bluuebunny/crossref_metadata_2025_split huggingface dataset:
caPeptides: Selectively targeting caPCNA and sensitizing gemcitabine in pancreatic cancer cells
Authors: Shen Fei , Hickey Robert J. , Malkas Linda H. , Kamran Jasmine 
Published: May 2015

Abstract
caPeptides that block the functions of caPCNA, cancer associated proliferating cell nuclear antigen in malignant cells has been developed by our laboratory and showed promising anti-cancer therapeutic activities. Previously, we have identified caPCNA, an acidic isoform of PCNA that presents in various cancer cells and appears to be associated, at least in part, with malignant transformation of cells. Since PCNA is involved in DNA replication and repair in prokaryote and eukaryote cells, we hypothesize that caPCNA is likely to perform similar functions specifically in cancer cells. Antibodies developed against caPCNA showed the inhibition of DNA replication in cancer cells. The investigation of the interaction of caPCNA with its binding partners including flap structure-specific endonuclease 1(Fen-1) and xeroderma pimentosum complementation group G (XPG) has led us to identify an amino acid domain sequence that confers the cancer cell specificity of caPCNA. We synthesized caPeptides, small caPCNA related peptides derived from this sequence to promote cancer cell cytotoxicity. caPeptides have the potential ability to compete with several cellular proteins that participate in DNA replication, repair, cell cycle control, transcription, and chromosomal recombination for their naturally occurring binding site on caPCNA and block binding of full length caPCNA to these proteins. The disruption of the interaction between caPCNA and its binding proteins prevents cancer cellular functions (vital cellular machinery) that recruit caPCNA and therefore may lead caPeptides to be cytotoxic by themselves or in combination with cancer chemotherapeutic drugs. Our results demonstrated that these peptides were cytotoxic to pancreatic cancer cells and more significantly they rendered resistant pancreatic cells to be 10-fold more sensitive to gemcitabine, a standard clinical chemotherapeutic agent for treating pancreatic cancer patients. Considering that pancreatic cancer is well known for its high mortality rate due to its chemotherapy ineffectiveness and resistances to gemcitabine our studies render further investigations on the anti-neoplastic action and mechanisms of the peptides in pancreatic cancer.
Creating value: The power of molecular diagnostic tests
Authors: Neff Deborah J. 
Published: May 2015

Abstract
The talk will review the real world example of how Pathwork Diagnostics approached both technical and commercial challenges during the development and launch of a new molecular diagnostic. Our technical challenges were to create a mechanism for handling large sets of gene expression data, to accurately answer complex clinical questions and to maintain robust performance levels appropriate for a clinical diagnostic test. Our commercial challenges were centered around the appropriate selection of our regulatory path and market channels, and how to drive adoption and reimbursement. We will discuss the resulting successful launch of the Pathwork ®Tissue of Origin Test and the clinical utility evidence that demonstrates the positive impact of this molecular diagnostic test on patient care and outcome.
Molecular characterization of cancer: Research tools or clinical diagnostics?
Authors: Wang Yixin 
Published: May 2015

Abstract
The recent advent of technologies has revealed a wealth of information about molecular processes and pathways that can be applied to the understanding of cancer. Use of PCR, microarray, and circulating cell-based technologies provide oncologists with new methods to determine appropriate treatments and assess response to therapy. Improvements in analytical methods have allowed researchers to interrogate biomarkers in clinically relevant specimens such as formalin-fixed, paraffin-embedded (FFPE) tissue, biopsies, bone barrow, urine and circulating tumor cells in blood. Our research has been focusing on the application of molecular technologies to support clinical decision-making and patient management. We have demonstrated that molecular assays on either tumor tissue or CTCs can enable a more accurate analysis of a patient's diseases and the response to a particular therapy. This presentation will review some of the opportunities and challenges facing assay development in molecular diagnostics. A couple of examples from OCD, Johnson & Johnson that aimed to develop molecular tests for therapeutic decisions will be discussed.
Transcriptomics from single cells
Authors: Grindberg Rashel , Lasken Roger S. 
Published: May 2015

