tbuckley/cabot-search huggingface dataset:
Abstract 476: Loss of chd5-mediated tumor suppression accelerates MYCN-driven neuroblastoma tumorigenesis in zebrafish
Authors: Mark W. Zimmerman, Shuning He, Jimann Shin, Shizhen Zhu, Marc Mansour, Keith Joung, Jinhua Quan, Timur Yusufzai, A. Thomas Look
Journal: Cancer Research (2015)

Abstract Neuroblastoma is a childhood tumor of the peripheral sympathetic nervous system (PSNS) that originates from cells of the primitive neural crest. For the 40% of patients with high-risk disease, current therapies are often ineffective and long-term survival remains obstinately low. A major risk factor in neuroblastoma is hemizygous loss of the 1p36 chromosomal region, which has long been suspected to harbor one or more powerful tumor suppressor genes. Our studies indicate that loss of Chromodomain helicase DNA-binding protein 5 (chd5), which is in this deleted region, cooperates with MYCN overexpression to accelerate in vivo neuroblastoma tumorigenesis. Zebrafish chd5-null alleles were created utilizing both zinc-finger nuclease and TALEN technology. The resulting chd5 mutant fish exhibit abnormal development of the PSNS in the form of expansion of the superior cervical ganglia and enlargement of the interrenal gland (adrenal medulla). In order to examine the effect of chd5 haploinsuficiency on in vivo neuroblastoma tumorigenesis, chd5 mutant fish were crossed with the dbh:MYCN transgenic model resulting in neuroblastoma tumors. Consistent with a tumor suppressor function, chd5 haploinsufficient fish exhibit an accelerated neuroblastoma phenotype with tumors present beginning as early as 6 weeks compared to 15 weeks observed in wildtype fish. The chd5 protein can serve as one of two enzymatic components of the nucleosome remodeling and histone deacetylase (NuRD) complex, which is a repressor of gene expression and is reported to have diverse roles in regulating chromatin organization, developmental signaling and gene stability. Future studies will examine the mechanism and function of chd5 so that the pathways mediating tumor suppression can be elucidated and that essential proteins in these pathways can be targeted in ways that exploit the synthetic lethal relationships that are established. Citation Format: Mark W. Zimmerman, Shuning He, Jimann Shin, Shizhen Zhu, Marc Mansour, Keith Joung, Jinhua Quan, Timur Yusufzai, A. Thomas Look. Loss of chd5-mediated tumor suppression accelerates MYCN-driven neuroblastoma tumorigenesis in zebrafish. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 476. doi:10.1158/1538-7445.AM2015-476
Herbal supplements: Boon or bane for older cancer patients?
Authors: J. M. Mckoy, A. S. Haleem, D. B. Liebling
Journal: Journal of Clinical Oncology (2011)

e16633 Background: Herbal supplements (supplements), defined as plant or plant part used for their therapeutic properties, are increasingly used with curative intent by geriatric (>age 65 years) cancer patients. However, use of supplements has the potential to interact adversely with chemotherapy and cause severe and even life-threatening toxicities. Herein, we report on relevant findings from a critical review of the published literature. Methods: We reviewed MedLine, PubMed (2002-2010); search terms herb-drug interactions, drug interactions, herbal supplements, dietary supplements, Chinese herbal drugs, herbal medicine, neoplasm, geriatric, oncology, and aged. Results: We identified 32 articles, 17 of which were excluded as they did not relate to the geriatric population. Of the 15 articles included, 5 (33.3%) concluded that supplements could affect cancer drug therapy. Patterns of use of supplement were contingent on age and intent (curative or palliative), age was inversely associated with likelihood to report herbal supplement use, and older patients (>65 yrs) were more likely to inform oncologists of herbal supplement use compared with younger cohorts (<65 yrs). Ten (66.6%) articles observed no significant association between age and concomitant supplement and cancer drug use. Finally, age was not an independent risk factor for adverse cancer drug supplement interaction. Conclusions: Elderly cancer patients are particularly vulnerable to supplement-cancer drug interactions due to parallel co-morbidities and polypharmacy. Oncologists need to be more cognizant of this potential interaction and must both educate their patients and calibrate cancer drug dosage with herbal supplements in mind in order to prevent attendant toxicities. Prospective studies to further assess this interaction are sorely needed.
68Ga-PSMA-HBED Uptake on Cervicothoracic (Stellate) Ganglia, a Common Pitfall on PET/CT
Authors: Mohsen Beheshti, Alireza Rezaee, Werner Langsteger
Journal: Clinical Nuclear Medicine (2016)

