tbuckley/cabot-search huggingface dataset:
KRAS and BRAF as prognostic biomarkers in patients undergoing surgical resection of colorectal cancer liver metastasis: A systematic review and meta-analysis.
Authors: Francesco Passiglia, Giuseppe Bronte, Antonio Galvano, Sergio Rizzo, Angela Listì, Nadia Barraco, Lavinia Insalaco, Rossella Maragliano, Enrico Bronte, Emmanuela Musso, Aurelia Guarini, Luisa Castellana, Marta Castiglia, Valentina Calò, Salvatore Vieni, Giuseppe Cicero, Christian Diego Rolfo, Viviana Bazan, Antonio Russo
Journal: Journal of Clinical Oncology (2016)

3565 Background: Clinical trials investigated the potential role of both KRAS and BRAF mutations, as prognostic biomarkers, in colorectal cancer (CRC) patients who underwent surgical treatment of liver metastasis (CLM), showing conflicting results. This meta-analysis aims to review all the studies reporting survival outcomes (recurrence free survival (RFS), and/or overall survival (OS)) of patients undergoing resection of CLM, stratified according to KRAS and/or BRAF mutation status. Methods: Data from all published studies reporting survival outcomes (RFS and/or OS) of CRC patients who received resection of CLM, stratified by KRAS and/or BRAF mutation status were collected by searching in PubMed, Cochrane Library, American Society of Clinical Oncology and European Society of Medical Oncology meeting proceedings. Pooled hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated for both the OS and/or RFS. Results: Seven eligible trials (1403 patients) were included. Pooled analysis showed that KRAS mutations predicted a significant worse both RFS (HR: 1.65; 95% CI: 1.23 – 2.21) and OS (HR: 1.86; 95% CI: 1.51 – 2.30) in patients who underwent surgical resection of CLM. BRAF mutations were also associated with a significant worse OS (HR: 3.90; 95% CI: 1.96 – 7.73) in this subgroup of patients. Conclusions: This meta-analysis suggests both KRAS and BRAF mutations as negative prognostic biomarkers associated with worse survival outcomes in patients undergoing hepatic resection of CLM. Such evidences support the introduction of new treatment decision models, taking into account the tumor molecular profile in order to individualize both systemic and loco-regional treatment strategies.
P0216 : Influence of previous decompensation of cirrhosis on hyperdynamic circulation and response to β-blockers in primary prophylaxis of variceal bleeding
Authors: E.A. Alvarado, O. Pavel, A. Ardèvol, I. Graupera, P. Huelin, A. Colomo, M. Martinez, N.C. Escajadillo, M.A. Ríos, C. Guarner Aguilar, C. Villanueva
Journal: Journal of Hepatology (2015)
Abstract 4437: DNA methylation analysis in cisplatin resistant ovarian cancer cells and recurrent ovarian cancer patient samples
Authors: Michaela L. Granados, Laurie G. Hudson, Li Luo, Sabrina L. Samudio-Ruiz
Journal: Cancer Research (2016)

