tbuckley/cabot-search huggingface dataset:
Abstract B33: Translational control pathways form a molecular hub that regulates tamoxifen resistance in ER+ breast cancer
Authors: Phillip A. Geter, Robert J. Schneider
Journal: Cancer Research (2017)

Abstract Currently, ER+ breast cancer is treated with adjuvant antiestrogen therapies (i.e. tamoxifen and raloxifene). Despite maintaining expression of the estrogen receptor, many women treated with adjuvant therapy develop resistance several years after curative care. In fact, resistance to tamoxifen therapy is responsible for a vast majority of deaths resulting from metastatic disease. Our lab and others have shown that upregulation of the abundance and/or activity of translation initiation factors eIF4E and eIF4G1 occurs widely in advanced breast cancer, selectively upregulating translation of certain mRNAs required for survival, proliferation, and metastasis. Therefore, we hypothesized that tamoxifen resistance in ER+ breast cancer involves selective mRNA translation mediated by hyperactivation of the mTORC1 translational control pathway via regulating the availability and activity of eIF4E. Tamoxifen resistant (R) and sensitive (S) ER+ cell lines have been developed by several labs by long-term cultivation in tamoxifen and are used in my work. We define here, using the aforementioned cell lines, a molecular hub consisting of the two translational control pathways, PI3K/Akt/mTOR and MAPK/ERK/MNK which converge on translation initiation factor 4E (eIF4E) increasing its availability and activity. We show that blocking eIF4E-mediated translation was able to resensitize drug resistant cells to tamoxifen; conversely, overexpression of eIF4E, without concurrent mTORC1 hyperactivity, was not sufficient to generate resistance. Furthermore, knockdown of two genes identified from our genome-wide translation state analysis, TEX14 and RUNX2, significantly impacted drug resistance and serve as a major regulators in disease progression. Our findings demonstrate that eIF4E is a key player regulating tamoxifen resistance in ER+ disease. Citation Format: Phillip A. Geter, Robert J. Schneider. Translational control pathways form a molecular hub that regulates tamoxifen resistance in ER+ breast 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 B33.
Two consecutive large outbreaks of Salmonella Muenchen linked to pig farming in Germany, 2013 to 2014: Is something missing in our regulatory framework?
Authors: Anika Schielke, Wolfgang Rabsch, Rita Prager, Sandra Simon, Angelika Fruth, Rüdiger Helling, Martin Schnabel, Claudia Siffczyk, Sina Wieczorek, Sabine Schroeder, Beate Ahrens, Hanna Oppermann, Stefan Pfeiffer, Sophie Susann Merbecks, Bettina Rosner, Christina Frank, Armin A. Weiser, Petra Luber, Andreas Gilsdorf, Klaus Stark, Dirk Werber
Journal: Eurosurveillance (2017)

In 2013, raw pork was the suspected vehicle of a large outbreak (n = 203 cases) of Salmonella Muenchen in the German federal state of Saxony. In 2014, we investigated an outbreak (n = 247 cases) caused by the same serovar affecting Saxony and three further federal states in the eastern part of Germany. Evidence from epidemiological, microbiological and trace-back investigations strongly implicated different raw pork products as outbreak vehicles. Trace-back analysis of S . Muenchen-contaminated raw pork sausages narrowed the possible source down to 54 pig farms, and S . Muenchen was detected in three of them, which traded animals with each other. One of these farms had already been the suspected source of the 2013 outbreak. S . Muenchen isolates from stool of patients in 2013 and 2014 as well as from food and environmental surface swabs of the three pig farms shared indistinguishable pulsed-field gel electrophoresis patterns. Our results indicate a common source of both outbreaks in the primary production of pigs. Current European regulations do not make provisions for Salmonella control measures on pig farms that have been involved in human disease outbreaks. In order to prevent future outbreaks, legislators should consider tightening regulations for Salmonella control in causative primary production settings.
T790M co-exists with other secondary resistance mechanisms in EGFR mutation positive NSCLC and are associated with inferior outcomes
Authors: R. Teng, A. Takano, W.-L. Tan, M.-K. Ang, C.-K. Toh, Q.-S. Ng, W.-T. Lim, E.-H. Tan, T. Lim, D. Tan
Journal: Annals of Oncology (2017)
IL6-dependent genomic instability heralds accelerated carcinogenesis following liver regeneration on a background of chronic hepatitis
Authors: J.H. Axelrod, T. Lanton, A. Shriki, Y. Nechemia-Arbely, R. Abramovitch, O. Levkovitch, R. Adar, N. Rosenberg, M. Paldor, D. Goldenberg, A. Sonnenblick, A. Peled, S. Rose-John, E. Galun
Journal: Journal of Hepatology (2017)
Access to hepatitis C treatment in Europe: findings from the 2016 Hep-CORE study
Authors: J.V. Lazarus, S.R. Stumo, K. Safreed-Harmon, F.H. Harmanci, M. Harris, G. Hendrickx, M. Jauffret-Roustide, T. Reic, J. Tallada, M. Maticic
Journal: Journal of Hepatology (2017)
Optimization of direct antiviral agent treatment schedule in hepatitis C virus genotype 3 infection: an Italian, multicentetric experience in real-life setting
Authors: R. Granata, M.R. Valvano, L. Donnarumma, S. Camera, M. Milella, P. Andreone, V. Messina, A.P. Termite, R. Cozzolongo, T. Santantono, P. Tundo, E. Ciracì, C. Masetti, A. Smedile, F. Morando, F. Morisco, N. Caporaso, A. Andriulli
Journal: Journal of Hepatology (2017)
The dynamics of response as measured by multiple composite outcome tools in the TIght COntrol of inflammation in early Psoriatic Arthritis (TICOPA) trial
Authors: Laura C Coates, Farrouq Mahmood, Paul Emery, Philip G Conaghan, Philip S Helliwell
Journal: Annals of the Rheumatic Diseases (2017)