68Ga-PSMA-HBED PET/CT showed promising results in staging and restaging of prostate cancer. However, nonspecific uptake has been reported in the celiac ganglia. In this case series, we showed faint radiotracer uptake on upper thoracic region in the location of cervicothoracic (stellate) ganglia. This ganglion is located anterior to the transverse process of C7 vertebra, inferior to subclavian artery, and superior to the neck of the first rib.
Expression of dachshund homolog 2 in ovarian serous adenocarcinoma.
Authors: K. M. Elias, J. Liu, M. S. Hirsch, R. Drapkin
Journal: Journal of Clinical Oncology (2011)

e15544 Background: Dachshund homolog 2 (DACH2) is one of two human genes that encode a protein similar to the Drosophila protein Dachshund, a nuclear transcription factor involved in normal development of the Drosophila eye, limbs, and genital disc and development of the Müllerian system in mice. It is located on the X chromosome and subject to inactivation by DNA methylation. The aim of this study was to investigate the expression of DACH2 protein expression in normal and neoplastic ovarian tissues. Methods: DACH2 protein expression in ovarian cancer cell lines and 24 different types of human tissues was determined by Western Blot analysis and immunohistochemistry. A role for DACH2 as a marker of Müllerian neoplasia was assessed by comparing DACH2 expression in primary and metastatic ovarian serous tumors (borderline tumors, low grade adenocarcinomas, and invasive implants) with peritoneal mesothelioma. Additionally, a tissue microarray containing normal human ovary and primary high grade serous adenocarcinomas and coincident metastases, were stained for DACH2. For the latter, survival analyses were performed with Kaplan-Meier curves and the log rank test. Results: DACH2 was expressed in ovarian cancer cell lines as well as normal fallopian tube samples; few other normal human tissues were immunoreactive. All well-differentiated serous carcinomas, invasive implants, and 33/35 (94%) serous borderline tumors had at least focal staining for DACH2. In contrast, only 2/24 (8%) peritoneal mesotheliomas were positive. 25/138 (18%) primary high grade serous tumors were strongly immunoreactive with DACH2. There was 83.3% concordance between the intensity of DACH2 staining in primary tumors and coincident metastases. The subset of patients with coincident high immunoreactivity in both primary and metastatic lesions appeared to have shorter overall survival. Conclusions: DACH2 has a narrow expression pattern in normal tissues, but is commonly expressed among established ovarian cancer cell lines and in the normal fallopian tube. DACH2 may differentiate low grade serous neoplasms from peritoneal mesothelioma, but is less discriminatory for high grade serous carcinomas. A subset of patients with diffuse expression of DACH2 may have a worse prognosis.
Identification of predictive markers to differentiate ixabepilone from paclitaxel activity in ER-negative breast cancer patients
Authors: S. Wu, S. Chasalow, H. Lee, L. Xu, B. Paul, O. Mokliatchouk, W. F. Symmans, K. E. Zerba, L. Pusztai, E. Clark
Journal: Journal of Clinical Oncology (2007)

2525 Background: Ixabepilone (BMS-247550) is a microtubule stabilizing agent with demonstrable therapeutic value in taxane- refractory breast cancer (BC) patients. Biomarkers to predict either ixabepilone or paclitaxel activity in BC patients have previously been reported. However, markers that differentiate response to the two agents have yet to be identified. This study sought to discover predictive markers that will enable patient selection to differentially enhance response to ixabepilone or paclitaxel in ER-negative (ER-) patients. Materials and Methodologies: Pre-treatment gene expression profiles were generated for 62 ER- patients treated with ixabepilone in clinical study CA163080, and 51 ER- patients treated with T/FAC (paclitaxel and fluorouracil-doxorubicin-cyclophosphamide) in clinical study MDA133. Biomarkers differentially predictive of complete pathological response in breast were identified through gene set enrichment analysis (GSEA) or classification by threshold gradient descent (TGD). Gene knockdown by siRNA was used to study some of these candidate markers. Results: Four candidate models that differentiate response to ixabepilone treatment and taxane-containing therapy were identified. Two of the models, found by GSEA, are based on expression levels for single microtubule-related genes: transforming, acidic coiled-coil containing protein 3 (TACC3) and chromosome condensation protein G (HCAP-G). The potential of HCAP-G as a differential marker was supported by siRNA studies. Two of the models, found by TGD, are based on expression levels for 26 and 20 genes. Areas under the ROC curves for the models applied to each study separately are given in the table . Conclusions: We have identified four predictive models that differentiate response in a clinical trial of ixabepilone from that in a trial of T/FAC. A clinical trial is under way to further evaluate their utility for differentiating response to ixabepilone- and taxane-containing regimens. [Table: see text] [Table: see text]
Identification of chromosomal regions that harbor novel genes important for pancreatic cancer pathogenesis by genome-wide screening methods
Authors: S. Thieltges, T. Kalinina, A. Krohn, R. Simon, M. Moeller-Krull, J. Dierlamm, J. Izbicki, E. Yekebas
Journal: Journal of Clinical Oncology (2009)