Abstract Acquisition of platinum resistance following first line platinum therapy is commonly observed in ovarian cancer patients and is a major obstacle to clinical effectiveness. Currently there are no options available to prevent platinum resistance; however, studies show that demethylating agents may resensitize patients to platinum therapy thereby demonstrating DNA methylation as a critical contributor to the development of platinum resistance. Using a cellular model of platinum resistance we have previously shown that resistant cells have increased DNA methyltransferase (DNMT) activity as well as increased global DNA methylation. These observations were dependent on cisplatin induced activation of the Epidermal Growth Factor Receptor (EGFR) which we previously identified as a novel a regulator of DNMT activity and DNA methylation. Inhibition of the EGFR conferred during a platinum resistance paradigm decreased DNMT activity, decreased global methylation and attenuated resistance in our platinum resistant model. We hypothesized that further genome wide analysis of DNA methylation in resistant, parental and EGFR inhibited cell lines at specific CG sites would reveal targets of methylation important for the development of platinum resistance. Using the Illumina 450K methylation array, we found few significant alterations in DNA methylation for given genes between control and cisplatin resistant (CPR) cells. However, additional DNA methylation analysis with the 450K methylation array of patient tumor samples at initial diagnosis as well as after relapse, while not significant, showed similar trends in the data for certain genes namely CSRNP3, LOC400904, LYPD6, MTMR9L, NIPAL4 and RBP7. We are still evaluating the effects of EGFR inhibition in vitro on DNA methylation patterns. We suggest that while the in vitro model of platinum resistance corresponds to patient samples in some aspects, ovarian cancer cells display a great deal of heterogeneity in DNA methylation as described by others and a much larger sample size is necessary to draw concrete conclusions. Current studies are evaluating gene expression in control and resistant cells to validate whether alterations in DNA methylation coincide with changes in expression. Citation Format: Michaela L. Granados, Laurie G. Hudson, Li Luo, Sabrina L. Samudio-Ruiz. DNA methylation analysis in cisplatin resistant ovarian cancer cells and recurrent ovarian cancer patient samples. [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 4437.
Patient-reported outcomes with sofosbuvir and velpatasvir with or without ribavirin for hepatitis C virus-related decompensated cirrhosis: an exploratory analysis from the randomised, open-label ASTRAL-4 phase 3 trial
Authors: Zobair M Younossi, Maria Stepanova, Michael Charlton, Michael P Curry, Jacqueline G O'Leary, Robert S Brown, Sharon Hunt
Journal: The Lancet. Gastroenterology & hepatology (2016)
Staff education, regular sedation and analgesia quality feedback, and a sedation monitoring technology for improving sedation and analgesia quality for critically ill, mechanically ventilated patients: a cluster randomised trial
Authors: Timothy S Walsh, Kalliopi Kydonaki, Jean Antonelli, Jacqueline Stephen, Robert J Lee, Kirsty Everingham, Janet Hanley, Emma C Phillips, Kimmo Uutela, Petra Peltola, Stephen Cole, Tara Quasim, James Ruddy, Marcia McDougall, Alan Davidson, John Rutherford, Jonathan Richards, Christopher J Weir
Journal: The Lancet Respiratory Medicine (2016)
A Phase I/II Study of Bi-Weekly Xeliri with Capecitabine 1,000 Mg/M2 Twice Daily and Irinotecan 180 Mg/M2 Plus Bevacizumab(Bv) for Patient with Metastatic Colorectal Cancer As Second-Line Chemotherapy (Bixer Study)
Authors: M. Suenaga, N. Mizunuma, S. Matsusaka, E. Shinozaki, M. Ozaka, M. Ogura, K. Chin, T. Yamaguchi
Journal: Annals of Oncology (2014)
Screening for Coxiella burnetii infection during pregnancy: pros and cons according to the Wilson and Jungner criteria
Authors: J M Munster, L M Steggerda, A C Leenders, J G Aarnoudse, E Hak
Journal: Eurosurveillance (2012)

In Europe the incidence of human Q fever has dramatically increased over the previous years. Untreated infections with Coxiella burnetii, the causal agent of Q fever, have been associated with both obstetric and maternal complications. The majority of pregnant women with a C. burnetii infection remain asymptomatic, hence screening could be of value to prevent unwanted outcomes in this high-risk group. We applied the updated Wilson and Jungner criteria to review the evidence for routine screening for C. burnetii infection during pregnancy. Since much uncertainty remains about the incidence, clinical consequences, diagnostics and treatment of C. burnetii infection during pregnancy, routine screening for C. burnetii infection during pregnancy should not be recommended. Rigorous studies to assess the effectiveness of C. burnetii screening are warranted.
Abstract 2403: Molecular mechanisms orchestrating intratumoral heterogeneity in Kras-driven carcinomas
Authors: Roxana Azimi
Journal: Cancer Research (2016)

Abstract The considerable variability within tissue microenvironments as well as the multiclonality of cancers leads to intratumoral heterogeneity. This increases the probablility of cellular states that promote resistance to therapy and eventually lead to reconstitution of the tumor by treatment-resistant cancer cells, which in some cases have properties of normal tissue stem cells. Wnt signals are important in the maintenance of stem cells in various epithelial tissues, including in lung development and regeneration. We hypothesized that Wnt signals contribute to tumor heterogeneity in genetically engineered KrasG12D; Tp53Δ/Δ (“KP”) mouse lung adenocarcinomas (LUAD). We observed that a subpopulation of LUAD cells exhibited high Wnt reporter activity and had increased tumor forming ability, which could be suppressed by silencing of Wnt signaling pathway components or by small molecule Wnt inhibitors in vitro and in vivo. KP LUAD cells show hierarchical features with two distinct populations, one with increased Wnt reporter activity and another forming a niche that provides the Wnt signal. Lineage-tracing experiments in the autochthonous KP tumors demonstrated that Wnt responder cells have increased tumor propagation ability in vivo. Strikingly, selective ablation of the Wnt responder cells resulted in tumor stasis. CRISPR-based targeting or small molecules targeting Wnt signaling reduced tumor growth and prolonged survival in the autochthonous KP mouse lung cancer model. Interestingly, we found that a similar Wnt-driven mechanism operates to establish an intratumoral hierarchy also in other Kras-driven carcinomas. These results indicate that maintenance of heterogeneity within tumors may be advantageous for the tumor cell population collectively, which may be utilized as a therapeutic target to homogenize cancer cell phenotypes within tumors. Citation Format: Roxana Azimi. Molecular mechanisms orchestrating intratumoral heterogeneity in Kras-driven carcinomas. [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 2403.
Abstract 4520: The effect of EPZ011989, an enhancer of Zeste homolog 2 inhibitor, in acute myeloid leukemia
Authors: Sydney Fobare, Cecelia Miller, Shelley J. Orwick, Heike Keilhack, Erin Hertlein, John C. Byrd
Journal: Cancer Research (2016)

