tbuckley/cabot-search huggingface dataset:
O8.08 * CIC MUTATION IS A POOR PROGNOSIS FACTOR IN 1P19Q CODELETED GLIOMAS, ASSOCIATED TO AN UP-REGULATION OF PROLIFERATION PATHWAYS
Authors: V. Gleize, A. Alentorn, L. Connen de Kerillis, M. Labussiere, S. Mangesius, F. Ducray, K. Mokhtari, C. Villa, M. Sanson
Journal: Neuro-Oncology (2014)

BACKGROUND: Mutations affecting the Capicua transcriptional repressor gene (CIC) on 19q13.2 are frequently associated with a chromosomes 1p and 19q codeletion in oligodendroglial tumors. However, their impact remains poorly understood. EXPERIMENTAL DESIGN: We sequenced the CIC gene on 132 oligodendroglial tumors (109 with 1p19q codeletion), analyzed the patients' outcomes, compared the transcriptomic profile of mutated vs. non mutated tumors, analyzed CIC expression on glioma sections, and transfected the Hs683 cell line with plasmids encoding mutant and wild type CIC. RESULTS: We found 62 (37 truncating and 25 missense) mutations affecting 58/109 codeleted gliomas vs. 1/23 non-codeleted. CIC mutations were associated with a poorer outcome, and a shorter time to anaplastic transformation in grade II codeleted gliomas. Transcriptomic analysis revealed an enrichment of proliferative pathways and oligodendrocyte precursor cell genes' expression profile. Of particular interest are the up-regulation of normally CIC repressed genes such as ETV1, ETV4, ETV5, which promote cell proliferation and invasion, and CCND1 (encoding cyclinD1), suggesting that CIC mutation results in an inactive protein. This hypothesis was further supported by the results of transfecting cells with a truncated form of the protein, resulting in a defect of nuclear addressing, and by the loss of protein expression observed in oligodendrogliomas affected by various mutations. Finally, survival analysis suggested a synergistic effect of CIC mutation and CDKN2A alteration in tumor progression. CONCLUSION: CIC mutations are associated with the activation of proliferative pathways, inhibition of differentiation, and poorer outcome in patients with a 1p19q codeleted gliomas.
MB-12 * INDUCED CISPLATIN RESISTANCE IN MEDULLOBLASTOMAS
Authors: M. Feldman, W. Ho, J. Heiss, M. Hall, Z. Zhuang
Journal: Neuro-Oncology (2015)

INTRODUCTION: Medulloblastoma is the most common malignant brain tumor in children.Treatment typically involves surgery followed by chemotherapy, incorporating cisplatin.Tumor recurrence is common after treatment, especially in type 3 (C-MYC-expressing) medulloblastomas, and less commonly in sonic-hedgehog-associated tumors (type 2).Though clinically devastating, little is known about recurrent medulloblastomas compared to primary tumors and almost nothing is known about the mechanisms of chemotherapeutic resistance in medulloblastoma.OBJECTIVES: Develop a
Resistance-Transfer Factor in Enterobacteriaceae
Authors: Sherwin A. Kabins, Sidney Cohen
Journal: New England Journal of Medicine (1966)

IN recent years pathogenic enterobacteriaceae have become increasingly resistant to many antibiotics.§ 1 2 3 Japanese workers showed in 1959 that resistance to multiple antibiotics in many strains of shigella was infectious — that is, that it could be transmitted by conjugation from resistant shigellas to sensitive strains of Escherichia coli.1 Further investigation showed this to be due to the transfer of an extrachromosomal genetic element, the resistance-transfer factor. The factor which is reproduced in the progeny endows them with resistance to multiple antibiotics. Similarly, infectious resistance has been demonstrated in many strains of salmonella, Esch. coli and other gram-negative bacilli . . .
Gene Therapy for Pyruvate Dehydrogenase E1α Deficiency Using Recombinant Adeno-Associated Virus 2 (rAAV2) Vectors
Authors: Renius Owen, Ronald J Mandel, Chandramohan V Ammini, Thomas J Conlon, Douglas S Kerr, Peter W Stacpoole, Terence R Flotte
Journal: Molecular Therapy (2002)

