tbuckley/cabot-search huggingface dataset:
Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms
Authors: Roderick C. Slieker, Maarten van Iterson, René Luijk, Marian Beekman, Daria V. Zhernakova, Matthijs H. Moed, Hailiang Mei, Michiel van Galen, Patrick Deelen, Marc Jan Bonder, Alexandra Zhernakova, André G. Uitterlinden, Ettje F. Tigchelaar, Coen D. A. Stehouwer, Casper G. Schalkwijk, Carla J. H. van der Kallen, Albert Hofman, Diana van Heemst, Eco J. de Geus, Jenny van Dongen, Joris Deelen, Leonard H. van den Berg, Joyce van Meurs, Rick Jansen, Peter A. C. ‘t Hoen, Lude Franke, Cisca Wijmenga, Jan H. Veldink, Morris A. Swertz, Marleen M. J. van Greevenbroek, Cornelia M. van Duijn, Dorret I. Boomsma, P. Eline Slagboom, Bastiaan T. Heijmans
Journal: Genome biology (2016)

Epigenetic change is a hallmark of ageing but its link to ageing mechanisms in humans remains poorly understood. While DNA methylation at many CpG sites closely tracks chronological age, DNA methylation changes relevant to biological age are expected to gradually dissociate from chronological age, mirroring the increased heterogeneity in health status at older ages.Here, we report on the large-scale identification of 6366 age-related variably methylated positions (aVMPs) identified in 3295 whole blood DNA methylation profiles, 2044 of which have a matching RNA-seq gene expression profile. aVMPs are enriched at polycomb repressed regions and, accordingly, methylation at those positions is associated with the expression of genes encoding components of polycomb repressive complex 2 (PRC2) in trans. Further analysis revealed trans-associations for 1816 aVMPs with an additional 854 genes. These trans-associated aVMPs are characterized by either an age-related gain of methylation at CpG islands marked by PRC2 or a loss of methylation at enhancers. This distinct pattern extends to other tissues and multiple cancer types. Finally, genes associated with aVMPs in trans whose expression is variably upregulated with age (733 genes) play a key role in DNA repair and apoptosis, whereas downregulated aVMP-associated genes (121 genes) are mapped to defined pathways in cellular metabolism.Our results link age-related changes in DNA methylation to fundamental mechanisms that are thought to drive human ageing.
Side effects are under-reported in peer reviewed journals
Authors: Jacqui Wise
Journal: BMJ (2016)

Much of the information on adverse events remains unpublished, a systematic review of the evidence published in Plos Medicine has found.

Su Golder, from the University of York, and colleagues reviewed 28 studies that compared published journal articles with unpublished information on the same trials gathered from conference reports, drug companies’ clinical study reports, …
Large Single Center Experience of Sofosbuvir and Ledipasvir Therapy for the Treatment of Patients with Hepatitis C Virus
Authors: J. Wedd, R. Ford, J. Norvell, S. Parekh, N. Cheng, N. Young, A. Patel, R. Maheshwari, R. Vora, O. Mgbemena, J. Spivey, A. Pillai
Journal: Journal of Hepatology (2016)
Inducible nitric oxide synthase expression is increased in the alveolar compartment of asthmatic patients
Authors: E. Tufvesson, C. Andersson, J. Weidner, J. S. Erjefält, L. Bjermer
Journal: Allergy (2016)

Increased exhaled nitric oxide (NO) levels in asthma are suggested to be through inducible NO synthase (iNOS). The aim of this study was to investigate the expression of iNOS in bronchoalveolar lavage (BAL) cells and tissue from central and peripheral airways and compare it with the exhaled bronchial and alveolar NO levels in patients with asthma vs a control group.Thirty-two patients with asthma (defined as controlled or uncontrolled according to Asthma Control Test score cut-off: 20) and eight healthy controls were included. Exhaled NO was measured, and alveolar concentration and bronchial flux were calculated. iNOS was measured in central and peripheral lung biopsies, as well as BAL cells. Bronchoalveolar lavage macrophages were stimulated in vitro, and iNOS expression and NO production were investigated.Expression of iNOS was increased in central airway tissue and the alveolar compartment in uncontrolled as compared to controlled asthmatics and healthy controls. There were no differences, however, in iNOS mRNA levels in total BAL cells in uncontrolled as compared to controlled asthma. Bronchoalveolar lavage cell mRNA levels of iNOS or iNOS expression in central and alveolar tissue did not relate to alveolar NO, nor to bronchial flux of NO. In vitro stimulation with leukotriene D4 increased iNOS mRNA levels and NO production in cultured BAL macrophages.The levels of both bronchial and alveolar iNOS are increased in uncontrolled as compared to controlled asthma. However, levels of iNOS in BAL macrophages were not reflected by alveolar NO. Both central and distal iNOS levels may reflect responsiveness to steroid treatment.
Connecting gene expression subtypes of colorectal cancer (CRC) with cell lines and drug resistance.
Authors: Eva Budinska, Jenny Wilding, Vlad Calin Popovici, Edoardo Missiaglia, Arnaud Roth, Fred Bosman, Mauro Delorenzi, Walter Bodmer, Sabine Tejpar
Journal: Journal of Clinical Oncology (2013)

