tbuckley/cabot-search huggingface dataset:
Abstract B07: Loss of APC induces a dependence on elevated eIF2B5 function in colorectal cancer
Authors: Stefanie Peter, Friedrich-Wilhelm Uthe, Martin Eilers, Christoph-Thomas Germer, Armin Wiegering
Journal: Cancer Research (2017)

Abstract Colorectal cancer (CRC) is the most common gastrointestinal malignancy and one of the leading causes of cancer death worldwide. Truncating mutations of the tumor suppressor APC that lead to deregulated WNT signaling are driver mutations in CRC. APC and its downstream effector, β-catenin, are regarded as non-druggable, prompting the search for novel interactions essential for survival of cells that have lost APC function. Here, we have restored doxycycline-inducible expression of full-length APC (APC wt) in SW480 cells, which carry truncated APC (APC mut). To identify genes that are essential for viability of APC mut cells, we conducted an shRNA screen targeting 5,000 genes with 25,000 shRNAs. The best scoring differential hits were multiple shRNAs that target the translation initiation factor eIF2B5, a subunit of the guanidine exchange factor (GEF) for eIF2. Validation experiments demonstrate a strong synthetic lethal effect of eIF2B5 knockdown with APC truncation in SW480 cells that can be rescued by APC induction. There is a clear survival window, which we can visualize using several shRNA sequences with different knockdown efficiencies. We confirm previous observations that loss of APC function results in an increase of global protein synthesis. Loss of APC also strongly induces expression of eIF2B5 and other subunits of eIF2B. Knockdown of eIF2B5 reduces overall protein translation. Although eIF2 function and overall ribosomal assembly are compromised upon depletion of eIF2B5, MYC protein levels are strongly upregulated, arguing that MYC can be translated in an eIF2-independent manner. Apoptosis upon eIF2B5 knockdown strictly depends on MYC upregulation. APC mut cells also display higher basal levels of the unfolded protein response (UPR) markers CHOP and ATF4, which are both further enhanced by eIF2B5 depletion. The UPR branch reflected by CHOP induction may contribute to cell death in our system. In conclusion, our data demonstrate a dual regulatory mechanism in which loss of APC induces expression of both MYC and eIF2B5. Full eIF2 activity is required to restrict the pro-apoptotic activity of MYC in APC mut cells. Thus, interfering with eIF2B5 function as GEF or GDF may be a promising treatment strategy for cells with truncated APC. Citation Format: Stefanie Peter, Friedrich-Wilhelm Uthe, Martin Eilers, Christoph-Thomas Germer, Armin Wiegering. Loss of APC induces a dependence on elevated eIF2B5 function in colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B07.
Bacterial DNA in blood is an independent risk factor for readmission and change of immunosuppression at one year in liver transplant recipients.
Authors: G. Rodriguez-Laiz, P. Zapater, P. Melgar, M. Franco, C.F. Alcazar, P. Gimenez, S. Pascual, P. Bellot, J.M. Palazon, M. Rodriguez, F. Carnicer, P. Mas, J. Such, F. Lluis, R. Frances
Journal: Journal of Hepatology (2017)
Metabolic and biochemical phenotypes can distinguish different patterns of histological severity in biopsy-proven NAFLD
Authors: E.V. Gómez, R. Aller, R. Gallego-Durán, J. Bañales, M.T.A. Loste, C. García-Monzón, H.P. Ramirez, M.L. García-Torres, J. Gómez-Camarero, J. Caballería, V. Aguilar-Urbano, J. Salmerón, J.L. Calleja, J. Abad, J.L. Olcoz-Goñi, A. Albillos, M. Diago, O.L. Iacono, R. Francés, C.M. Fernández-Rodríguez, J. García-Samaniego, S. Benlloch, P. Aspichueta, R.J. Andrade, J. Ampuero, L.C. Bertot, L.A. Adams, M. Romero-Gómez
Journal: Journal of Hepatology (2017)
Albumin use and acute kidney injury in a large real-world analysis of cirrhotic inpatients
Authors: J.S.S. Bajaj, J. O’leary, F. Wong, G. Garcia-Tsao, P. Tandon, S. Biggins, P.S. Kamath, J. Lai, M. Fallon, R. Subramanian, B. Maliakkal, P. Thuluvath, H. Vargas, L. Thacker, R. Reddy
Journal: Journal of Hepatology (2017)
The prognostic role of serum albumin in patients receiving induction chemotherapy for acute myeloid leukemia (AML).
Authors: Hossein Sadrzadeh, Andrew Mark Brunner, Benjamin Jacob Drapkin, Loren Babirak, Lillian Werner, Karen K. Ballen, Philip C. Amrein, Eyal C. Attar, Yi-Bin Albert Chen, Thomas R. Spitzer, Steven L McAfee, Donna S. Neuberg, Amir Tahmasb Fathi
Journal: Journal of Clinical Oncology (2012)

