tbuckley/cabot-search huggingface dataset:
Abstract 4932: Stratification markers for the risk of recurrence after curative resection of stage II or III gastric cancer and potential clinical applications
Authors: Takashi Oshima, Yayoi Kimura, Kentaro Sakamaki, Yohei Miyagi, Takaki Yoshikawa, Yasushi Rino, Kazuhiro Sentani, Naohide Oue, Wataru Yasui, Toshio Imada, Munetaka Munetaka
Journal: Cancer Research (2016)

Abstract Objective: Standard treatment for stage II or III gastric cancer is curative resection followed by adjuvant chemotherapy. Treatment outcomes are expected to be further improved by individualized therapy based on biomarker analysis. We extracted mRNA and protein from frozen specimens of gastric cancer and analyzed markers for stratifying the risk of recurrence after curative resection of stage II or III gastric cancer. We report our currently available findings. Methods: Candidate markers for stratification of recurrence risk were identified by quantitative real-time polymerase chain reaction (Q-PCR) at the gene level and liquid chromatography-tandem mass spectrometry (LC-MS/MS) at the protein level. The study group for quantitative real-time PCR comprised 255 patients with stage II or III gastric cancer (training set, 145 patients; validation set, 110 patients). The relative expression levels of 127 genes were measured in gastric cancer tissue. Genes identified be independent predictors of poor outcomes in the training set were verified in the validation set. The study group for exploratory proteomics analysis LC-MS/MS comprised 24 patients with T4a Nx M0, Stage III gastric cancer (recurrence and death, 12 patients; relapse-free survival &amp;gt;5 years, 12 patients). Proteins with max fold change &amp;gt;2 and Anova (P) &amp;lt;0.001 were searched. Results: On Q-PCR, 5 genes; SPARC, HER2, CXCR4, INHBA, and VSNL1 were identified as candidate markers. On exploratory proteomics analysis by LC-MS-MS, 4 proteins were identified as candidate markers for recurrence risk stratification. Conclusions: Promising candidate markers for stratification of the risk of recurrence after curative resection of stage II or III gastric cancer were identified at the gene and protein levels. These candidate markers are now being analyzed by tissue microarray, using specimens from about 500 patients each at two high-volume centers, with the goal of developing clinical applications. Citation Format: Takashi Oshima, Yayoi Kimura, Kentaro Sakamaki, Yohei Miyagi, Takaki Yoshikawa, Yasushi Rino, Kazuhiro Sentani, Naohide Oue, Wataru Yasui, Toshio Imada, Munetaka Munetaka. Stratification markers for the risk of recurrence after curative resection of stage II or III gastric cancer and potential clinical applications. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4932.
Abstract 4050: Bovine leukemia virus small noncoding RNAs are functional elements that regulate replication and contribute to oncogenesis in vivo
Authors: Nicolas Gillet, Malik Hamaidia, Alix de Brogniez, Geronimo Gutierrez, Nathalie Renotte, Michal Reichert, Karina Trono, Luc Willems
Journal: Cancer Research (2016)

Abstract Bovine leukemia virus (BLV), a retrovirus closely related to the human T-lymphotropic virus type 1 (HTLV-1), induces lymphocytosis and B-cell leukemia/lymphoma in ruminants. Although the provirus undergoes transcriptional silencing during transformation, BLV-infected tumor cells massively express viral miRNAs from internal Pol III promoters. To understand the mechanisms involved, a provirus isogenic to a wild type molecular clone but devoid of miRNAs was inoculated into calves. High-throughput RNA-sequencing and bioinformatic analyzes indicated that BLV miRNAs modulate expression of genes involved in B-cell receptor signaling, apoptosis, cell activation and immune response (GZMA, FOS, PPT1, ANXA1, MAP2K1 and PIK3CG). Direct and indirect interactions within these regulatory pathways were validated by luciferase reporter assays. In vivo, the deletion of BLV miRNAs reduced proviral loads in the natural host, indicating their biological relevance in viral replication and persistence. Furthermore, oncogenesis was abolished in the ovine experimental model. These observations thus show that BLV miRNAs affect key signaling pathways, promote viral replication and drive oncogenesis. Citation Format: Nicolas Gillet, Malik Hamaidia, Alix de Brogniez, Geronimo Gutierrez, Nathalie Renotte, Michal Reichert, Karina Trono, Luc Willems. Bovine leukemia virus small noncoding RNAs are functional elements that regulate replication and contribute to oncogenesis in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4050.
Distribution and geographic accessibility of prostate cancer clinical trials in the United States.
Authors: Matt D. Galsky, Asma Latif, Kristian D. Stensland, Erin L. Moshier, Russell McBride, Ryan Hendricks, Guru Sonpavde, James H. Godbold, Simon J Hall, William K. Oh, Juan P. Wisnivesky
Journal: Journal of Clinical Oncology (2014)

