bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting cancer with cys-diabody conjugated polymerized liposomal nanoparticles (PLNs)
Authors: Girgis Mark D. , McCabe Katelyn , Federman Noah , Wu Anna M. , Denny Christopher , Denny Christopher , Tomlinson James S.
Published: May 2015

Background: Polymerized liposomal nanoparticles (PLNs) are a promising new technology for delivery of chemotherapeutic drugs to cancer cells. They are easy to prepare, biocompatible, and can carry a wide variety of therapeutics. Additionally, PLNs have the potential to be conjugated to a tumor targeting agent in hopes of delivering a cytotoxic payload directly to the cancer cells, thus minimizing systemic toxicity. Cys-diabodies are the smallest tumor antibody fragment (55 Kd) that retain the bivalency of an intact antibody. The goal of this study was to determine our ability to conjugate various engineered cys-diabody fragments to PLNs and to evaluate the ability to specifically target tumor cells based on the specificity of the diabody-tumor antigen interaction.

Methods: Cys-diabody constructs against tumor antigens (ALCAM, HER2/neu, Ca19.9) were engineered, expressed in NSO myeloma cells and purified using HPLC. A cysteine residue was inserted at the C-terminus to provide the free sulhydryl group necessary for the conjugation reaction. Using malemide chemistry, cys-diabodies were conjugated to PLNs. Immunofluorescence and flow cytometry were performed to evaluate targeting of conjugated PLNs to human pancreatic and breast cancer cell lines. Unconjugated PLNs and tumor antigen negative cell lines were used as controls.

Results: Anti-HER2/neu, ALCAM, and CA19.9 cys-diabodies were characterized by flow cytometry showing specific binding to MCF7 (HER2/neu positive), HPAF (ALCAM positive), and BxPC3 (CA19.9 positive) cell lines, respectively. No binding was observed to antigen-negative cell lines nor with the unconjugated PLNs. Conjugation of cys-diabodies to PLNs was indicated by immunofluorescence showing specific binding of PLN-cys-diabody conjugates to breast and pancreatic cancer cells in vitro (Figure 1). These data were also confirmed by flow cytometry.

Conclusions: We have demonstrated the ability to conjugate our PLN with engineered anti-tumor cys-diabodies. Furthermore, we have demonstrated that after conjugation, the PLNs demonstrate specific tumor-cell targeting based on the specificity of the diabody-tumor antigen affinity. These studies represent an important first step in the development of targeted PLNs with the ultimate goal of delivering high doses of a chemotherapeutic directly to the cancer cells.
Comparison of PTEN protein loss and PI3K gene mutation status in breast cancer
Authors: Gelb Arnold B. , Deng Lynn , Freeman Vicki A. , Astrow Stephanie H.
Published: May 2015

Background: The phosphatidylinositol 3-kinase (PI3K) family of enzymes plays key roles in the transduction of cell signals, and several inhibitors of this pathway are currently in clinical development for the treatment of breast and other cancers. PI3K signaling is activated by growth factor receptors and regulated and terminated by multiple factors including dephosphorylation of the 3′ phosphate of PIP3 by the phosphatase PTEN. Reduced PTEN expression in breast cancer confers susceptibility to inhibitors of the PI3 kinase/Akt pathway. In a subset of breast cancer cases, PTEN protein has been found to be expressed at lower levels (e.g., as compared with normal breast epithelium), however, human breast cancer cells rarely have PTEN mutations. On the other hand PI3K gene mutations have been found in a majority of breast tumors.

Methods: To examine the relationship between PTEN protein loss and PI3K gene mutation, PTEN immunoreactivity was assessed semi-quantitatively using histoscores in freshly-cut sections of paraffin blocks from 26 anonymized breast cancer specimens. Sections from the same tumor blocks were used for PI3K mutation detection. One H&E-stained section was used to mark the area of tumor and 2-4 additional unstained sections were macrodissected to enrich for tumor cells, which then underwent DNA extraction. The DNA was analyzed with a commercial PI3K mutation test kit (DxS PI3K Mutation Test Kit, Manchester, UK) that detects 4 somatic mutations in exons 9 and 20 of PIK3CA in three discrete mutation groups or “buckets.”

