tbuckley/cabot-search huggingface dataset:
Tolerance induction by surface immobilization of Jagged-1 for immunoprotection of pancreatic islets
Authors: Zhila Izadi, Ensiyeh Hajizadeh-Saffar, Jamshid Hadjati, Mahdi Habibi-Anbouhi, Mohammad Hossein Ghanian, Hamid Sadeghi-Abandansari, Mohammad Kazemi Ashtiani, Zakieh Samsonchi, Mohammad Raoufi, Maedeh Moazenchi, Mahmoud Izadi, Anava sadat Sadr Hashemi Nejad, Haideh Namdari, Yaser Tahamtani, Seyed Nasser Ostad, Hamid Akbari-Javar, Hossein Baharvand
Journal: Biomaterials (2018)
A Phase I Trial of a Guadecitabine (SGI-110) and Irinotecan in Metastatic Colorectal Cancer Patients Previously Exposed to Irinotecan
Authors: Valerie Lee, Judy Wang, Marianna Zahurak, Elske Gootjes, Henk M. Verheul, Rose Parkinson, Zachary Kerner, Anup Sharma, Gary Rosner, Ana De Jesus-Acosta, Daniel Laheru, Dung T. Le, Aram Oganesian, Ellen Lilly, Thomas Brown, Peter Jones, Stephen Baylin, Nita Ahuja, Nilofer Azad
Journal: Clinical Cancer Research (2018)

Chemotherapeutic resistance eventually develops in all patients with metastatic colorectal cancer (mCRC). Gene silencing through promoter demethylation is one potential reversible mechanism of resistance with administration of hypomethylating agents. We evaluated the safety and tolerability of guadecitabine and irinotecan in patients with mCRC previously treated with irinotecan.In this 3+3 dose-escalation study, patients with mCRC previously exposed to irinotecan received guadecitabine days 1 to 5 of a 28-day cycle and irinotecan 125 mg/m2 days 8 and 15 [dose level (DL) 1, guadecitabine 45 mg/m2; DL -1: guadecitabine 30 mg/m2; DL -1G: guadecitabine 30 mg/m2 with growth factor support (GFS); DL 1G: guadecitabine 45 mg/m2 with GFS].Twenty-two patients were treated across four DLs. Dose-limiting toxicities were neutropenic fever (DL 1 and -1G), biliary drain infection (DL -1), colonic obstruction (DL -1), and severe dehydration (DL 1G). Most common toxicities were neutropenia (82% any grade, 77% Grade 3/4), neutropenic fever (23%), leukopenia (73% any grade, 50% Grade 3/4), and injection site reactions (64% total, 0% Grade 3/4). Patients received a median of 4.5 cycles of treatment; 12/17 evaluable patients had stable disease as best response, with one having initial disease progression but subsequently durable partial response. Circulating tumor DNA showed decrease in global demethylation by LINE-1 after treatment.We report the first study of chemo-priming with epigenetic therapy in gastrointestinal cancers. Guadecitabine 45 mg/m2 and irinotecan 125 mg/m2 with GFS was safe and tolerable in patients with mCRC, with early indication of benefit. These data have provided the basis for an ongoing phase II randomized, multicenter trial.
Long-Term Outcome of Mustard/Senning Correction for Transposition of the Great Arteries in Sweden and Denmark
Authors: NielsVejlstrup, KeldSørensen, EvaMattsson, UlfThilén, PerKvidal, BengtJohansson, KasperIversen, LarsSøndergaard, MikaelDellborg, PeterEriksson
Journal: Circulation (2015)

Background—The atrial switch operation, the Mustard or Senning operation, for the transposition of the great arteries (TGA) was introduced in the late 1950s and was the preferred surgery for TGA until the early 1990s. The Mustard and Senning operation involves extensive surgery in the atria and leaves the right ventricle as the systemic ventricle. The Mustard and Senning cohort is now well into adulthood and we begin to see the long-term outcome. Methods and Results—All the 6 surgical centers that performed Mustard and Senning operations in Sweden and Denmark identified all operated TGA patients. Information about death was obtained in late 2007 and early 2008 from the Danish and Swedish Centralised Civil Register by using the patients’ unique national Civil Registration Numbers. Four hundred sixty-eight patients undergoing the atrial switch operation were identified. Perioperative 30-day mortality was 20%, and 60% were alive after 30 years of follow-up. Perioperative mortality was significantly increased...
Molecular subtypes of clear cell renal cell carcinoma: Impact of diabetes mellitus, metformin, and immunotherapy on patient outcomes.
Authors: Scott Mattox Haake, Samira A Brooks, Eric Welsh, Anders Berglund, William J. Fulp, Dung-Tsa Chen, Eric B. Haura, Wade Jeffers Sexton, Philippe E. Spiess, Julio Pow-Sang, Kimryn Rathmell, Mayer N. Fishman
Journal: Journal of Clinical Oncology (2014)