To determine the feasibility of gene transfer to correct defects in the E1α subunit of the pyruvate dehydrogenase (PDH) complex (PDC), we constructed rAAV vectors that expressed PDH E1α, either alone or with a green fluorescent protein tag, from a hybrid cytomegalovirus (CMV) enhancer/chicken β-actin (CB) promoter. These vectors were functional <i>in vitro</i>, as judged by increased expression of mRNA in vector-transduced deficient cell lines and correction of the biochemical defect in PDH activity in these cells. Approximately 30% of wild-type levels of PDH activity were restored under conditions with which only about 15% of cells were transduced. These same vectors were then used <i>in vivo</i> to transduce neurons within the rat striatum. Gene transfer, expression, and translocation into mitochondria were observed, without any obvious untoward effects. <i>In vivo</i> vector-mediated PDH expression persisted for at least 1 year after injection, indicating the stability of gene transfer. These studies provide the basis for future efforts to develop a recombinant AAV (rAAV)-based gene therapy approach for the correction of PDC deficiency.
Adoption of the double dummy trial design to reduce observer bias in testing treatments
Authors: Ana Marušić, Stella Fatović Ferenčić
Journal: Journal of the Royal Society of Medicine (2013)

Careful reading of these 1970s studies, however, revealed that the Croatian study was not the earliest to report the use of the double dummy trial design. The earliest reports that we have identified so far were two published in 1964 and 1965. Percy et al.,17 at the Royal Victoria Infirmary in Newcastle-upon-Tyne, UK, compared indomethacin and phenylbutazone in the treatment of a variety of rheumatic diseases. Their description of a double dummy design is clear:

As it was not possible to produce identical tablets of both drugs, an inert tablet corresponding to each active compound was made and the four resultant tablet types (active Indomethacin; dummy Indomethacin; active phenylbutazone; dummy phenylbutazone) were so dispensed that a week's supply of each drug was given together with dummy tablets identical with the other drug.



The following year, Dudley Hart and Boardman,18 at the Westminster Hospital in London, UK, compared indomethacin and phenylbutazone in the treatment of rheumatoid arthritis. Their article also clearly describes a double dummy design:

To provide double-blind conditions they received active indomethacin and dummy phenylbutazone in one month, and in the other active phenylbutazone and dummy indomethacin.



In 1969, the report of a comparison of indomethacin and phenylbutazone by Wright et al.19 also carries a clear explanation of a double dummy trial design:

The trial was conducted in three periods of 4 weeks, during each of which the patient received either red phenylbutazone tablets (100 mg. each) and yellow placebo capsules, or yellow indomethacin capsules (50 mg. each) and red placebo tablets, or yellow placebo capsules and red placebo tablets.



Although they did not use the term ‘double dummy’, Figure 1 [not shown in this article] in a paper published by the same authors two years later20 makes clear that the two preparations compared (indomethacin as a capsule and phenybutazone as a tablet) were given using the double dummy trial design.

The National Library of Medicine did not use the term ‘double dummy’ in indexing any of the articles published before the 1970s. Although some of them used the term ‘dummy’, search using ‘dummy’ as a keyword did not identify any of the trials that we found by following leads from reports published in the 1970s. It thus seems that double dummy method originated in rheumatological research in the 1960s, but its introduction may have been even earlier.
A Controlled Trial of Fish Oil in IgA Nephropathy
Authors: James V. Donadio, Erik J. Bergstralh, Kenneth P. Offord, Dorothy C. Spencer, Keith E. Holley
Journal: New England Journal of Medicine (1994)

The n-3 fatty acids in fish oil affect eicosanoid and cytokine production and therefore have the potential to alter renal hemodynamics and inflammation. The effects of fish oil could prevent immunologic renal injury in patients with IgA nephropathy.
Abstract P5-06-10: ErbB Signaling Is Required for Activation of Phosphatidylinositol-3 Kinase and Transformation of Mammary Epithelial Cells by Polyomavirus Middle T Antigen
Authors: RS Cook, C Rinehart, J Garrett, A Chakravarti, CL. Arteaga
Journal: Cancer Research (2010)