59 Background: An extremely small proportion of patients with cancer in the United States (US) enroll in clinical trials. While several barriers to trial accrual have been described, the geographic distribution and accessibility of clinical trial sites has not been comprehensively explored. Methods: ClinicalTrials.gov was queried to identify all active US clinical trials exploring first-line therapies for metastatic prostate cancer (PCa) on 9/16/2012. We evaluated the geographic distribution of trial sites and determined the relationship between the number of sites and the number of patients with advanced PCa per county and evaluated heterogeneity using Lorenz curves. We also estimated the minimum driving distance required to access a clinical trial site from each ZIP code in the continguous US; a distance &gt;30 miles was defined as high travel burden consistent with prior studies. Results: We identified 958 sites associated with 42 PCa clinical trials (Table). The geographic distribution of clinical trial sites was very inhomogeneous with several states having only 1-2 trial sites. Among 3185 US counties, 2,669 (83.8%) had no clinical trials available for first-line treatment of metastatic PCa. Counties with larger populations of patients with advanced PCa had significantly higher numbers of clinical trial sites. For every 100 additional patients with advanced PCa per county, the number of available trial sites increased by 21.0% (95% CI: 16.5-25.7%). However, Lorenz curves indicated a high degree of inequality in trial accessibility (Gini index 0.71). Approximately 31% of the US population resided &gt;30 miles from a PCa trial site. Conclusions: Clinical trials sites are poorly accessible, geographically, to a large subset of US PCa patients, a finding that likely contributes to dismal accrual. Innovative solutions are required to address geographic barriers to access. [Table: see text]
Recommandations pour la surveillance de l'infection à VIH en Europe
Authors: F F Hamers
Journal: Eurosurveillance (1998)

L’epidemie de VIH/SIDA en Europe est actuellement a un tournant important de son histoire. En Europe de l’Ouest, l’incidence du SIDA diminue depuis 1996 du fait notamment de la diffusion de traitements de l’infection a VIH plus efficaces qu’auparavant. Ces nouveaux traitements retardent l’evolution de la maladie. Les tendances du SIDA en sont des lors fortement affectees et le nombre de cas de SIDA ne reflete plus celui des malades severement immunodeprimes devant etre soignes.
Abstract 233: Identification of cancer vulnerabilities to metabolic perturbation using genome wide CRISPR screens
Authors: Megha Chandrashekhar, Michael Arreger, Ashwin Seetharaman, Traver Hart, Jason Moffat
Journal: Cancer Research (2016)