4579 Background: A 34-gene subtype classifier was previously developed to define clear cell renal cell carcinoma (ccRCC) tumors as either clear cell A (ccA) or B (ccB). The objective of this study was to investigate clinical factors and immunotherapies in the context of these subtypes. Methods: In this retrospective analysis, the Total Cancer Care (TCC) database at Moffitt Cancer Center was queried and 255 patients with ccRCC were identified with primary tumor gene expression analyses. The TCC database and medical record were queried to define patient characteristics, treatments, and outcomes. Results: The classifier identified tumors as ccA (206) and ccB (49). Prognostic outcomes including overall survival (OS) in all patients (p<0.01), stage IV patients (p=0.01), and recurrence free survival (p<0.01) were confirmed. The superior prognostic group, ccA, had higher BMI (29.7 vs. 27.8 kg/m2, p=0.03). There was a trend towards a higher rate of DM2 in ccA patients (26% vs. 12%, p=0.058). Thus, we analyzed the impact of metformin on survival in ccA patients. The nondiabetic ccA patients had a similar outcome to diabetic ccA patients treated with metformin but diabetic ccA patients not treated with metformin had decreased survival (p=0.02). For the 37 stage IV patients treated with cytoreductive nephrectomy (CRN), ccA patients demonstrated superior OS (median survival 39 vs. 15 months, p=0.02) and remained significant in multivariate analysis that included age, gender, nuclear grade, and tumor size. Among 12 patients treated with interleukin-2 (IL2), the six ccA patients had a nonsignificant (p=0.12) better outcome. Conclusions: The ccA patients have a higher BMI and a trend towards higher frequency of DM2. When compared to nondiabetic ccA patients, ccA diabetic patients have decreased survival that is improved in those treated with metformin. The ccB patients have a worse prognosis and decreased survival when treated with CRN or IL2. Overall, ccA and ccB patients represent distinct populations that may have differential responses to therapies.
Abstract 4980: Regulating the regulator: Long noncoding RNAs in the p53 network in colorectal cancer
Authors: Ritu Chaudhary, Xiao Ling Li, Ashish Lal
Journal: Cancer Research (2018)

Abstract Thousands of long noncoding RNA (lncRNA) genes are transcribed from the human genome, yet the biology of the vast majority remains to be investigated. To identify lncRNAs that could be important, we functionally integrate lncRNAs into tumor suppressor pathways, more specifically the p53 pathway. We identified and functionally characterized two intergenic nuclear-retained lncRNAs that we named PINCR (p53 induced noncoding RNA) and PURPL (p53-upregulated regulator of p53 levels). Our results show that both PINCR (Chaudhary et al, eLife, 2017) and PURPL (Li et al, Cell Reports, 2017), function as pro-survival p53-regulated genes during DNA damage and in mouse xenografts. Mechanistically, PINCR and PURPL mediate the effects of p53 in colorectal cancer (CRC) cells by regulating p53 itself or by modulating the expression of a subset of p53 targets via interactions with unique proteins in the nucleus. Targeted deletion of PINCR in CRC cells significantly impaired G1 arrest and induced apoptosis to chemotherapeutic drugs. PINCR regulates the induction of a subset of p53 targets including BTG2, RRM2B and GPX1. Silencing these PINCR targets phenocopies the effect of loss of PINCR in response to DNA damage suggesting that they could be important downstream effectors of this lncRNA. Using CRISPR-Cas9-mediated knock-in of a single S1-tag at the 3'end of PINCR followed by an RNA pulldown approach that utilized endogenous S1-tagged PINCR, we found that PINCR associates with the enhancer region of these genes by binding to RNA-and DNA-binding protein Matrin 3 that, in turn, associates with p53. We show that PINCR is important for the recruitment of Matrin 3 to the enhancer region of these genes and for their complete p53-dependent induction after DNA damage. In addition, our unpublished data provide further insights on the molecular function of these lncRNAs in CRC. Collectively, our studies reveal critical roles of PINCR and PURPL in the p53 network and uncover unique modes by which lncRNAs can function. Citation Format: Ritu Chaudhary, Xiao Ling Li, Ashish Lal. Regulating the regulator: Long noncoding RNAs in the p53 network in colorectal 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 4980.
Abstract 4429: FOXP3 transcriptional regulation of MicroRNAs in human breast cancer
Authors: Baozhu Yi, Ming Li, Ying Liu, Runhua Liu
Journal: Cancer Research (2018)