Abstract
New technologies are making it possible to measure gene expression from single cells. Reverse transcriptase is used to convert the few picograms of mRNA in a cell to cDNA. Next generation sequencing methods, such as SOLiD sequencing, provide a low cost means to sequence the cDNA allowing quantification as well as genotyping. Unlike RT-PCR which enables single cell measurement of one or a limited number of transcripts, the entire transcriptome can be accessed. It will be possible to discover new correlations between genes and their role in diseases. We have begun testing this method on a variety of cell types including cultured cancer cells and human stem cells. Methods are in development to test circulating cancer cells. Progress has also been made on a different technology that addresses genotyping of the genomic DNA from one cell. Whole genome amplification by a method called Multiple Displacement Amplification (MDA) provides sufficient DNA for use in sequencing and genotyping. This enables analysis of unexpressed regions of the genome which are lost in transcriptional studies. Together, single cell methods for transcriptomics and genotyping of the genomic DNA will be useful in studying disease processes at the level of the individual cell. It will be possible to isolated specific cell types based on their phenotypic characteristics and then determine their genetic and transcriptional signatures.
Cancer research in Asia: Challenges and opportunities
Authors: Wong John E.L. 
Published: May 2015

Abstract
Cancer is a leading cause of death in Asia, and within the next 20 years, Asia will bear more than half of the world's cancer burden. In Singapore, cancer represents the largest recipient of funding for biomedical research and the leading therapeutic area for clinical trials. Clinical trials should be conducted in Asia for a number of important reasons. First, the phenotypic expression of certain cancers is different between Asia and the West. A commonly cited difference is in non-small cell lung cancer, where the high expression of a mutated epidermal growth factor receptor (EGFR) in nonsmoking Asians, especially women, confers on them a greater sensitivity to EGFR tyrosine kinase inhibitors, e.g. gefitinib and erlotinib. This has led to a change in the management of first line non-small cell lung cancer, with mutation positive patients benefitting from gefitinib more than paclitaxel and carboplatin as first line treatment (NEJM 2009; 361(10): 947-57). The metabolism of certain common cytotoxic drugs, such as doxorubicin, is affected by genotypes that are different in Chinese and Malay populations, compared to Indian and Caucasian populations, leading to differences in toxicities and thus possibly dosages (Pharmacogenetics and Genomics 2008, 18:621—629). Asia has well-trained doctors and scientists who can provide yet another site to accelerate drug development. Singapore was the site of the first-in-world trial of linifanib, a highly active oral inhibitor of vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF). It has moved from phase I to phase III testing in 3 years and has shown promising activity in several common cancers (J Clin Oncol 2009; 27:4718-4726). Asia's economic growth and increasingly educated population has led to a demand for cancer care as well as the means to afford it. Asia is also one of the fastest growing markets for the pharmaceutical industry. For these reasons, universities and research institutes in Asia have formed centers of excellence to complement those in the West.
Blazing the pharmacologic audit trail: Pharmacodynamic biomarkers in early drug development
Authors: Takimoto Chris H. 
Published: May 2015

Abstract
Pharmacodynamic (PD) biomarkers of drug action are common components of early clinical trials in oncology. However, how to optimally apply biomarker endpoints to rationale decision making is less clear cut. As a consequence, many biomarker programs represent expensive scientific investments in drug development infrastructure yielding little or no practical advantage at the end of the day. The Pharmacologic Audit Trail (PhAT), first proposed by Workman and colleagues, represents a well designed strategic paradigm for the rationale incorporation of PD and mechanism of action biomarkers into early drug development. The PhAT is comprised of a series of key questions addressed sequentially in early clinical trials to assess the pharmacological behavior of an experimental agent. It includes evaluation of target expression, pharmacokinetics, pharmacodynamics, target engagement, pathway modulation, biological effects and, ultimately, clinical activity in early clinical trials. This approach promotes rigorous scientific evaluation and rational decision making in early oncology drug development, culminating in the demonstration of proof of concept. However, success application of this process requires a substantial investment in target evaluation and in vivo preclinical studies. A detailed discussion of the PhAT and its application to the early drug development in oncology therapeutics will be described.
Exome sequencing of multiple metastases from a lethal prostate cancer reveals BRCA1 deficiency and additional somatic alterations which suggest alternate therapeutic options
Authors: Nickerson Michael L. , Im Kate McGee , Dean Michael , Bova G. Steven 
Published: May 2015