e14544 Background: We identified CRC gene expression subtypes (ASCO 2012, #3511), which associate with established parameters of outcome as well as relevant biological motifs. We now substantiate their biological and potentially clinical significance by linking them with cell line data and drug sensitivity, primarily attempting to identify models for the poor prognosis subtypes Mesenchymal and CIMP-H like (characterized by EMT/stroma and immune-associated gene modules, respectively). Methods: We analyzed gene expression profiles of 35 publicly available cell lines with sensitivity data for 82 drug compounds, and our 94 cell lines with data on sensitivity for 7 compounds and colony morphology. As in vitro, stromal and immune-associated genes loose their relevance, we trained a new classifier based on genes expressed in both systems, which identifies the subtypes in both tissue and cell cultures. Cell line subtypes were validated by comparing their enrichment for molecular markers with that of our CRC subtypes. Drug sensitivity was assessed by linking original subtypes with 92 drug response signatures (MsigDB) via gene set enrichment analysis, and by screening drug sensitivity of cell line panels against our subtypes (Kruskal-Wallis test). Results: Of the cell lines 70% could be assigned to a subtype with a probability as high as 0.95. The cell line subtypes were significantly associated with their KRAS, BRAF and MSI status and corresponded to our CRC subtypes. Interestingly, the cell lines which in matrigel created a network of undifferentiated cells were assigned to the Mesenchymal subtype. Drug response studies revealed potential sensitivity of subtypes to multiple compounds, in addition to what could be predicted based on their mutational profile (e.g. sensitivity of the CIMP-H subtype to Dasatinib, p&lt;0.01). Conclusions: Our data support the biological and potentially clinical significance of the CRC subtypes in their association with cell line models, including results of drug sensitivity analysis. Our subtypes might not only have prognostic value but might also be predictive for response to drugs. Subtyping cell lines further substantiates their significance as relevant model for functional studies.
Abstract 1956: Age-associated Changes In Left Ventricular Contractility And Ventricular-vascular Stiffness In Apolipoprotein E-deficient Mice
Authors: An Van den Bergh, Paul Holvoet, Paul Herijgers
Journal: Circulation (2007)

Objectives . To assess left ventricular contractile function and characteristics in the apolipoprotein E-deficient mouse model of severe atherosclerosis. Methods . We studied cardiac performance in 24- and 60-weeks-old ApoE−/− mice and age-matched wild type (WT) mice, using a miniature pressure-volume (PV) conductance catheter. Load-independent contractility was assessed using preload recruitable stroke work (PRSW) and preload-corrected dP/dt max (dP/dt max /V ed ). Results (Table ). The two genotypes exhibited comparable contractile parameters at 24 weeks. Contracility (PRSW and dP/dt max /V ed ) of WT mice at 60 weeks was lower than at 24 weeks, as was arterial (E a ) and left ventricular end-systolic (E es ) elastance. In 60-week-old ApoE−/− mice, E a and E es were less reduced than in WT. End-diastolic left ventricular stiffness (EDPVR) increased with age in ApoE−/− mice. This was accompanied by a higher heart to body weight ratio and a reduced end-diastolic volume (V ed ) indicating the presence of concentric hypertrophy in these mice. Load-independent contractility parameters decreased less in ApoE−/− than in WT, which can be explained by the left ventricular hypertrophy. Conclusions. Our findings indicate that contractility is impaired at old age. In old ApoE−/− mice, exhibiting extensive atherosclerosis, ventricular-vascular stiffness is higher than in WT, end-diastolic left ventricular stiffness is increased, and concentric left ventricular hypertrophy develops.
Panitumumab plus irinotecan, both given every 3 weeks (Q3W), as second-line treatment for irinotecan-naïve metastatic colorectal cancer (mCRC).
Authors: A. Carrato, A. Gomez, M. P. Escudero, M. Chaves, F. Rivera, E. Marcuello, E. González Flores, C. Grávalos, M. Constenla, E. Aranda
Journal: Journal of Clinical Oncology (2010)

