vermani, N Senthil Kumar, Anuradha Talukdar, Monoj Deka, Ravi Kannan, Rajeev Kumar. High ALDH1 expression in colorectal carcinoma could predict early onset of the disease [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 4924.
Abstract 5183: ONC201 induces acetylation of histone binding within the p21 (CDKN1A) gene promoter
Authors: Yiqun Zhang, Lanlan Zhou, Shengliang Zhang, Marie D. Ralff, Shuai Zhao, Philip H. Abbosh, Rahmat Sidker, Wafik S. El-Deiry
Journal: Cancer Research (2019)

Abstract ONC201/TIC10 is a promising anticancer agent that upregulates cytotoxic TRAIL pathway signaling in cancer cells. Preliminary clinical data indicates ONC201 induces clinical benefit in a subset of patients with histone H3 K27M glioma, among other tumors. Since H3 K27M mutation reduces levels of H3K27 di- and tri-methylation and in turn alters the expression of genes by epigenetic modulation, we investigated ONC201 effects on epigenetic regulation in cancer. We treated the colorectal cancer cell line HCT116 with the histone deacetylase inhibitor entinostat or ONC201. Chromatin immunoprecipitation (ChIP) was performed with anti-histone H3 (acetyl K9) antibody using lysates from drug-treated tumor cells. Immunoprecipitated DNA was probed by PCR using primers across the promoter of p21 (WAF1; CDKN1A). The results indicate that both ONC201 and entinostat induce the acetylation of histone H3 binding within the p21 promoter. We further observed that ONC201 plus entinostat have synergistic effects in this p21 promoter acetylation activity. Activation of p21 gene expression by enhancing histone acetylation may be relevant in cancer suppression by ONC201. Citation Format: Yiqun Zhang, Lanlan Zhou, Shengliang Zhang, Marie D. Ralff, Shuai Zhao, Philip H. Abbosh, Rahmat Sidker, Wafik S. El-Deiry. ONC201 induces acetylation of histone binding within the p21 (CDKN1A) gene promoter [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 5183.
Abstract 1595: Functional genomic analysis of 18q21.1 locus identifies potential functional variants and genes for colorectal cancer
Authors: Jifeng Wang, Xingyi Guo, Shimian Qu, Joshua A. Bauer, Jirong Long, Wei Zheng, Qiuyin Cai
Journal: Cancer Research (2019)

Abstract Colorectal cancer (CRC) is one of the most commonly diagnosed cancers in the world. Genome-wide association studies have identified approximately 50 genetic risk loci for CRC. We have previously identified SNP rs7229639, located in the second intronic region of the SMAD7 gene at locus 18q21.1, in relation to CRC risk in Asians. In this study, we performed functional genomic analysis to identify potential functional variants and target genes for this association. Functional annotation analysis using epigenetic data from ENCODE and Roadmap projects showed functional evidence of promoter and/or enhancer activities for four highly correlated potential functional SNPs, including rs7229639, rs77544449, rs112540150 and rs57668004. Using in vitro luciferase reporter assays in colon cancer HCT116 and PKO cells, we showed that the risk alleles of rs7229639 and rs77544449 increase promoter or enhancer activities, compared to reference alleles. The risk alleles of both SNPs also affect the ability of interacting with nuclear proteins in the electrophoretic mobility shift assays, compared to reference alleles. To identify candidate target genes for this risk locus, we performed cis-expression quantitative trait loci (eQTL) analysis using transcriptome data from the Genotype-Tissue Expression (GTEx) project, The Cancer Genome Atlas (TCGA) and Colonmics. We identified putative target gene LIPG, located 500 kb downstream of rs7229639, in all three datasets. No associations were observed for SMAD7, or eight other genes in the region, via eQTL analysis. To investigate the biological functions of LIPG gene in colorectal cancer, we knock-downed LIPG gene expression using siRNA in HCT116 and PKO cells, which resulted in a significant decrease in cell proliferation, colony formation, migration and invasion in both HCT116 and PKO cells. These results suggest that LIPG gene plays a significant role in colorectal tumorigenesis via disruption of cell behaviors. Taken together, results from our study suggest that the association between the rs7229639/18q21.1 locus and CRC risk may be mediated through SNPs that regulate expression of the LIPG gene. Citation Format: Jifeng Wang, Xingyi Guo, Shimian Qu, Joshua A. Bauer, Jirong Long, Wei Zheng, Qiuyin Cai. Functional genomic analysis of 18q21.1 locus identifies potential functional variants and genes for colorectal 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 1595.
Getting More Savings from ACOs — Can the Pace Be Pushed?
Authors: J. Michael McWilliams, Bruce E. Landon, Vinay K. Rathi, Michael E. Chernew
Journal: New England Journal of Medicine (2019)