Abstract
Exome libraries were prepared from five metastatic tumors and healthy tissue from an Ashkenazi Jewish man who died from metastatic prostate cancer. A total of 6.77 × 109 bases were sequenced using a 454 FLX. Germline alteration and somatic loss of heterozygosity of the BRCA1 tumor suppressor gene were observed. Novel, somatic variants in the catalytic domain of two kinases and alteration of two oncogenes were also potential drivers of this cancer. We identified an insertion in the TMPRSS2 gene in addition to fusion with ERG. Alteration of several signaling pathways was predicted as a result of a surprising combination of germline and somatic alterations. Clonal as well as subclonal variants were identified that allow a ‘natural history’ of this individual's cancer to be described. Several alterations, including BRCA1 loss, suggest therapeutic options that may have been effective in this patient.
This talk is also presented as Poster B17.
From network to hierarchy: the evolution of the Estonian senior civil service development system
Authors: Randma-Liiv Tiina , Uudelepp Annika , Sarapuu Külli 
Published: May 2015

The aim of this article is to explore the opportunities for and constraints of the establishment of a central coordination instrument in a highly fragmented central government. The article is based on a case study which examines the creation of a development system for Estonian senior civil servants. It describes and explains shifts in the coordination mechanisms within this initiative over the last decade. The study concludes that networks may offer an alternative to hierarchy for the creation of new coordination practices in fragmented administrative systems. However, networks may prove to be insufficient and require further institutionalization and formalization through the inclusion of hierarchical elements once the coordination instrument matures. The study also shows that the funding arrangements may trigger a shift in basic coordination mechanisms. It is therefore suggested that future research should systematically examine funding practices as an integral part of coordination arrangements. Points for practitioners This article shows how civil servants can launch a major coordination initiative without the input of the legislator, and build a governmental ‘island of excellence’ with the help of the EU’s structural funds. The establishment of a sound basis for the initiative in the form of a competency model and subsequently an assessment system was crucial in the evolvement of the senior civil service development system in Estonia. Constant learning and the gradual winning of the target group’s trust and support laid the groundwork for institutionalizing a coordination instrument initially designed to operate on a voluntary basis. The article also shows how addressing one coordination problem may raise new issues of accountability, sustainability and coordination.
Focus on participation for children and youth with disabilities: Supporting therapy practice through a guided knowledge translation process
Authors: Anaby Dana , Korner-Bitensky Nicol , Law Mary , Cormier Isabelle 
Published: May 2015

Introduction Participation in community leisure occupations of children with disabilities is important, yet poorly integrated into practice. This knowledge translation strategy tested an intervention to increase clinicians' awareness and to bring about change in practice toward a focus on participation. Method During this qualitative study, 14 clinicians participated in six learning sessions facilitated by a knowledge broker. Three months post-intervention, clinicians were individually interviewed, by drawing on the Professional Evaluation and Reflection on Change Tool, to evaluate potential change in practice. Two researchers independently performed thematic data analysis. Results Impact on practice emerged in both the personal and professional levels (for example, empowerment, validation of clinical wisdom, change in thinking and behavior). Clinicians suggested strategies for integrating participation in their day-to-day practice, illustrating a substantial intention for change, while describing barriers and facilitators for implementation (for example, organizational mandate). Two additional themes described the overall experience of the intervention: motivation to learn (for example, desire to link research to practice) and elements of the learning environment (for example, meeting informational needs). Conclusion This strategy was effective in redirecting clinicians' focus toward the notion of participation and establishing readiness for change. This shift can potentially facilitate new programs in occupational therapy that are participation-based and community-focused.
Toward a pragmatic migraine model for drug testing: 1. Cilostazol in healthy volunteers
Authors: Hansen Emma Katrine , Guo Song , Ashina Messoud , Olesen Jes 
Published: May 2015