e14025 Background: Panitumumab, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody, has shown efficacy and is well tolerated in combination with chemotherapy (CT) for the treatment of mCRC. The main objective of this study was to evaluate the efficacy and safety of panitumumab plus irinotecan as second-line treatment for irinotecan-naïve mCRC patients (pts). K-RAS status as a negative predictive marker for panitumumab efficacy was not established by the time the trial was planned and started. A protocol amendment was performed to recruit only wild-type (WT) K-RAS tumors when 44 pts were already included. Methods: This was a prospective phase II, multicenter, single-arm study (clinicaltrials.gov identifier NCT00475293). Pts with confirmed mCRC, ECOG score 0-2, measurable disease, and progression to first-line treatment with oxaliplatin-based CT, were included. Panitumumab 9 mg/kg plus irinotecan 350 mg/m2 (300 mg/m2 in pts > 70 years-old or ECOG 2) were administered Q3W until progressive disease (PD) or unacceptable toxicity. Tumor assessments (modified RECIST criteria) were performed Q9W until PD. Primary endpoint was objective response rate (ORR) and secondary endpoints included disease control rate (DCR), progression-free survival (PFS) and adverse events (AEs). Results: From the 85 pts enrolled in the study, 53 pts had WT K-RAS tumour status. Only these pts have been included in this analysis performed on an intention-to-treat basis. Median age was 67.0 years (range 37.0–83.0), 66.0% men and 90.6% ECOG 0-1. ORR was 22.6% (95% confidence interval [CI] 12.3–36.2), and median time duration of response was 4.2 months (range 2.5–10.8). DCR was 62.3% (95%CI 47.9–75.2). Median PFS was 5.5 months (95%CI 4.2–8.0). Most frequent (> 10% of pts) grade 3/4 related AEs included: diarrhoea (35,8%), acne-like rash (32.1%), asthenia (17%) and neutropenia (13,2%). Conclusions: The combination of panitumumab and irinotecan both administered Q3W was feasible with a manageable toxicity profile and showed a promising anti-tumour activity as second-line therapy in WT K-RAS, irinotecan-naïve, mCRC pts. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen
Hepatitis Delta Virus Evolution Rate is High in Patients with Chronic Delta Infection, but Tends to Stabilize Over Time
Authors: M. Horns, F. Rodriguez-Frias, J. Gregori, R. Casillas, P. Reimundo, A. Ruiz, C. Godoy, D. Tabernero, J. Quer, M. Riveiro-Barciela, R. Esteban, M. Buti
Journal: Journal of Hepatology (2016)
Pathological Analysis of the Liver of Patients with Cirrhosis and Hepatopulmonary Syndrome Reveals a Vascular Pattern of Damages
Authors: C. Lejealle, V. Paradis, C. Francoz, O. Soubrane, D. Lebrec, D. Valla, F. Durand, P.E. Rautou
Journal: Journal of Hepatology (2016)
Autologous stem cell transplantation in dialysis-dependent myeloma patients.
Authors: Riad Omar El Fakih, Yago Nieto, Patricia S Fox, Nina Shah, Simrit Parmar, Betul Oran, Stefan O. Ciurea, Partow Kebriaei, Chitra Hosing, Uday R. Popat, Sairah Ahmed, Jatin J. Shah, Robert Z. Orlowski, Yvonne Dinh, Richard E. Champlin, Muzaffar H. Qazilbash, Qaiser Bashir
Journal: Journal of Clinical Oncology (2014)