Results: Of the 26 breast cancer specimens examined, 7 (27%) had absence of PTEN protein expression (histoscore=0) and an additional 4 (15%) had a reduction in PTEN expression (histoscore>0 to <50), with positive internal controls. PI3K mutations were detected in 8 (31%) of the 26 breast cancer specimens examined. Of the mutations detected, there were 4 (15%) mutations of H1047R (3140 A>G), 1 (4%) of E542K (1624 G>A), and 3 (12%) of E545D (1635 G>T) or E545K (1633 G>A).

Conclusions: There was a statistically significant correlation between PTEN loss (histoscore<50) and the detection of PI3K mutations (Fisher's exact test, 2-tail P=0.003). The percentage of cases with overall PTEN loss in this specimen set was similar to previous reports of PTEN loss in breast tumors. In contrast, another report did not find concomitant PTEN loss and PI3K mutations. However, the investigators evaluated fewer samples, studied HER2 amplified breast cancer specifically, and used a different method (sequencing) to detect mutations. A three-way study that includes HER2 amplification or overexpression may be necessary to explain the discrepancy.
A second-generation microRNA-based assay for diagnosing tumor tissue origin
Authors: Aharonov Ranit , Chajut Ayelet , Spector Yael , Rosenwald Shai , Edmonston Tina B. , Barshack Iris , Feinmesser Meora , Huszar Monica , Mueller Wolf , Fogt Franz , Faerman Alexander , Meiri Eti
Published: May 2015

Background: Cancer of unknown primary (CUP) constitutes 3%~5% of all newly diagnosed cancer cases. It presents a major diagnostic challenge due to the therapeutic implications of the tissue origin of the cancer. Accurate tumor of origin (ToO) assignment could help guide use of specific therapy which may impact survival. MicroRNAs are a family of noncoding, regulatory RNA genes that are involved in development, differentiation and cell cycle and were shown to be involved in oncogenesis. MicroRNAs are highly tissue specific and therefore ideal candidates for CUP diagnosis. We have previously presented a biologically-motivated classification assay to identify the tissue of origin using a set of 48 microRNAs measured on a qRT-PCR platform. This assay can differentiate 25 different tumor types from 17 origins. We present here the development and validation of a second generation assay that can identify 43 different tumor types using a custom array platform. The assay is based on the normalized expression of less than 70 microRNAs. We will present performance data including inter-laboratory concordance from the validation of the assay.

Methods: Over 1200 primary and metastatic tumor FFPE samples were used for the training and development of the next generation assay. High-quality RNA, including the well-preserved microRNA fraction, was extracted from the FFPE blocks using proprietary protocols previously described. Expression levels of all known and additional Rosetta's proprietary microRNAs were profiled using a custom array platform. MicroRNAs containing information about the ToO were identified and two classifiers were developed to utilize the information of the microRNA expression patterns for the diagnosis of ToO. The assay reports a ToO based on these two classifications, where in most cases the assay result is a single ToO reported.

Results: The developed assay is able to accurately identify more than 40 tumor types based on the expression of only several dozens microRNAs. The results of a comprehensive validation study using hundreds of independent tumor and metastases FFPE samples will be presented, including inter-laboratory concordance data.

Conclusions: Previous studies have highlighted the tissue-specificity of microRNA expression, and have demonstrated their potential use for classification of human malignancies. An assay utilizing microRNA expression in a biopsy for identifying the tissue of origin was developed. Here we present the development and the performance of a second generation assay, designed to identify over 40 tumor types. This assay will provide an important new tool for diagnosing tumor tissue origin.
A streamlined, aptamer-based multiplex proteomic assay for diagnostic applications
Authors: Bock Chris , Katilius Evaldas , Keeney Tracy , Kraemer Stephan , Saccomano Nick , Sanders Glenn , Vaught Jonathan , Zichi Dom
Published: May 2015

To enable the application of protein signatures identified in our highly multiplexed biomarker discovery platform to real-world diagnostics, we developed a streamlined, plate-based assay that employs the same principles as the larger SOMAScan assay. The plate-based assay is sensitive (sub-picomolar), robust, rapid, automatable, and can multiplex upwards of 60 analytes. We have used this platform to seamlessly translate sets of biomarkers identified in our SOMAScan assay to a practical non-small cell lung cancer diagnostic.
Gene expression signatures associated with protracted stromal responses to therapeutically relevant cytotoxic stimuli predict breast cancer chemoresponsiveness
Authors: Lee Michael T.-L. , Su Jimmy J.-M. , Li Chi-Rong , Chu Patrick Y.-W. , Liu Ming-Sheng , Chiang Jung-Hsien , Tsai Kelvin K.-C. , Tan Kok-Tong
Published: May 2015