Abstract Summary Polyomavirus middle T (PyVmT) transforms cells through phosphatidylinositol 3-kinase (PI3K). Overexpression of ErbB2/ErbB3 heterodimers, potent activators of PI3K, occurs in PyVmT-driven mouse mammary tumors, but without known cause and consequence. Inhibition of ErbB2 with lapatinib, or genetically engineered loss of ErbB3, decreased PI3K signaling and tumor growth in mice, suggesting ErbB2/ErbB3 is required by PyVmT. ErbB2/ErbB3 formed signaling complexes containing PyVmT, p85 and Src. EZN-3920, a novel high-affinity oligonucleotide targeting ErbB3 transcripts, impaired ErbB3 expression in vivo, decreased PI3K signaling, cell survival, and growth of tumors, and improved response to lapatinib. Therefore, PyVmT utilizes ErbB2/ErbB3 overexpression to drive PI3K signaling. Furthermore, the challenge of ErbB3 as a kinase-inactive therapeutic target can be overcome by targeting ErbB3 mRNA transcripts in vivo. Significance Given the widespread use of, and knowledge gained from the MMTV-PyVmT transgenic mouse breast cancer model, understanding how PyVmT utilizes existing cell signaling programs is necessary to interpret how results impact our understanding/treatment of human breast cancers. We found that ErbB2/ErbB3 heterodimers were a necessary part of PyVmT signaling complexes involving Src and PI3K, and that PyVmT depends on ErbB3 in the breast epithelium for PI3K activity and tumor growth. Because ErbB3 harbors a weak/inactive tyrosine kinase, therapeutic anti-ErbB3 interventions present with challenges. Further, anti-ErbB3 antibodies that block ligand interaction with ErbB3 do not alter ligand-independent ErbB3 signaling. However. these challenges were overcome using high-affinity oligonucleotides targeting ErbB3 mRNA. Use of the oligonucleotide EZN-3920 effectively reduced ErbB3 expression, inhibited PyVmT tumor growth, and improved the response of tumors to lapatinib. These results support oligonucleotide knock-down of targets as potential therapeutic strategy. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-06-10.
Boosting antibiotic activity via ROS
Authors: Charlotte Harrison
Journal: Nature Reviews Drug Discovery (2013)

Toll-like receptor 4 agonist shows benefit in ADCompounds that stimulate the immune system to clear amyloid-β (Aβ) could have therapeutic potential in Alzheimer's disease (AD).Michaud et al. showed that systemic injections of monophosphoryl lipid A (MPLA) -a Toll-like receptor 4 agonist that has immunomodulatory properties -reduced Aβ load in the brain and enhanced cognitive function in a mouse model.At a cellular level, MPLA induced a strong phagocytic response by microglia (but only triggered a low inflammatory response).
Hypoxic Signaling and the Cellular Redox Tumor Environment Determine Sensitivity to MTH1 Inhibition
Authors: Lars Bräutigam, Linda Pudelko, Ann-Sofie Jemth, Helge Gad, Mohit Narwal, Robert Gustafsson, Stella Karsten, Jordi Carreras Puigvert, Evert Homan, Carsten Berndt, Ulrika Warpman Berglund, Pål Stenmark, Thomas Helleday
Journal: Cancer Research (2016)

Abstract Cancer cells are commonly in a state of redox imbalance that drives their growth and survival. To compensate for oxidative stress induced by the tumor redox environment, cancer cells upregulate specific nononcogenic addiction enzymes, such as MTH1 (NUDT1), which detoxifies oxidized nucleotides. Here, we show that increasing oxidative stress in nonmalignant cells induced their sensitization to the effects of MTH1 inhibition, whereas decreasing oxidative pressure in cancer cells protected against inhibition. Furthermore, we purified zebrafish MTH1 and solved the crystal structure of MTH1 bound to its inhibitor, highlighting the zebrafish as a relevant tool to study MTH1 biology. Delivery of 8-oxo-dGTP and 2-OH-dATP to zebrafish embryos was highly toxic in the absence of MTH1 activity. Moreover, chemically or genetically mimicking activated hypoxia signaling in zebrafish revealed that pathologic upregulation of the HIF1α response, often observed in cancer and linked to poor prognosis, sensitized embryos to MTH1 inhibition. Using a transgenic zebrafish line, in which the cellular redox status can be monitored in vivo, we detected an increase in oxidative pressure upon activation of hypoxic signaling. Pretreatment with the antioxidant N-acetyl-L-cysteine protected embryos with activated hypoxia signaling against MTH1 inhibition, suggesting that the aberrant redox environment likely causes sensitization. In summary, MTH1 inhibition may offer a general approach to treat cancers characterized by deregulated hypoxia signaling or redox imbalance. Cancer Res; 76(8); 2366–75. ©2016 AACR.
Tc-99m Sestamibi and In-111 DTPA Octreotide Uptake in Breast Carcinoma With Neurendocrine Differentiation
Authors: GIUSEPPE RUBINI, GIOVANNI D’EREDITÀ
Journal: Clinical Nuclear Medicine (2000)

From the Department of Nuclear Medicine and Institute of Semeiotica Chirurgica, University of Bari, Bari, Italy Received June 21, 1999. Revision accepted September 27, 1999. Reprint requests: Giuseppe Rubini, M.D., Department of Nuclear Medicine Policlinico, Piazza G. Cesare 11, Bari 70124, Italy. E-mail: [email protected]
Abstract 1136: Detection and characterization of circulating tumor cells in localized and metastatic prostate cancer patients using CTC-Chip microfluidic technology
Authors: Sunitha Nagrath, Shannon L. Stott, Richard J. Lee, Min Yu, Lindsey L. Ulkus, John A. Iafrate, Mathew R. Smith, Ronald G. Tompkins, Lecia V. Sequist, Daniel A. Haber, Shyamala Maheswaran, Mehmet Toner
Journal: Cancer Research (2010)