6618 Background: Serum albumin has been investigated as a prognostic tool in the care of patients with hematologic malignancies, including multiple myeloma and myelodysplastic syndromes. However, its prognostic utility in patients with AML is unknown. We hypothesized that a lower serum albumin is associated with worse outcomes following induction chemotherapy for AML. Methods: We conducted a retrospective medical record review of 166 adult, non-promyelocytic AML patients who had received induction chemotherapy at Massachusetts General Hospital from 1992 to 2007. Patient characteristics were summarized as numbers and percentages for categorical variables. The Kaplan Meier method was used to estimate median disease-free survival (DFS) and overall survival (OS). We dichotomized our patients by serum albumin ≥3 and &lt;3, and determined the association of albumin with 60-day survival and complete remission (CR) rate using Fisher’s exact test. Association of albumin with DFS and OS was summarized using Cox regression in both univariate and multivariable analyses. Results: Of 166 patients, 125 (75%) achieved CR and 143 (86%) were alive at 60 days following diagnosis. After risk-adjusting for age and LDH, we found that a serum albumin level &lt;3 mg/dL was associated with decreased 60-day survival (OR 0.30, p=0.015) and CR rate (OR 0.41, p=0.02) compared to patients with serum albumin ≥3. There was no association between serum albumin and DFS (p=0.88) or OS (p=0.31). As expected, younger age was associated with better induction outcomes. Conclusions: Serum albumin was negatively associated with short-term outcomes in patients receiving induction chemotherapy. A serum albumin level less than 3, clinically relevant to oncologic patients, was associated with a significantly decreased CR rate and lower 60-day survival after induction chemotherapy. This data suggests that serum albumin, a surrogate commonly used for nutritional status and suppressed in inflammatory comorbid states, has prognostic utility for AML patients undergoing induction chemotherapy.
The role of recipient epithelial cells in regeneration after liver transplantation: different kinetics of chimerism for hepatocytes and bile duct epithelial cells
Authors: F.J.M. Roos, J.W. Selten, W.G. Polak, M.M.A. Verstegen, H.F. Sleddens, M. Doukas, H.J. Metselaar, J.N. IJzermans, L.J. van der Laan
Journal: Journal of Hepatology (2017)
Smaller decreases in bone mineral density in chronic hepatitis B patients receiving tenofovir alafenamide compared with tenofovir disoproxil fumarate over 96 weeks
Authors: S. Fung, W.L. Chuang, S. Nishiguchi, W.K. Seto, W.Y. Tak, E.M. Erne, M. Jablkowski, V. Morozov, A.H. Lau, V. Suri, J.F. Flaherty, K. Kim, A. Gaggar, G.M. Subramanian, M. Celen, S.-G. Lim, H.L. Chan
Journal: Journal of Hepatology (2017)
Extracellular Vesicles in Cardiovascular Disease
Authors: Felix Jansen, Georg Nickenig, Nikos Werner
Journal: Circulation Research (2017)