Abstract Enhancer of Zeste Homolog 2 (EZH2) is a catalytic core subunit of the Polycomb repressive complex 2, PRC2. EZH2 catalyzes the tri-methylation of lysine 27 on histone H3 (H3K27me3) which often results in the silencing of associated gene promoters. The over-expression of EZH2 is associated with cancer progression and poor prognosis in solid tumors and hematological malignances. EZH2 mutations in lymphoma generally are activating whereas those in myelodysplasia and acute myeloid leukemia are typically loss of function. Additionally, EZH2 mutations are not isolated to a hotspot and therefore discerning phenotype is challenging. The purpose of this study was to determine if the inhibition of EZH2 induces cell differentiation or apoptosis in AML, and to determine the significance of EZH2 mutations in AML patients. As H3K27me3 deposition is catalyzed by EZH2, we hypothesized that analysis of H3K27me3 levels could differentiate an inactivating EZH2 mutation. We analyzed H3K27me3 levels in AML patient samples with wild type (N = 5) and mutant (N = 3) EZH2, and found that overall H3K27me3 is reduced in the mutant patient samples. Furthermore, the sample with the highest variant allele frequency (VAF) of the EZH2 mutation had noticeably lower levels of H3K27me3 compared to those that had a lower VAF. This finding demonstrates that diminished H3K27me3 levels can predict the presence of an inactivating EZH2 mutation in AML cells. We next assessed if the EZH2 tool molecule EPZ011989 produced a similar phenotype in wild-type EZH2 AML cell lines (Kasumi-1, MOLM-13, and MV4-11). EPZ011989 inhibited H3K27me3 in all of the cell lines at a concentration of 0.625 μM after only four days of treatment. At these concentrations and this time point we demonstrated no change in viability among these three cell lines and only minimal proliferation inhibition in MV4-11 and MOLM-13 cells. Longer time points are currently being investigated as EZH2 inhibitors often induce anti-proliferative effects only after longer incubation periods. Therefore, our results support that inactivation of EZH2 with EZP011989 in AML cell lines induces the same cell-biochemical consequence (i.e. H3K27me3 loss) associated with EZH2 mutations in AML patients. This potentially will allow diverse pharmacologic studies in cell lines relative to gene targets and also synergistic lethality studies utilizing genetic and pharmacologic screening techniques to potentially develop therapeutic agents to treat this subtype of AML. Citation Format: Sydney Fobare, Cecelia Miller, Shelley J. Orwick, Heike Keilhack, Erin Hertlein, John C. Byrd. The effect of EPZ011989, an enhancer of Zeste homolog 2 inhibitor, in acute myeloid leukemia. [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 4520.
Validation of a novel [2-<sup>13</sup>C]-uracil breath test (UraBT) to detect dihydropyrimidine dehydrogenase (DPD) deficiency by LC-MS-MS analysis of [2-<sup>13</sup>C]-uracil (URA) and [2-<sup>13</sup>C]-dihydrouracil (DHU) plasma levels
Authors: L. K. Mattison, M. R. Johnson, W. Saif, A. S. Modak, Y. Hirao, T. Koga, T. Shimizu, R. B. Diasio
Journal: Journal of Clinical Oncology (2004)

