tbuckley/cabot-search huggingface dataset:
Identification of candidate biomarkers of therapeutic response to docetaxel in hormone-refractory prostate cancer by proteomic profiling
Authors: L. Horvath, L. Zhao, B. Lee, D. Brown, M. Molloy, G. Marx, M. Boyer, S. Breit, R. Sutherland, S. Henshall
Journal: Journal of Clinical Oncology (2009)

11010 Background: Docetaxel (DTX)-based chemotherapy improves symptoms and survival in men with advanced hormone-refractory prostate cancer (HRPC). However, approximately 50% of patients do not respond to DTX but are exposed to significant toxicity without direct benefit. This study aimed to identify novel therapeutic targets and predictive biomarkers of DTX-resistance in HRPC. Methods: Protein profiling using iTRAQ mass spectrometry compared the PC3-Rx and DTX-sensitive PC3 cells and DTX-resistant PC3-Rx developed by DTX dose-escalation. Functional validation experiments were performed using recombinant protein treatment and siRNA knockdown experiments. Plasma/serum samples were collected from 41 men with metastatic HRPC treated with DTX-based chemotherapy (36 with paired samples pre- and post- cycle 1 DTX). Serum/plasma levels of MIC-1 were measured by ELISA. The association between MIC-1 levels, PSA response and overall survival (OS) were assessed by non-parametric tests and Kaplan-Meier survival analysis. Results: The IC50 for DTX in PC3-Rx was 10-fold higher than that in parent PC-3 cells. Protein profiling identified that MIC-1 levels were elevated 2.4 fold and AGR2 decreased 2.4 fold in DTX resistant cells. Knockdown of AGR2 expression in PC3 cells resulted in increased DTX resistance (p=0.03). PC-3 cells treated with recombinant MIC-1 also became resistant to DTX (p=0.001). Conversely, treating PC3-Rx cells with MIC1-siRNA restored sensitivity to DTX (p=0.002). In HRPC patients, pre-treatment MIC-1 levels did not correlate with PSA response to treatment (p=0.6). In contrast, increased serum/plasma levels of MIC-1 after cycle one of chemotherapy were associated with DTX resistance (p=0.006) and shorter overall survival (p=0.002). Conclusions: These results suggest that both AGR2 and MIC-1 play a role in DTX resistance in HRPC. Furthermore, changes in serum/plasma MIC-1 levels are associated with DTX resistance in a correlative human cohort. While a larger study is needed to validate these findings, the data provide evidence that MIC-1 as a potential predictive biomarker and both MIC-1 and AGR2 are potential therapeutic targets in DTX resistance. No significant financial relationships to disclose.
Combination of sorafenib and weekly gemcitabine in patients (pts) with metastatic renal cell Cancer (MRCC): A phase II study, preliminary results
Authors: L. Tomasello, M. R. Sertoli, A. Rubagotti, P. Guglielmini, L. Tacchini, D. Bedognetti, F. Ricci, S. Sanguineti, A. Cassata, F. Boccardo
Journal: Journal of Clinical Oncology (2008)