Abstract The CRISPR-Cas9 system provides an effective way to introduce targeted loss-of-function mutations in mammalian cells. The advance that the CRISPR-Cas9 technology brings to human genetics sets the stage for identifying cellular fitness genes that operate either globally (core fitness genes) or specifically within a particular genetic background or environmental context (context-specific fitness genes). In tumors, this is the foundation for the concept of synthetic lethality as genes required in tumor cells but not in adjacent normal tissues should make ideal therapeutic targets with high effectiveness and minimal side effects. Towards this goal, we have developed a second-generation CRISPR gRNA library of 176,500 guides targeting 17,661 human protein-coding genes. We used the library to screen five human cell lines, representing a cross-section of wild type and cancer tissues, to identify genes whose knockouts induce significant fitness defects. Our screens accurately recapitulate pathway-specific genetic vulnerabilities induced by known oncogenes and identify novel context-specific vulnerabilities. Interestingly, we identified a specific dependency on mitochondrial activity and we validated this using various complex I inhibitors. This strongly supports the idea that oxidative phosphorylation (OXPHOS) dependency - a clear exception to the Warburg effect - is a targetable weakness of some tumors. In order to further understand this metabolic vulnerability, we performed a synthetic lethal screen to identify sensitizers of OXPHOS inhibition. Our screen revealed that inhibition of mitochondrial OXPHOS sensitizes the cells to loss of other metabolic pathways such as glycolysis, pentose phosphate pathway and lipid biosynthesis. Furthermore, loss of the cytosolic aspartate aminotransferase GOT1 was found to be synthetic lethal with perturbation of OXPHOS. This is consistent with the essential role of the electron transport chain in cell proliferation, which is to enable aspartate synthesis. Additionally, we also find novel genes, whose loss of function might alleviate the affect of OXPHOS perturbation. Our findings demonstrate that CRISPR-Cas9 screens enable a high-resolution view of the genetic vulnerabilities of a cell that may represent therapeutic opportunities in cancer. Further, synthetic lethal chemical-genetic screens can reveal novel functional drug combinations, which will enhance the efficacy of targeted therapies. Citation Format: Megha Chandrashekhar, Michael Arreger, Ashwin Seetharaman, Traver Hart, Jason Moffat. Identification of cancer vulnerabilities to metabolic perturbation using genome wide CRISPR screens. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 233.
P0636 : Antiviral efficacy and induction of host immune responses with SB 9200, an oral prodrug of the dinucleotide SB 9000, in the woodchuck model of chronic hepatitis B virus (HBV) infection
Authors: K. Korolowicz, S. Czerwinski, R. Iyer, J. Skell, J. Yang, R. Tucker, S. Menne
Journal: Journal of Hepatology (2015)
Abstract 4728: Histone deacetylase inhibitors induce apoptosis in multiple tumor types through induction of ATF3
Authors: Anderly C. Chueh, Janson Tse, Paul Ioannidis, Lars Tögel, Bee S. Tan, Mercedes Davlos-Salas, Rebecca Nightingale, Matthew R. Thompson, Bryan Williams, Michael Dickinson, Amardeep S. Dhillon, John M. Mariadason
Journal: Cancer Research (2016)

Abstract Histone deacetylase inhibitors (HDACi) are approved for the treatment of cutaneous T-Cell lymphoma (CTCL) and Multiple Myeloma. In colon cancer cells HDACi-induced apoptosis is linked to induction of a specific transcriptional response involving upregulation of the immediate-early (IE) response genes FOS, JUN, EGR1, EGR3 and ATF3. To determine if this transcriptional response underpins HDACi-induced apoptosis across multiple tumour types, including CTCL and MM, 50 cell lines derived from common solid and haematological cancers were screened for sensitivity to HDACi-induced apoptosis, and response correlated with IE gene induction. HDACi treatment robustly induced IE gene mRNA and protein expression in multiple tumour lines. IE gene induction was sustained over 24 hours and dependent on the Sp1/Sp3 transcription factors and was also observed in vivo in CTCL patients treated with the HDACi panobinostat. The magnitude of induction of FOS, JUN and ATF3 expression correlated significantly with HDACi-induced apoptosis. The induction of ATF3 was critical for HDACi induced apoptosis as ATF3 downregulation markedly attenuated HDACi-induced apoptosis in multiple tumour lines, and ATF3 knockout MEFs were refractory to HDACi-induced apoptosis. To identify downstream targets of ATF3, the magnitude of ATF3 induction following HDACi treatment was correlated with altered expression of pro and anti-apoptotic genes involved in the intrinsic apoptotic pathway. The magnitude of ATF3 induction correlated inversely with repression of the anti-apoptotic gene Bcl-XL, and ATF3 knockdown attenuated HDACi-mediated Bcl-XL repression. Notably, combinatorial treatment of refractory cell lines with an HDACi and a Bcl-XL inhibitor significantly enhanced HDACi-induced apoptosis. This study demonstrates that IE gene induction is a universal feature of HDACi-induced apoptosis, and that ATF3 as a key driver of HDACi-induced apoptosis through repression of Bcl-XL. These findings establish a method for rapid assessment of HDACi response, and identify a combination strategy for enhancing the activity of these compounds. Citation Format: Anderly C. Chueh, Janson Tse, Paul Ioannidis, Lars Tögel, Bee S. Tan, Mercedes Davlos-Salas, Rebecca Nightingale, Matthew R. Thompson, Bryan Williams, Michael Dickinson, Amardeep S. Dhillon, John M. Mariadason. Histone deacetylase inhibitors induce apoptosis in multiple tumor types through induction of ATF3. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4728.
The MBOAT7 variant rs641738 alters hepatic phosphatidylinositols and increases severity of non-alcoholic fatty liver disease in humans
Authors: Panu K. Luukkonen, You Zhou, Tuulia Hyötyläinen, Marja Leivonen, Johanna Arola, Marju Orho-Melander, Matej Orešič, Hannele Yki-Järvinen
Journal: Journal of Hepatology (2016)
A feasibility study of [11C]choline for the molecular imaging of human breast cancer in vivo using positron emission tomography (PET)
Authors: L. M. Kenny, R. C. Coombes, A. Al-Nahhas, S. Osman, C. Lowdell, E. Aboagye
Journal: Journal of Clinical Oncology (2006)