2130 Background: DPD deficiency is a pharmacogenetic syndrome which occurs in approximately 5–7 % of cancer patients as potentially lethal 5-fluorouracil (FU) toxicity. Currently, there are no clinically feasible assays to routinely screen prior to FU administration. We recently reported a novel breath test (UraBT) to rapidly detect partially (PDef) and completely (CDef) DPD deficient individuals. * Objective: Determine if plasma URA and DHU correlate with 13CO2 breath levels obtained from healthy or DPD deficient subjects. Methods: 13CO2 breath levels from 10 healthy, 9 PDef and 1 CDef subjects were determined by infrared spectrophotometry using UraBT methodology. * Twelve plasma samples were obtained over 180 min. post URA ingestion; LC-MS-MS quantified URA and DHU plasma levels. Breath (13CO2) and plasma (URA and DHU) levels of the subject groups were analyzed for significance (T and Mann-Whitney U tests). Results: The CDef subject had no detectable plasma DHU with minimal expired 13CO2 (Cmax = 3.6, Tmax = 120 min., AUC = 5.81). Differences were observed (p≤0.01; Table1) in breath (13CO2) and plasma (URA and DHU) levels of healthy and PDef deficient subjects. Conclusions: The significant differences in URA and DHU plasma levels are consistent with alterations in 13CO2 levels observed from PDef and CDef DPD deficient individuals, suggesting that the UraBT is reflective of in vivo uracil catabolism, further supporting the value of the UraBT as a screening test (CA62164). * Proc. ASCO 2003, Abstract #494; Clin Can Res, in press Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cambridge Isotope; Otsuka Pharmaceutical Co. Diagnostics Division Aphton Corporation
Improved efficacy with sequential use of histone deacetylase inhibitor, LAQ824, with common chemotherapeutic agents in head and neck squamous carcinoma cell lines
Authors: Young-Ju Kim, Eun Kyung Bae, Kwang-Sung Ahn, Jong-Seok Lee, Seonyang Park, Byoung Kook Kim, Sung-Soo Yoon
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

5097 

Imatinib mesylate (Glivec, Gleevec, STI571) is highly effective in patients with chronic myeloid leukemia (CML). Despite high rates of hematologic and cytogenetic responses to Glivec therapy, the emergence of resistance to Glivec has been recognized as a major problem in the treatment of CML. To investigate the mechanisms of resistance to Glivec, Glivec resistant cell line (K562 derivatives) was established. Using those cell line, we found that SK-7068, one of HDAC inhibitors, did enhance the apoptosis with increasing levels of cytochrome C, caspase 7, and caspase 3. In additions, the expression levels of STAT1 and STAT5 was down-regulated. Based on our findings, combined treatment of SK-7068 and Glivec could be novel therapy for CML being resistant to Glivec. To investigate the effect of combined treatment, the expression levels of pro-apoptotic genes related genes, such as Bcl-2 family, caspase-3, and its cell cycle proteins, such as p53, p21, and cyclin D1, CDKs and PCNA were examined by western analysis. Our results showed that Bcl-2, -XL, and Bid were more down-regulated with combined treatment compared with single treatment controls (either Glivec or curcumin alone). Under the same conditions, the activity of caspase 3 was dramatically increased. Increasing levels of p21 expression was found in combined treatment whereas its expression was not detected when K562 cells were treated with either SK-7068 or Glivec. Our results indicated that increasing level of p21 expression may enhance the apoptosis. For further investigation of the genes affected by combination therapy, DNA chip analysis was performed. The expression of candidate genes, which we selected in chip analysis, was confirmed using real-time PCR. Our result indicated that apoptosis related genes were up-regulated and were down-regulated. Also, several genes (protein phosphatase 2C, ERBB3, JARID2, INSIG1, RNF41, RGSIPIP1, PRSS12, HUMPPA, PDCD4)) were more down-regulated in combined treatment, showing 2-fold difference. Those genes may be associated with the progression of chronic myeloid leukemia. Taken together, our data suggested that combined treatment with SK-7068 could be effective to overcome the problems of Imatinib mesylate therapy.
Case 60-1962
Authors: Clement A. Smith, Robert E. Scully
Journal: New England Journal of Medicine (1962)

Presentation of CaseA five-week-old boy was referred to the hospital because of unresponsiveness.The child was the product of a normal pregnancy and delivery of an eighteen-year-old gravida 1, para 1 mother. He breathed spontaneously at birth, the physical examination was normal and the weight was 7 pounds, 10 ounces. The immediate neonatal period was uneventful except that there were only one or two daily stools, which were small, very hard and passed with difficulty. He was discharged on the fifth hospital day. At home an average of 1 ounce of Similac was taken six times daily. At eight . . .
Abstract 2555: Promoter DNA methylation patterns in breast tumor and matched adjacent non-tumor tissues in the breast cancer family registry
Authors: Hui-Chen Wu, Hanina Hibshoosh, Regina Santella, Mary Beth Terry
Journal: Cancer Research (2016)