16011 Background: Treatment options of advanced MRCC are unsatisfactory and new therapeutic approach are mandatory. Sorafenib (BAY 43–9006), an oral tyrosine kinase inhibitor, targeting signal transduction and angiogenic pathways, was recently approved for MRCC. Few data are currently available about the combination of Sorafenib with chemotherapy. Gemcitabine is a pyrimidine antimetabolite with documented MRCC activity. On the basis of a previous phase I study (Clin Cancer Res, 2006;12:144) we investigated the association of BAY 43 plus Gemcitabine in a phase II study in MRCC due to their compatibility in preclinical models and nonoverlapping clinical toxicities. Methods: Eligibility criteria included advanced, histologically confirmed RCC; age >18 years; ECOG PS ≤ 2, adequate bone marrow, renal and hepatic function; measurable/evaluable lesions; UISS 3 cathegory or immunotherapy refractory disease. Treatment consisted of Gemcitabine at a dose of 800 mg/m2 i.v. on days 1, 8 and 15 every 28 days and Sorafenib 400 mg bid orally every day. Aim of the study was to assess activity and toxicity of the combination. The trial had a two stages design. During the first step 13 pts were to be enrolled. If less than 3 of them reached tumor response or stabilization after 6 months of treatment the trial had to be terminated. Otherwise the accrual for the second step would include a total of 43 patients in order to achieve a 80% statistical power with an alpha error less or equal to 5%. Results: At a median follow-up time of 9 months (range 1–20) the first step of the trial has been completed. Patients’ characteristics are: median age 58 years (range 41–75); 60% of pts ECOG PS=0; 9 pts (69.0%) pretreated with immunotherapy. Thirteen patients were evaluable for toxicity. Main grade 3 toxicities were hand-foot syndrome (15.4%), fever (7.7%), fatigue (7.7%), vomiting (7.7%) and grade 4 was hemoptysis (7.7%). Two early deaths occurred (15.3%). Among 13 RECIST evaluable pts, a clinical benefit (PR and SD) was obtained in 7/13 (53.9%) pts Conclusions: These findings suggest that the combination is active with no significant incidence of side effects. Therefore further evaluation is warrented and in fact the second step of recruiting is ongoing. No significant financial relationships to disclose.
A randomized trial comparing endosonography followed by surgical staging versus surgical mediastinal staging alone in non-small cell lung cancer: The ASTER study.
Authors: K. G. Tournoy, C. A. Dooms, R. C. Rintoul, P. Deleyn, A. G. Nicholson, E. Deschepper, O. Dekkers, K. F. Rabe, J. P. Van Meerbeeck, J. T. Annema
Journal: Journal of Clinical Oncology (2010)

7000 Background: Invasive mediastinal staging in patients with resectable non-small cell lung cancer (NSCLC) can be performed with endosonography (ES) followed by surgical staging (SS; for negative findings) or SS alone. We conducted a prospective randomized multicenter trial to compare both strategies. Primary endpoint was detection of nodal metastasis (N2/3), secondary endpoints were the rate of futile thoracotomy and complications. Methods: Consecutive patientswith (suspected) resectableNSCLC in whom invasive mediastinal staging was indicated based on computed or positron emission tomography were randomly assigned between ES [combined transoesophageal and endobronchial ultrasound (EUS-FNA and EBUS-TBNA)] followed by SS (in case of negative findings) or SS (mediastinoscopy, mediastinotomy or video-assisted thoracoscopic surgery) alone. Thoracotomy with systematic mediastinal lymph node dissection was performed in the absence of mediastinal metastases after SS in both arms. Results: 241 patients were randomized as planned: 123 to ES+SS and 118 to SS alone. Nodal metastases were found in 62 patients (50%) (56 by EUS/EBUS + 6 by subsequent SS) vs. 41 (35%) by SS alone (p = 0.019). The sensitivity for mediastinal metastases for ES+SS was 94% (95% CI, 85- 98) versus 80 % (95 CI, 68-89) for SS alone (p = 0.042). Thoracotomy was futile in 8 patients (7%) staged by ES+SS vs. 21 (18%) in those staged by SS alone (p = 0.009). The rate of complications during staging was similar in both arms (6 vs. 7 patients, p = 0.8), however 12/13 were due to SS. Conclusions: Starting mediastinal staging with endosonography in resectable NSCLC 1) improves the detection of nodal metastasis 2) reduces futile thoracotomies 3) and has a similar complication rate, as compared to surgical staging alone. No significant financial relationships to disclose.
Abstract 13816: Relation Between the Atrial Fibrillation and the Endothelial Function: Effect of Sinus Rhythm Restoration by Catheter Ablation
Authors: Hisanori Kanazawa, Hiroshige Yamabe, Seigo Sugiyama, Satomi Iwashita, Junjiroh Koyama, Tadashi Hoshiyama, Miwa Ito, Hisao Ogawa
Journal: Circulation (2013)