8601 Background: The incidence of renal insufficiency at presentation is approximately 30% in patients with multiple myeloma (MM). 5% of these patients are dialysis dependent. Presence of renal dysfunction is associated with increased treatment related toxicity and poor survival. Methods: We retrospectively analyzed our transplant database from July 2000 to June 2012 to identify myeloma patients who received autologous hematopoietic stem cell transplantation (autoHCT) while they were dialysis dependent. Univariate Cox proportional hazards regression was performed to assess the association between survival and covariates of interest. Kaplan Meier curve was used to estimate progression free survival (PFS) and overall survival (OS). Results: 2,091 patients underwent autoHCT during this interval. 24 (1.1%) were dialysis dependent (21 on hemodialysis and 3 on peritoneal dialysis). Median age was 53 (29-70) years. 63% were male. ISS stage at diagnosis was I & II in 4%, III in 54%, and unknown in 38%. Median duration of dialysis prior to auto-HCT was 235 (1-1481) days. Four patients had high risk cytogenetics. Melphalan dose was 200 mg/m2 in 58% and < 200 mg/m2 in 42%. The median collected CD34+ cells count was 4.35 x 106/Kg. All patients engrafted. 100 day and 6 month treatment related mortality (TRM) was 0%. The incidence of grade II-IV non hematological toxicity was similar across different melphalan doses. Overall response rate was 92% (CR = 25%, VGPR = 29.2%, PR = 37.5%). Two patients had SD. The median follow up is 6.7 years. At the time of last follow up, 13 patients had died and 11 (45.8%) were still alive. The median PFS and OS were 1.9 years and 3.8 years, respectively. In univariate analysis, high-risk cytogenetics was a significant predictor of poor PFS (p0.04) and OS (p<0.009). A multivariate analysis was not performed due to the small sample size. Only 3 patients (12.5%) became dialysis independent after transplant. No variable was predictive of becoming dialysis independent. Conclusions: AutoHCT can be safely performed in dialysis dependent myeloma patients. While majority of patients continue to require dialysis after transplant, long term disease control can be expected. Dialysis dependent renal failure should not be an exclusion for autoHCT.
PD2.01 (also presented as P1.13): Lung Cancer Chromosomal Aberrations and Gene Expression Profiles of Hispanics Living in the US or Latin America are Similar
Authors: Luis E. Raez, Edgardo S. Santos, Jennifer Mourafetis, Alice Y. Kim, Brian Hunis, Candice Sareli, Lilibeth Castillero, Evelio Velis
Journal: Journal of Thoracic Oncology (2016)
Phase I study of anti-CD25 mab daclizumab to deplete regulatory T cells prior to telomerase/survivin peptide vaccination in patients (pts) with metastatic breast cancer (MBC).
Authors: A. J. Rech, R. Mick, A. Recio, A. DeMichele, C. K. Tweed, K. R. Fox, S. M. Domchek, R. H. Vonderheide
Journal: Journal of Clinical Oncology (2010)

2508 Background: CD4+ regulatory T cells (Tregs) inhibit tumor immunity and represent an obstacle for cancer immunotherapy, but an effective strategy to deplete Tregs in pts has not been identified. In mice, anti-CD25 mAb depletes CD25+ FoxP3+ Tregs and promotes immunity. We therefore evaluated the FDA-approved anti-CD25 mab daclizumab for its effect on Tregs in a phase I clinical study. Methods: Ten HLA-A2+ pts with progressive MBC received an intravenous infusion (1 mg/kg) of daclizumab one week before an experimental vaccine consisting of 4 telomerase and survivin peptides and a cytomegalovirus (CMV) control peptide, emulsified in incomplete Freund's adjuvant (Montanide ISA-51-VG) and administered subcutaneously with GM-CSF every other week (×4) then monthly until disease progression. The pneumococcal-conjugate vaccine (Prevnar), containing CRM-197 antigen to engage T cell help, was also administered. Immune assessment was performed using blood samples obtained at baseline and regularly thereafter. Results: Daclizumab and vaccines were extremely well-tolerated. A median of 4 vaccines per pt (range 2 to 17) were given. Five pts had stable disease as the best response. Both percentage and absolute counts of CD25+ FoxP3+ CD4+ T cells decreased dramatically after daclizumab (p<0.001), based on monitoring with a CD25 antibody not blocked by daclizumab. Total FoxP3+ CD4+ T cells also decreased (p<0.001) but total CD4+ cells did not. The decrease of CD25+ FoxP3+ T cells was rapid (<1 week), marked (mean decrease of 83%), and prolonged (at least 7 weeks). Despite CD25 expression on effector T cells, 80% of pts exhibited CD8 responses to one or more tumor peptides, and 80% had CRM197-specific T cell responses. Two of five CMV seronegative pts exhibited CD8 T cell priming to CMV peptide. Conclusions: A single infusion of anti- CD25 mab daclizumab results in rapid, marked, and prolonged loss of CD25+ FoxP3+ CD4+ Tregs without toxicity in pts with MBC. Robust T cell priming and boosting to all vaccine antigens was observed despite CD25 blockade. These results demonstrate the utility of anti-CD25 mab for achieving extensive depletion of Tregs in patients. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Patent owned by Dana Farber and Whitehead
P0391 : Prior history of arterial hypertension is not a contraindication to sorafenib and is associated to a better survival in patients with advanced HCC
Authors: R. Di Donato, A. Gazzola, M. Reig, A. Garcia Alvarez, E. Santiago, F. Torres, A. Forner, A. Darnell, C. Ayuso, J. Bruix
Journal: Journal of Hepatology (2015)
Impact of dose-intensity of adjuvant CMF on disease-free (DFS) and overall survival (OS) in breast cancer (BC): a retrospective analysis
Authors: Robert Paridaens, J. Wildiers, Herlinde Dumez, José Thomas, Caroline Weltens, Walter Van den Bogaert, Erik Van Limbergen, A. Aerts, L. Kaufmann, Allan Van Oosterom
Journal: Annals of Oncology (2002)
Systematic Assessment of Potential Cardiac Effects of the Novel Histone Deacetylase (HDAC) Inhibitor Romidepsin.
Authors: Christopher Cabell, Susan Bates, Richard Piekarz, Sean Whittaker, Youn H Kim, Michelle Currie, C. J Godfrey, Christopher Schoonmaker, Jean Nichols, Darrell Nix, Howard A. Burris
Journal: Blood (2009)
The Impact of Driver Mutations of JAK2, Calr, or MPL in Patients with Myelofibrosis Undergoing Hemopoietic Stem Cell Transplantation
Authors: Andrea Bacigalupo, Sarah Pozzi, Maria Teresa van Lint, Stefania Bregante, Gianni Barosi, Daniela Pietra, Elisa Rumi, Chiara Milanesi, Mario Cazzola
Journal: Blood (2015)
Targeting argininosuccinate synthetase-deficient advanced solid tumors in a phase I trial of ADI-PEG20 plus cisplatin.
Authors: Siqing Fu, Eevy Nguyen, Filip Janku, Vivek Subbiah, Sapna Pradyuman Patel, Gerald Steven Falchook, Ralph Zinner, Apostolia Maria Tsimberidou, David S. Hong, Sarina Anne Piha-Paul, Jennifer J. Wheler, Naiyi Shi, John S. Bomalaski, Patrick Hwu, Funda Meric-Bernstam
Journal: Journal of Clinical Oncology (2014)