Under the new "Pathways to Success," the Medicare Shared Savings Program may unravel into a large subsidy for providers with already-low spending: the evidence raises concerns about strategies for accelerating savings by holding ACOs to a specified pace.
Abstract 53: Hydrocortisone for the Treatment of Post--Cardiac Arrest Shock: A Prospective, Randomized Trial
Authors: Michael Donino, Katherine Berg, Maureen Chase, Lars W Andersen, Peter Zimetbaum, Donald Cutlip, Howard Smithline, Robert Sherwin, Parth Patel, Michael N Cocchi
Journal: Circulation (2014)

Background: Previous studies have shown that relative adrenal insufficiency is prevalent in post-arrest patients and associated with worse outcome. Whether the provision of steroids improves time t...
Erythrocyte Adenosine A2B Receptor-Mediated AMPK Activation: A Missing Component Counteracting CKD by Promoting Oxygen Delivery
Authors: Zhangzhe Peng, Renna Luo, Tingting Xie, Weiru Zhang, Hong Liu, Wei Wang, Lijian Tao, Rodney E. Kellems, Yang Xia
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement Oxygen deprivation or hypoxia drives CKD and contributes to end organ damage. The erythrocyte’s role in delivery of oxygen (O 2 ) is regulated by hypoxia, but the effects of CKD are unknown. The authors use untargeted metabolomics to show that 2,3-BPG, an erythrocyte-specific metabolite that triggers O 2 release, increases in a mouse model of CKD. Mouse genetic and human studies revealed that increased erythrocyte 2,3-BPG production and O 2 release mediated by the ADORA2B-AMPK signaling cascade counteracts CKD. Enhancing AMPK activation in mice promotes 2,3-BPG production and O 2 release, reducing kidney hypoxia and CKD progression. More study is needed to determine if therapies boosting 2,3-BPG production and O 2 delivery slow CKD progression. Background Oxygen deprivation or hypoxia in the kidney drives CKD and contributes to end organ damage. The erythrocyte’s role in delivery of oxygen (O 2 ) is regulated by hypoxia, but the effects of CKD are unknown. Methods We screened all of the metabolites in the whole blood of mice infused with angiotensin II (Ang II) at 140 ng/kg per minute up to 14 days to simulate CKD and compared their metabolites with those from untreated mice. Mice lacking a receptor on their erythrocytes called ADORA2B, which increases O 2 delivery, and patients with CKD were studied to assess the role of ADORA2B-mediated O 2 delivery in CKD. Results Untargeted metabolomics showed increased production of 2,3-biphosphoglycerate (2,3-BPG), an erythrocyte-specific metabolite promoting O 2 delivery, in mice given Ang II to induce CKD. Genetic studies in mice revealed that erythrocyte ADORA2B signaling leads to AMPK-stimulated activation of BPG mutase, promoting 2,3-BPG production and O 2 delivery to counteract kidney hypoxia, tissue damage, and disease progression in Ang II–induced CKD. Enhancing AMPK activation in mice offset kidney hypoxia by triggering 2,3-BPG production and O 2 delivery. Patients with CKD had higher 2,3-BPG levels, AMPK activity, and O 2 delivery in their erythrocytes compared with controls. Changes were proportional to disease severity, suggesting a protective effect. Conclusions Mouse and human evidence reveals that ADORA2B-AMPK signaling cascade–induced 2,3-BPG production promotes O 2 delivery by erythrocytes to counteract kidney hypoxia and progression of CKD. These findings pave a way to novel therapeutic avenues in CKD targeting this pathway.
Abstract 5022: iGRAMMy: Cloud-based characterization of microbial landscape in colorectal cancers
Authors: Li C. Xia, Dongmei Ai, Man Guo, Hanlee Ji
Journal: Cancer Research (2019)