Background:  Endothelial function has been shown to be correlated significantly with the severity of cardiovascular disease. Meanwhile, atrial fibrillation (AF) is an independent risk factor which worsens the cardiac function.   Objectives:   The purpose of this study was to elucidate the correlation between the endothelial function and AF. Thus, we examined the effect of the restoration of sinus rhythm by AF catheter ablation (CA) on the endothelial function.   Methods:  The consecutive 83 patients with AF (63 paroxysmal and 20 persistent) who underwent CA for AF were included in this study. All patients assessed their endothelial function by the reactive hyperemia-peripheral arterial tonometry (RH-PAT) and the RH-PAT index (RHI) was measured before and 6 months after CA. To evaluate the relation of between AF and the endothelial function, the correlation between RHI and clinical variables were assessed by the univariate and multivariate linear regression analysis before CA. Then, the change in the RHI following CA was compared between patients with and without recurrence of AF.   Results:  Before CA, 66 patients showed sinus rhythm and 17 patients showed AF. RHI in sinus rhythm was significantly higher than that in AF (1.93±0.44 vs. 1.59±0.18, p   Conclusion:  The presence of AF was independently correlated with the impaired endothelial function. Long-term sinus rhythm restoration by CA of AF resulted in the improvement of endothelial function, whereas recurrence of AF caused an endothelial dysfunction.
Intestinal Phospholipid Remodeling Is Required for Dietary-Lipid Uptake and Survival on a High-Fat Diet
Authors: Bo Wang, Xin Rong, Mark A. Duerr, Daniel J. Hermanson, Per Niklas Hedde, Jinny S. Wong, Thomas Q. de Aguiar Vallim, Benjamin F. Cravatt, Enrico Gratton, David A. Ford, Peter Tontonoz
Journal: Cell Metabolism (2016)
Comparing patients’ and their partners’ preferences for adjuvant chemotherapy (ACT) in early breast cancer (EBC)
Authors: V. Duric, M. R. Stockler, P. Butow, L. Sharpe, S. Heritier, J. Beith, F. Boyle, N. Wilcken, A. Coates, R. J. Simes
Journal: Journal of Clinical Oncology (2005)

6074 Background: Cancer patients are encouraged to include their partners in making decisions about treatment. We compared the preferences of women who had ACT for EBC with those of their partners. Methods: 46 women and their partners were interviewed separately, 3–34 months after ACT. Preferences were elicited using validated, hypothetical trade-off scenarios based on known survival times (5 and 15 yrs) and rates (65% and 85% at 5 yrs) with and without ACT. Differences within couples were assessed with Wilcoxon’s test for related samples. Agreement within couples was assessed with the intraclass correlation coefficient (ICC) and the proportions agreeing exactly and approximately (within 1 year or 3%). Associations between baseline characteristics and preferences were assessed with linear regression after normal score transformation and logistic regression. Results: The women’s mean age (range) was 55 (25–73) and the partners’ was 60 (40–74). Half the women were employed (57%), tertiary educated (48%) and had dependent children (50%); most couples were married (91%). Plausible survival benefits (an extra 1 year in times or 3% in rates) were judged sufficient to make ACT worthwhile by most patients (83–87%) and partners (63–89%). Patients required smaller benefits sufficient than their partners when expressed as rates (p=0.01 & 0.02), but not times (p=0.3 & 0.6). Negligible benefits (an extra 1 day or 0.1%) were judged sufficient by 59–65% of patients and 54–59% of partners. Reasons given for judging negligible benefits sufficient included: minimising regret; parenting concerns; doubts about information; and, feeling they had no choice. Agreement was exact for 35–41% of couples and approximate for 59–83%. Agreement was better for scenarios with a bad prognosis (ICC 0.67 & 0.35) than for scenarios with a good prognosis (ICC 0.13 & 0.05). Having dependent children made partners require larger benefits but patients require smaller benefits (interaction p=0.001). Conclusions: Partners may be unreliable surrogates for decision making about ACT, especially for couples with dependent children. Direct benefits and harms are not the only factors influencing patients’ and partners’ preferences for ACT. No significant financial relationships to disclose.
Dabigatran Etexilate and Risk Of Myocardial Infarction, Major Bleeding and All-Cause Mortality: A Systematic Review and Meta-Analysis Of Randomized Controlled Trials
Authors: Jonathan Douxfils, Fanny Buckinx, François Mullier, Valentine Minet, Véronique Rabenda, Jean-Yves Reginster, Christian Chatelain, Philippe Hainaut, Olivier Bruyère, Jean-Michel Dogné
Journal: Blood (2013)
Abstract B1-18: Integrative analysis of gene expression and metabolism in isocitrate dehydrogenase 1 mutant acute myeloid leukemia and myeloid knock in mouse model
Authors: Alan Tseng, Wanda Li, Kim-Chung Lee, Karrie Yung, Ching-Wan Lam, Tak Mak
Journal: Cancer Research (2015)