Systemic chemotherapy inflicts cytotoxic injuries on tumor cells and cells in the stromal compartment and their complex interplay may critically affect therapeutic response and outcome. Evidence has shown that gene expression profiles associated with reactive tumor stroma link to prognosis and treatment outcome in breast cancer; however, the specific stromal alterations underlying these associations await further exploration. We here show that breast carcinoma-associated fibroblasts (CAFs) responded to therapeutically relevant magnitudes of cytotoxic stimuli (TRCS) by engaging in a series of cytostatic and pro-death cell programs in a time-dependent manner. By interrogating clinical samples we found a considerable number of CAFs with similar characteristics in the stroma of breast cancer following neoadjuvant chemotherapy (NACT). Profiling the TRCS-induced transcriptomal changes of breast CAFs demonstrated that the genes involved in the protracted (day 3-7) instead of the early (day 1-3) responses were significantly associated with the responsiveness of breast cancer to NACT. To further substantiate this finding we prioritized gene markers and identified a 30-gene chemotherapy-associated stroma signature (CASS) that can predict pathological complete remission (pCR) of breast cancer following NACT with remarkable accuracy (overall accuracy 80%, P < 0.01). The CASS outperformed and complemented standard clinicopathological variables and existing gene expression signatures for the prediction of pCR in several independent data sets. Thus, by exploiting the distinct pathological role of the stromal cytotoxic responses we identified strong and robust predictive markers for the intrinsic chemosensitivity of breast cancer (Supported by NHRI CA-099-PP-19 and Department of Health of Taiwan H99-TD-C-111-004 to KKT).
Navitoclax enhances the activity of taxanes in non-small cell lung carcinoma (NSCLC) models
Authors: Tan Nguyen , Malek Mehnaz , Zha Jiping , Kassees Robert , Berry Leanne , Fairbrother Wayne J. , Sampath Deepak , Belmont Lisa
Published: May 2015

Navitoclax (formerly ABT-263) is a small molecule that potently antagonizes the activity of Bcl-2, Bcl-xL, and Bcl-w. To determine the potential of this molecule in combination with taxane-based chemotherapy, we evaluated a panel of 33 human NSCLC cell lines with a dose matrix of paclitaxel and navitoclax. All cell lines exhibited a greater than additive response to the combination, suggesting a synergistic interaction. These results were extended to mouse xenograft tumor models, in which the combination was more efficacious than either single agent docetaxel or navitoclax. Live cell time-lapse microscopy was used to demonstrate that the addition of navitoclax to paclitaxel decreases the time from mitotic entry to cell death and changes cell fate from mitotic slippage to death during mitotic arrest. The relative levels of Bcl-xL and Mcl-1 correlate with the extent of synergy as measured by a Bliss independence model, suggesting that cancers with high levels of Bcl-xL will be relatively resistant to taxane-based therapy, but could benefit from addition of navitoclax to taxane treatment. Finally, a significant percentage of NSCLC patient samples exhibit high Bcl-xL levels, indicating the potential for broad utility of this combination in lung cancer.
Prostatic acid phosphatase expression in human tissues
Authors: Graddis Thomas J. , McMahan Catherine J. , Tamman Jennifer , Page Keith J. , Trager James B.
Published: May 2015

Introduction: Active cellular immunotherapy seeks to induce tumor-specific immunity in the patient and is consequently dependent on a suitable target tumor antigen. Sipuleucel-T is an autologous cellular immunotherapy that targets prostatic acid phosphatase (PAP), and has demonstrated evidence of survival prolongation in men with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer in randomized clinical trials. PAP has been tested as a target antigen due to its high, and relatively specific, expression in the prostate. PAP expression in other human tissues was examined to help anticipate potential safety concerns associated with the development of immunity in this target.

Methods: We used a variety of approaches to analyze PAP expression, including immunohistochemistry, in situ hybridization, and quantitative polymerase chain reaction. These laboratory-based techniques were complemented with an in silico analysis of reported PAP expression in human cDNA libraries.

Results: Our studies confirmed that, while PAP expression is not restricted to prostate tissues, its expression in other human tissues is approx. 1 to 2 orders of magnitude less than that observed in the prostate.