613 Background: [ 11 C]Choline is a novel PET radiotracer. Preclinical studies suggest that it may be promising in breast cancer. [ 11 C]Choline has been recently evaluated as a screening agent in prostate cancer, but no studies have yet investigated its potential in breast cancer. We report a pilot study evaluating the utility and reproducibility of [ 11 C]Choline-PET in breast cancer. Methods: Dynamic imaging was performed on an ECAT962 HR+ PET scanner for 65 min after intravenous injection with 190–369 MBq [ 11 C]choline. Patients with locally advanced and metastatic breast cancer were eligible. All histological subtypes were included (ductal, lobular, and inflammatory). Arterial blood samples were taken continuously for 10 min, with 8 discrete samples up to 60 min to measure [ 11 C]choline and metabolites. Tissue uptake was determined by standardised uptake value at 60 min (SUV, dose and BSA corrected) and Ki (irreversible trapping) calculated using Patlak (corrected for [ 11 C]choline metabolites in plasma) and modified Patlak analysis (corrected for plasma + tissue metabolites). Reproduciblilty scans were performed 2–17 days later in the absence of treatment. Results: Tumour [ 11 C]choline uptake was observed in 10 out of 11 patients (12 out of 13 distinct lesions). There was a significant difference between tumour and normal tissue (breast/lung) in [ 11 C]choline uptake for Ki (p&lt;0.0001) and SUV (p&lt;0.0001). Tissue uptake was of the order lung ≤ normal breast &lt; tumour &lt; liver ≤ spleen. [ 11 C]choline was rapidly metabolised, at 60 min the mean ± S.E. plasma radioactivity due to [ 11 C]choline was 16.4 ± 2.9%. [ 11 C]Choline uptake was found to be reproducible for Ki (modified Patlak: r=0.93, p&lt;0.0001, Patlak: r=0.85, p=0.002) and SUV (r=0.94, p&lt;0.0001) - measured in 8 patients (median of 2 days after the 1 st scan). Tumour Patlak Ki was 13.2% &gt; Ki calculated using modified Patlak analysis. Conclusions: [ 11 C]Choline-PET imaging of breast cancer is promising and warrants further evaluation. Tumour [ 11 C]Choline uptake measured by Ki and SUV is reproducible. We plan to study the relationship between choline uptake measured by PET and immunoassays of tumour samples. Functional imaging could have a vital role to determine the efficacy of target-specific agents. No significant financial relationships to disclose.
Re-treatment with radium-223: An international, prospective, open-label study in patients with castration-resistant prostate cancer and bone metastases.
Authors: A. Oliver Sartor, Daniel Heinrich, Neil Mariados, María José Méndez-Vidal, Daniel Keizman, Camilla Thellenberg-Karlsson, Avivit Peer, Giuseppe Procopio, Stephen Jay Frank, Kalevi Pulkkanen, Eli Rosenbaum, Stefano Severi, Jose Manuel Trigo Perez, Paul Schwarzenberger, Rui Li, Luke T. Nordquist
Journal: Journal of Clinical Oncology (2016)