Extracellular vesicles originate from diverse subcellular compartments and are released in the extracellular space. By transferring their cargoes into target cells and tissues, they now emerge as novel regulators of intercellular communication between adjacent and remote cells. Because vesicle composition and biological content are specific signatures of cellular activation and injury, their potential as diagnostic and prognostic biomarkers has raised significant interest in cardiovascular diseases. Characterization of circulating vesicles- or nonvesicles-bound nucleic acids represents a valuable tool for diagnosing and monitoring cardiovascular diseases, recently referred to as a liquid biopsy. Circulating extracellular vesicles offer a noninvasive and almost continuous access to circulating information on the disease state in epidemiological investigations. Finally, genetic engineering and cell-specific application of extracellular vesicles could display a novel therapeutic option for the treatment of cardiovascular diseases. In this review, we summarize the current knowledge about extracellular vesicles as diagnostic and prognostic biomarkers, as well as their potential applications for longitudinal epidemiological studies in cardiovascular diseases.
Adverse events and the development of acute on chronic liver failure in patients with cirrhosis undergoing endoscopic retrograde cholangiopancreatography: a retrospective, multicenter, case-control study
Authors: C. Leal, V. Prado, J. Colan, K.C. Rivera, O. Sendino, A. Blasi, P. Roura, C.R. de Miguel, J. Salo, J. Fernandez, C. Guarner-Argente, A. Cardenas
Journal: Journal of Hepatology (2017)
Whistleblowing junior doctor scores victory in Court of Appeal
Authors: Clare Dyer
Journal: BMJ (2017)

A whistleblowing junior doctor who said that his career was destroyed by Health Education England (HEE) has scored an important victory in the Court of Appeal.

Chris Day claimed that HEE treated him unfairly after he blew the whistle on unsafe staffing levels at Lewisham and Greenwich NHS Trust, where he was working as a specialist registrar in emergency medicine.

In May 2016 his case against HEE, which arranges junior doctors’ training contracts, was thrown out by the Employment …
Hepatitis prevention, control, and elimination program in Mongolia: national hepatitis elimination program in a country with the highest burden of viral hepatitis in the world
Authors: N. Dashdorj, N. Dashdorj, A.S. Bungert, Z. Genden, B. Dendev, D. Duger, A. Dagvadorj, D. Yagaanbuyant
Journal: Journal of Hepatology (2017)
Phase I study of ADI-PEG 20 in combination with pemetrexed and cisplatin (TRAP) in patients with ASS1-deficient mesothelioma and non-squamous lung cancer.
Authors: Peter Wojciech Szlosarek, James F. Spicer, Teresa Szyszko, Gary J. R. Cook, Pui Ying Chan, Mirela Hategan, Dimitra Repana, Jeremy Peter Steele, Peter Schmid, Monica Diaz, Amanda Johnston, Michael Sheaff, Ramsay Khadeir, John S. Bomalaski, Simon Pacey
Journal: Journal of Clinical Oncology (2015)