Conclusion: The relative specificity of PAP expression in prostate tissues supports its use in immunotherapies targeting prostate carcinoma. A greater knowledge of the expression of immunotherapy targets through a range of human cancers will better define appropriate clinical settings for their use; detailed assessment of their normal tissue distribution will aid the design of future clinical protocols for monitoring the safety of these potential therapeutic regimens.
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

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

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

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

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

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

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

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.
O jogo triste da vida: a sinuca dos excluídos em duas canções de João Bosco e Aldir Blanc
Authors: Pinho Marcio Giacomin , Vicente Rodrigo Aparecido
Published: May 2015

Consagrada na década de 1970, a parceria João Bosco e Aldir Blanc é uma das mais prolíficas da música popular brasileira. Suas canções traduziram de forma original temas e questões candentes no cenário político, social e cultural da época, que vão desde a repressão e a censura promovidas pelo governo militar, até a experiência sensível e as condições de existência dos marginalizados nas grandes cidades. Nesse contexto surgiram as composições “Jogador” e “Tabelas”, lançadas no disco Tiro de Misericórdia (1977). O jogo de sinuca e o ambiente do subúrbio constituem o espaço real e metafórico que alinhava as canções, onde a figura do malandro assume o papel central. O presente artigo procura explicitar os modos como tais composições representam, poética e musicalmente, os conflitos e as contradições inerentes ao universo dos excluídos em tempos marcados pelo “milagre econômico”.
A new species of Cyrtodactylus (Squamata: Gekkonidae) from western Papua New Guinea
Authors: KRAUS FRED
Published: May 2015

I describe a new gecko, Cyrtodactylus serratus, from the Star Mts. of the western extreme of Papua New Guinea. The new species differs from all Papuan congeners in having a row of enlarged, dentate tubercles extending the length of each lateral skin fold. Further differences with the other species of Papuan Cyrtodactylus are identified and serve to highlight the uniqueness of the new species. I speculate that relationships of the new species may lie closest to C. loriae Boulenger among named forms, but numerous additional species of Cyrtodactylus remain to be described from New Guinea and this suggestion can only be considered tentative.
The correct spelling of the specific name of the Double-barred Finch, Taeniopygia bichenovii (Vigors & Horsfield, 1827) (Passeriformes: Estrildidae)
Authors: SCHODDE RICHARD , LONGMORE WAYNE
Published: May 2015

In the just-published edition of the influential Howard & Moore global checklist of birds (Dickinson & Christidis 2014, Appendix 8), David and Dickinson introduced the novel spelling bichenoii to replace the specific name for the Double-barred Finch. This finch, which is endemic to Australia and familiar as a cage bird world-wide, is currently known as Taeniopygia bichenovii (Vigors & Horsfield, 1827). The name was spelled bichenovii in its original description by Vigors & Horsfield (1827, p. 258), in the combination Fringilla bichenovii. Until David & Dickinson (l.c.), that spelling had been in unvaried use, in a multitude of checklists, manuals, regional Australian lists and field guides, as well as in hundreds of scientific and natural history papers both printed and electronic. Vigors & Horsfield had explicitly named the finch for James E. Bicheno, then secretary of the Linnean Society. This in turn led David & Dickinson (l.c., p.10) to replace bichenovii with bichenoii under Article 32.5.1 of the International Code of Zoological Nomenclature, hereafter the Code (ICZN 1999).
Thresholds of Central Systolic Blood Pressure in a Normotensive Chinese Middle-Aged Population
Authors: Hao Guang , Wang Zengwu , Zhang Linfeng , Chen Zuo , Wang Xin , Guo Min , Tian Ye , Shao Lan , Zhu Manlu
Published: May 2015

An increasing body of evidence has emerged showing that the central systolic blood pressure (CSBP) is more relevant to the risk of cardiovascular (CV) diseases than brachial blood pressure. However, there are no agreed CSBP threshold values above which the risk of CV disease is increased. The aim of our study was to define the threshold values of the CSBP in a normotensive Chinese population; 10 012 adults 35 to 65 years of age were eligible for analysis. We excluded 3765 participants with hypertension, and the final normotensive reference sample consisted of 6247 participants. We defined abnormally high CSBP as exceeding the 90th percentile age- and sex-specific values in the normotensive population. The 90th percentile cutoff value for CSBP in the reference sample was 125 mm Hg in men and 126 mm Hg in women. The CSBP was significantly higher in participants with diabetes, history of CV disease, and hyperlipidemia ( P < .001). The CSBP values increased with age ( P < .001). We established that the 90th percentile of the CSBP threshold value in normotensive Chinese middle-aged population is 125 mm Hg for men and 126 mm Hg for women.
A review of the physical and metabolic effects of cross-sex hormonal therapy in the treatment of gender dysphoria
Authors: Seal Leighton J
Published: May 2015