Abstract Isocitrate dehydrogenase 1 (IDH1) mutations are common drivers of acute myeloid leukemia (AML). While mutant IDH1 is known to disrupt DNA methylation, gene expression, and metabolism in cell lines, it is not known how mutant IDH1 alters global metabolism in vivo. The purpose of this study is to find differential enzymes and metabolites in IDH1 wild type versus mutant AML and knock in mice by integrating differential genes and metabolites in a metabolic network. Differential genes were found by comparing gene expression and DNA methylation in IDH1 mutant (n = 12) and wild type (n = 89) cytogenetically normal AML patients from The Cancer Genome Atlas. Differential metabolites were found by untargeted liquid chromatography-mass spectrometry of urine, plasma, and bone marrow hematopoietic stem and progenitor cells from unpaired 1-2 year old mixed-sex IDH1 myeloid knock in (n = 13) and control mice (n = 14). Integrative analysis was performed using the MetScape 2 Cytoscape plugin. 71 differential genes and 52 differential metabolites were mapped to the global metabolic network. The set of differential genes and metabolites formed 10 connected subnetworks containing reactions in sphingolipid, phospholipid, and bile acid metabolism. Two enzymes in the subnetworks were differentially expressed in an independent IDH1 mutant versus wild type AML dataset: acyl-CoA thioesterase 4 (ACOT4) and galactosylceramidase (GALC) (P &amp;lt; 0.05, false discovery rate ≤ 0.3). ACOT4 and GALC were significantly upregulated (P &amp;lt; 0.02) in acute promyelocytic leukemia cells treated with all-trans retinoic acid. In conclusion, we have found novel differential genes and metabolites in IDH1 mutant systems which may be relevant to leukemia differentiation treatment. Integrative analysis of gene expression and metabolite levels could be useful for finding dysregulated metabolic subnetworks in cancer. Citation Format: Alan Tseng, Wanda Li, Kim-Chung Lee, Karrie Yung, Ching-Wan Lam, Tak Mak. Integrative analysis of gene expression and metabolism in isocitrate dehydrogenase 1 mutant acute myeloid leukemia and myeloid knock in mouse model. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-18.
A pilot study of protracted venous infusion of 5-fluorouracil and concomitant radiation therapy.
Authors: T A Rich, J J Lokich, J T Chaffey
Journal: Journal of Clinical Oncology (1985)