Abstract Many studies have identified pervasive tumor-infiltrating bacteria in colon, gastric, kidney, and other tumors. Infiltrating bacteria have functional significance, affecting the immune system state, affecting a tumor’s ability to metastasize, and modifying patient’s response to therapies. Only a few tools can infer infiltrating bacteria based on the RNA-and DNA-Seq data of tumor samples. These tools are not optimized for cloud-based computation, where large public datasets such as The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) now reside. Here, we present a novel cloud-based bioinformatics tool - iGRAMMy, that accurately, efficiently, and robustly estimate microbial relative abundance in sequenced tumor and matched normal samples. We developed iGRAMMy by integrating read filtering, remapping, and relative abundance estimation steps of whole genome (WGS-seq) and/or transcriptome (RNA-seq) based microbiome analysis. We validated iGRAMMy by comparing estimated abundance to positive and negative controls of a published dataset as golden standard. We applied iGRAMMy to study all colorectal cancer samples within the TCGA cohort and reported the microbial landscape of these tumors. We identified a significantly higher abundance of overall bacterial infiltration in tumor as compared to normal samples. We found species like Bacteroides fragilis, Bacteroides dorei and Fusobacterium nucleatum were significantly higher in tumors, which were corroborated by previous reports. We uniquely identified Bacteroides intestinalis was also significantly more abundant in tumor samples. We released iGRAMMy and the entire analysis as a workflow pipeline on cancer genomics cloud, where researchers can easily replicate the study and use the tool for their own data. Citation Format: Li C. Xia, Dongmei Ai, Man Guo, Hanlee Ji. iGRAMMy: Cloud-based characterization of microbial landscape in colorectal 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 5022.
Abstract 709: Cordycepin induces apoptosis of human ovarian cancer cells by inhibiting CCL5-mediated Akt/NF-κB signaling pathway
Authors: Ik-Soon Jang
Journal: Cancer Research (2019)

Abstract The chemokine, CCL5, is a key mediator for the recruitment of immune cells into tumors and tissues. Akt/NF-κB signaling is significantly activated by CCL5. However, the role of NF-κB inactivation in apoptosis induced by negative regulation of CCL5 remains unclear. Here, we analyzed the effect of cordycepin on NF-κB activity in SKOV-3 cells and found that cordycepin-mediated inhibition of NF-κB signaling induced apoptosis in SKOV-3 cells via the serial activation of caspases. In addition, immune-blotting analysis showed that CCL5 is highly expressed in SKOV-3 cells. In addition to activating caspases, we show that, cordycepin prevents TNF-α-induced increase in CCL5, Akt, NF-κB, and c-FLIPLactivation and that CCL5 siRNA could inhibit Akt/NF-κB signaling. Moreover, cordycepin negatively regulated the TNF-α-mediated IκB/NF-κB pathway and c-FLIPL activation to promote JNK phosphorylation, resulting in caspase-3 activation and apoptosis. Also, we show that c-FLIPL is rapidly lost in NF-κB activation-deficient. siRNA mediated c-FLIP inhibition increased JNK. SP600125, a selective JNK inhibitor, downregulated p-JNK expression in cordycepin-treated SKOV-3 cells, leading to suppression of cordycepin-induced apoptosis. Thus, these results indicate that cordycepin inhibits CCL5-mediated Akt/NF-κB signaling, which upregulates caspase-3 activation in SKOV-3 cells, supporting the potential of cordycepin as a therapeutic agent for ovarian cancer. Note: This abstract was not presented at the meeting. Citation Format: Ik-Soon Jang. Cordycepin induces apoptosis of human ovarian cancer cells by inhibiting CCL5-mediated Akt/NF-κB signaling pathway [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 709.
Abstract 17748: MAPK Pathway Plays an Important Role in a Novel Mice Model of Stress Induced Cardiomyopathy
Authors: Yuko Soyama, Yoshiro Naito, Akiko Goda, Yoshitaka Okuhara, Koichi Nishimura, Makiko Oboshi, Yoshiyuki Orihara, Keisuke Okuno, Seiki Yasumura, Masanori Asakura, Masaharu Ishihara, Tohru Masuyama
Journal: Circulation (2017)

Background: Stress induced cardiomyopathy (SIC) is characterized as transient left ventricular (LV) dysfunction. Although adrenergic overstimulation plays a crucial role in the mechanism of SIC, th...
Phase II results of mitoxantrone in combination with clofarabine in children with relapsed/refractory acute leukemia.
Authors: Jessica Hochberg, Javier E. Oesterheld, Allyson Flower, Liana Klejmont, Jaclyn Basso, Lauren Harrison, Qiuhu Shi, Michael J. Borowitz, Michael Loken, Mitchell S. Cairo
Journal: Journal of Clinical Oncology (2019)