e15609 Background: Pancreatic adenocarcinoma is a genetically highly complex and heterogenous tumor type with strong genetic instability which makes it resistant to therapy. Known amplifications of oncogenes such as KRAS or MYC and deletions of tumor suppresor genes such as CDKN2A and SMAD4 have demonstrated the importance of genetic alteration in this tumor type. Methods: We report the use of an Affymetrix Genome-Wide Human single nucleotide polymorphism (SNP) Array 6.0 (906,600 SNPs) to screen for gene copy number changes and allelic imbalances in 8 microdissected primary pancreatic tumors and 7 established pancreatic cancer cell lines. Gene Chip Human Genome U133 2.0 Array was used to make an RNA expression profile. Mutation analysis of KRAS and M-FISH analysis of cell lines was performed. Results: SNP arrays confirmed the presence of previously reported cytogenetic abnormalities in the cell lines and primary tumor probes, including MYC amplifikation at 8q24, gain of 17q12 (ERBB2/HER2), 7p12 (EGFR) and 12p12.1 (KRAS). KRAS mutation was seen in 71% of cell lines (5/7). We identified several alterations in signaling pathways such as Wnt/Notch Signaling and KRAS signaling. A sizeable subset ( 7 of 15 cases; 47%) showed an amplikon at 19q13.1–13.2 in which the serine/threonine kinase Mirk/Dyrk1B is localized, a downstream effector of oncogenic k-ras. There was also strong concordance between primary tumors and cell lines with respect to gains on 8q, 12p and 18q. Analysis of gene expression was used to localize potential target genes. M-FISH analysis showed complex karyotypes with chromosomal deletions in 9p and 18q, regions that are known to harbor tumor suppressor genes (CDKN2A, SMAD4 and TP53). Conclusions: Several signaling pathways mediate tumor cell survival. Analysis of gene amplification and RNA expression profile provide molecular biological characteristics and an individual gene signature of the tumor which allow us to choose more efficient drugs to an individualized treatment. Pathways activated by KRAS such as DYRK1B may offer new therapeutic targets. Further functional characterization is needed to provide evidence for the actual role of any putative target gene. No significant financial relationships to disclose.
Crenolanib (CP-868,596) Is a Potent and Selective Type I FLT3 Inhibitor That Retains Activity Against AC220 Resistance-Causing FLT3 Kinase Domain Mutants
Authors: Catherine C Smith, Elisabeth Lasater, Melissa Mccreery, Kimberly Lin, Whitney Stewart, Lauren E Damon, Alexander E Perl, Grace R Jeschke, Mayumi Sugita, Martin Carroll, Scott C. Kogan, Neil Shah
Journal: Blood (2012)
Abstract 1761: Small molecule restoration of wildtype structure and function of mutant p53 using a novel zinc metallochaperone based mechanism
Authors: Xin Yu, Adam R. Blanden, Sumana Narayanan, Lalithapriya Jayakumar, David Lubin, David J. Augeri, S. David Kimball, Stewart N. Loh, Darren R. Carpizo
Journal: Cancer Research (2015)

