tbuckley/cabot-search huggingface dataset:
Older age should not be barrier for organ donation after death, study suggests
Authors: Susan Mayor
Journal: BMJ (2016)

The survival of donated kidneys and the patients who receive them is similar with kidneys from donors aged over 80 and with those from younger donors, a retrospective study has shown.1

The gap between demand for transplant organs and supply in recent years has resulted in extending the criteria applied to organ donors, including increasing the upper age limit. In many countries one to two …
Abstract 4630: Heterogeneity revealed through meta-analysis might link geographical differences with nasopharyngeal carcinoma incidence in Han Chinese
Authors: Wen-Hui Su, Chi-Cking Chiu, Yin Yao Shugart
Journal: Cancer Research (2015)

Abstract Nasopharyngeal carcinoma (NPC) is an epithelial malignancy highly prevalent in Southern China with varying incidence rates among Han Chinese in different geographic regions. Recently, three independent genome-wide association studies (GWAS) confirmed that the HLA-A was the main risk gene of NPC. However, studies from regions with different incidence rates led to contradictory claims regarding whether HLA-A was the sole risk gene and the association of rs29232 was independent from the HLA-A effect in chromosome 6p21.3 region. To explore whether the differences were caused by genetic factors underlying the varying incidence rates by region in NPC incidence, we performed a meta-analysis by selecting 5 single-nucleotide polymorphisms (SNPs) in chromosome 6p21.3 from 3 published GWAS studies and 3 published case-control studies from Southern China (Taiwan, Guangdong and Guangxi) involving 7 828 NPC patients and 8 813 healthy controls from Han Chinese. The rs29232 SNP exhibited a moderate level of heterogeneity (I2 = 43%) that disappeared (I2 = 0% and 4%) after stratifying the studies according to moderate- and high-incidence NPC regions. The estimated odds ratio (OR) of rs29232 (OR: 1.70, 95% confidence interval [CI]: 1.47-1.95) was higher in the moderate-incidence region than in the high-incidence region (OR: 1.42, 95% CI: 1.30-1.56). The heterogeneity revealed by meta-analysis of rs29232 might be associated with differences in NPC incidence in Han Chinese between geographic regions. Therefore, we postulate that moderate heterogeneity in rs29232 might contribute to the varying incidence rates between regions due to a genetic cause in NPC incidence. The higher OR of rs29232 and the fact that it was independent of the HLA-A effect in the moderate-incidence population suggested that rs29232 might have greater relevance to NPC in a moderate-incidence population than to a high-incidence population. To our knowledge, this is the first study to demonstrate that genetic factors might involve in the varying disease incidence rates by region. This further suggests that the disease incidence rate should be considered as a potential confounding factor when conducting large, cross-region meta-analysis in NPC. Citation Format: Wen-Hui Su, Chi-Cking Chiu, Yin Yao Shugart. Heterogeneity revealed through meta-analysis might link geographical differences with nasopharyngeal carcinoma incidence in Han Chinese. [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 4630. doi:10.1158/1538-7445.AM2015-4630
Case 39-2016
Authors: Theodore S. Hong, Phillip J. Gray, Jill N. Allen, Paul C. Shellito, Kathryn P. Lowry, Lawrence R. Zukerberg
Journal: New England Journal of Medicine (2016)

A 74-year-old man with a history of prostate cancer presented with rectal bleeding of 6 months' duration. Examination revealed a rectal mass. A diagnostic procedure was performed, and management decisions were made.
Nutritional and environmental risk factors of nasopharyngeal carcinoma in Morocco
Authors: N. Bouras, A. Tahri, S. Ammor, A. Baali, F. Tahiri
Journal: Journal of Clinical Oncology (2006)