Background A model for the testing of novel antimigraine drugs should ideally use healthy volunteers for ease of recruiting. Cilostazol provokes headache in healthy volunteers with some migraine features such as pulsating pain quality and aggravation by physical activity. Therefore, this headache might respond to sumatriptan, a requirement for validation. The hypothesis of the present study was that sumatriptan but not placebo is effective in cilostazol-induced headache in healthy individuals. Methods In a double-blind, randomized, cross-over design, 30 healthy volunteers of both sexes received cilostazol 200 mg on two separate days, each day followed by oral self-administered placebo or sumatriptan 50 mg. Headache response and accompanying symptoms were registered in a questionnaire by the participants themselves. Results Cilostazol induced a reproducible headache in 90% of the participants. The headache had several migraine-like features in most individuals. Median peak headache score was 2 on the sumatriptan day and 3 on the placebo day ( p = 0.17). There was no reduction in headache intensity two hours after sumatriptan ( p = 0.97) and difference in AUC 0 to four hours between two experimental days was not significant ( p = 0.18). On the placebo day eight participants took rescue medication compared to 3 on the sumatriptan day ( p = 0.13). Conclusion Despite similarities with migraine headache, cilostazol-induced headache in healthy volunteers does not respond to sumatriptan.
China Angioplasty and Stenting for Symptomatic Intracranial Severe Stenosis (CASSISS): A new, prospective, multicenter, randomized controlled trial in China
Authors: Gao Peng , Zhao Zhenwei , Wang Daming , Wu Jian , Cai Yiling , Li Tianxiao , Wu Wei , Shi Huaizhang , He Weiwen , Zhu Fengshui , Jiao Liqun , Ling Feng 
Published: May 2015

Background Patients with symptomatic stenosis of intradural arteries are at high risk for subsequent stroke. Since the SAMMPRIS trial, stenting is no longer recommended as primary treatment; however, the results of this trial, its inclusion criteria and its center selection received significant criticism and did not appear to reflect our experience regarding natural history nor treatment complications rate. As intracranial atherosclerosis (ICAS) is the most common cause for stroke in Asian countries, we are hereby proposing a refined prospective, randomized, multicenter study in an Asian population with strictly defined patient and participating center inclusion criteria. Methods The China Angioplasty and Stenting for Symptomatic Intracranial Severe Stenosis (CASSISS) trial is an ongoing, government-funded, prospective, multicenter, randomized trial. It recruits patients with recent TIA or stroke caused by 70%–99% stenosis of a major intracranial artery. Patients with previous stroke related to perforator ischemia will not be included. Only high-volume centers with a proven track record will enroll patients as determined by a lead-in phase. Patients will be randomized (1:1) to best medical therapy alone or medical therapy plus stenting. Primary endpoints are any stroke or death within 30 days after enrollment or after any revascularization procedure of the qualifying lesion during follow-up, or stroke in the territory of the symptomatic intracranial artery beyond 30 days. The CASSISS trial will be conducted in eight sites in China with core imaging lab review at a North American site and aims to have a sample size of 380 participants (stenting, 190; medical therapy, 190). Recruitment is expected to be finished by December 2016. Patients will be followed for at least three years. The trial is scheduled to complete in 2019. Conclusion In the proposed trial, certain shortcomings of SAMMPRIS including patient and participating center selection will be addressed. The present manuscript outlines the rationale and design of the study. We estimate that this trial will allow for a critical reappraisal of the role of intracranial stenting for selected patients in high-volume centers.
MDMA for the treatment of mood disorder: all talk no substance?
Authors: Patel Rachel , Titheradge Daniel 
Published: May 2015