A method to potentially increase the effectiveness of combination 5-fluorouracil (5-FU) and radiation therapy (XRT) using protracted (more than 30 days) venous infusion (PVI) of 5-FU with conventionally fractionated XRT (180 to 200 cGy per day) (100 cGy = 100 rad) is described. Forty-one patients were treated with this combination with acceptable acute toxicity. In 95% of patients, the toxicity was mild or moderate and symptom control was achieved with medications or a short treatment interruption. In two patients (5%), severe gastrointestinal side effects resulted in cessation of all therapy. This method of administration of 5-FU is feasible, and we have demonstrated that it can be safely used with a course of conventionally fractionated, high-dose (approximately to 6,500 cGy) radiation therapy.
Evolutionary Transition of Promoter and Gene Body DNA Methylation across Invertebrate–Vertebrate Boundary
Authors: Thomas E. Keller, Priscilla Han, Soojin V. Yi
Journal: Molecular Biology and Evolution (2015)

Genomes of invertebrates and vertebrates exhibit highly divergent patterns of DNA methylation. Invertebrate genomes tend to be sparsely methylated, and DNA methylation is mostly targeted to a subset of transcription units (gene bodies). In a drastic contrast, vertebrate genomes are generally globally and heavily methylated, punctuated by the limited local hypo-methylation of putative regulatory regions such as promoters. These genomic differences also translate into functional differences in DNA methylation and gene regulation. Although promoter DNA methylation is an important regulatory component of vertebrate gene expression, its role in invertebrate gene regulation has been little explored. Instead, gene body DNA methylation is associated with expression of invertebrate genes. However, the evolutionary steps leading to the differentiation of invertebrate and vertebrate genomic DNA methylation remain unresolved. Here we analyzed experimentally determined DNA methylation maps of several species across the invertebrate-vertebrate boundary, to elucidate how vertebrate gene methylation has evolved. We show that, in contrast to the prevailing idea, a substantial number of promoters in an invertebrate basal chordate Ciona intestinalis are methylated. Moreover, gene expression data indicate significant, epigenomic context-dependent associations between promoter methylation and expression in C. intestinalis. However, there is no evidence that promoter methylation in invertebrate chordate has been evolutionarily maintained across the invertebrate-vertebrate boundary. Rather, body-methylated invertebrate genes preferentially obtain hypo-methylated promoters among vertebrates. Conversely, promoter methylation is preferentially found in lineage- and tissue-specific vertebrate genes. These results provide important insights into the evolutionary origin of epigenetic regulation of vertebrate gene expression.
Bevacizumab and albumin-bound paclitaxel treatment in metastatic breast cancer
Authors: J. S. Link, J. R. Waisman, B. Nguyen, C. I. Jacobs
Journal: Journal of Clinical Oncology (2007)

1101 Background: Miller, et al demonstrated the combination of bevacizumab and paclitaxel has significant activity in metastatic breast cancer. Because paclitaxel albumin bound (PAB) has been shown to have less toxicity, a better tumor delivery and possibly better response for metastatic breast cancer, we combined it with bevacizumab (B) to treat women with metastatic breast cancer. Methods: This is a retrospective analysis. Billing records from March 2005 through December 2006 were reviewed to obtain all patients treated consecutively with a combination of PAB (80–125mg/m 2 days 1,8,15 or 170–200 mg/m 2 every 14 days on a 28 day cycle) and B (10mg/kg every 14 days). A total of 40 women were identified. A minimum of two courses were given. All women had received a minimum of 3 prior chemotherapy regimens including anthracyclines 34/40 and taxanes 35/40. Patients were monitored for response using RECIST criteria based on PE, and PET/CT imaging. Six women with bone only disease were monitored with PET, CT/MRI and tumor markers. All response data were confirmed by independent review. Results: 20 women had objective responses to the PAB/B regimen (3CRs and 17PRs) for an overall response rate of 50%. Another seven women had stable disease (SD) for a mean duration of 212 days. Thirteen women progressed. The mean time to progression for the responders was 132 days. Toxicity was acceptable with fatigue (9 gr 2), neuropathy (4 gr 2, 1 gr 3), anemia (2 gr 2, 2 gr 3), and hypertension (3 gr 2) being the most common complaints. Two patients were discontinued due to a possible CNS hemorrhage into a metastatic brain lesion. There were no other treatment discontinuations due to non-tolerance Conclusions: In our limited series of consecutive woman with advanced, heavily pretreated metastatic breast cancer treated with PAB (Abraxane) and bevacizumab (Avastin), we saw a 50% objective response rate (3CR, 17PR). The regimen was well tolerated with acceptable toxicity. Another seven women had stable disease for an average duration of &gt;200days giving an objective response rate + SD of 67%. No significant financial relationships to disclose.
Improving asthma discharge through staff engagement and patient participation using the patient and family centred care technique
Authors: Hesham Abdalla, Caroline Whyte, Emma Hughes
Journal: European Respiratory Journal (2014)