TPS2612 Background: Loss of the metabolic tumor suppressor, argininosuccinate synthetase (ASS1), a rate-limiting enzyme in arginine biosynthesis, sensitizes mesothelioma and lung carcinoma cells to apoptosis following arginine withdrawal. Recently, we showed potentiation of the cytotoxic effect of pemetrexed by the arginine depletor pegylated arginine deiminase (ADI-PEG 20) in ASS1-negative tumor cells, which was accompanied by suppression of de novo pyrimidine synthesis and the pyrimidine salvage pathway (Allen et al, Cancer Res 2014). Consequently, we have initiated a phase I study (NCT02029690) to assess the maximum tolerated dose (MTD), safety and toxicity, and preliminary efficacy of ADI-PEG 20 combined with first-line pemetrexed and cisplatin chemotherapy in patients with ASS1-deficient mesothelioma or non-squamous non-small cell lung cancer (NSCLC). Methods: Up to 47 good performance (ECOG 0-1) patients are being enrolled in a 3+3+3 phase 1 design using tumoral ASS1 loss as a selection biomarker. Weekly ADI-PEG 20 is being dose escalated (18, 27 and 36 mg/m2 IM), with pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 both given every 3 weeks, for a maximum of 18 weeks of treatment. Cohorts 1 and 2 have been completed without dose-limiting toxicity and enrollment to cohort 3 began in January 2015 at the maximum ADI-PEG 20 dose of 36mg/m2. A further 10 patients with mesothelioma and 10 patients with non-squamous NSCLC will be recruited at the MTD with pharmacodynamic monitoring of response using plasma arginine and citrulline, and assessment of tumor proliferation with [(18)F]-fluoro-L-thymidine (FLT)-positron emission tomography (PET). In summary, TRAP is the first triplet chemotherapy combination study to assess the role of arginine deprivation with ADI-PEG 20 in solid cancers using ASS1 as a selection biomarker. Patient accrual at the MTD cohort is nearing completion and ADI-PEG 20 in combination with cisplatin and pemetrexed will be evaluated further in the planned expansion cohorts. Clinical trial information: NCT02029690.
CXCR6-dependent hepatic iNKT cells limit hepatocarcinogenesis in vivo by promoting clearance of senescent hepatocytes
Authors: J.C. Mossanen, A. Wehr, M. Kohlhepp, O. Krenkel, A. Liepelt, T. Lüdde, C. Trautwein, F. Tacke
Journal: Journal of Hepatology (2017)
Efficacy of the Telemedical Lifestyle intervention Program TeLiPro in Advanced Stages of Type 2 Diabetes: A Randomized Controlled Trial
Authors: Kerstin Kempf, Bernd Altpeter, Janine Berger, Oliver Reuß, Matthias Fuchs, Michael Schneider, Babette Gärtner, Katja Niedermeier, Stephan Martin
Journal: Diabetes Care (2017)

OBJECTIVE Lifestyle interventions are the foundation of treatment in newly diagnosed type 2 diabetes. However, their therapeutic potential in advanced disease stages is unknown. We evaluated the efficacy of the Telemedical Lifestyle intervention Program (TeLiPro) in improving metabolic control in advanced-stage type 2 diabetes. RESEARCH DESIGN AND METHODS In this single-blind, active comparator, intervention study, patients with type 2 diabetes (with glycated hemoglobin [HbA1c] ≥7.5% [58.5 mmol/mol]), and BMI ≥27 kg/m2 and on ≥2 antidiabetes medications) were recruited in Germany and randomized 1:1 using an electronically generated random list and sealed envelopes into two parallel groups. The data analyst was blinded after assignment. The control group (n = 100) got weighing scales and step counters and remained in routine care. The TeLiPro group (n = 102) additionally received telemedical coaching including medical-mental motivation, a formula diet, and self-monitored blood glucose for 12 weeks. The primary end point was the estimated treatment difference in HbA1c reduction after 12 weeks. All available values per patient (n = 202) were analyzed. Analyses were also performed at 26 and 52 weeks of follow-up. RESULTS HbA1c reduction was significantly higher in the TeLiPro group (mean ± SD −1.1 ± 1.2% vs. −0.2 ± 0.8%; P &amp;lt; 0.0001). The estimated treatment difference in the fully adjusted model was 0.8% (95% CI 1.1; 0.5) (P &amp;lt; 0.0001). Treatment superiority of TeLiPro was maintained during follow-up (week 26: 0.6% [95% CI 1.0; 0.3], P = 0.0001; week 52: 0.6% [0.9; 0.2], P &amp;lt; 0.001). The same applies for secondary outcomes: weight (TeLiPro −6.2 ± 4.6 kg vs. control −1.0 ± 3.4 kg), BMI (−2.1 ± 1.5 kg/m2 vs. −0.3 ± 1.1 kg/m2), systolic blood pressure (−5.7 ± 15.3 mmHg vs. −1.6 ± 13.8 mmHg), 10-year cardiovascular disease risk, antidiabetes medication, and quality of life and eating behavior (P &amp;lt; 0.01 for all). The effects were maintained long-term. No adverse events were reported. CONCLUSIONS In advanced-stage type 2 diabetes, TeLiPro can improve glycemic control and may offer new options to avoid pharmacological intensification.
Small-diameter covered stents do not affect efficacy but reduce hepatic encephalopathy in transjugular intrahepatic portosystemic shunt for the prevention of variceal rebleeding in cirrhosis
Authors: Q. Wang, C. He, Z. Yin, M. Bai, Z. Wang, W. Guo, H. Cai, J. Xia, H. Chen, Y. Lv, J. Shao, L. Zuo, D. Fan, G. Han
Journal: Journal of Hepatology (2017)
Long-term survivorship in adult primary glioblastoma: Clinical and neurological outcomes of a large, single-center study.
Authors: Katherine B. Peters, Sarah Woodring, Mary Lou Affronti, Frances McSherry, James Emmett Herndon, Annick Desjardins, Tulika Ranjan, Gordana Vlahovic, Allan H. Friedman, Henry S. Friedman
Journal: Journal of Clinical Oncology (2014)