We aimed to evaluate the dynamics of treatment response with different composite measures in the TIght COntrol of inflammation in early Psoriatic Arthritis (TICOPA) trial.Participants with early disease-modifying antirheumatic drug-naïve psoriatic arthritis (PsA) were randomised 1:1 to either tight control (TC; 4 weekly review with therapy escalation if criteria not met) or standard care (SC; 12 weekly review). We calculated modified versions of the Psoriatic ArthritiS Disease Activity Score (PASDAS), Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) Composite scorE (GRACE) and Composite Psoriatic Disease Activity Index (CPDAI) at baseline and 12 weekly to 48 weeks by blinded assessor. For missing data, we used the last observation carried forward. Comparison between groups was made by analysis of covariance and comparison of area under the curve (AUC).206 people were randomised to TC (n=101) or SC (n=105). Significant differences between treatment groups were seen (p<0.0001 for all composite measures). AUC analysis demonstrated a significant difference between groups for the PASDAS but not GRACE and CPDAI. For participants with oligoarthritis, a significant difference between groups was seen for each measure, although the significance levels were greatly diminished (PASDAS, p=0.04; GRACE p=0.01; CPDAI p=0.04). For oligoarthritis using AUC analysis, none of the measures could distinguish between groups.Composite measures of disease activity were able to distinguish between TICOPA treatment arms, although differences were diminished for those with oligoarthritis. Further data are needed to inform the preferred composite measure for use as the primary outcome in PsA trials.ClinicalTrials.gov (NCT01106079) and ISCRCTN registry (ISCRCTN30147736).
Effect of a novel agent, SL-401, targeting interleukin-3 receptor (IL-3R) on plasmacytoid dendritic cell (pDC)-induced myeloma cell growth and osteolytic bone disease.
Authors: Dharminder Chauhan, Arghya Ray, Deepika Sharma Das, Vincent Macri, Christopher Brooks, Paul G. Richardson, Eric K. Rowinsky, Kenneth Carl Anderson
Journal: Journal of Clinical Oncology (2014)

8599 Background: Multiple myeloma (MM) remains incurable despite novel therapies, highlighting the need for further identification of factors mediating disease progression and resistance. We showed that plasmacytoid dendritic cells (pDCs) in the MM bone marrow promote MM cell growth (Chauhan et al., Cancer Cell 2009, 16:309-323). pDC-MM interactions trigger secretion of interleukin-3 (IL-3), which in turn, induces MM cell growth, and pDCs survival. Additionally, IL-3 contributes to the progression of osteolytic bone disease in MM. Here, we examined the effect of SL-401, a novel targeted therapy directed to IL-3R, on pDC-induced MM cell growth and osteoclast (OCL) formation. Methods: Patient MM cells, pDCs, and MNCs were obtained from normal donors or MM patients. Cell growth/viability was analyzed using MTT assays. OCL function and bone resorption was measured using the OsteoAssays and TRAP staining. Results: SL-401 decreased the viability of pDCs even at low concentrations (IC50: 0.83 ng/ml; 14.6 pM). SL-401 decreased the viability of MM cells at clinically achievable doses without significantly affecting the viability of normal PBMCs. Co-culture of MM patient-derived pDCs triggered proliferation of MM cell lines and primary MM cells; and importantly, SL-401 inhibited pDC-triggered MM cell growth (P < 0.005). Moreover, 3 of 5 samples were obtained from patients whose disease was progressing while on bortezomib, dexamethasone, and lenalidomide therapies. SL-401 blocked pDC-induced growth of dexamethasone-, doxorubicin- or melphalan-resistant MM cells.Combination of SL-401 with bortezomib, melphalan, lenalidomide, or pomalidomide showed synergistic anti-MM activity. Finally, SL-401 inhibited monocyte-derived osteoclast formation in a dose-dependent manner as well as stabilized MM patient BM-derived osteoblast formation. Conclusions: Our study provides the basis for directly targeting pDCs and inhibiting the pDC-MM interaction, as well as targeting osteolytic bone disease, in novel therapeutic strategies with SL-401 to enhance MM cytotoxicity, overcome drug-resistance, and improve patient outcome.
Abstract 13145: Ventriculoarterial Coupling Ratio is Associated With Adverse Outcomes in Repaired Tetralogy of Fallot
Authors: Max E Godfrey, Tal Geva, Lynn A Sleeper, Minmin Lu, Anne Marie Valente, Ashwin Prakash
Journal: Circulation (2016)