15535 Background: The nasopharyngeal carcinoma (NPC) has a high incidence in north Africa and in southeast Asia. The goal of this study is to analyze the implication of nutritional and environmental factors in the raise of this cancer. Methods: It is a retrospective investigation with 274 affected by the NPC and 394 witnesses. Results: The nasopharyngeal carcinoma affects mens more then womens with a sex ratio of 1.8. We observed a peak between 20 and 29 years with the women and between 40 and 49 years with the men. We noted also a high frequency of the young population touched by this disease: 10.5% less than 20 years old, which was also observed in Tunisia, Algeria and Sudan while the young patients are rarerly affected in the Asian southeast. The patients have mostly rural origin with agricultural parents, having lived during their childhood in precarious habitat and hygiene conditions and with an instruction level generally low, often without function or exercising in the primary or secondary sector. The study of nutritional and environmental risk factors showed a statistically meaningful relation between this cancer and some factors bound to the food: consumption of pickle, of smen (butter fermented), and to the environment: life in agricultural environment, practice of the farm, absence of drinkable water and contact with toxic substances. Conclusions: It seems that the exposition to environmental risk factors could increase the risk to contract this cancer, especially with the already exposed persons to nutritional risk factors. We observed a territorial variability of the exposition to the NPC risk factors that explains the gradient south north of the incidence of this cancer in Morocco. The results of this study show the complexity of factors being able to take to a cancerogenesis. No significant financial relationships to disclose.
Abstract 2095: DEPTOR is a direct NOTCH1 target that regulates proliferation, metabolism and glucocorticoid resistance in T cell leukemia
Authors: Yufeng Hu, Hexiu Su, Qi Ye, Zhaojing Wang, Liang Huang, Qian Wang, Shuangyou Liu, Suning Chen, Jianfeng Zhou, Peng Li, Guoliang Qing, Hudan Liu
Journal: Cancer Research (2015)

Abstract DEP-Domain Containing mTOR-Interacting Protein (DEPTOR) is frequently overexpressed in multiple myelomas and required for cell survival. However, its implications in other hematological malignancies and the precise mechanisms of regulation remain largely undefined. Here, we systematically analyzed DEPTOR expression in human acute lymphoblastic leukemia (ALL), a hematological malignancy accounting for 80% of pediatric leukemia. Whereas substantially inhibited in B-ALLs, unexpectedly, expression of DEPTOR is significantly elevated in a subset of T-ALLs where NOTCH1 is aberrantly activated. Mechanistically, we show DEPTOR expression is dependent on NOTCH signaling in T-ALL cell lines and primary specimens, and demonstrate NOTCH1 directly binds to and activates human DEPTOR promoter. DEPTOR depletion in T-ALL cells abolishes proliferation, attenuates glucose metabolism, enhances apoptosis and sensitizes resistant cells to γ-secretase inhibitor or dexamethasone treatments. Conversely, ectopically expressed DEPTOR promotes proliferation and aerobic glycolysis, and confers dexamethasone resistance. DEPTOR functions through AKT-dependent mechanisms to sustain cell proliferation and drug resistance, while the AKT-independent roles of DEPTOR appear to promote glucose metabolism. We therefore define a novel mechanism that, in addition to the previously reported HES1/PTEN-mediated regulation of AKT, NOTCH1 alternatively activates AKT through inducing the downstream target gene DEPTOR. Our findings thereby highlight DEPTOR as a critical mediator in leukemogenesis and suggest DEPTOR expression may serve as a potential biomarker predicting glucocorticoid resistance and targeting DEPTOR may achieve better therapeutic benefits. Citation Format: Yufeng Hu, Hexiu Su, Qi Ye, Zhaojing Wang, Liang Huang, Qian Wang, Shuangyou Liu, Suning Chen, Jianfeng Zhou, Peng Li, Guoliang Qing, Hudan Liu. DEPTOR is a direct NOTCH1 target that regulates proliferation, metabolism and glucocorticoid resistance in T cell leukemia. [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 2095. doi:10.1158/1538-7445.AM2015-2095
Efficacy of a Brief, Cyclophosphamide-Intensive Regimen for Older Patients with Newly Diagnosed Burkitt's or Atypical Burkitt's Lymphoma/Leukemia.
Authors: Yvette L. Kasamon, Robert A. Brodsky, Michael J. Borowitz, Pamela A. Crilley, Richard F. Ambinder, Richard J. Jones, Lode J. Swinnen
Journal: Blood (2009)
129. Does Transcription Influence AAV-Mediated Homologous Recombination?
Authors: Laura P. Spector, Mark A. Kay
Journal: Molecular Therapy (2016)