Abstract NSC319726 (ZMC1) is a small molecule that reactivates mutant p53 by restoration of WT structure/function to the most common p53 missense mutant (p53-R175H). We investigated the mechanism by which ZMC1 reactivates p53-R175H and provide evidence that ZMC1: 1) restores WT structure by functioning as a zinc-metallochaperone, providing an optimal concentration of zinc to facilitate proper folding; 2) increases cellular reactive oxygen species that transactivate the newly conformed p53-R175H (via post-translational modifications), inducing an apoptotic program. We not only demonstrate that this zinc metallochaperone function is possessed by other zinc-binding small molecules, but that it can reactivate other p53 mutants with impaired zinc binding. This represents a novel mechanism for an anti-cancer drug and a new pathway to drug mutant p53. Citation Format: Xin Yu, Adam R. Blanden, Sumana Narayanan, Lalithapriya Jayakumar, David Lubin, David J. Augeri, S. David Kimball, Stewart N. Loh, Darren R. Carpizo. Small molecule restoration of wildtype structure and function of mutant p53 using a novel zinc metallochaperone based mechanism. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1761. doi:10.1158/1538-7445.AM2015-1761
A phase I/II study of cancer peptide vaccine S-288310 in patients with advanced urothelial carcinoma of the bladder
Authors: W. Obara, M. Eto, H. Mimata, K. Kohri, N. Mitsuhata, I. Miura, T. Shuin, T. Miki, T. Koie, H. Fujimoto, K. Minami, Y. Enomoto, T. Nasu, T. Yoshida, H. Fuse, I. Hara, K. Kawaguchi, A. Arimura, T. Fujioka
Journal: Annals of Oncology (2016)
Abstract 2942: TRAIL pathway inducer ONC201/TIC10 primes multiple myeloma cells (MM) for apoptosis by downregulating X-linked inhibitor of apoptosis
Authors: Christina Leah Kline, Amriti R. Lulla, David Dicker, Joshua E. Allen, Wafik El-Deiry
Journal: Cancer Research (2015)

Abstract MM cells inherently have a high protein turnover rate that makes them heavily dependent on the proteasome and uniquely sensitive to ER stress induction. Proteasome inhibitors, such as bortezomib, are used in front-line therapy for MM to elicit the ER stress response that results in apoptosis of MM cells. Despite significantly improved clinical outcomes in MM patients treated with proteasome inhibitors, resistance to therapy invariably emerges and MM remains an incurable disease. The objective of this study is to assess the utility of the TRAIL pathway inducer ONC201/TIC10 in MM due to preliminary evidence that suggests ONC201/TIC10 activates the integrated stress response (ISR) in tumor cells. We found that MM cells are uniquely sensitive to ONC201/TIC10, with EC50 values in the nanomolar range. In addition, ONC201/TIC10 was effective as a single agent against bortezomib-resistant MM cells and exhibited an additive effect with bortezomib against these cells. Sub-G1 analyses of MM cells co-treated with ONC201/TIC10 and a pan-caspase inhibitor indicated that MM cells undergo ONC201/TIC10-induced apoptosis in a caspase-dependent manner. Given that ONC201/TIC10 can inactivate both Akt and ERK signaling pathways, we assessed Akt and ERK phosphorylation in ONC201/TIC10-treated KMS18 and MM1S MM cells. These MM cell lines showed no inhibition of Akt and ERK phosphorylation or decrease in the downstream phosphorylation of Fox3a in response to ONC201/TIC10 treatment. These results suggested that alternative mechanisms of cytotoxicity are operative in myeloma cells treated with ONC201/TIC10. Given that downregulation of X-linked inhibitor of apoptosis (XIAP) has been linked to the ISR, we assessed the effect of ONC201/TIC10 treatment on XIAP expression. In agreement with ISR activation, XIAP levels were significantly downregulated in MM cells in response to ONC201/TIC10. Ongoing experiments are unraveling the mechanistic basis for lowered XIAP expression in ONC201/TIC10-treated MM cells. In summary, our results indicate that ONC201/TIC10 is highly effective in preclinical MM models by engaging antitumor mechanisms that include the ISR and downstream attenuation of XIAP expression. ONC201/TIC10 appears to have significant therapeutic potential in MM as a monoagent and in combination with bortezomib. Citation Format: Christina Leah Kline, Amriti R. Lulla, David Dicker, Joshua E. Allen, Wafik El-Deiry. TRAIL pathway inducer ONC201/TIC10 primes multiple myeloma cells (MM) for apoptosis by downregulating X-linked inhibitor of apoptosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2942. doi:10.1158/1538-7445.AM2015-2942
Depletion of the CD1d-Restricted NKT Cells Suppresses In Vitro Alloreactivity: A Possible Means To Prevent aGVHD.
Authors: S. Patterson, I. Kotsianidis, A. Almeida, M. Politou, R. David, A. Rahemtulla, V. Cerundolo, I. Roberts, A. Karadimitris
Journal: Blood (2004)
Complications of the Arteriovenous Fistula: A Systematic Review
Authors: Ahmed A. Al-Jaishi, Aiden R. Liu, Charmaine E. Lok, Joyce C. Zhang, Louise M. Moist
Journal: Journal of the American Society of Nephrology (2016)