Introduction: Patients with repaired tetralogy of Fallot (TOF) are at risk of premature death and ventricular arrhythmias. The ventriculoarterial coupling (VAC) ratio, the ratio of arterial elastance (Ea) and ventricular end-systolic elastance (Ees), is a measure of cardiac efficiency. Little is known about the VAC ratio in this population. We used a previously described cardiac magnetic resonance (CMR) method to measure right and left VAC ratios in patients with repaired TOF, and assessed the hypothesis that this is related to outcomes. Methods and Results: We measured VAC from CMR data at a single institution on 593 TOF patients (age 21.5 ± 14.4 years) and 58 controls (age 13.2 ± 4.0 years). Frequency matching based on age and gender yielded 326 TOF patients to compare with controls. VAC ratio was calculated for both right (RV) and left (LV) ventricles as Ea/Ees = end-systolic volume/stroke volume. TOF patients had higher RV and LV VAC ratios (p&lt;0.001) (RV results, figure A). Within the TOF cohort, RV VAC ratio correlated positively with LV VAC (r=0.43, p&lt;0.001), but not with pulmonary regurgitation fraction. After a median follow-up of 5.0 (IQR 2.4-8.5) years, 26 patients (4.4%) reached a composite endpoint of death (n=16), aborted sudden cardiac death (n=5), or sustained ventricular tachycardia (VT, n=5). An RV VAC ratio in the highest tertile (T3) was associated with higher risk of the outcome (p&lt;0.001, figure B). Controlling for known risk factors (RV mass-to-volume ratio, atrial arrhythmia and non-sustained VT), an RV VAC ratio ≥1.11 (highest tertile) was independently associated with the composite outcome (hazard ratio 7.3, 95% CI 2.7-19.9, p&lt;0.001). Conclusion: In this cohort, TOF patients demonstrated inefficient VAC as compared with controls. A higher RV VAC ratio was independently associated with the composite outcome of death, aborted sudden cardiac death, or sustained VT. Further investigation of the significance of VAC in this population is warranted.
Hepatic proton density fat fraction correlates with histologic measures of steatosis and is responsive to change in those measures in a multi-center nonalcoholic steatohepatitis clinical trial
Authors: M.S. Middleton, E. Lawitz, S. Jayakumar, P. Mantry, S. Caldwell, A.M. Diehl, M. Peach, R. Xu, G. Chen, C.S. Djedjos, R.P. Myers, G.M. Subramanian, Z. Goodman, M. Charlton, N.H. Afdhal, C. Sirlin, R. Loomba
Journal: Journal of Hepatology (2017)
Noninvasive models to predict liver fibrosis in patients with chronic hepatitis B: a study from Turkey
Authors: P. Korkmaz, N. Demirtürk, A. Batırel, A.C. Yardımcı, Ü. Çağır, S.A. Nemli, F. Korkmaz, F.Z. Akçam, H.S. Barut, B. Bayrak, F. Karakeçili, H. Tarakçı, Z. Yuluğkural, E. Yüksel, N.A. Demir, O. Ural, S. Sümer, R. Harman, A. Kadanalı, S. Öztürk, S.Ç. Akhan, N.E. Tülek, D. Keten, A. Sener, B. Aygen, A.K. Çelikbaş, F.Y. Karadağ, G. Aydın, E. Arslan, C. Saçlıgil, G.A. Öcal, A. Tanoğlu, A. Ülçay, E. Karagöz, N. Saltoğlu, F. Sırmatel, H. Akdeniz, A. Aynıoğlu, S.A. Özel, S.D. Çaylak, İ. Çelik, Y. Alpay, Z.B. Dursun, M. Bekçibaşı, G.T. Ertem, A. Tığlı, E.S. Altunok, K. Avşar, K. Suer, M. Sayan
Journal: Journal of Hepatology (2017)
Macrophage activation markers sCD163 and mannose receptor predict survival and correlate with markers of gut permeability in patients with liver cirrhosis
Authors: F. Rainer, A. Horvath, T.D. Sandahl, B. Leber, B. Schmerboeck, A. Blesl, E. Krones, F. Baumann-Durchschein, P. Douschan, W. Spindelboeck, G. Zollner, R.E. Stauber, P. Fickert, P. Stiegler, H.J. Møller, H. Grønbæk, V. Stadlbauer
Journal: Journal of Hepatology (2017)
Chk2 DNA damage response protein mislocalization further enhances chromosomal instability and human hepatocellular carcinoma progression
Authors: V. Carloni, M. Lulli, S. Madiai, T. Mello, A. Hall, T.V. Luong, M. Pinzani, K. Rombouts, A.G. Galli
Journal: Journal of Hepatology (2017)
The risk of chronic kidney disease after liver transplantation is rising in parallel with the increased use of higher risk grafts
Authors: N. Owen, M.J. Armstrong, C.R. Chimakurthi, J. Davidson, E. Gonsalkorala, D. Houlihan, M. Hudson, M.S. Ismail, R. Jones, D. Joshi, M. Alastair, A. Marshall, D. Mirza, A. Majumdar, J. Orr, J. Powell, D. Thorburn, D. Tripathi, V. Upasani, J.A. Leithead
Journal: Journal of Hepatology (2017)
Abstract A41: Crosstalk between adipocytes and breast cancer promotes epithelial-mesenchymal transition
Authors: Kim Eun-Sol, Koo Ja Seung
Journal: Cancer Research (2017)