This review focuses on the effect that cross-gender sex steroid therapy has on metabolic and hormonal parameters. There is an emphasis on those changes that result in significant clinical effects such as the positive effects of the development of secondary sexual characteristics and negative effects such as haemostatic effects and thromboembolism in transwomen or dyslipidaemia in transmen. There is also a description of the current hormonal regimens used at the largest UK gender identity clinic. The overall safety of these treatments in the context of long-term outcome data is reviewed.
Seeing sex, gender, and sexuality in international security
Authors: Sjoberg Laura
Published: May 2015

This essay examines the roles that sex, gender, and sexuality can play in the study of international security. It makes the argument that “hard” security pressing questions like wars, genocides, and terrorist attacks and issues of gender, sex, and sexuality are linked. It begins by providing information about the recent and ongoing conflict in Libya as a case study. Then, it explores some of the questions that feminist and queer scholars have asked about international security in turn: where are the “women” in global politics? Where is “gender” and what does it matter? How do gender dynamics influence war and conflict? Do issues of sex and sexuality matter to war and conflict? If so, how? What tools are available to study these questions and produce answers in any given political situation?
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.
To Lend Helping Hands
Authors: Smith Peter B.
Published: May 2015

Nation-level differences in individuals’ reports of helping strangers, donating money to charity, and volunteering time were analyzed, drawing on nationally representative survey data from 135 nations. Frequency of these three behaviors yielded a reliable index of pro-social behavior. All three behaviors were found to be more frequent in nations that score low on an index of in-group favoritism and score low on uncertainty avoidance. Helping a stranger was also more frequent in nations with greater income inequality. The use of a wide sample of nations provides a more valid understanding of what kinds of cultures favor pro-social actions and indicates that national wealth is a less important contributor to the differences that are found than is the case in other aspects of cultural difference.
Caricature and Hyperbole in Preservice Teacher Professional Development for Diversity
Authors: Pollock Mica , Bocala Candice , Deckman Sherry L. , Dickstein-Staub Shari
Published: May 2015

Professional development (PD) “for diversity” aims to prepare teachers to support students from varying backgrounds to succeed, often in under-resourced contexts. Although many teachers invite such inquiry as part of learning to teach, others resist “diversity” inquiry as extra to teaching, saying they cannot “do it all.” In this article, we discuss how preservice teachers at times caricature the requests of PD for diversity, hearing the task as a call to undertake superhuman tasks and to be people other than who they are. We argue that these caricatures require direct acknowledgment by both preservice teachers and teacher educators working in diverse contexts.
Right-of-way gentrification: Conflict, commodification and cosmopolitanism
Authors: Langegger Sig
Published: May 2015

As gentrification processes accelerate in American cities, how do newcomers become solidly in-place while longtime residents become hopelessly out-of-place in neighbourhood public spaces? Bringing focus to the often-overlooked public right-of-way – streets, sidewalks and alleys – I examine social rhythms comprising this network of public spaces when used as an everyday infrastructure of transportation and socialisation or when configured for special events. Using the notion of symbolic economy to link the social production of public space with the municipal regulation of public space, this essay approaches gentrification from three perspectives: conflict, commodification and cosmopolitanism. Focusing on Highland, a rapidly gentrifying neighbourhood in Denver, Colorado, I first delve into skirmishes over street legitimacy. I then unpack quiet workaday measures used by cities to regulate the public right-of-way, namely parking policy and liquor license issuances. I move on to the commodification of ethnic culture by those who ultimately benefit from the displacement of Latino families from North Denver. Lastly, I engage with the concept cosmopolitanism, arguing that diversity discourses, both in the academy and on the street, obscure important relationships between asymmetrically positioned symbolic economies and low-level regulation of public space. Foregrounding routine urban governance over neoliberal agendas, this study critiques gentrification as a commonsense urban policy.
Mispricing in the Medicare Advantage Risk Adjustment Model
Authors: Chen Jing , Ellis Randall P. , Toro Katherine H. , Ash Arlene S.
Published: May 2015