Abstract MicroRNA (miR)-155 has been found to be overexpressed in breast cancer cells, but its transcriptional regulation remains elusive. The role of miR-155 is also not determined in breast cancer development and progression. In this study, we identified a FOXP3-BRCA1-miR155 axis in breast cancer cells. MiR-155 is induced by FOXP3 through a transcriptional repression of BRCA1 in breast cancer cells. Likewise, overexpression of miR-155 was found in patients with early stage or triple negative breast cancer, but not in patients with high stage or metastatic breast cancer. Of note, expression of miR-155 in blood cells was higher in patients with localized but not metastatic tumors. In addition, although miR-155 in tumor cells is induced by FOXP3, free or exosomal miR-155 in culture medium was not changed with induction of FOXP3. There is a transcriptional axis of FOXP3-BRCA1-miR-155 in breast cancer cells. MiR-155 is a potential biomarker for early stage breast cancer. Plasma miR-155 appears to be related to that in blood cells but not in tumor cells. Citation Format: Baozhu Yi, Ming Li, Ying Liu, Runhua Liu. FOXP3 transcriptional regulation of MicroRNAs in human breast 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 4429.
Abstract 5556: Combining adenosine receptor inhibition with AB928 and chemotherapy results in greater immune activation and tumor control
Authors: Matt J. Walters, Dana Piovesan, Joanne Tan, Daniel DiRenzo, Fangfang Yin, Dillon Miles, Manmohan R. Leleti, Tim Park, Ferdie Soriano, Eshan Sharif, Ulrike Schindler, Jay P. Powers
Journal: Cancer Research (2018)

Abstract INTRODUCTION: Extracellular adenosine triphosphate (ATP) is efficiently hydrolyzed to adenosine by ecto-nucleotidases CD39 and CD73, which converts adenosine-monophosphate (AMP) into adenosine (ADO). ADO suppresses immune responses including those of T cells, natural killer (NK) cells, and dendritic cells (DC) through activation of A2aR and A2bR receptors. Treatment of cancer cells with platinum-based and anthracycline chemotherapy has been shown to induce immunogenic cell death (ICD), characterized by increased extracellular ATP levels, and upregulation of CD39 and CD73, leading to the enhanced generation of adenosine. METHODS: The ability of AB928 to inhibit adenosine-mediated suppression of immune cell function was assessed using human CD4 and CD8 cells. BALB/c mice were inoculated with AT-3-OVA tumors, which express the model antigen ovalbumin, and subsequently treated with chemotherapy or AB928 alone, or a combination of both. The growth rate and immune composition of the tumors were assessed (flow cytometry). RESULTS: Consistent with the ability of adenosine to suppress immune function, AB928 inhibited the ability of adenosine to suppress CD4 or CD8 T cell activation. Tumor-bearing mice that have been treated with either doxorubicin (DOX, an anthracycline) or oxaliplatin (OX) exhibit increased expression of CD39 and CD73. Established AT-3-OVA tumors treated with AB928 alone had a small but significant decrease in their growth rate; similarly, tumors treated with chemotherapy exhibited a reduction in growth rate. Consistent with the ICD hypothesis, treatment of AT-3-OVA-bearing mice with DOX or OX resulted in an increase in OVA-specific CD8 T cells in the tumor. Concurrent treatment with AB928 and chemotherapy resulted in significantly reduced tumor growth rates, when compared to chemotherapy alone. Analysis of the tumor-infiltrating cell populations showed a significant increase in OVA-specific CD8 T cells, relative to those treated with chemotherapy alone. CONCLUSIONS: Treatment of tumor-bearing mice with a combination of AB928, a dual A2aR and A2bR antagonist, and ICD-inducing chemotherapy results in increased tumor antigen-specific CD8 T cell responses and significantly reduced tumor growth. AB928 is currently undergoing clinical evaluation. Citation Format: Matt J. Walters, Dana Piovesan, Joanne Tan, Daniel DiRenzo, Fangfang Yin, Dillon Miles, Manmohan R. Leleti, Tim Park, Ferdie Soriano, Eshan Sharif, Ulrike Schindler, Jay P. Powers. Combining adenosine receptor inhibition with AB928 and chemotherapy results in greater immune activation and tumor control [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 5556.
Abstract IA24: Identification of therapies for plexiform neurofibromas, a precursor of malignant peripheral nerve sheath tumors
Authors: D. Wade Clapp
Journal: Clinical Cancer Research (2018)