Abstract Alterations in DNA methylation occur frequently in breast carcinogenesis, but little is known about the DNA methylation changes in familial breast tumors. To examine whether the DNA methylation profiles in breast cancer tissues from high risk women from breast cancer families are similar to breast tumor tissues from The Cancer Genome Atlas project (TCGA), we measured DNA methylation by next generation sequencing in 48 genes identified in TCGA in 40 formalin-fixed, paraffin-embedded tumor tissues, and the corresponding adjacent non-tumor tissues from women with invasive breast cancer at the New York site of the Breast Cancer Family Registry (BCFR). We observed differences in DNA methylation patterns between tumor and normal adjacent tissue for five of the selected genes (RYR2, C1orf14, SLC7A14, SEPW1, and RPTOR). The methylation levels in tumor and adjacent tissues, respectively were 24% and 14% for RYR2, (p = 0.01), 55% and 29% for C1orf14 (p = 0.01), 32% and 21% for SLC7A14 (p = 0.002), 53% and 28% for RPTOR (p = 0.01) and 74% and 38% SEPW1 (p&amp;lt;0.0001). We only confirmed 5 of the 48 loci identified in TCGA in our sample of high risk women, suggesting genes identified from TCGA may be different than those in high-risk women. As tissue-specific methylation may prove to have strong prognostic significance, this suggests a critical need to engage in large-scale studies examining genome-wide DNA methylation profiles in high risk women in order to understand the etiology of familial breast cancer. Citation Format: Hui-Chen Wu, Hanina Hibshoosh, Regina Santella, Mary Beth Terry. Promoter DNA methylation patterns in breast tumor and matched adjacent non-tumor tissues in the breast cancer family registry. [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 2555.
Higher Expression Levels of the Adhesion Molecules VLA-4 and ICAM-1 on Multiple Myeloma Cells after Chemotherapy Are Associated with Survival of a Multidrug Resistant Subpopulation in Vivo.
Authors: Ralf Schmidmaier, Kerstin Mörsdorf, Philipp Baumann, Bertold Emmerich, Gerold Meinhardt
Journal: Blood (2004)
Abstract 4403: SMYD2-mediated lysine methylation regulates nuclear transport of beta-catenin in human cancer cells
Authors: Xiaolan Deng, Yusuke Nakamura, Ryuji Hamamoto
Journal: Cancer Research (2016)

Abstract The canonical Wnt-signal pathway is a major signaling system in cancer cells as well as stem/progenitor cells. It is well-known that binding of Wnt molecules to cell surface receptors, including a Frizzled (Fz) protein and LDL receptor-related protein 6, initiates a transduction cascade leading to stabilization of the transcription coactivator β-catenin, which then enters the nucleus to form a transcriptional complex with T cell factor (TCF) or lymphoid enhancer factor (LEF) to activate the expression of TCF/LEF downstream genes, such as cyclin D1 (CCND1) and c-Myc. However, the molecular mechanisms that regulate nuclear localization of β-catenin and its transcriptional activation are not fully understood. Here we demonstrate that the protein lysine methyltransferase SMYD2 methylates β-catenin at lysine 133, which is located in an amino-terminal domain (NTD), and regulates nuclear transport of β-catenin. After treatment with SMYD2-specific siRNAs in hepatocellular carcinoma SNU475 and SNU449 cells, we fractionated cell components and conducted western blot analysis and found that nuclear localization of β-catenin was significantly decreased after knockdown of SMYD2; we also confirmed this result by immunocytochemistry. In addition, we prepared a lysine 133-substituted β-catenin mutant expression vector and transfected it into 293T cells with a SMYD2 expression vector. We observed that protein amount of lysine 133-substituted β-catenin in the nucleus is significantly lower than that of wild-type β-catenin by western-blot and immunocytochemical analyses. These results indicate that SMYD2-mediated methylation plays a critical role in the nuclear transport of β-catenin in cancer cells. This is a novel mechanism of the canonical Wnt-signal pathway regulated by lysine methylation. Citation Format: Xiaolan Deng, Yusuke Nakamura, Ryuji Hamamoto. SMYD2-mediated lysine methylation regulates nuclear transport of beta-catenin in human cancer cells. [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 4403.
<i>Borrelia recurrentis</i>Infection
Authors: Ulrich von Both, Martin Alberer
Journal: New England Journal of Medicine (2016)

After collapsing in Munich, a 16-year-old male Somalian refugee was brought to a local hospital with severe headache and abdominal pain. His vital signs were notable for a temperature of 41°C, a heart rate of 105 bpm, and blood pressure of 95/50 mm Hg.