The implementation of patient-centered care requires an individualized approach to hemodialysis vascular access, on the basis of each patient’s unique balance of risks and benefits. This systematic review aimed to summarize current literature on fistula risks, including rates of complications, to assist with patient-centered decision making. We searched Medline from 2000 to 2014 for English-language studies with prospectively captured data on ≥100 fistulas. We assessed study quality and extracted data on study design, patient characteristics, and outcomes. After screening 2292 citations, 43 articles met our inclusion criteria (61 unique cohorts; n &gt;11,374 fistulas). Median complication rates per 1000 patient days were as follows: 0.04 aneurysms (14 unique cohorts; n =1827 fistulas), 0.11 infections (16 cohorts; n &gt;6439 fistulas), 0.05 steal events (15 cohorts; n &gt;2543 fistulas), 0.24 thrombotic events (26 cohorts; n =4232 fistulas), and 0.03 venous hypertensive events (1 cohort; n =350 fistulas). Risk of bias was high in many studies and event rates were variable, thus we could not present pooled results. Studies generally did not report variables associated with fistula complications, patient comorbidities, vessel characteristics, surgeon experience, or nursing cannulation skill. Overall, we found marked variability in complication rates, partly due to poor quality studies, significant heterogeneity of study populations, and inconsistent definitions. There is an urgent need to standardize reporting of methods and definitions of vascular access complications in future clinical studies to better inform patient and provider decision making.
Detection of Activation-Induced Cytidine Deaminase RNA In CLL Cells Correlates with Shorter Patient Survival and High Numbers of CD38+ Cells
Authors: Charles C Chu, Piers EM Patten, Emilia Albesiano, Linda P Johnson, William J Kennedy, Lu Zhang, Amanda R Magli, Rajendra N Damle, Xiao-Jie Yan, Shabirul Haque, Patricia K Mongini, Jonathan E Kolitz, Steven L Allen, Kanti R Rai, Nicholas Chiorazzi
Journal: Blood (2010)
Abstract 1187: Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma
Authors: Simone Hettmer, Anna C. Schinzel, Daria Tchessalova, Nigel GJ Richards, William C. Hahn, Amy J. Wagers
Journal: Cancer Research (2015)

Abstract Background. Currently available therapies for sarcomas are often inadequate. This study sought to identify actionable gene targets in sarcomas by selective targeting of the molecular networks that support sarcoma cell proliferation. Experimental approach. Mouse sarcomas driven by expression of oncogenic Kras(G12v) and disruption of CDKN2A (p16p19) were induced by ex-vivo transduction and intramuscular injection of mouse satellite cells. Kras; p16p19null sarcomas identified a cluster of genes upregulated in mouse sarcomas and human rhabdomyosarcoma compared to normal skeletal muscle. A customized shRNA proliferation screen was used to identify transcripts within this cluster that reduced sarcoma cell proliferation. Target gene effects on sarcoma growth were evaluated in mouse and human sarcoma cell lines and xenografts. Results. Silencing of asparagine synthetase (ASNS), an amidotransferase that converts aspartate into asparagine, produced the strongest inhibitory effect on sarcoma growth in a functional genomic screen of mouse sarcomas generated by oncogenic Kras and Cdkn2a. ASNS silencing in mouse and human sarcoma cell lines reduced the percentage of S phase cells and impeded new polypeptide synthesis. These effects of ASNS silencing were reversed by exogenous supplementation with asparagine. Also, asparagine depletion via the ASNS inhibitor amino sulfoximine 5 (AS5) or asparaginase inhibited mouse and human sarcoma growth in vitro, and genetic silencing of ASNS in mouse sarcoma cells combined with depletion of plasma asparagine inhibited tumor growth in vivo. Conclusions. The generation of new protein mass by rapidly proliferating sarcoma cells requires adequate Asparagine availability. Asparagine reliance of sarcoma cells may represent an actionable, metabolic vulnerability with potential anti-rhabdomyosarcoma therapeutic value. Citation Format: Simone Hettmer, Anna C. Schinzel, Daria Tchessalova, Nigel GJ Richards, William C. Hahn, Amy J. Wagers. Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1187. doi:10.1158/1538-7445.AM2015-1187