Abstract Plexiform neurofibromas (PNs) are complex nerve and soft tissue tumors that affect 25-50% of individuals with neurofibromatosis type 1 (NF1), the most common genetic disease in man with a predisposition to cancer. PNs cause lifelong morbidity ranging from deformity to paralysis and mortality due to organ compression, and progress to MPNST in ~8-13% of patients. The generation of genetically engineered mouse models that closely recapitulate the development of human plexiform neurofibromas has allowed our laboratory and others to pursue genetic and pharmacologic studies to identify novel therapies. Genetic and adoptive transfer studies conducted by our lab in collaboration with Dr. Luis Parada identified a key role for c-kit/kit-ligand in tumor initiation and progression. These data led to a clinical trial administering imatinib mesylate to target aberrant stem cell factor (SCF)/c-kit signaling in the tumor microenvironment, which induced the only objective clinical responses ever obtained in a therapeutic clinical trial in pNF. Based on the observation that young children with head, neck, and airway tumors were most likely to have partial tumor regression, a registration trial in this patient population is currently being pursued. Further, additional phase 2 trials using other receptor tyrosine kinases that include c-kit are under way as well. More recently, studies in GEM models informed clinical trials of MEK inhibitors led by Dr. Brigitte Widemann (Pediatric Branch of NCI) to directly inhibit aberrant Ras signaling in PN cells. Studies are ongoing to extend these promising initial clinical findings to investigate the developmental, molecular, and pharmacokinetic effects of c-kit and MEK inhibition alone and in combination in preclinical models. Specifically, studies to explore adaptive responses to MEK inhibition monotherapy in mice and patients treated with selumetinib via integrated exome, RNAseq, and kinome studies in pre- and post-treatment tumor tissue are under way. Citation Format: D. Wade Clapp. Identification of therapies for plexiform neurofibromas, a precursor of malignant peripheral nerve sheath tumors [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr IA24.
Abstract 2170: Single mouse preclinical trial: A tool for translational research
Authors: C Mignard, M Hillairet de boisferon, F Bichat, D France, O Duchamp
Journal: Cancer Research (2018)

Abstract Roughly, 85% of preclinical agents entering oncology clinical trials fail to demonstrate sufficient safety or efficacy to gain regulatory approval. Hence, there is a need for experimental systems which better mimic the inter-patient response heterogeneity observed in the clinic. Patient-derived tumor xenograft (PDX) mouse models have emerged as a relevant oncology research tool to study tumor evolution, drug response, biomarkers, resistance phenomenon and adjusting chemotherapeutic approaches for individual patients. We will here expose the effectiveness of the single mouse preclinical trial paradigm for evaluating drug response, as mono or combo therapy using our well-characterized PDX collection. Based on the “1 PDX tumor/1 mouse/1 treatment” experimental design, a cohort of colorectal, breast, pancreas, lungs PDX models (minimum 20 of each) was used to explore response to Standard Of Care (SOC) and combo therapy used in clinic. We compared single-animal response data with treatment group data taken from historical experiments. We demonstrated that about &amp;gt;80% of the individual response matched the treatment group data, supporting the idea of using one single animal to predict the drug response. The response of each PDX to treatment was correlated to their histological and genetic profiles. This approach represents a new experimental design to address the tumor biology of cancer patients, and investigate targeted therapies in relevant mouse models, which could improve our ability to predict clinical trial responses, stratify patients for clinical trial, identify drug resistance mechanism, responsive sub-populations as well as biomarker. By combining genomic profiling data and drug screening data, and clinical data from patients, SMPT process is a helpful tool for precision cancer medicine and individualized drug selection. Citation Format: C Mignard, M Hillairet de boisferon, F Bichat, D France, O Duchamp. Single mouse preclinical trial: A tool for translational research [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 2170.
Abstract 974: Alternative polyadenylation of androgen receptor variants in castration-resistant prostate cancer
Authors: Jamie L. Van Etten, Michael Nyquist, Yingming Li, Rebecca LaRue, Yeung Ho, Rendong Yang, Daniel F. Voytas, Christine Henzler, Scott M. Dehm
Journal: Cancer Research (2018)