9519 Background: Primary brain tumors represent 1% of all diagnosed cancers, but the survival rates of patients (pts) with the most malignant form of these tumors, glioblastoma (GBM), continues to be poor with <3% of pts surviving at 5 yrs and median OS ranging from 12-14 months. A trend to tailor care to survivorship in oncology has included survivors of other cancers such as breast and prostate, but little has been done to define long-term survivorship in primary GBM and the particular concerns of this population. We sought to identify adult long-term survivors (LTS) in primary GBM and define the clinical and neurological outcomes in this population. Methods: In a single-center retrospective study, we evaluated over 9,000 records from January 1, 1998 to February 8, 2010 to identify adult primary GBM pts that survived ≥5 yrs and these were defined as LTS. Results: We identified 155 LTS of primary GBM with a median OS of 11.0 yrs (95% CI 9.0, 13.1) and a median follow-up of 9.6 yrs (95% CI 8.7, 10.7). LTS were younger with a mean age of 44.9 yrs (sd=12.1) at diagnosis and had good functional status with KPS≥ 90 for 77.3% (N=120). Most patients had gross total resection (87.7%) and all patients received radiotherapy and chemotherapy (100%). For these LTS, continued oncologic care was required as 52.2% (N=81) had 1-7 recurrences and 52.2% (N=81) had treatment with ≥ 5 chemotherapy regimens. At time of identification of pts for this analysis, there was a reduction in KPS with only 87 pts (56.2%) having a KPS≥ 90. Neurologically, a majority of LTS were on anti-epileptic medications (N=107 (69.1%)) at time of identification. Neurocognitive testing was available for 43 LTS (27.7%) and 39 pts (90.7%) had measurable impairment on testing. Other neurological sequelae included radiation necrosis (N=25), cerebrovascular accident (N=10), hydrocephalus requiring VP shunting (N=6), and dementia (N=3). Conclusions: To date, this is the largest single-center retrospective analysis of primary GBM LTS and clinical and neurological outcomes in this population. LTS of primary GBM continue to require specialized oncologic and neurological care and considerations to provide specialized survivorship care for this group are warranted.
Abstract 335: Regulation of Muscle Contractility by a Family of SERCA-Inhibitory Micropeptides
Authors: Douglas M Anderson, Kelly M Anderson, Chi-Lun Chang, Catherine A Makarewich, Benjamin R Nelson, John R McAnally, John M Shelton, Jen Liou, Rhonda Bassel-Duby, Eric N Olson
Journal: Circulation Research (2015)