Abstract Despite recent molecular advances, the treatment of localized and metastatic prostate cancer has changed little in recent decades and it remains a major cause of cancer deaths in men. Localized prostate cancer may be either indolent or invasive, without reliable distinguishing markers, and the absence of tumor tissue from patients with metastatic bone disease has hampered understanding of acquired resistance to primary hormonal therapy. Given the predominant hematogenous spread of prostate cancer, circulating tumor cells (CTCs) may provide an indicator of vascular invasiveness, as well as a source of tumor specimens for molecular analysis, but available technologies have been limited by relatively low sensitivity. Huge strides in engineering at smaller scales have lead to the tremendous progress in microfabricated devices to facilitate both applied and basic research. Applying a multi-disciplinary approach, we have developed a microfluidic technology “CTC-Chip” for diagnosis and monitoring of non-hematological cancers. Using the CTC-Chip, we were able to isolate CTCs in patients with both localized and metastatic prostate cancer. In patients with advanced cancer, CTCs were present at a frequency of 34 CTCs/mL (range 14-653), with a profound decline in numbers during response to hormone withdrawal therapy. Molecular markers, including the characteristic TMPRSS2-ERG translocation, are readily identified in CTCs. In patients with early stage, resectable prostate cancer, we have monitored CTC load in circulation following surgical resection of the primary tumor. CTCs were examined the day following surgical resection, at postoperative day 9, and at greater than 3 months, coincident with scheduled postoperative clinical visits. Longitudinal monitoring of CTCs revealed all CTC-positive cases showed disappearance of CTCs following prostate resection, with some having an immediate decline and others having a delayed (&amp;gt;24 hours) response. No evident differences in tumor pathology or operative procedure distinguished patients with a rapid versus delayed postoperative CTC decline. Dual staining of captured CTCs for PSA and Ki67 indicated a broad range in proliferative index of CTCs among patients with different clinical courses. Thus, the quantitative isolation and analysis of CTCs in both localized and metastatic prostate cancer provides novel insights into early hematogenous dissemination and enables molecular analyses of treatment-responsive and -resistant disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1136.
Abstract 936: Phytoestrogen level modifies the association of ornithine decarboxylase-polyamine pathway related gene polymorphisms and gastric cancer risk
Authors: Lisa Y. Cho, Jae Jeong Yang, Kwang-Pil Ko, Boyoung Park, Aesun Shin, Jin Gwack, Soung Hoon Chang, Hai-Rim Shin, Keun-Young Yoo, Sue K. Park
Journal: Cancer Research (2010)

Abstract Objective: We investigated the role of single nucleotide polymorphisms (SNP) ODC-polyamine pathway related genes (ODC1, AMD1, OAZ2, NQO1, NOS2A) for gastric cancer risk. Additionally, we examined whether phytoestrogen levels modify the association of ODC-polyamine pathway SNPs and risk of gastric cancer. Materials and Methods: Twenty-five SNPs in five genes were genotyped in 59 incident gastric cancer cases and 175 matched controls recruited from the Korea Multi-Center Cancer Cohort. Candidate genes were selected based on genotype databases, and genotype assay was performed using Goldengate platform (Illumina). We calculated the unadjusted Wald p-value between each SNP and phytoestrogen level, as well as the false discovery rate (FDR) corrected p-values of the 25 SNPs according to each phytoestrogen biomarker. Unconditional logistic regression model was used to calculate the adjusted odds ratios (OR) and 95% CI for smoking history. Results: There was a significant association for NQO1 (rs1800566, rs1437135) and daidzein, AMD1 (rs1279599, rs7768897, rs811921) and equol, AMD1 (rs1279599, rs7768897, rs811921) and enterolactone (FDR p-value&amp;lt;0.2). Conclusion: Certain phytoestrogens and ODC-polyamine related genes polymorphisms may interact to affect development of gastric cancer. Additional studies are needed to further elucidate the gene-environment interaction for gastric cancer risk. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 936.
Abstract 5173: Adipocytes attract leukemia cells
Authors: Rocky Pramanik, Xia Sheng, Steven D. Mittelman
Journal: Cancer Research (2010)