5074 Background: Radium-223 (Ra-223) treatment (tx) with 6 injections (inj) given at 4-week intervals is indicated for patients (pts) with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases. Ra-223 re-tx after an initial course of 6 Ra-223 inj was well tolerated, and rates of bone scan progression are low (Sartor. ASCO GU 2016). Herein we report a first analysis of overall survival (OS), symptomatic skeletal events (SSEs), and pain findings of Ra-223 re-tx in metastatic CRPC. Methods: Eligible pts had CRPC and ≥ 2 bone metastases and completed 6 initial Ra-223 inj with no disease progression in bone during tx. All pts enrolled had radiologic or clinical progression after initial Ra-223 tx, and had adequate hematologic values. Pts who started subsequent anticancer tx must have demonstrated disease progression while on their last anticancer tx. Concomitant agents were allowed at investigator discretion, excluding cytotoxic tx. Notably, initiation of new abiraterone and enzalutamide tx was not allowed during Ra-223 re-tx. Primary end point was safety; exploratory end points included OS, time to first SSE, SSE-free survival (SSE-FS), and time to pain progression. First patient first visit was January 19, 2014; data cutoff date was June 11, 2015. The follow-up time will be up to 2 years after last Ra-223 dose. Results: Of 44 re-tx pts with Ra-223, 29 (66%) received all 6 inj. Median time from the end of initial Ra-223 tx was 6 months. Three (7%) pts had grade 3 or 4 tx-related TEAEs (thrombocytopenia, anemia, and dehydration). No grade 5 hematologic TEAEs occurred. Thus far, 5 (11%) pts died, and 8 (18%) experienced first SSEs (external beam radiation therapy [6 (14%)] or pathologic bone fracture [2 (5%)]). Median OS and time to first SSE and SSE-FS were not reached. Five (14%) of 36 evaluable pts (baseline worst pain score ≤ 7) had pain progression. Median time to pain progression was not reached, and pain progression rate at 24 weeks was 20%. Conclusions: Re-tx with Ra-223 was well tolerated, with minimal hematologic toxicity reported. Early effects on OS, SSEs, and pain indicate that re-tx with Ra-223 should be studied in larger prospective trials. Clinical trial information: NCT01934790.
Abstract 3936: Identification and validation of the potential biomarker insulin-like growth factor binding protein acid-labile subunit for breast cancer in African American women
Authors: Padma P. Tadi Uppala, Carlos Garberoglio, Sharon Lum, Willie Davis, Hon-Chiu Eastwood Leung, Michael Liebman, Keiji Oda, Utkarsh P. Patel
Journal: Cancer Research (2016)

Abstract Breast cancer is the most frequently diagnosed cancer in women, with an estimated 40, 730 breast cancer deaths in the US in 2015. African American (AA) women have a lower breast cancer incidence rate, but a higher breast cancer death rate, than non-Hispanic White women. Research indicates that breast tumor biology in AA women is different from that in Caucasian women. AA women are more likely to be diagnosed with breast cancer at an earlier age and with more aggressive form of the disease, characterized by higher grade and negative estrogen and progesterone receptor status. Because of the aggressive nature of these tumors and current lack of targeted therapies, identification of novel relevant protein markers is of great importance. The purpose of this study was to validate serum proteins that were previously identified by serum proteomic profiling in 22 serum samples by 2D-DIGE/MS analysis and a subset of samples by shotgun LC/MS technology. Methods and new data: The current study included serum samples from 15 African American breast cancer patients and 12 healthy controls. Patients were grouped into triple negative (TN), HER2 and Luminal A and B subtypes. Proteins of biological significance were validated using western blot analysis. For ceruloplasmin, and insulin-like growth factor binding protein acid-labile subunit (IGFBP-ALS), one-way ANOVA was used to compare mean density among the three groups. For Vitamin D Binding protein (VDB), a two-sample t-test was used to compare the density between the groups. Due to the small sample size, we have also conducted nonparametric tests. IGFBP-ALS was significantly lower in triple negative breast cancer patients (p = 0.016) and in HER2 (p = 0.025) subtypes. There was no significant difference in VDB protein in the luminal A and B subtypes (p = 0.98). Future efforts will focus on validating the identified panel of biomarkers to gain insight into their role(s) in the etiology of aggressive breast tumors. Funded by Susan G Komen for the Cure and SEED grant SPH. Citation Format: Padma P. Tadi Uppala, Carlos Garberoglio, Sharon Lum, Willie Davis, Hon-Chiu Eastwood Leung, Michael Liebman, Keiji Oda, Utkarsh P. Patel. Identification and validation of the potential biomarker insulin-like growth factor binding protein acid-labile subunit for breast cancer in African American women. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3936.