Abstract The androgen receptor (AR), which is activated by androgens, functions in the normal prostate as a master transcriptional regulator. Accordingly, prostate cancer (PCa) presents as an androgen- and AR-dependent disease. Inhibition of AR transcriptional activity with androgen-deprivation therapy (ADT) is effective for patients with locally advanced and metastatic disease. All ADT suppresses AR via interference with its ligand binding domain (LBD)-dependent transcriptional activity. However, development of therapy resistance and transition to castration-resistant prostate cancer (CRPC) represents a major clinical challenge. CRPC circumvents ADT by expressing constitutively active AR variants (AR-Vs) that lack the LBD. Therapies targeting constitutively active AR variants are not currently available. To address this problem, we investigated the mechanisms underlying AR-V expression in CRPC. One particular AR-V, called AR-V7, consists of contiguously spliced exons 1, 2, 3, and a cryptic exon, CE3, and has been shown to be associated with clinical resistance to second-generation AR inhibitors abiraterone and enzalutamide. We noted that CE3 contains a consensus hexameric AAUAAA polyadenylation signal (PAS). We hypothesized that intronic polyadenylation promotes AR-V7 expression in CRPC. To test this, we developed a morpholino that sterically blocked the CE3 PAS to prevent splicing of AR-V7. We have demonstrated that the PAS in CE3 controls expression of AR-V7, as well as a broad array of AR variants arising by splicing of adjacent cryptic exons that use the shared CE3 PAS. Furthermore, our data demonstrate that the cleavage and polyadenylation complex (CPSF complex) is enriched in primary PCa tumors relative to normal tissues. We have also demonstrated that CPSF1, a member of the CPSF complex, controls expression of AR-Vs relative to full length AR and plays a global role in the determination of mRNA isoform length in prostate cancer cells. Collectively, these findings reveal alterations in the cellular machinery governing mRNA cleavage and polyadenylation in prostate cancer, and identify specific opportunities for therapeutic intervention. Citation Format: Jamie L. Van Etten, Michael Nyquist, Yingming Li, Rebecca LaRue, Yeung Ho, Rendong Yang, Daniel F. Voytas, Christine Henzler, Scott M. Dehm. Alternative polyadenylation of androgen receptor variants in castration-resistant prostate 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 974.
Deletion Allele of Angiotensin-Converting Enzyme Gene Increases Risk of Essential Hypertension in Japanese Men
Authors: JitsuoHigaki, ShunrokuBaba, TomohiroKatsuya, NoriyukiSato, KazuhikoIshikawa, ToshihumiMannami, JunOgata, ToshioOgihara
Journal: Circulation (2000)

Background—The Framingham Study recently revealed that the homozygous deletion polymorphism of the angiotensin-converting enzyme gene (ACE DD) is associated with increased risk for essential hypertension in a male-specific manner. However, this association has not been confirmed in races other than whites. Methods and Results—Using a large number of Japanese subjects (n=5014) that were randomly selected from the general population (the Suita Study), we examined the association between ACE DD and hypertension. The frequency of DD (17.1%) in hypertensive men was significantly higher (P<0.0015) than that (11.8%) in other mildly hypertensive or normotensive men, and the estimated odds prevalence for hypertension (DD vs II) was 1.75 (95% CI 1.21 to 2.53). In contrast, no significant association was confirmed in women (OR 1.17, 95% CI 0.79 to 1.72). Conclusions—Despite the lower frequency of the DD genotype in Japanese than in whites, the ACE gene polymorphism was associated with increased risk for hypertension...
Circulating Adipose Fatty Acid Binding Protein Is a New Link Underlying Obesity-Associated Breast/Mammary Tumor Development
Authors: Jiaqing Hao, Yuwen Zhang, Xiaofang Yan, Fei Yan, Yanwen Sun, Jun Zeng, Sabine Waigel, Yanhui Yin, Mostafa M. Fraig, Nejat K. Egilmez, Jill Suttles, Maiying Kong, Shujun Liu, Margot P. Cleary, Edward Sauter, Bing Li
Journal: Cell Metabolism (2018)