Introduction 

Annual BTS asthma audits have shown persistently poor concordance with evidence-based guidelines to asthma discharge- consistent with national figures of 40% .

Aims 

1. Deliver consistent, evidence-based discharge

2. Empower patients to manage their asthma

Objectives 

80% of asthmatics arriving on the Paediatric Assessment Unit in Walsall, by October 2013 will receive all of an evidenced discharge bundle.

Methodology 

Using the Patient and Family Centred Care technique and with the support of the Kings Fund, we used the following to understand patient and staff experience. Drivers for excellence were identified and projects developed to work on these drivers.

•Staff engagement 

Team days to generate ideas and enthusiasm.

•Staff questionnaires 

Systematic data collection about staff thoughts and feelings

•Patient Shadowing 

Observation of the patients' journey by staff

•Patient questionnaires 

Asking patients systematically about their care

Results 

We have surpassed our target, with 95% of patients consistently receiving the discharge bundle, as shown below:

![Figure][1] 



Families now give consistently excellent feedback:

The department has exceeded our expectations 

I am very happy to look after my daughter now 

Moreover, staff are enthused and take great pride in their environment, initiating further improvements. Six are now studying an asthma diploma.

 [1]: pending:yes
Genomic Profiling of Penile Squamous Cell Carcinoma Reveals New Opportunities for Targeted Therapy
Authors: Andrew S. McDaniel, Daniel H. Hovelson, Andi K. Cani, Chia-Jen Liu, Yali Zhai, Yajia Zhang, Alon Z. Weizer, Rohit Mehra, Felix Y. Feng, Ajjai S. Alva, Todd M. Morgan, Jeffrey S. Montgomery, Javed Siddiqui, Seth Sadis, Santhoshi Bandla, Paul D. Williams, Kathleen R. Cho, Daniel R. Rhodes, Scott A. Tomlins
Journal: Cancer Research (2015)

Abstract Penile squamous cell carcinoma (PeSCCA) is a rare malignancy for which there are limited treatment options due to a poor understanding of the molecular alterations underlying disease development and progression. Therefore, we performed comprehensive, targeted next-generation sequencing to identify relevant somatic genomic alterations in a retrospective cohort of 60 fixed tumor samples from 43 PeSCCA cases (including 14 matched primary/metastasis pairs). We identified a median of two relevant somatic mutations and one high-level copy-number alteration per sample (range, 0–5 and 0–6, respectively). Expression of HPV and p16 was detectable in 12% and 28% of patients, respectively. Furthermore, advanced clinical stage, lack of p16 expression, and MYC and CCND1 amplifications were significantly associated with shorter time to progression or PeSCCA-specific survival. Notably, four cases harbored EGFR amplifications and one demonstrated CDK4 amplification, genes for which approved and investigational targeted therapies are available. Importantly, although paired primary tumors and lymph node metastases were largely homogeneous for relevant somatic mutations, we identified heterogeneous EGFR amplification in primary tumor/lymph node metastases in 4 of 14 cases, despite uniform EGFR protein overexpression. Likewise, activating HRAS mutations occurred in 8 of 43 cases. Taken together, we provide the first comprehensive molecular PeSCCA analysis, which offers new insight into potential precision medicine approaches for this disease, including strategies targeting EGFR. Cancer Res; 75(24); 5219–27. ©2015 AACR.