The Centers for Medicare and Medicaid Services (CMS) implemented hierarchical condition category (HCC) models in 2004 to adjust payments to Medicare Advantage (MA) plans to reflect enrollees’ expected health care costs. We use Verisk Health’s diagnostic cost group (DxCG) Medicare models, refined “descendants” of the same HCC framework with 189 comprehensive clinical categories available to CMS in 2004, to reveal 2 mispricing errors resulting from CMS’ implementation. One comes from ignoring all diagnostic information for “new enrollees” (those with less than 12 months of prior claims). Another comes from continuing to use the simplified models that were originally adopted in response to assertions from some capitated health plans that submitting the claims-like data that facilitate richer models was too burdensome. Even the main CMS model being used in 2014 recognizes only 79 condition categories, excluding many diagnoses and merging conditions with somewhat heterogeneous costs. Omitted conditions are typically lower cost or “vague” and not easily audited from simplified data submissions. In contrast, DxCG Medicare models use a comprehensive, 394-HCC classification system. Applying both models to Medicare’s 2010-2011 fee-for-service 5% sample, we find mispricing and lower predictive accuracy for the CMS implementation. For example, in 2010, 13% of beneficiaries had at least 1 higher cost DxCG-recognized condition but no CMS-recognized condition; their 2011 actual costs averaged US$6628, almost one-third more than the CMS model prediction. As MA plans must now supply encounter data, CMS should consider using more refined and comprehensive (DxCG-like) models.
The Opportunity Cost of Capital
Authors: Chit Ayman , Chit Ahmad , Papadimitropoulos Manny , Krahn Murray , Parker Jayson , Grootendorst Paul
Published: May 2015

The opportunity cost of the capital invested in pharmaceutical research and development (R&D) to bring a new drug to market makes up as much as half the total cost. However, the literature on the cost of pharmaceutical R&D is mixed on how, exactly, one should calculate this “hidden” cost. Some authors attempt to adopt models from the field of finance, whereas other prominent authors dismiss this practice as biased, arguing that it artificially inflates the R&D cost to justify higher prices for pharmaceuticals. In this article, we examine the arguments made by both sides of the debate and then explain the cost of capital concept and describe in detail how this value is calculated. Given the significant contribution of the cost of capital to the overall cost of new drug R&D, a clear understanding of the concept is critical for policy makers, investors, and those involved directly in the R&D.
A Progressive Supervised-learning Approach to Generating Rich Civil Strife Data
Authors: Nardulli Peter F. , Althaus Scott L. , Hayes Matthew
Published: May 2015

“Big data” in the form of unstructured text pose challenges and opportunities to social scientists committed to advancing research frontiers. Because machine-based and human-centric approaches to content analysis have different strengths for extracting information from unstructured text, the authors argue for a collaborative, hybrid approach that combines their comparative advantages. The notion of a progressive supervised-learning approach that combines data science techniques and human coders is developed and illustrated using the Social, Political and Economic Event Database (SPEED) project’s Societal Stability Protocol. SPEED’s rich event data on civil strife reveal that conventional machine-based approaches for generating event data miss a great deal of within-category variance, while conventional human-based efforts to categorize periods of civil war or political instability routinely misspecify periods of calm and unrest. To demonstrate the potential of hybrid data collection methods, SPEED data on event intensities and origins are used to trace the changing role of political, socioeconomic, and sociocultural factors in generating global civil strife in the post–World War II era.
Multiscale Functional and Molecular Photoacoustic Tomography
Authors: Yao Junjie , Xia Jun , Wang Lihong V.
Published: May 2015

Photoacoustic tomography (PAT) combines rich optical absorption contrast with the high spatial resolution of ultrasound at depths in tissue. The high scalability of PAT has enabled anatomical imaging of biological structures ranging from organelles to organs. The inherent functional and molecular imaging capabilities of PAT have further allowed it to measure important physiological parameters and track critical cellular activities. Integration of PAT with other imaging technologies provides complementary capabilities and can potentially accelerate the clinical translation of PAT.
Diagnostic Criteria and Accuracy of Categorizing Malignant Thyroid Nodules by Ultrasonography and Ultrasound Elastography with Pathologic Correlation
Authors: elsayed Naglaa Mostafa , Elkhatib Yasser Atta
Published: May 2015