Background: Unipolar depression is the third highest contributor to the global burden of disease, yet current pharmacotherapies typically take about 6 weeks to have an effect. A rapid-onset agent is an attractive prospect, not only to alleviate symptoms before first-line antidepressants display therapeutic action, but as a further treatment option in nonresponsive cases. It has been suggested that 3,4-methylene-dioxymethamphetamine (MDMA) could play a part in the treatment of depression, either as a rapid-onset pharmacological agent or as an adjunct to psychotherapy. Whilst these hypotheses are in keeping with the monoamine theory of depression and the principles surrounding psychotherapy, explicit experimental evidence of an antidepressant effect of MDMA has rarely been established. Aims: To address the hypothesis surrounding MDMA as a rapid-onset antidepressant by examining pharmacological, psychological and behavioural studies. We consider whether this therapy could be safe by looking at the translation of neurotoxicity data from animals to humans. Method: A literature review of the evidence supporting this hypothesis was performed. Conclusions: The pharmacology of MDMA offers a promising target as a rapid-onset agent and MDMA is currently being investigated for use in psychotherapy in anxiety disorders; translation from these studies for use in depression may be possible. However, experimental evidence and safety analysis are insufficient to confirm or reject this theory at present.
The Effect of Intra-articular Corticosteroids on Articular Cartilage
Authors: Wernecke Chloe , Braun Hillary J. , Dragoo Jason L. 
Published: May 2015

Background: Intra-articular (IA) corticosteroid therapy has been used for the treatment of inflammation and pain in the knee since the 1950s. Purpose: To review the current literature on the effects of IA corticosteroids on articular cartilage. Study Design: Systematic review. Methods: A MEDLINE and SCOPUS database search was performed, and studies were selected for basic science and clinical trial research on corticosteroids with direct outcome measures of cartilage health. Preliminary searches yielded 1929 articles, and final analysis includes 40 studies. Results: Methylprednisolone, dexamethasone, hydrocortisone, betamethasone, prednisolone, and triamcinolone were reported to display dose-dependent deleterious effects on cartilage morphology, histology, and viability in both in vitro and in vivo models. The beneficial animal in vivo effects of methylprednisolone, hydrocortisone, and triamcinolone occurred at low doses (usually <2-3 mg/dose or 8-12 mg/cumulative total dose in vivo), at which increased cell growth and recovery from damage was observed; the single human clinical trial indicated a beneficial effect of triamcinolone. However, at higher doses (>3 mg/dose or 18-24 mg/cumulative total dose in vivo), corticosteroids were associated with significant gross cartilage damage and chondrocyte toxicity. Dose and time dependency of corticosteroid chondrotoxicity was supported in the in vitro results, however, without clear dose thresholds. Conclusion: Corticosteroids have a time- and dose-dependent effect on articular cartilage, with beneficial effects occurring at low doses and durations and detrimental effects at high doses and durations. Clinically, beneficial effects are supported for IA administration, but the lowest efficacious dose should be used.
Effects of deferasirox-deferoxamine on myocardial and liver iron in patients with severe transfusional iron overload
Authors: Aydinok Yesim , Kattamis Antonis , Cappellini M. Domenica , El-Beshlawy Amal , Origa Raffaella , Elalfy Mohsen , Kilinç Yurdanur , Perrotta Silverio , Karakas Zeynep , Viprakasit Vip , Habr Dany , Constantinovici Niculae , Shen Junwu , Porter John B. 
Published: May 2015

Key Points
DFX-DFO combination followed by DFX monotherapy led to a meaningful decrease in myocardial and liver iron in severe siderosis patients. Substantial liver iron reduction may be helpful in patients needing rapid control of liver iron (eg, pretransplant or planned pregnancy).
Genetic variants in the ADAMTS13 and SUPT3H genes are associated with ADAMTS13 activity
Authors: de Vries Paul S. , Boender Johan , Sonneveld Michelle A. H. , Rivadeneira Fernando , Ikram M. Arfan , Rottensteiner Hanspeter , Hofman Albert , Uitterlinden André G. , Leebeek Frank W. G. , Franco Oscar H. , Dehghan Abbas , de Maat Moniek P. M. 
Published: May 2015

Key Points
We identify rs41314453 as the strongest genetic predictor of ADAMTS13 activity, associated with a decrease of >20%. We present evidence of further independent associations with a common variant in SUPT3H, as well as 5 variants at the ADAMTS13 locus.