Recombinant adeno-associated viral (AAV) vectors constitute one of the most promising tools for gene transfer. While the majority of AAV transduction events are episomal, our laboratory recently exploited the vector's ability to induce homologous recombination (HR) to design promoterless vectors that utilize chromosomal homology arms flanking a ribosomal skipping P2A-therapeutic coding sequence construct to integrate sequences just upstream of the stop codon of an endogenous gene. When targeting the albumin gene in the liver, a chimeric mRNA transcript capable of producing both albumin and a second therapeutic protein is consequently created. Not only do these vectors offer the permanence of gene transfer associated with integration, but a vector lacking a promoter reduces the chance for oncogene activation from off-target vector integration. AAV-mediated HR appears to be more efficient when targeting transcriptionally active loci, yet it is unclear if transcription itself or other factors that secondarily influence transcription, such as chromatin state, are directly linked to AAV-mediated HR. We therefore set out to establish if the transcriptional rate in particular is a major determinant for this type of HR. To do this, we developed a strategy to quantify precision AAV-mediated transgene integration by exploiting an engineered locus whose transcriptional rates could be controlled by drug administration. To this end, we used lentiviral vectors to generate a series of clonal HeLa cell populations each harboring a single-copy, doxycycline-inducible genomic site expressing the human alpha 1-antitrypsin (hAAT) cDNA. Upon induction with doxycycline, transgene expression from this site increases by greater than 1,000-fold. Each clonal cell population was infected with an AAV serotype DJ vector containing homology arms to the integrated hAAT cDNA and a P2A- codon-optimized human coagulation factor IX (hFIX) cDNA or P2A-eGFP construct that would allow for multicistronic genomic expression of both peptides from a single mRNA only if HR occurred. Transgene hFIX or eGFP expression as a measure of HR is established by quantitative RT-PCR and by transgene protein measurements. By modulating the rate of transcription just prior to rAAV vector administration, we can establish if transcription from a given genomic locus influences the frequency of AAV-mediated HR. Our preliminary results suggest that transcription per se might not be the predominant factor influencing the rate of HR. Further studies will provide more insight into the mechanism of gene targeting by AAV, optimal target site selection, and potentially expand the use of AAV-mediated gene targeting for treating various genetic and acquired diseases.
Targeted Sequencing of Sorted Peripheral Blood Cells Reveals Novel Germline and Somatic Variants in the Polymorphonuclear and Mononuclear Cells of Patients with Essential Thrombocythemia, Polycythemia Vera and Primary Myelofibrosis
Authors: Chieh Lee Wong, Gareth Gerrard, Martyna Adamowicz-Brice, Zainul Abidin Norziha, Nor Rafeah Tumian, Soon Keng Cheong, Chooi Fun Leong, Ping Chong Bee, Gin Gin Gan, Jameela Sathar, Baoshan Ma, Liming Liang, Tim Aitman, Letizia Foroni, Michael Laffan
Journal: Blood (2015)
470. New Insights into rAAV Integration Mechanisms by Targeted Enrichment Sequencing
Authors: Stefan Wilkening, Saira Afzal, Elena Senís, Raffaele Fronza, Christof von Kalle, Dirk Grimm, Manfred Schmidt
Journal: Molecular Therapy (2016)