Thyroid nodules are a common medical and surgical concern. Thyroid ultrasound (US) is the primary imaging modality used for initial evaluation and assortment of nodules for fine needle aspiration (FNA) cytology/biopsy. Ultrasound elastography (USE) is believed to improve the diagnostic accuracy of US in distinguishing benign from malignant nodules. The aim of the work described here is to evaluate the diagnostic criteria and accuracy of US and USE in the diagnosis of malignant thyroid nodules. A prospective study of 88 patients who have thyroid nodules was performed. US, color Doppler, and USE were evaluated using a Philips iU22 equipped with a 5 to 12 MHz, linear transducer, followed by FNA of the each scanned nodule. The most sensitive US criteria for malignant nodules were a height-to-width ratio greater than one and the absence of a halo sign (sensitivity 0.875% and 1.000%, respectively). The most specific criteria for malignancy were a spiculated/blurred margin and the presence of microcalcifications (specificity 0.968% and 0.888%, respectively). The receiver operating characteristic curve showed that the cutoff diagnostic criteria of malignancy are two US characteristics and an elastography score of 4. The diagnostic accuracy of US for malignant thyroid nodules increases by combining US and USE.
Perspective-Taking, Inferred Motive, and Perceived Accommodation in Nonaccommodative Conversations
Authors: Gasiorek Jessica
Published: May 2015

Recent extensions of communication accommodation theory have emphasized the importance of inferred motives in understanding and predicting responses to nonaccommodation. This study explored the association between perspective-taking, motive inferences, and perceptions of accommodation in recalled conversations ( N = 193). Higher levels of self-reported perspective-taking were found associated with more positively valenced motive inferences. Higher levels of perspective-taking also predicted more positive perceptions of accommodation for overaccommodative conversations, but not for underaccommodative conversations.
Facebook Displays as Predictors of Binge Drinking
Authors: D’Angelo Jonathan , Kerr Bradley , Moreno Megan A.
Published: May 2015

Given the prevalence of social media, a nascent but important area of research is the effect of social media posting on one’s own self. It is possible that an individual’s social media posts may have predictive capacity, especially in relation to health behavior. Researchers have long used concepts from the theory of reasoned action to predict health behaviors. The theory does not account for social media, which may influence or predict health behaviors. The purpose of this study was to test a model including Facebook alcohol displays and constructs from the theory of reasoned action to predict binge drinking. Incoming college freshmen from two schools (312 participants between 18 and 19 years old) were interviewed prior to (T1) and 1 year into college (T2), and their Facebook profiles were evaluated for displayed alcohol content. Path modeling was used to evaluate direct and indirect paths predicting binge drinking. Path analysis suggested that Facebook alcohol displays at T1 directly predict binge drinking at T2, while alcohol attitude both directly and indirectly predicts binge drinking. Based on these results, a preliminary model of social media presentation and action is discussed.
A memetic analysis of a phrase by Beethoven: Calvinian perspectives on similarity and lexicon-abstraction
Authors: Jan Steven
Published: May 2015

This article discusses some general issues arising from the study of similarity in music, both human-conducted and computer-aided, and then progresses to a consideration of similarity relationships between patterns in a phrase by Beethoven, from the first movement of the Piano Sonata in A flat major op. 110 (1821), and various potential memetic precursors. This analysis is followed by a consideration of how the kinds of similarity identified in the Beethoven phrase might be understood in psychological/conceptual and then neurobiological terms, the latter by means of William Calvin’s Hexagonal Cloning Theory. This theory offers a mechanism for the operation of David Cope’s concept of the lexicon, conceived here as a museme allele-class. I conclude by attempting to correlate and map the various spaces within which memetic replication occurs.
Defining the environment to support occupational therapy intervention in mental health practice
Authors: Harrison Michele , Angarola Rocco , Forsyth Kirsty , Irvine Linda
Published: May 2015

More than 450 million people have been estimated to have mental health disorders worldwide with many more experiencing mental health challenges, according to the World Health Organization. People with mental health challenges can find their environments not supportive of their engagement in meaningful daily activities of self-care, work and leisure. While occupational therapists value having an understanding of how the environment impacts on a person’s occupational participation, it has been argued that the concept has been poorly defined. The Model of Human Occupation provides a clinically useful definition of the environment. Moreover, the Model of Human Occupation provides clinical assessments and outcome measures that measure how the environment facilitates occupational participation.