7036 Background: Despite improved outcomes in pediatric acute leukemia, those who relapse or are refractory do poorly. Mitoxantrone and clofarabine as single agents have proven efficacy in pediatric leukemia. Our previously reported phase I results demonstrated the MTD of this combination to be clofarabine 35 mg/m 2 x 5 days and mitoxantrone 12 mg/m 2 x 4 days. Here, we present our phase II data utilizing the RP2D. Methods: Prospective, open label safety and efficacy study (NCT01842672). Patients 0-30.99 yr old with ALL or AML with relapse OR induction failure were given 1 to 3 cycles of clofarabine (RP2D 35 mg/m2/day) Day 1-5, in combination with mitoxantrone 12 mg/m2/day on Day 3-6. Dexrazoxane was given prior to mitoxantrone. CNS prophylaxis was achieved with intrathecal liposomal cytarabine. MRD was defined by flow cytometry (≥ 0.01%). Results: Total 21 patients have enrolled at the RP2D clofarabine. Median age 8 yrs (0.5-22 yrs). Patient characteristics include 13 ALL (8=Induction Failure, 4=Relapse 1, 1=Relapse 2) and 8 AML (4=Induction Failure, 4=Relapse 1). Overall regimen was well tolerated. One patient with grade IV prolonged myelosuppression. Median time to neutrophil recovery was 24 days. Eighteen of 21 (85.7%) patients achieved an MRD negative CR. Three patients died of progressive disease. All 18 patients achieving CR went on to receive an allogeneic HSCT with no documented transplant associated toxicities attributed to prior MITCL therapy. One patient developed MRD (2.6%) at Day +270 post HSCT and underwent subsequent therapy. The remaining 17 patients continue to demonstrate MRD negativity. Two patients died of transplant associated complications. The overall and event free survival for patients who responded to therapy are 89% (CI 95 0.64-0.98) and 83% (CI 95 0.58-0.96), respectively at a median follow up time of 24 months (range 2-58). Conclusions: The combination of clofarabine and mitoxantrone reinduction therapy for relapsed or refractory acute leukemia has been demonstrated to be safe and well tolerated at a RP2D of 35 mg/m 2 clofarabine in children with poor risk acute leukemias. Phase II data is encouraging with 85.7% MRD negative CR rate in leukemic patients allowing patients to safely proceed to AlloHSCT with a 2 year survival rate of 89%. Longer follow up and a larger cohort is planned and ongoing. Clinical trial information: NCT01842672.
Management of Antithrombotic Therapy in Atrial Fibrillation Patients Undergoing PCI
Authors: Davide Capodanno, Kurt Huber, Roxana Mehran, Gregory Y.H. Lip, David P. Faxon, Christopher B. Granger, Pascal Vranckx, Renato D. Lopes, Gilles Montalescot, Christopher P. Cannon, Jurien Ten Berg, Bernard J. Gersh, Deepak L. Bhatt, Dominick J. Angiolillo
Journal: Journal of the American College of Cardiology (2019)
Abstract 17128: Transapical Aortic Valve Implantation (TA-AVI) Using the SYMETIS ACURATE TA™ Transapical Aortic Bioprosthesis - 1 Year Outcomes
Authors: Joerg Kempfert, Ardawan Rastan, David Holzhey, Markus Schoenburg, Hendrik Treede, Matthias Thielmann, Stefan Sorg, Friedrich Mohr, Thomas Walther, Arnaud van Linden
Journal: Circulation (2011)

OBJECTIVES: Transapical aortic valve implantation (TA-AVI) is a standard approach for high-risk elderly patients using the balloon expandable Edwards SAPIEN prosthesis. As an alternative we are evaluating a new self-expanding transapical bioprosthesis in a First-In-Man (FIM) study. METHODS: This novel device (SYMETIS ACURATE TA™ Transapical Aortic Bioprosthesis), composed of a porcine biologic valve attached to a self-expandable nitinol stent, is unsheathed proximally towards the apex and is designed for anatomical orientation of the commissures and for subcoronary implantation. A unique two-step implantation procedure provides simple positioning and tactile feedback during implant. RESULTS: 40 patients have been treated, patient age was 82.8±4 years, 60% were female, NYHA Class III/IV, logistic EuroSCORE was 21.5±10.9% and STS Score was 9.0±4.6%. All implants were delivered successfully in the intra-annular and subcoronary position. Two patients required a valve-in-a-valve (SAPIEN), one of which was followed with a conversion to conventional surgery. 95% of patients were treated off-pump. Two patients required a pacemaker implantation due to new onset AV-block post-implant. At 6 months post-procedure, this novel 2nd generation TA-AVI device highlights a PV leak rate of 0 - 1 in 97% of followed patients and functional improvement from baseline in 90% with a NYHA Class I/II. The pacemaker rate remains at 5%. Seven patients expired (respiratory complications=4, right heart failure=2, unclear=1). Two patients suffered a secondary stroke. CONCLUSIONS: The ACURATE TA™ has demonstrated proof of concept with promising clinical results in this FIM study. The 1 year data will be available in October 2011.