Comprehensive analysis of deep sequencing data originating from the newly introduced Targeted Enrichment Sequencing (TES) indicates so far undescribed recombinations within the Inverted Terminal Repeats of recombinant Adeno-Associated Viruses (rAAVs). For the detection of vector integration sites into the host genome we routinely apply LAM-PCR. However, TES, in which we enrich for genomic regions that include vector sequences, has major advantages over LAM-PCR, as it neither depends on the existence of a vector-specific primer binding site (often lost during rAAV integration) nor on a restriction site in the vicinity of the vector insertion site. Furthermore, regions that are captured together with the vector allow for relative quantification of vector copies per genome. As the entire vector can be sequenced by TES, mutations within the vector and transgene can be detected. In summary, we here provide new and so far unpublished information about rAAV integration patterns and show how we optimized TES to become an important complementary tool to primer-based approaches (like LAM-PCR) for mapping of vector/viral integration sites.
The Impact of Cytogenetic Response At 6 Months of Therapy in Global Survival of Patients with Chronic Myeloid Leukemia Treated with Imatinib in the South of Brazil
Authors: Laura Fogliatto, Marcelo Capra, Mariza Schaan, Mario Sérgio Fernandes, Tito Vanelli Costa, Mayde Seadi Torriani, Katia Fassina, Christina G S Fraga, Mayla Baron, Dayane Koshiyama, Natássia Machado, Liane Esteves Daudt, Lucia Silla
Journal: Blood (2012)
Abstract 2914: Gold magneto nanoparticles induced apoptosis in liver cancer cells through changes of Ca channel pump detected by LIBS Technique and RT-PCR array
Authors: Ola Ahmed, Hisham Imam, Abdel-Rahman N. Zekri
Journal: Cancer Research (2015)

Abstract Laser-induced breakdown spectroscopy technique (LIBS) was used in thesis study to address the effect of gold magneto nanoparticles on the liver cancer cells (HepG2) by examining the variation in genotoxicity and cytotoxicity. HepG2 cell line was cultured at 105 cells/ml and expanded, after which, they were incubated with gold magneto nanoparticles at concentrations 10, 25, 50 μg/ml respectively for 12 hours. The effect of these nanoparticles in cell apoptosis as well as in autophagy was evaluated by acridine orange staining and Annexin V/propidium iodide double staining as well as apoptosis specific PCR array assay for evaluation of apoptosis in the treated cells. At a concentration of nanocomposite 10, 25, 50 μg/ml, cells showed increase in the apoptosis figure from 11.25% ± 3.1% to 28% ± 2.04%, 39% ± 3.6%, 60% ± 4.3% respectively. Apoptosis specific PCR array also, showed very high expression of TNF, BIRC3 and NFKB1 with increasing in the fold regulation ratio of 155.03,158.03 and 149.2- fold respectively. On the other hand, extra investigation of these treated cells by LIBS shows an increasing in the iron oxide nanoparticles concentration as well as calcium concentration. This increase in the calcium content in the treated cells may play an important role in the program cell apoptosis which was prove in our study by both Flow cytometry as well as by profile apoptosis PCR array. Finally, our data showed the possibility of the using LIBS as inductor of cells apoptosis by measurement Ca concentration changes in liver cancer cells (HepG2 cells). Keywords: Apaptosis, LIBS; HepG2 cell; Genotoxicity Citation Format: Ola Ahmed, Hisham Imam, Abdel-Rahman N. Zekri. Gold magneto nanoparticles induced apoptosis in liver cancer cells through changes of Ca channel pump detected by LIBS Technique and RT-PCR array. [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 2914. doi:10.1158/1538-7445.AM2015-2914
Abstract 5547: Anti-proliferative activity of hydnocarpin, a natural lignan, is associated with the inhibition of Wnt/β-catenin signaling pathway via axin turnover in colon cancer cells
Authors: Won Kyung KIM, Min Ai LEE, Hyen Joo PARK, Ji-Young HONG, Sam Sik KANG, Sang Kook LEE
Journal: Cancer Research (2015)