Abstract Introduction: Adipocytes are known to be involved in epithelial-mesenchymal transition (EMT) associated with tumor cell invasion and metastasis in several cancers. However, the role of adipocytes in the EMT of breast cancer cells is poorly understood. The purpose of this study was to investigate the involvement of adipocytes in the EMT in breast cancer. Methods: We investigated that co-culture with adipocytes induces morphological changes, proliferation activity, EMT markers expression, status of migration and invasion in MCF-7, MDA-MB-453, MDA-MB-435S, MDA-MB-231, and MDA-MB-468 cell lines. By tissue microarray (TMA) of 296 cases of human breast cancer, immunochemical staining for estrogen receptor (ER), progesterone (PR), HER2, Ki-67, N-cadherin, Twist1, HMGA2, TGFb, and S100A4 was conducted. We classified into fibrous stroma and adipose stroma (when adipose tissue is at least 50% of the entire tumor stroma) based on standard histological classification. Results: After co-culture with adipocytes, MCF-7, MDA-MB-435S, and MDA-MB-231 cells exhibited elongated spindle-like morphology and increased proliferation; MDA-MB-435S and MDA-MB-231 cells also showed increased dispersion. In all tested breast cancer cells, adipocytes induced migration and invasion. The EMT-like phenotypic changes and increased cell migration and invasion were accompanied by the upregulation of matrix metallopeptidase 9 and TWIST1. Consistently, breast cancer tumors with the adipose stroma showed higher TWIST1 expression than those with the adipose stroma; however, no difference was observed in the levels of other EMT-related proteins. Conclusion: Adipocytes enable breast cancer cells to acquire aggressive tumor biology by inducing EMT features, and breast cancer with adipose stroma expresses EMT markers as breast cancer with fibrous stroma. Citation Format: Lee YuKyung, Kim Eun-Sol, Koo Ja Seung. Crosstalk between adipocytes and breast cancer promotes epithelial-mesenchymal transition. [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 A41.
Resistance matters in EARNEST
Authors: Gary Maartens, Graeme Meintjes
Journal: The Lancet HIV (2017)

A high proportion of patients in whom efavirenz-based or nevirapine-based first-line antiretroviral therapy (ART) fail in resource limited settings have high level resistance to nucleoside reverse transcriptase inhibitors (NRTIs), or non-NRTIs, or both.1 Many of the NRTI resistance mutations acquired during first line ART compromise the activity of NRTIs available for second-line protease inhibitor-based ART regimens, which could limit the efficacy of second-line ART and expose patients to toxic effects of drugs that might have minimal activity.
Red meat: another inconvenient truth
Authors: Fiona Godlee
Journal: BMJ (2017)