Functional micropeptides can be concealed within RNA transcripts that have been putatively annotated as non-coding. We recently discovered a muscle-specific micropeptide, named myoregulin (MLN), that inhibits the activity of SERCA, the membrane pump that controls muscle relaxation by regulating Ca2+ uptake into the sarcoplasmic reticulum (SR). Genetic deletion of MLN in mice enhances Ca2+ handling in skeletal muscle and improves exercise performance. MLN shares structural and functional similarity with phospholamban (PLN) and sarcolipin (SLN), two well-studied micropeptides that regulate cardiac contractility and disease. Here we identify an additional member of this micropeptide family, named endoregulin (ELN), that specifically overlaps with the expression of SERCA3, the dominant Ca2+ ATPase in endothelial cells that controls the contractility of vascular and visceral smooth muscles. ELN encodes a single transmembrane alpha helix that localizes to the endoplasmic reticulum (ER), where it forms a stable complex with SERCA3. In cell based assays, ELN inhibits SERCA-dependent Ca2+ uptake into the ER and controls ER calcium levels. Due to the essential role of SERCA3 in regulating vascular smooth muscle contractility, ELN represents a potential regulator of vascular tone and novel therapeutic target for the treatment of cardiovascular disease.
Morbidity and mortality in compensated cirrhosis type C: relationship to interferon alpha therapy
Authors: G. Fattovich, G. Giustina, F. Degos, G. Diodati, F. Tremolada, F. Nevens, P. Almasio, A. Solinas, J.T. Brouwer, H. Thomas, G. Realdi, S.W. Schalm
Journal: Journal of Hepatology (1997)
Self‐Targeting, Immune Transparent Plasma Protein Coated Nanocomplex for Noninvasive Photothermal Anticancer Therapy
Authors: Fwu‐Long Mi, Thierry Burnouf, Shih‐Yuan Lu, Yu‐Jen Lu, Kun‐Ying Lu, Yi‐Cheng Ho, Chang‐Yi Kuo, Er‐Yuan Chuang
Journal: Advanced Healthcare Materials (2017)

Cancer cells exhibit specific physiological differences compared to normal cells. Most surface membranes of cancer cells are characterized by high expression of given protein receptors, such as albumin, transferrin, and growth factors that are also present in the plasma of patients themselves, but are lacking on the surface of normal cells. These distinct features between cancer and normal cells can serve as a niche for developing specific treatment strategies. Near‐infrared (NIR)‐light‐triggered therapy platforms are an interesting novel avenue for use in clinical nanomedicine. As a photothermal agent, conducting polymer nanoparticles, such as polypyrrole (PPy), of great NIR light photothermal effects and good biocompatibility, show promising applications in cancer treatments through the hyperthermia mechanism. Autologous plasma proteins coated PPy nanoparticles for hyperthermia therapy as a novel core technology platform to treat cancers through secreted protein acid and rich in cysteine targeting are developed here. This approach can provide unique features of specific targeting toward cancer cell surface markers and immune transparency to avoid recognition and attack by defense cells and achieve prolonged circulation half‐life. This technology platform unveils new clinical options for treatment of cancer patients, supporting the emergence of innovative clinical products.
NEURAL RESPIRATORY DRIVE ASSESSED BY PARASTERNAL EMG ACTIVITY IN CYSTIC FIBROSIS PATIENTS DURING EXERCISE
Authors: C. Reilly, C. Jolley, K. Ward, A. Lunt, J. Steier, J. Seymour, T. Mathieson, C. Elston, Gerrard Rafferty, John Moxham
Journal: Thorax (2008)
The impact of sustained virological response on long term risk of decompensated cirrhosis: the BC hepatitis testers cohort
Authors: N.Z. Janjua, M. Chong, Z.A. Butt, N. Chapinal, N. Islam, H. Samji, M. Darvishian, D. Cook, M. Alvarez, M. Tyndall, M. Krajden
Journal: Journal of Hepatology (2017)
Dynamic molecular imaging of signal transduction pathways in vivo
Authors: David Piwnica-Worms
Journal: Clinical Cancer Research (2008)

ED03-02  Genetically-encoded imaging reporters introduced into cells and transgenic animals enable noninvasive, longitudinal studies of dynamic biological processes in intact cells and living animals. The most common reporters include firefly luciferase (bioluminescence imaging), green fluorescence protein (fluorescence imaging), Herpes Simplex Virus-1 thymidine kinase (positron emission tomography) and variants with enhanced spectral and kinetic properties optimized for use in vivo. When cloned into promoter/enhancer sequences or engineered into fusion proteins, imaging reporters enable fundamental processes such as transcriptional regulation, signal transduction cascades, protein-protein interactions, oncogenic transformation, immunologic response and targeted drug action to be temporally and spatially registered in vivo. Spying on cancer with genetically-encoded imaging reporters provides new insight into cell-specific molecular and regulatory machinery within the contextual environment of the whole animal.