2563 Background: Besides its selective activity to induce autophagy and caspase-independent apoptosis in argininosuccinate synthetase (ASS)-deficient cancer cells, ADI-PEG20 (pegylated arginine deiminase) synergized with the antitumor activity of cisplatin in vitro and in vivo. Accordingly we conducted a phase I study of ADI-PEG20 plus cisplatin in patients with ASS-deficient advanced solid tumors (NCT01665183). Methods: Primary objective was to establish the maximum tolerated dosage (MTD) following a standard 3+3 design. Secondary objectives were safety, antitumor activity and pharmacodynamics and immunogenicity effects. Patients with adequate organ functions, ECOG performance status of 1 or better, and ASS deficient advanced solid tumors were eligible. Dose escalation over 6 dose levels starting at ADI-PEG20 18 mg/m2 IM weekly plus cisplatin 20 mg/m2 IV weekly x 3 every 4 weeks and dose expansion at the MTD were included. Toxicity and efficacy were evaluated according to CTCAE 4.0 and RECIST 1.1, respectively. Results: A total of 37 patients with a median age of 62 were enrolled: 26 melanoma (18 cutaneous, 7 uveal, and 1 mucosal), 8 sarcoma, 1 prostate, 1 cervical, and 1 head and neck cancer. The MTD was established at ADI-PEG 36 mg/m2 IM weekly plus cisplatin 30 mg/m2 IV weekly x 3 every 4 weeks. Dose limited toxicities (DLT) included grade 4 neutropenia and neutropenic fever. Antitumor activity showed 2 partial responses (PR, 5%) and 8 stable disease ≥ 4 months (SD≥4 months, 22.2%). In patients with cutaneous melanoma, 2/18 PR (11 %) and 2/18 SD≥4 months (11%) were observed, associated with a median progression-free (PFS) and overall survivals of 2.6, and 5.8 months, respectively. Of 7 uveal melanoma patients, a median PFS of 4.7+ months was observed with 3 still on study, 2 off study but still alive, and 2 off study and dead (survived 11.6 and 1.5 months respectively). Conclusions: ADI-PEG 36 mg/m2 IM weekly plus cisplatin 30 mg/m2 IV weekly x 3 every 4 weeks was determined as the recommended phase 2 dosage, which was safe and demonstrated antitumor activity in patients with ASS-deficient advanced solid tumors. Further evaluation in patients with metastatic uveal and cutaneous melanoma is warranted. Clinical trial information: NCT01665183.