Abstract Abnormal activation of the canonical Wnt/β-catenin pathway and up-regulation of the β-catenin/T-cell factor (TCF) response to transcriptional signaling play critical roles early in colorectal carcinogenesis. Therefore, the Wnt/β-catenin signaling is considered an attractive target for cancer chemotherapeutic of chemopreventive agents, natural compounds were evaluated for β-catenin-mediated transcriptional activity. Hydnocarpin (HC), a natural lignan from Lonicera japonica was identified as a promising candidate because it effectively inhibited β-catenin/TCF reporter gene (TOPflash) activity. HC also exhibited potent growth inhibition of SW480 human colon cancer cells. Further investigation of HC on the regulation of the Wnt/β-catenin signaling revealed that HC had minimal effect on GSKβ and CK1α, while the protein levels of both axin1 and axin2 were remarkably increased by HC treatment. In addition, the interaction of axin and β-catenin by HC was significantly increased as analyzed by immunoprecipitation assay. These events led to up-regulation of the β-catenin destruction complex formation and phosphorylation of β-catenin. To further explore the role of axin1 up-regulation by HC in the mechanism of action of Wnt inhibitory effects on SW480 cells, siRNA experiments were conducted. The growth inhibitory effects of HC on SW480 cells were abolished by axin1 siRNA, implying that HC inhibited the Wnt/β-catenin signaling in an axin-dependent fashion. These finding suggests that HC might be a novel Wnt inhibitor and has a potential of signaling regulator in β-catenin-mediated signaling pathways. Citation Format: Won Kyung KIM, Min Ai LEE, Hyen Joo PARK, Ji-Young HONG, Sam Sik KANG, Sang Kook LEE. Anti-proliferative activity of hydnocarpin, a natural lignan, is associated with the inhibition of Wnt/β-catenin signaling pathway via axin turnover in colon cancer cells. [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 5547. doi:10.1158/1538-7445.AM2015-5547
Abstract 4521: Evaluation of the relationship between serum exposure, receptor (GITR) availability and tumor suppression following administration of the anti-GITR antibody DX400 in mouse syngeneic tumor models
Authors: Ayse Meric Ovacik, Natalie Shinsky-Bjorde, Douglas Hodges, Svetlana Antonenko, Roanna Ueda, Smita Mauze, Danling Gu, Derek Wiswell, Shuli Zhang, Amy Beebe, Mohammad Tabrizi
Journal: Cancer Research (2015)

Abstract GITR is a type I transmembrane protein of the tumor necrosis factor receptor superfamily which is expressed primarily on T lymphocytes and natural killer cells. Ligation of GITR on activated T cells provides a costimulatory signal that positively modulates antigen-specific T cell responses, leading to enhanced cellular and humoral immunity. The anti-GITR antibody DX400 is a murinized agonistic monoclonal antibody that targets mouse GITR, and has shown tumor growth inhibition in mouse syngeneic tumor models. In this study we examined the pharmacokinetic/pharmacodynamics (PK/PD) properties of DX400. Studies were conducted to examine the potential relationships between anti-GITR antibody serum exposure (PK) and receptor availability (PD) on the relevant T-cell subsets. The concentrations of DX400 in serum were determined using an electrochemiluminescence (ECL) assay, and the availability of receptor (GITR) was determined using flow cytometry. Non-linear PK properties for DX400 were observed over the dose range examined. In line with changes in serum concentration-time profiles for the antibody, a dose dependent effect in receptor availability was also observed. The relationships between receptor availability, serum concentrations of DX400 and tumor suppression were described by a mechanistic PK/PD model. This analysis provided an estimated potency (EC50) value of 4.2 ng/mL for blood receptor engagement on T-cell subsets. Citation Format: Ayse Meric Ovacik, Natalie Shinsky-Bjorde, Douglas Hodges, Svetlana Antonenko, Roanna Ueda, Smita Mauze, Danling Gu, Derek Wiswell, Shuli Zhang, Amy Beebe, Mohammad Tabrizi. Evaluation of the relationship between serum exposure, receptor (GITR) availability and tumor suppression following administration of the anti-GITR antibody DX400 in mouse syngeneic tumor models. [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 4521. doi:10.1158/1538-7445.AM2015-4521
Leukemic Promyelocytes Possess Self-Renewal Capacity and Leukemia Stem Cell Properties in a Mouse Model of Acute Promyelocytic Leukemia.
Authors: Sarah A. Wojiski, Benjamin Lee, Thomas Kindler, Maricel Gozo, Dena Leeman, Elizabeth McDowell, Attila Fabian, Florence Guibal, Daniel Tenen, D. Gary Gilliland
Journal: Blood (2007)
Role of Gene Mutations in Adult Acute Myeloid Leukemia Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Sheng-Chieh Chou, Jih-Luh Tang, Liang-In Lin, Hsin-An Hou, Chien-Yuan Chen, Szu-Chun Hsu, Bo-Sheng Ko, Shang-Yi Huang, Wen-Chien Chou, Ming Yao, Woei Tsay, Yao-Chang Chen, Hwei-Fang Tien
Journal: Blood (2009)