Evidence continues to emerge linking high meat consumption with increased mortality.This week Arash Etemadi and colleagues provide further support for the association (doi:10.1136/bmj.j1957).Their population based cohort study links high intake of red and processed meat with increased deaths from all causes and from nine specific ones.Dietary epidemiology studies are of course fraught with pitfalls.At their worst they attract ridicule for supporting every conceivable association, fuelling public confusion and fake news.This week's study is large, with more than 7.5 million American person years of observation, and it's well done.Although its main findings are based on a single dietary assessment, a subgroup had two assessments done on separate occasions, and these associations were if anything stronger.Importantly, death rates were lower in groups who ate a higher proportion of fish and poultry than red meat.
Correlation of hepatitis B virus genomic variants with HBsAg Titers and HBV-DNA levels in a large European study cohort of patients with chronic hepatitis B
Authors: K.-H. Peiffer, L. Sommer, S. Susser, J. Dietz, J. Vermehren, V. Knop, S. Zeuzem, E. Hildt, C. Sarrazin
Journal: Journal of Hepatology (2017)
Patient-reported outcomes from MA.17R: A randomized trial of extending adjuvant letrozole for 5 years after completing an initial 5 years of aromatase inhibitor therapy alone or preceded by tamoxifen in postmenopausal women with early-stage breast cancer.
Authors: Julie Lemieux, Paul E. Goss, Wendy R. Parulekar, James N. Ingle, Kathleen I. Pritchard, Nicholas J. Robert, Hyman Muss, Julie Gralow, Kathrin Strasser-Weippl, Michael Donald Brundage, Kate Whelan, Dongsheng Tu, Timothy Joseph Whelan
Journal: Journal of Clinical Oncology (2016)

LBA506 Background: MA.17R is a Canadian Cancer Trials Group (CCTG) led phase III randomized controlled trial comparing letrozole to placebo after 5 years of aromatase inhibitor (AI) as adjuvant therapy for hormone-receptor positive breast cancer. The primary endpoint was disease-free survival. Quality of life (QOL) was a secondary endpoint. Methods: QOL was measured with the SF-36 (2 summary scores and 8 domains) and menopause-specific QOL (MENQOL) (4 symptom domains) at baseline and every 12 months (mo) up to 60 mo. QOL assessment was mandatory for CCTG centres but optional to centres in other groups. Mean change scores from baseline were calculated at 12 and 36 mo. Between-arm differences were assessed with the Wilcoxon test. Results: 1918 patients were randomized and 1428 patients completed the baseline QOL assessment. Compliance with QOL measures was over 85%. Baseline summary scores for SF-36 physical (PCS, 47.5 for letrozole and 47.9 for placebo) and mental (MCS, 55.5 for letrozole and 54.8 for placebo) were close to population norms (50). No differences were seen between groups in mean change scores for the SF-36 PCS and MCS and the other 8 QOL domains. Patients randomized to letrozole reported worse vasomotor symptoms (12 mo p = 0.02, 36 mo p = 0.03) and worse sexual functioning (12 mo p = 0.01, 36 mo p = 0.01). Further analyses with follow up to 60 months will be presented. Conclusions: No differences were seen in overall QOL measured by the SF 36 summary measures between letrozole and placebo groups. Differences existed for vasomotor symptoms and sexual functioning which were worse in the letrozole group and attributed to improvements in mean scores seen for women randomized to placebo. The data indicate that continuation of AI therapy after 5 years prior treatment is not associated with a deterioration of overall QOL. Treatment related vasomotor and sexual functioning alterations occur with ongoing treatment. Clinical trial information: NCT00754845.
Hepatic encephalopathy in cirrhotic patients with bacterial infections: prevalence, clinical characteristics and correlation with prognosis: a prospective study
Authors: J. Piedade, L. Guimarães, T. Rocha, L. Victor, C. Baldin, B. Rodrigues, Z. Veiga, L. Agoglia, F. Fernandes, G.H.S. Pereira
Journal: Journal of Hepatology (2017)
Reliability criteria for the diagnosis of fatty liver using controlled attenuation parameter by transient elastography – A multicentre study of 754 patients
Authors: V.W.-S. Wong, S. Petta, J.-B. Hiriart, C. Cammà, G.L.-H. Wong, F. Marra, J. Vergniol, A.W.-H. Chan, V. Di Marco, W. Merrouche, H.L.-Y. Chan, B. Le Bail, U. Arena, A. Craxì, V. de Lédinghen
Journal: Journal of Hepatology (2017)