Abstract Obesity is associated with increased progression and relapse of various types of cancer. We have previously found that obesity impairs leukemia treatment by mitigating chemotherapeutic drug. In addition, we observed the presence of acute lymphoblastic leukemia (ALL) cells in adipose tissue during chemotherapy treatment. Therefore, we have investigated whether adipocytes stimulate leukemia cell migration in addition to exerting their protective effect against chemotherapies. We used a cell migration assay in which murine ALL cells were cultured in 5μm pore Transwell inserts in an upper chamber, and test medium or adipocyte-conditioned medium (ACM) was used in the bottom chamber. The number of cells which migrated into the lower chamber in 90 minutes was counted using trypan blue exclusion and expressed as % of total cells initially plated in the transwell. When the upper Transwell inserts contained regular medium and the lower chamber contained ACM, 31.2±5.8% of cells migrated to the lower chamber. By contrast, when the lower chamber contained regular medium, only 0.3±0.2% of cells migrated (p&amp;lt;0.01, vs ACM, n=4). Preadipocyte-conditioned medium also stimulated migration, but less than ACM (18.2±4.8% cells migrated, p&amp;lt;0.05 vs. ACM, n=4). The ACM-stimulated migration had both directional and non-directional components, in that when both the upper and lower chamber contained ACM, 13.2±0.2% of cells migrated to the lower chamber, which was significantly more than with regular media (p&amp;lt;0.05), but less than with ACM (p&amp;lt;0.01). The above results suggest that adipocyte-secreted molecules increase ALL cell motility and attract leukemia cells in a directional fashion. It is plausible that adipose tissue, particularly in obese people, might attract leukemia cells and act as a safe heaven for leukemia cells against chemotherapy, thereby promoting leukemia relapse. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5173.
Abstract 5341: Combinatorial regulation of E2F target genes by the oncogenic ETS transcription factor EWS-FLI1
Authors: Raphaela Schwentner, Maximilian Kauer, Sven Bilke, Gunhild Jug, Paul S. Meltzer, Heinrich Kovar
Journal: Cancer Research (2011)

Abstract Ewing's sarcoma (ESFT) is a highly aggressive pediatric cancer of the bone characterized by the chimeric ETS transcription factor EWS-FLI1 as a result of a chromosomal translocation. By whole genome gene expression and ChIP-seq analyses we obtained evidence that EWS-FLI1 directly binds 50% of E2F target genes and possibly cooperates with E2F transcription factors. Furthermore, several E2F factors were themselves found to be direct targets of EWS-FLI1. To unravel the hierarchical structure of this EWS-FLI1/E2F transcriptional network module we performed luciferase reporter gene assays in combination with DNA motif mutation analyses and ChIP-PCR. The promoter regions of ten candidates for direct target genes of EWS-FLI1 and E2F factors were chosen for in-depth analysis. Corroborating the transcriptomic data, promoter activity of all ten genes showed reduced levels upon knockdown of EWS-FLI1. By chromatin immunoprecipitation, we confirmed that EWS-FLI1 directly binds to the promoter regions. For some of those genes, mutation of only a single ETS binding site leads to a reduction of luciferase activity comparable to knockdown of EWS-FLI1 (for example the E2F promoters). For the other selected EWS-FLI1 target candidates, mutation analysis and ChIP-PCR revealed more complex regulatory patterns. In one example, simultaneous mutation of two ETS binding sites within the region directly bound by EWS-FLI1 resulted in a significant reduction of transcriptional activity. However, mutation of the single E2F binding site rendered the promoter completely insensitive to EWS-FLI1 regulation. Furthermore, ChIP-PCR revealed that upon EWS-FLI1 repression an EWS-FLI1 induced activating E2F factor is exchanged for a repressing E2F factor on the promoter of this gene. Our results imply that EWS-FLI1 uses several modes of interaction with E2F factors to control shared target genes. This study was supported by grant 22328-B09 from the Austrian Science Fund FWF. R. Schwentner is a recipient of a DOC-fFORTE-fellowship of the Austrian Academy of Sciences. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5341. doi:10.1158/1538-7445.AM2011-5341
IMPLICATION OF NIGHT-TIME MEAN SYSTOLIC BLOOD PRESSURE FOR PREDICTING SUBCLINICAL TARGET ORGAN DAMAGE IN HYPERTENSION: COMPARISON WITH OFFICE CENTRAL BLOOD PRESSURES
Authors: Darae Kim, Chi Young Shim, Geu-Ru Hong, In Jeong Cho, Hyuk-Jae Chang, Jong-Won Ha, Namsik Chung
Journal: Journal of the American College of Cardiology (2016)